A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Effect of Alirocumab (SAR236553/REGN727) on the Occurrence of Cardiovascular Events in Patients Who Have Recently Experienced an Acute Coronary Syndrome
Phase: PHASE3
Conditions: Atherosclerotic Cardiovascular Disease
Sponsor: Sanofi

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disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 11 
COMPOUND: alirocumab (SAR236553/REGN727) 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Effect of Alirocumab (SAR236553/REGN727) on the Occurrence of 
Cardiovascular Events in Patients Who Have Recently Experienced an Acute 
Coronary Syndrome 
STUDY NUMBER: EFC11570 
VERSION DATE/STATUS: 25-Feb-2016 
STUDY NAME: ODYSSEY Outcomes 
EudraCT  
2011-005698-21 
Version Number: 
1 
IND Number(s) 
105574 
Date: 
25-Feb-2016
Total number of pages: 
171 
(electronic 1.0)
NCT01663402

Amended Clinical Trial Protocol No. 11  
25-Feb-2016
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 2 
HISTORY 
Amended Clinical Trial Protocol 11 
Version number:  1  
Date:  25-Feb-2016
Protocol Amendment 11 
Version number:  1 
Date:  25-Feb-2016
Amended Clinical Trial Protocol 10 - Colombia 
Version number:  1 
Date:  27-Jan-2016 
Protocol Amendment 10 - Colombia 
Version number:  1 
Date:  27-Jan-2016 
Amended Clinical Trial Protocol 09 - China 
Version number:  1 
Date:  10-Dec-2015
Protocol Amendment 09 - China 
Version number:  1 
Date:  10-Dec-2015
Amended Clinical Trial Protocol 08 - Germany 
Version number:  1 
Date:  08-Dec-2015
Amended Clinical Trial Protocol 08 - Latvia 
Version number:  1 
Date:  08-Dec-2015
Amended Clinical Trial Protocol 08 - France 
Version number:  1 
Date:  08-Dec-2015
Amended Clinical Trial Protocol 08 
Version number:  1 
Date:  16-Apr-2015 
Protocol Amendment 08 
Version number:  1 
Date:  16-Apr-2015 
Amended Clinical Trial Protocol 07 - China 
Version number:  1 
Date:  11-Apr-2014 
Protocol Amendment 07 - China 
Version number:  1 
Date:  11-Apr-2014 
Amended Clinical Trial Protocol 06 - Germany 
Version number:  1 
Date:  13-Jan-2014 
Amended Clinical Trial Protocol 06 - Latvia 
Version number:  1 
Date:  13-Jan-2014 
Amended Clinical Trial Protocol 06 - France 
Version number:  1 
Date:  13-Jan-2014 
Amended Clinical Trial Protocol 06 
Version number:  2 
Date:  05-Dec-2013
Protocol Amendment 06 
Version number:  2 
Date:  05-Dec-2013
Amended Clinical Trial Protocol 05 - China 
Version number:  1 
Date:  29-Jul-2013 
Protocol Amendment 05 - China 
Version number:  1 
Date:  29-Jul-2013 
Amended Clinical Trial Protocol 04 - Germany 
Version number:  1 
Date:  25-Mar-2013
Protocol Amendment 04 - Germany 
Version number:  1 
Date:  25-Mar-2013
Amended Clinical Trial Protocol 03 - Latvia 
Version number:  1 
Date:  22-Mar-2013
Protocol Amendment 03 - Latvia 
Version number:  1 
Date:  22-Mar-2013
Amended Clinical Trial Protocol 02 - France 
Version number:  1 
Date:  01-Mar-2013
Protocol Amendment 02 - France 
Version number:  1 
Date:  01-Mar-2013
Amended Clinical Trial Protocol 01 
Version number:  1 
Date:  17-Sep-2012
Protocol Amendment 01 
Version number:  1 
Date:  17-Sep-2012
Clinical Trial Protocol 
Version number:  1 
Date:  19-Jul-2012 
(electronic 1.0)

Amended Clinical Trial Protocol No. 11  
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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NAMES AND ADDRESSES 
COORDINATING 
INVESTIGATOR 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail:
SPONSOR 
Company: 
Address: 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
(electronic 
 
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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CLINICAL TRIAL SUMMARY 
COMPOUND: ALIROCUMAB (SAR236553/REGN727) 
STUDY No: EFC11570 
 STUDY NAME: ODYSSEY Outcomes 
TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to 
Evaluate the Effect of Alirocumab (SAR236553/REGN727) on the Occurrence 
of Cardiovascular Events in Patients Who Have Recently Experienced an Acute 
Coronary Syndrome 
INVESTIGATOR/TRIAL LOCATION 
Worldwide – multicenter study 
PHASE OF DEVELOPMENT 
IIIb 
STUDY OBJECTIVE(S) 
Primary objective 
The primary objective of this study is to compare the effect of alirocumab with 
placebo on the occurrence of cardiovascular events (composite endpoint of 
coronary heart disease (CHD) death, non-fatal myocardial infarction (MI), fatal 
and non-fatal ischemic stroke, unstable angina requiring hospitalization) in 
patients who have experienced an acute coronary syndrome (ACS) event 4 to 
52 weeks prior to randomization and are treated with an LMT regimen that is 
statin-intensive  (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 
40 mg) or  at maximally tolerated dose of these given statins and optimized for 
long-term chronic use with other non-statin LMT(s) at investigator’s discretion. 
Secondary objective(s) 
To compare the efficacy of alirocumab versus placebo on secondary endpoints 
(any CHD event, major CHD event, any CV event, composite of all-cause 
mortality/non-fatal MI/non-fatal ischemic stroke, all-cause mortality). 
A Clinical Events Committee (CEC) will be established to adjudicate, in a 
blinded fashion, events corresponding to the primary and secondary 
cardiovascular endpoints as well as all causes of death. 
•
To evaluate the safety and tolerability of alirocumab throughout the
study.
•
To evaluate the development of anti- alirocumab antibodies.
•
To evaluate the effect of alirocumab on low-density lipoprotein
cholesterol (LDL-C), apolipoprotein B (ApoB), and non-high-density
lipoprotein cholesterol (non-HDL-C).
(electronic 
 
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Amended Clinical Trial Protocol No. 11  
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 5 
STUDY DESIGN 
This is a double-blind, randomized, placebo-controlled, parallel-group study, 
multi-national, multicenter study. Randomization will be stratified according to 
country. 
The study will comprise 2 periods: 
• 
A run-in period (~2 to 16 weeks) during which the background lipid-
modifying therapy (LMT) will be adjusted as needed, to ascertain the 
patient is receiving the required intensive statin treatment (defined as 
atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or the 
maximally tolerated doses of these given statins, or other non-statin 
LMTs prior to randomization, and to stabilize this treatment. 
• 
A double-blind treatment period (~2 to 5 years) during which the  
following should be emphasized and reinforced: 
- 
compliance with study visits and assessments (all randomized 
patients, including those who permanently discontinued 
treatment early, must remain in the study and be followed until 
the end of the study) 
- 
compliance with blinded study treatment (IMP) 
- 
compliance with required background LMT regimen (which 
should be continued for as long as it remains well tolerated) 
- 
compliance with requirement to not check cholesterol levels 
 
1/ The Run-in period starts with a screening visit (V1), continues with a 
qualifying visit (V2), and ends with a randomization visit (V3). V1 and V2 visits 
can be separate or combined. 
 The main goals of the run-in period are to ensure that: 
• 
patient has received prior to V2 a required LMT regimen that is 
- 
statin-intensive (defined as atorvastatin 40 or 80 mg or 
rosuvastatin 20 or 40 mg) or maximal tolerated dose of one 
these 2 statins 
- 
optimized for long-term chronic use with addition of non-statin 
LMTs (at Investigator’s discretion) 
- 
well tolerated after at least 2 weeks of stable dose 
• 
lipid criteria outlined in the inclusion criteria are met at V2 
• 
patient (and family) has been adequately informed and agrees to 
participate in a long-term study with an injection every 2 weeks 
• 
patient has been trained to self-administer study drug injections 
• 
there are no exclusion criteria 
 
The run-in period should be planned carefully, keeping in mind 3 elements: 
• 
 The visit and time interval requirements with respect to: 
- 
Index ACS event 
- 
V1 (start of run-in period) 
- 
V2/V2b (collection of lipid qualifying labs) 
- 
V3 (randomization) 
• 
 The required background lipid-modifying therapy (LMT) 
• 
The coronary revascularization strategy 
(electronic 
 
 
 
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Visit and Time Intervals during Run-In Period 
• 
Interval between index ACS event and V1 is flexible: 
- 
 V1 can be performed as early as on the day of the index ACS 
event and no later than 50 weeks after the index ACS event if V1 
and V2 are separate visits (or 50 weeks + 5 days after ACS 
event, if combined V1/V2) 
• 
Run-In Period (from V1 to V3) includes 2 time interval requirements 
(and both should be met): 
- 
Time from V1 to V3 (i.e. from start of run-in period to 
randomization): this is the duration of the overall run-in period. It 
should be between 2 weeks (14 days) and 16 weeks (+5 days). 
- 
Time from index ACS event to randomization (V3): this includes 
the time between index ACS event and V1 (start of run-in period) 
plus time from V1 to V3 (randomization). V3 (randomization) 
should occur no earlier than 4 weeks (28 days) and no later than 
52 weeks (+ 5 days) post index ACS event 
The run-in period can be conducted in one of 2 ways, depending on whether the 
required LMT regimen prior to V2 was already administered for at least 2 weeks 
(and found well tolerated) prior to V1 or not. 
- 
If required LMT regimen was not already administered for at 
least 2 weeks prior to V1, then V1 and V2 should be separate 
visits with an interval of at least 2 weeks, during which required 
LMT regimen is administered. V3 (randomization) can occur as 
soon as the qualifying lipid lab results from V2 are obtained from 
the central lab (typically within 2-5 days of collection), pending 
patients meets all eligibility criteria 
- 
If it is documented that required LMT regimen was already 
administered for at least 2 weeks (and found well tolerated) prior 
to V1, then V1 and V2 can be combined. V3 (randomization) 
should then occur at least 2 weeks (14 days) after the combined 
V1/V2 visit 
An optional additional V2 visit (V2b) with repeat central laboratory lipid 
assessments may be scheduled if needed. 
 
Required background LMT during the run-in period 
Investigator must have identified prior to V2 (or combined V1/V2), a background 
LMT regimen that is: 
• 
Statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 
20 or 40 mg), or maximally tolerated dose of these given statins; 
statins other than atorvastatin, rosuvastatin are not allowed 
• 
Optimized for long-term chronic use, with addition of non-statin 
LMT(s), as per Investigator’s discretion; no fibrate allowed (other than 
fenofibrate or fenofibric acid) 
- 
In statin-intolerant patients (defined as intolerance to 2 or more 
statins), LMT can be optimized with non-statins LMT only (e.g. 
ezetimibe, or other non-statin LMT) 
• 
Well tolerated for at least 2 weeks (at stable dose) prior to V2 
 
(electronic 
 
 
 
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Coronary revascularization strategy 
When indicated for the treatment of the qualifying index ACS event, a coronary 
revascularization (PCI, CABG) may have taken place before V1, but may also 
occur during the run-in period. 
If a PCI and/or CABG occur during the run-in period, randomization should be 
scheduled to allow for a minimum 2 week interval between the last coronary 
procedure and the randomization visit V3. 
Rescreening 
A patient who fails screening and left the study may undergo rescreening and 
re-enter the study (only once) - see Section 6.1.3. 
2/ The double-blind treatment period will continue for 24 months after the 
closing of randomization ex-China (ie, last date of randomization in all countries 
except China) or until the target number of events (1613) is reached whichever 
comes last. 
•
Closing of randomization ex-China will occur shortly after a total of
18,000 patients have been randomized (these may or may not include
some patients randomized in China).
•
Closing of randomization in China will occur shortly after a total of 600
patients have been randomized in China or at the common study end
date (see Section 6.2.2), whichever comes first.
Therefore, at the end of the double-blind treatment period, the overall 
population will include about 18,000 randomized patients who have either died 
or been followed for a minimum of 24 months, supplemented with an additional 
subset of patients from China (~600) who may be followed for less than 
24 months. The corresponding estimated study duration is 64 months (as 
described in the sample size considerations – Section 11.1). 
During this double-blind treatment period, the dosing of alirocumab is intended 
to achieve LDL-C levels of 30-50 mg/dL (0.78-1.29 mmol/L)  which is 
considered as the physiologic ideal level and to avoid levels of LDL-C that are 
clearly below the physiologic range (ie,<15 mg/dL or 0.39 mmol/L)). To achieve 
this goal the following up-titration or down-titration scheme (including 
discontinuation if needed) will be applied: 
•
At randomization Visit (V3), the starting dose of alirocumab will be
75 mg every 2 weeks (Q2W). At Month 2,  patients randomized to
alirocumab will, in a blinded manner, either:
-
Continue alirocumab 75 mg Q2W, if the Month 1 LDL-C is
<50 mg/dL (1.29 mmol/L) OR
-
Be up-titrated to alirocumab 150 mg Q2W, if the Month 1 LDL-C
is ≥50 mg/dL (1.29 mmol/L).
•
At subsequent visits, for patients on alirocumab, the following
adjustments may be applied depending on the dose received:
-
For patients receiving 150 mg Q2W: if LDL-C <25 mg/dL
(0.65 mmol/L) (including LDL-C < 15 mg/dL [0.39 mmol/L]) on
2 consecutive measurements, down-titration to 75 mg Q2W will
be done in a blinded manner at the next visit. Additional
monitoring will be implemented until the down-titration is done.
(electronic 1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 8 
- 
For patients receiving 75 mg Q2W: 
o 
If LDL-C <25 mg/dL (0.65 mmol/L) but ≥ 15 mg/dL 
(0.39 mmol/L) on 2 consecutive measurements: alirocumab 
will be continued but additional monitoring will be 
implemented, to further confirm the safety of low LDL-C 
levels. 
o 
If LDL-C <15 mg/dL (0.39 mmol/L) on 2 consecutive 
measurements: alirocumab treatment will be discontinued 
at the next visit.  In order to maintain the blind there will be 
blinded substitution to placebo injections for the remaining 
duration of the study. Additional monitoring will be 
implemented until the study treatment discontinuation is 
done. 
As lipid values will not be communicated to investigators after randomization to 
maintain the blind, the continuation of the 75 mg dose, the up-titration to the 
150 mg dose, the down-titration from 150 to 75 mg, or discontinuation will occur 
automatically, without site or patient awareness. Moreover, blinded dose 
adjustment will avoid the need for dummy titrations in the placebo group. 
Atorvastatin or rosuvastatin daily dose, as well as dose of other non-statin LMT 
(if applicable), is required to be stable from randomization up to the end of the 
study, unless safety reasons prompt dose reduction or discontinuation. 
Patients should be on stable diet (NCEP-ATPIII TLC diet or equivalent) 
throughout the entire study duration from screening to the end of the study. 
STUDY POPULATION 
Main selection criteria 
Inclusion criteria 
• 
Hospitalization for ACS (ST-elevation MI, non-ST elevation MI or 
high-risk unstable angina) defined by: 
- 
Ischemic symptoms with unstable pattern, occurring at rest or 
minimal exertion within 72 hrs of an unscheduled hospital 
admission, due to presumed or proven obstructive coronary 
disease AND at least one of the following: 
o 
Elevated cardiac biomarkers, OR 
o 
Resting ECG changes consistent with ischemia or infarction 
AND additional evidence of obstructive coronary disease 
• 
Patient lipid levels not adequately controlled at V2 (qualifying visit), 
despite evidence-based lipid lowering therapy (including intensive 
atorvastatin/rosuvastatin therapy or maximally tolerated dose of either 
of these 2 statins), or other non-statin LMTs. Inadequate lipid control 
means that patient must meet at least one of the following criteria at 
V2 to qualify: 
- 
LDL-C ≥ 70 mg/dL (≥1.81 mmol/L), or 
- 
ApoB ≥ 80 mg/dL (≥ 0.8 g/L), or 
- 
non-HDL-C ≥ 100 mg/dL (≥2.59 mmol/L) 
Exclusion criteria 
• 
All of the 3 following criteria are concomitantly present at the 
qualifying visit (V2): 
- 
LDL-C <70 mg/dL (<1.81 mmol/L), and 
- 
ApoB < 80 mg/dL (< 0.8 g/L), and 
- 
non-HDL-C <100 mg/dL (<2.59 mmol/L) 
(electronic 
 
 
 
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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NOTE: If not all 3 but only 1 or 2 criteria are present then the patient may 
qualify. 
•
Age < 40 years
•
Patients in whom the qualifying index ACS event occurred less than 4
weeks (28 days) or more than 52 weeks (+ 5 days) prior to
randomization visit (V3)
•
Not on stable LMT doses (statin and/or non-statin LMT) for at least 2
weeks prior to qualifying visit (V2)
•
Uncontrolled hypertension (multiple readings with SBP > 180 mmHg
or DBP > 110 mmHg) at V3
•
New York Heart Association Class III or IV congestive heart failure
persisting despite treatment or if measured LVEF <25%
•
Known history of hemorrhagic stroke
•
Fasting serum triglycerides (TG) >400 mg/dL (>4.52 mmol/L) prior to
randomization
•
New ACS event occurring within 2 weeks prior to the randomization
Visit (V3)
•
Coronary revascularization (PCI or CABG) planned after
randomization and/or performed within 2 weeks prior to the
randomization Visit (V3)
Total expected number of patients 
Approximately 18,600 patients should be randomized (9,300 patients / group). 
Approximately 1400 sites 
STUDY TREATMENT(s) 
Investigational medicinal product(s)
Formulation 
Alirocumab 
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  
Route(s) of administration 
Subcutaneous (SC) injection in the abdomen, thigh or outer area of upper arm 
Dose regimen 
75 mg every 2 weeks OR 
75 mg every 2 weeks up to Month 2 followed by 150 mg every 2 weeks at 
Month 2 onwards (with criteria for up-titration and down-titration as indicated 
above) 
INJECTION FOR TRAINING AND 
PLACEBO COMPARATOR 
Investigational medicinal product(s) 
(if applicable) 
Formulation 
Placebo 
Same formulation as alirocumab without the addition of protein. 
Route(s) of administration 
Subcutaneous (SC) injection in the abdomen, thigh or outer area of upper arm. 
(electronic 1.0)

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Page 10 
ENDPOINT(S) 
 
Primary endpoint 
• 
Time from randomization to first occurrence of one of the following 
Clinical Events, as determined by the CEC: 
- 
CHD death 
- 
Any non-fatal MI 
- 
Fatal and non-fatal ischemic stroke 
- 
Unstable angina requiring hospitalization 
Main Secondary Efficacy Endpoint(s): 
• 
Time from randomization to first occurrence of any CHD event (major 
CHD event, unstable angina requiring hospitalization, ischemia-driven 
coronary revascularization procedure) 
• 
Time from randomization to first occurrence of any major CHD event 
(CHD death, non-fatal MI) 
• 
Time from randomization to first occurrence of any CV event defined 
as follows: any non-fatal CHD event, any CV death, and non-fatal 
ischemic stroke 
• 
Time from randomization to first occurrence of all-cause mortality, 
non-fatal MI, non-fatal ischemic stroke 
• 
Time from randomization to death (all-cause mortality) 
 
Other Secondary Efficacy Endpoint(s): 
• 
Components of the primary end point considered individually: CHD 
death, or non-fatal MI, or fatal and non-fatal ischemic stroke, unstable 
angina requiring hospitalization 
• 
Ischemia-driven coronary revascularization procedure 
• 
Congestive heart failure requiring hospitalization 
 
Safety Endpoint(s): 
• 
Safety endpoints: all adverse events, heart rate and blood pressure, 
hematology and biochemistry assessments 
 
Other Endpoint(s): 
• 
Anti- alirocumab antibodies assessed throughout the study 
• 
The percent change in calculated LDL-C, in ApoB and non HDL-C 
(electronic 
 
 
 
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ASSESSMENT SCHEDULE 
Visits scheduled during the run-in period: 
Please refer to Run-In Period section under ‘Study Design’ 
 
Visits schedule during the double-blind treatment period: 
• 
Clinic/On-site visits: 
- 
For the first year: visit at Month1, Month 2, Month 4 and then 
every 4 months (Month 8, Month 12) 
- 
For the second year: visit every 4 months 
- 
For the subsequent years: visit every 6 months up to the end of 
the study 
Contacts schedule during the double-blind treatment period: 
• 
A phone call or contact via internet (as permitted by institutional 
privacy policies) should occur in between clinic visits throughout the 
study with the goal of maintaining a contact with the patient about 
every 2 months during first 24 months, and about every 3 months 
thereafter.   
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Based on the targeted population for the study, a Kaplan-Meier event rate in 
placebo group of 11.4% at 48 months (3.8% at 12 months, 6.4% at 24 months, 
9.0% at 36 months) is assumed. With a 40-month recruitment period, a 64-
month total study duration, 9300 patients per group (total 18,600), and 1,613 
patients experiencing at least one primary endpoint event,  the study has 90% 
power (one-sided Logrank test at the overall 0.025 alpha level) assuming a 15% 
risk reduction associated with alirocumab treatment. The sample size 
calculation takes into account two interim analyses. 
Analysis Populations: 
Randomized population includes any patients who have been allocated to a 
randomized treatment regardless of whether the treatment kit was used or not. 
Efficacy analyses will be performed on the intention-to-treat (ITT) population, 
consisting of all randomized patients. Patients in the ITT population 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 analyzed according to the 
treatment actually received. 
Primary Analysis: 
The primary endpoint will be compared between treatment groups by a log-rank 
test, stratified by region (North America, South America, Western Europe, 
Eastern Europe, Asia, other region).  The distribution will be estimated by 
treatment group with Kaplan-Meier methodology.  Treatment hazard ratios 
(HRs) for the primary endpoint will be estimated from Cox regression models 
stratified by region. 
 
Analysis of the main secondary endpoints 
A hierarchical procedure will be used to control the type I error and handle 
multiple endpoints. If the primary endpoint analysis is significant (at the 0.0001 
one-sided alpha level at the second interim analysis or at the 0.0249 one-sided 
alpha level at the final analysis), main secondary efficacy endpoints will be 
tested sequentially, using the order defined in section “Primary and secondary 
(electronic 
 
 
 
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endpoints”. 
Secondary endpoints will be analyzed in the ITT population using the same 
statistical methodology as for the primary endpoint (time-to-event analysis). 
Safety analysis 
Safety analysis (adverse events, laboratory, and vital signs) will be descriptive, 
based on the safety population. The safety analysis will focus on the Treatment 
Emergent Adverse Event (TEAE) period. This period is defined as the time from 
the first to the last dose of double-blind IMP + 70 days (10 weeks). 
Interim analyses: 
Patients will be followed until 1,613 patients experience at least one primary 
endpoint event or for approximately 24 months after the closing of 
randomization ex-China, whichever comes last. 
Interim analyses for futility will be performed, under the supervision of the CV 
DMC, when 50% and 75% of events have occurred. An interim analysis for 
efficacy will be performed when 75% of events have occurred. Control of the 
type I and type II error will be ensured using gamma (-5) spending function for 
type II error (futility) and Gamma (-22) for type I error (efficacy). Stopping rules 
details are further described in Section 11.5. 
DURATION OF STUDY PERIOD (per 
patient)  
The duration of the run-in period (V1 to V3) should be between 2 weeks (14 
days) and 16 weeks (+ 5 days). Randomization must occur no earlier than 4 
weeks (28 days) and no later than 52 weeks (+ 5 days) after the index ACS 
event. 
The double-blind treatment period will continue for 24 months after the closing 
of randomization ex-China (last date for randomization in all countries except 
China) or until the target number of events (1613) is reached whichever comes 
last. The corresponding estimated study duration is 64 months (as described in 
the sample size considerations). 
All patients, even those who have achieved an endpoint or prematurely 
discontinued study treatment, will be followed from randomization until the 
common study end date. 
(electronic 
 
 
 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
Until Month 2:
75 mg every 2w
RR
Placebo (n = 9300)
R
V1         V2 
V3
R
Double-Blind Treatment Period
(~ 24 to 64 months)
Suspected efficacy endpoints should be collected in all 
randomized patients (including those who discontinued
treatment early) until Common Study End-date Visit
Randomization (V3)
At Month 2 and beyond: 
75 mg / 150 mg   every 2w
M64
(V30)
D1
(V3)
M4
(V6)
M24
(V16)
……
M1
(V4)
Clinic/On-site 
Visit
M2
(V5)
LMT (atorvastatin 40/80mg, or rosuvastatin 20/40 mg or at MTD** or non-statin LMT) from > 2w before V2 until final visit
Diet (NCEP-ATPIII TLC or equivalent ) throughout study
Alirocumab (n = 9300) 
After randomization
-
Final clinic visit (Common Study End Date Visit, V30 M64) should be completed in all randomized patients (regardless of whether they are still on
treatment or had discontinued treatment early) and should occur between Common Study End Date (CSED) and CSED+30days. 
Qualifying
Index ACS 
Event 
Contact phone calls / 
Internet
Run-In Period
duration: 2w to 16w(+5d)
V1, V2 
separate or  
combined
Run-In Period (duration between 2w and 16w+5d)
- V1: earliest is on day of ACS; latest is 50w post ACS (if V1, V2 separate) or 50w (+5d) post ACS (if combined V1/V2)
- V2: collection qualifying lipid labs after receiving lipid-modifying therapy (LMT) that is statin-intensive (atorvastatin 40/80mg, or rosuvastatin 20/40 mg or at
max. tolerated dose), optimized for long-term chronic use (with addition of non-statin LMT at Inv. Discretion) and well tolerated after > 2w of stable LMT dose
- V3: earliest is 4w and latest is 52w(+5d) post-index ACS
From M4 until M24: 
clinic visit every 4 months
From M24 until Final visit: 
clinic visit every 6 months
Contact phone call / internet in between clinic visits from M4 until Final clinic visit
……
……
……
M2 (V5)
V1
V2
ACS: acute coronary syndrome, LMT: lipid-modifying therapy, MTD: maximal tolerated dose
4w to 52w prior to 
randomization (V3)
(electronic 1.0)

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25-Feb-2016
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 14 
1.2 
STUDY FLOW CHART 
1.2.1 On-site/Clinic visits during the study 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Design: 
Informed Consent / 
Patient Demography 
X 
Inclusion / Exclusion 
Criteria 
X 
X 
X 
Medical / surgical 
history (incl. relevant 
family history e.g. 
allergy), alcohol /  
smoking habits 
X 
Prior Medication 
Historyc 
X 
Physical Examination 
X 
X 
X 
X 
X 
X 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Randomization 
X 
(electronic 1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 15 
 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n  
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2 
       
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12 
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Patient diary 
dispensation/ review /  
collectiond 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
IVRS/IWRS contact 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment: 
Injection training  
Xe 
Xe 
Xf 
 
 
 
 
 
 
 
 
 
 
Double Blind 
Investigational 
Medicinal Product (IMP) 
kit dispensation  
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Compliance check of 
IMP (review patient 
diary and treatment kit) 
and data collection on 
IMP administration 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Compliance check for 
atorvastatin, 
rosuvastatin, ± other 
LMTs 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (statin, 
ezetimibe 
only) 
X 
Concomitant 
Medicationc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n  
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2 
       
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12 
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Vital signs: 
Heart rate, blood 
pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X  
Efficacy Endpoints (primary and secondary) and Cardiovascular Events of Interest (other than efficacy endpoints) 
Update patient contact 
information (incl. 
patient’s family, 
patient’s 
GP/cardiologist)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Check patient card (with 
mention of study 
participation and site 
contact information) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Collect information on 
suspected efficacy 
endpoints 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 17 
 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n  
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2 
       
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12 
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Collect cardiovascular 
events of interest other 
than efficacy endpoints 
(related to peripheral 
arterial disease, venous 
thromboembolic events) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety: 
AE /SAE recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(related 
and/or 
serious AE) 
X 
12-lead ECG 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Laboratory Testing / Efficacy: 
TC, LDL-C, HDL-C, TG, 
non-HDL-C 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
 ApoB 
X 
X 
X 
 
 
X 
 
X 
 
X (M24 only) 
X 
X 
X 
ApoA-1, ratio 
ApoB/ApoA-1, Lp (a) 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 18 
 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n  
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2 
       
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12 
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Laboratory Testing / Safety: 
Hematology and 
chemistryg 
X 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
Creatine phosphokinase 
(CPK)  
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Liver panelh 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Hepatitis B surface 
antigen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C antibodyh 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Serum pregnancy testh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy testh 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X 
Urinalysis (at selected 
sites only)  h 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
X 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 19 
 
Screening 
(run-in period) 
Double-blind period  
On-site / Clinic Visit  
V1 
(or 
combined 
V1/V2) 
V2b 
V3 
V4 
V5 
V6 
V8 
V10 
V12/V14/V18/V22/V26 
V16/V20/V24/V28 
V30 m 
V70 n  
M64 
 Final visit (common study 
end date visit) 
Week(W) / Month(M) a 
≥ 2w prior 
to V3 
AND 
0 to 50w 
post index 
ACS 
W-2 
       
After 
≥2w 
required 
LMT 
M0 (D1) 
4 to 52w 
post 
index 
ACS 
M1  
M2 
M4 
M8 
M12 
M16/M20/M30/M42/M54 
M24/M36/M48/M60 
Study  
completers  
Prematurely  
discontinued 
patients m 
Early end 
of 
treatment 
visit 
Laboratory Testing / Other: 
HbA1c 
X 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
High sensitivity          C-
reactive protein   (hs-
CRP) 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Anti- alirocumab 
antibodies  
 
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
X 
Library samplesj  
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
Genomics 
Genomics consent 
(optional) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect specimen (if 
genomics consent)k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Quality of Life Variables 
EQ-5D patient 
questionnairel 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 20 
a Window period for visits: randomization visit (V3) should be performed no earlier than 4w(28d) post-index ACS, and no later than 52w(+5d) post index ACS,  window at Months 1 and 2 is ± 7 days,  and for all other 
subsequent visits it is ± 14 days (in case of major IMP issue, please refer to Section 8.9). 
b V2 is main visit for collection of qualifying lipid labs (sent to Central Labs) following > 2w of well tolerated, stable required LMT (i.e. statin-intensive, and optimized for long-term chronic use with addition of non-
statin LMT, at Investigator’s discretion). If required LMT treatment was already administered prior to V1 for ≥ 2w, V1 and V2 visits can be combined as one visit. Otherwise, interval between V1 and V2 should be 
≥2w. After 2 to 5 days, V2 lab results are obtained, and patient may be randomized if all eligibility criteria are met. Overall, duration of run-in period (between V1 and V3, or between combined V1/V2 and V3) 
should be between 2w (14 days) and 16w(+5 days). V3 (randomization) should occur no earlier than 4w (28 days) and no later than 52w (+5days) post ACS index event. An optional visit (V2b) with repeat Central 
Laboratory assessments may be scheduled during run-in after V2 in the following scenario: V2 labs are not met, however patient was kept in run-in period after ‘failed’ V2 and subsequently develops intolerance to 
statin leading to lower statin dose; patient may then be retested with lower statin dose. A V2b visit should be performed if V2 labs are met but statin dose (or non-statin LMT regimen) was subsequently increased, 
after V2. 
c Prior medication: prior to screening visit V1 and randomization (IMP administration); only restrictions pertain to fibrates (other than fenofibrate, fenofibric acid) and statins (other than atorvastatin, rosuvastatin) 
which should be discontinued at V1. Concomitant medication: received concomitantly to the IMP, from first IMP to the end of treatment + 70 days. 
d Along with kit dispensation, the treatment administration package should be given as well as the IMP diary and injection instruction manual, as needed. 
e At least 2 training injections are required on 2 different occasions. These can take place at V1, V2, Combined V1/V2, or V3 at the discretion of the study site.  First training injection (with placebo) must be done 
before V3. The initial IMP double-blind injection (active or placebo) performed at V3 may serve as second training injection. If needed, additional training injections (with placebo) are available 
f 
Injection is performed at randomization Visit Month 0/Day 1 on site with double-blind study treatment kit allocated by IVRS (can serve as training injection). 
g Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell count, reticulocyte count, white blood cell count with differential count, and platelets (Note: reticulocyte not 
done at V1).  Chemistry includes: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT. 
h Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin. Hepatitis C antibody: In case of positive hepatitis C antibody test, a blood sample will be collected at a subsequent visit and sent to Covance 
Central Lab for further confirmatory testing 
i 
Pregnancy tests (serum, urine) in Women of Child Bearing Potential (WOCBP) only. Urinalysis to be performed only at selected sites (see Section 10). 
j 
Library samples should be collected, as permitted by local regulatory policies. They may be stored for up to 10 years or as permitted by local regulatory policies, whichever is shorter, for exploratory research of 
PCSK9 levels, PCSK9 function, effect(s) of PCSK9 inhibition with a monoclonal antibody, lipoprotein sub-fraction, inflammation, and cardiovascular risk markers (eg, lipoprotein–associated phospholipase A2). 
k If blood sample not collected at randomization, could be collected at any time during the study. 
l 
EQ-5D patient questionnaire will only be administered in patients still on treatment, for prematurely (permanently) discontinued patients the last administration will be done at the early end of treatment visit. 
m Common study end date (CSED) will occur 24 months after the closing of randomization ex-China or after the target number of events (1613) is reached whichever comes last. A final clinic visit V30 (CSED visit, 
Month 64) should be completed within 30 days of CSED for all randomized patients regardless of the compliance with study treatment (see Section 10.1.5.1.4). Reduced assessments in ‘Prematurely discontinued 
patients’ column apply only if V30 occurs more than 6 months after V70 (see Section 10.3.4). 
n For patients who prematurely discontinue blinded study treatment (IMP): as a general rule, any IMP treatment discontinuation should be initially considered temporary, and Investigator should make best effort to 
resume IMP treatment as early as practically possible, after several weeks or months (pending there are no safety concerns), and perform all study visits and assessments as usual. Investigator is strongly 
encouraged to discuss with monitoring team before considering any treatment discontinuation as permanent. A discussion with National Coordinator may occur regarding other possible options If and when a 
treatment discontinuation is considered ‘permanent’, an extra visit (early end of treatment visit V70) should be performed as soon as practically possible (within 1 month) after IMP discontinuation is considered 
permanent by Investigator. Such patients (with premature permanent treatment discontinuation) must continue to remain in the study and should return for all study visits until the common study end date (final visit 
V30). Complete usual study assessments should be performed for 6 months following V70. Thereafter, assessments are reduced to collection of suspected efficacy endpoints, cardiovascular events of interest 
other than efficacy endpoints (peripheral arterial disease, venous thromboembolic events – see Section 9.3.7), related and/or serious AEs , selected concomitant medications (statins, ezetimibe) and selected labs 
(anti- alirocumab antibodies, lipid panel, ApoB, HbA1c)  (See Section 10.3.4). 
 
(electronic 
 
 
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Amended Clinical Trial Protocol No. 11  
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Property of the Sanofi Group - strictly confidential 
Page 21 
1.2.2 Contacts (phone calls or contacts via internet) during the study 
 
Month (M)a  
M6/ M10/ M14/ M18/ M22/ M27/ M33/ M39/ M45/ M51/ M57/ M62 
Visit 
V7/ V9/ V11/ V13/ V15/ V17/ V19/ V21/ V23/ V25/ V27/ V29 
Phone Call 
 or Internet contact b 
Update patient contact information (incl.patient’s family, patient’s 
GP/cardiologist) d 
 X 
Review compliance with statins, other LMTs d 
X 
Collect information on IMP administration (and remind patient to 
complete diary) 
X 
Collect information on possible occurrence of efficacy endpoints 
(and remind patient to call site in case of hospitalization and not 
wait until next visit) d  
X 
Reminders c 
X 
a Although flexibility is allowed in the timing of phone call in between the on-site/clinic visits, it should be scheduled with the goal of maintaining a contact with the patient about every 2 months during first 24 months,
and about every 3  months thereafter. Having no phone or e mail contact with a patient for a prolonged period (>4 months) should be avoided as much as possible. Some additional instructions for scheduling
phone call may be provided at time of interim analysis. 
b In addition, an optional service will be made available for sites to send via SMS/text messages appointment and injection reminders to any patient who wishes to and is able to receive them.  These contacts will
conform with privacy regulations at each site. 
c 
Reminders as applicable for IMP administration schedule, timing of next appointments, fasting conditions for next lab assessments, bring the diary, and used and unused kits at the next study site visit. 
d  In patients who have permanently discontinued treatment, contacts will include: update of patient contact information (incl. family and patient’s GP/cardiologist), collection of suspected efficacy endpoints during
entire study until common study end-date, and review of compliance with statin and other LMT for 6 months following V70, and with statin and ezetimibe thereafter. 
 
(electronic 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 22 
2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL NO. 11.......................................................................................1 
1 
FLOW CHARTS.............................................................................................................................13 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
1.2.1 
On-site/Clinic visits during the study..............................................................................................14 
1.2.2 
Contacts (phone calls or contacts via internet) during the study...................................................21 
2 
TABLE OF CONTENTS ................................................................................................................22 
3 
LIST OF ABBREVIATIONS ..........................................................................................................28 
4 
INTRODUCTION AND RATIONALE.............................................................................................31 
5 
STUDY OBJECTIVES ...................................................................................................................38 
5.1 
PRIMARY.......................................................................................................................................38 
5.2 
SECONDARY ................................................................................................................................38 
6 
STUDY DESIGN ............................................................................................................................39 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................40 
6.1.1 
Run-in period..................................................................................................................................41 
6.1.1.1 
Overview of run-in period...............................................................................................................41 
6.1.1.2 
Visit and Time Intervals during Run-In Period ...............................................................................42 
6.1.1.3 
Required background LMT during the run-in period......................................................................44 
6.1.2 
Coronary revascularization strategy ..............................................................................................47 
6.1.3 
Screen failures and Rescreening...................................................................................................47 
6.1.3.1 
Screen failure.................................................................................................................................47 
6.1.3.2 
Rescreening...................................................................................................................................47 
6.1.4 
Double-blind treatment period........................................................................................................48 
6.2 
DURATION OF STUDY PARTICIPATION. ...................................................................................50 
6.2.1 
Duration of study participation for each patient .............................................................................50 
6.2.2 
Determination of end of clinical trial (all patients) - Common Study End Date..............................50 
6.3 
INTERIM ANALYSIS......................................................................................................................50 
6.4 
STUDY COMMITTEES..................................................................................................................51 
7 
SELECTION OF PATIENTS..........................................................................................................53 
(electronic 
 
 
 
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 23 
7.1 
INCLUSION CRITERIA..................................................................................................................53 
7.2 
EXCLUSION CRITERIA ................................................................................................................54 
7.2.1 
Exclusion criteria related to study methodology ............................................................................54 
7.2.2 
Exclusion criteria related to the background therapy.....................................................................56 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................56 
8 
STUDY TREATMENTS .................................................................................................................57 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................57 
8.1.1 
Route and method of administration..............................................................................................57 
8.1.2 
Timing of administration.................................................................................................................58 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................59 
8.3 
BLINDING PROCEDURES............................................................................................................59 
8.3.1 
Methods of blinding........................................................................................................................59 
8.3.2 
Lipid parameters ............................................................................................................................59 
8.3.3 
Anti-alirocumab antibodies.............................................................................................................61 
8.3.4 
Committees....................................................................................................................................61 
8.3.5 
Data Analysis .................................................................................................................................61 
8.3.6 
Randomization code breaking during the study.............................................................................62 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................62 
8.5 
PACKAGING AND LABELING ......................................................................................................63 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................64 
8.7 
RESPONSIBILITIES ......................................................................................................................64 
8.7.1 
Treatment accountability and compliance......................................................................................65 
8.7.2 
Return and/or destruction of treatments ........................................................................................65 
8.8 
CONCOMITANT MEDICATION.....................................................................................................66 
8.8.1 
Background Lipid-Modifying Therapy ............................................................................................66 
8.8.2 
Other Concomitant Medications.....................................................................................................67 
8.9 
MITIGATION PLAN IN CASE OF IMP ISSUE...............................................................................68 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................69 
9.1 
EFFICACY ENDPOINTS ...............................................................................................................69 
9.1.1 
Primary efficacy endpoint...............................................................................................................69 
9.1.2 
Secondary efficacy endpoints........................................................................................................69 
9.1.3 
Main Secondary Efficacy Endpoint(s):...........................................................................................69 
(electronic 
 
 
 
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ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 24 
9.1.4 
Other Secondary Efficacy Endpoint(s):..........................................................................................70 
9.1.5 
Efficacy assessment methods .......................................................................................................70 
9.1.6 
Definitions of components of the composite primary efficacy endpoint.........................................70 
9.1.6.1 
Coronary Heart Disease (CHD) Death...........................................................................................70 
9.1.6.2 
Non-fatal myocardial infarction (MI)...............................................................................................72 
9.1.6.3 
Fatal and Non-fatal stroke..............................................................................................................75 
9.1.6.4 
Unstable angina requiring hospitalization ......................................................................................76 
9.1.7 
Definitions of the secondary efficacy endpoints.............................................................................77 
9.1.7.1 
Death..............................................................................................................................................77 
9.1.7.2 
Ischemia-driven coronary revascularization procedure .................................................................79 
9.1.7.3 
Congestive Heart Failure requiring hospitalization. .......................................................................80 
9.2 
SAFETY ENDPOINT(S):................................................................................................................81 
9.2.1 
Adverse event ................................................................................................................................82 
9.2.2 
Safety laboratory............................................................................................................................82 
9.2.3 
Vital signs measurement................................................................................................................82 
9.2.4 
Electrocardiogram measurement...................................................................................................82 
9.3 
OTHER ENDPOINT(S): .................................................................................................................83 
9.3.1 
Anti-alirocumab antibody assessments .........................................................................................83 
9.3.1.1 
Sampling time ................................................................................................................................83 
9.3.1.2 
Sampling procedure.......................................................................................................................83 
9.3.1.3 
Bioanalytical method......................................................................................................................83 
9.3.2 
Lipid parameters ............................................................................................................................84 
9.3.2.1 
Endpoints .......................................................................................................................................84 
9.3.2.2 
Assessment method.......................................................................................................................84 
9.3.3 
hs-CRP...........................................................................................................................................84 
9.3.4 
HbA1C .............................................................................................................................................84 
9.3.5 
EQ-5D Patient Questionnaire ........................................................................................................84 
9.3.6 
Pharmacogenomic Samples..........................................................................................................85 
9.3.7 
Cardiovascular events of interest (other than efficacy endpoints).................................................86 
10 
STUDY PROCEDURES ................................................................................................................87 
10.1 
VISIT SCHEDULE..........................................................................................................................91 
10.1.1 
Screening visit - Visit 1 (at least 2 weeks prior to randomization visit) and entry in the run-in 
period .............................................................................................................................................91 
10.1.2 
Qualifying visit - Visit 2...................................................................................................................93 
10.1.3 
Combined V1/V2 Visit ....................................................................................................................94 
10.1.4 
Optional qualifying visit - Visit 2b ...................................................................................................94 
10.1.5 
Double-blind treatment period........................................................................................................95 
10.1.5.1 Study site visits from Visit 3 (Month 0, D1) to Visit 30 (Month 64).................................................95 
10.1.5.2 Contacts (phone calls, text messages or contacts via internet) from randomization ..................107 
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10.1.5.3 Early end of treatment visit – Visit 70...........................................................................................107 
10.1.5.4 Common study end date visit (Final Visit) – Visit 30 (~Month 64, between CSED and 
CSED + 30 days) .........................................................................................................................108 
10.2 
DEFINITION OF SOURCE DATA................................................................................................111 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.....................................112 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) .........................112 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) .........................113 
10.3.3 
List of criteria for permanent treatment discontinuation...............................................................113 
10.3.4 
Handling of patients after permanent treatment discontinuation .................................................114 
10.3.5 
Procedure and consequence for patient withdrawal from study..................................................115 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ........................116 
10.4.1 
Definitions of adverse events.......................................................................................................116 
10.4.1.1 Adverse event ..............................................................................................................................116 
10.4.1.2 Serious adverse event .................................................................................................................116 
10.4.2 
Adverse event of special interest.................................................................................................117 
10.4.3 
Serious adverse events waived from expedited regulatory reporting to health authorities .........117 
10.4.4 
General guidelines for reporting adverse events .........................................................................118 
10.4.5 
Instructions for reporting serious adverse events ........................................................................119 
10.4.6 
Guidelines for reporting adverse events of special interest.........................................................119 
10.4.6.1 Reporting of adverse events of special interest with immediate notification ...............................119 
10.4.6.2 Reporting of adverse events of special interest without immediate notification ..........................120 
10.4.7 
Guidelines for management of specific laboratory abnormalities ................................................121 
10.4.7.1 Hemoglobin decrease ..................................................................................................................122 
10.5 
OBLIGATIONS OF THE SPONSOR ...........................................................................................123 
10.6 
SAFETY INSTRUCTIONS ...........................................................................................................123 
10.6.1 
Local tolerability (Local Injection Site Reactions) ........................................................................123 
10.6.2 
Allergic adverse events (See Section 10.4.6.1 and Section 10.4.6.2).........................................123 
10.6.2.1 Allergic adverse event with cutaneous involvement ....................................................................124 
10.6.2.2 Acute allergic injection reactions (Section 10.4.6.2)....................................................................124 
10.6.3 
Monitoring related to two consecutive LDL-C <25 mg/dL (0.65 mmol/L) ....................................125 
10.7 
ADVERSE EVENTS MONITORING............................................................................................125 
11 
STATISTICAL CONSIDERATIONS............................................................................................126 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................126 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................127 
11.3 
ANALYSIS POPULATIONS.........................................................................................................127 
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11.3.1 
Efficacy populations .....................................................................................................................127 
11.3.1.1 Intent–to-treat population .............................................................................................................127 
11.3.2 
Safety population .........................................................................................................................128 
11.3.3 
Other analysis populations...........................................................................................................128 
11.4 
STATISTICAL METHODS ...........................................................................................................128 
11.4.1 
Extent of study treatment exposure and compliance...................................................................128 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................129 
11.4.1.2 Compliance ..................................................................................................................................129 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................129 
11.4.2.1 Analysis of primary efficacy endpoint(s) ......................................................................................130 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................131 
11.4.2.3 Multiplicity consideration ..............................................................................................................131 
11.4.3 
Analyses of safety data................................................................................................................132 
11.4.3.1 Adverse events ............................................................................................................................133 
11.4.3.2 Laboratory data and vital signs....................................................................................................134 
11.4.4 
Other endpoints:...........................................................................................................................134 
11.4.4.1 Cardiovascular events of interest (other than efficacy endpoints)...............................................134 
11.4.4.2 Other endpoints............................................................................................................................135 
11.5 
INTERIM ANALYSIS....................................................................................................................135 
12 
ETHICAL AND REGULATORY STANDARDS...........................................................................137 
12.1 
ETHICAL PRINCIPLES ...............................................................................................................137 
12.2 
LAWS AND REGULATIONS .......................................................................................................137 
12.3 
INFORMED CONSENT ...............................................................................................................137 
12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............138 
13 
STUDY MONITORING.................................................................................................................139 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................139 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................139 
13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................140 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (eCRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................140 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................140 
14 
ADMINISTRATIVE EXPECTATIONS .........................................................................................141 
14.1 
CURRICULUM VITAE..................................................................................................................141 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................141 
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14.3 
CONFIDENTIALITY .....................................................................................................................141 
14.4 
PROPERTY RIGHTS...................................................................................................................142 
14.5 
DATA PROTECTION...................................................................................................................142 
14.6 
INSURANCE COMPENSATION..................................................................................................142 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................143 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................143 
14.8.1 
Decided by the Sponsor...............................................................................................................143 
14.8.2 
Decided by the Investigator .........................................................................................................144 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................144 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................144 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................146 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................147 
17 
APPENDICES..............................................................................................................................151 
APPENDIX A 
MONITORING AND MANAGEMENT PLAN FOR LDL-C < 25 MG/DL (0.65 
MMOL/L) ......................................................................................................................................152 
APPENDIX B 
DNA STORAGE SAMPLES...............................................................................................154 
APPENDIX C GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................156 
APPENDIX D GUIDELINES FOR HEMOGLOBIN (HB) DECREASE ≥ 1.5   G/DL.................................162 
APPENDIX E 
SUMMARY OF ADVERSE EVENT AND SUSPECTED EFFICACY ENDPOINT 
REPORTING INSTRUCTIONS....................................................................................................163 
APPENDIX F ASSESSMENT OF LOCAL INJECTION SITE REACTIONS ............................................168 
APPENDIX G 
EQ-5D PATIENT QUESTIONNAIRE ................................................................................169 
APPENDIX H NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION .........................170 
APPENDIX I 
STROKE FUNCTIONAL DISABILITY SCORE (ADAPTED FROM MODIFIED 
RANKIN SCALE)..........................................................................................................................171 
 
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3 
LIST OF ABBREVIATIONS 
 
ACS  
Acute coronary syndrome 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
Apo 
Apolipoprotein 
ARF 
Acute renal failure 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BP 
Blood pressure 
CABG  
Coronary artery bypass graft surgery 
CEC 
Clinical Events Committee 
CHD 
Coronary Heart Disease 
CI 
Confidence interval 
CIB 
Clinical Investigator's brochure 
CPK 
Creatine Phosphokinase 
CSED 
Common Study End Date 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
DBTP 
Double Blind Treatment Period 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic acid 
DRF 
Discrepancy resolution form 
ECG 
Electrocardiogram 
eg 
Exempli gratia = for example 
e-SMS 
Emergency Scientific & Medical Services 
eCRF 
Electronic case report form 
EDTA 
Ethylene diamine tetra-acetic acid 
eGFR 
Estimated Glomerular Filtration Rate 
FH 
Familial hypercholesterolemia 
FPI 
First patient in 
FU 
Follow-up 
GCP 
Good Clinical Practice 
γGT 
Gamma-glutamyl Transferase 
HbA1c 
Glycated hemoglobin A1c 
HDL-C 
High-density lipoprotein cholesterol 
HeFH 
Heterozygous familial hypercholesterolemia 
HLGT 
High Level Group Term 
HLT 
High level term 
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HR 
Hazard ratio 
hs-CRP 
High-sensitivity C-reactive protein 
IA 
Interim Analysis 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ie 
Id est = that is 
IEC 
Independent ethics committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional review board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
LDL-C 
Low-density lipoprotein cholesterol 
LDL-R 
Low-density lipoprotein receptor 
LLN 
Lower limit of normal range 
LMT  
Lipid modifying therapy 
Lp(a) 
Lipoprotein a 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
mmHg 
Millimeter of mercury 
NCEPATPIII  
National Cholesterol Education Program Adult Treatment Panel III 
NYHA 
New York heart association 
NIMP 
Non-Investigational Medicinal Product 
PAD 
Peripheral Arterial Disease 
PCI 
Percutaneous coronary intervention 
PCSA 
Potentially Clinically Significant Abnormality 
PCSK9 
Proprotein convertase subtilisin/kexin type 9 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred term 
PTC 
Product technical complaint 
Q2W 
every 2 weeks 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SNP 
Single nucleotide polymorphisms 
SOC 
System organ class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TOTAL-C 
Total cholesterol 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
 
 
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TLC 
Therapeutic lifestyle changes 
ULN 
Upper limit of normal range 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
 
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4 
INTRODUCTION AND RATIONALE 
Alirocumab is a fully human monoclonal antibody that binds PCSK9. All relevant information 
concerning the compound is available in the latest version of the Clinical Investigator’s Brochure 
(CIB) (1). 
Alirocumab is also referred to as SAR236557/REGN727. However, for this study protocol 
ODYSSEY Outcomes (EFC11570), it will be referred to as alirocumab. 
Patients with recent acute coronary syndrome (ACS) are at very high risk for suffering recurrent 
coronary events in the near term. In approximately 10% of patients with ACS, cardiovascular 
death, recurrent myocardial infarction (MI), or stroke, occur within 1 year (2).  Based on the 
results of large clinical trials, early intensive statin therapy has become formally endorsed as a 
treatment recommendation (3) (4) for patients with ACS (5). The use of high-dose statins has been 
largely demonstrated to be safe and well tolerated (6). 
Both epidemiological and pharmacological intervention trials have demonstrated a strong and 
linear relationship between the levels of low-density lipoprotein cholesterol (LDL-C) and 
cardiovascular (CV) events.  Three of the most recent statin trials, the TNT trial (7), the PROVE-
IT trial (8), and the JUPITER trial (9), have provided new information on the relationship between 
low levels of LDL-C and CV event rates, with demonstration that treatment of LDL-C to a mean 
level of 77 mg/dL, 62 mg/dL, or 55 mg/dL was associated with a greater reduction in CV events. 
The overall results of these trials have helped to demonstrate the continued linear relationship 
between LDL-C and CV events to these levels and to support the establishment of 70 mg/dL as a 
treatment goal for high-risk patients (10) (11).  The lack of a demonstrated existing threshold or 
plateau between LDL-C and CV risk from these studies begs the question that even further 
reductions beyond the 55-77 mg/dL observed in these trials could provide additional benefits in 
CV event reduction.  In the above three trials post-hoc analyses were conducted analyzing both 
the efficacy (in regards to CV event rates) and safety of achieving LDL-C levels at the lower end 
of the treatment spectrum. 
• The PROVE-IT/TIMI-22 trial examined patients with LDL-C <100 mg/dL in the 
atorvastatin arm and found a lower rate of CV events in the patients with achieved LDL-C 
levels in the <40 mg/dL and the 40-60 mg/dL groups than those patients with higher 
achieved LDL-C levels (12). 
• In the TNT trial, patients in the lowest quartile of achieved LDL-C had value <64 mg/dL 
and a mean LDL-C level of 54 mg/dL as compared to means of 70, 83, 97 and 122 mg/dL 
in the remaining quintiles.  Within these quintiles, there was a strong and significant 
relationship between the lower achieved LDL-C levels and lower rates of major CV events 
(p<0.0001) (13). 
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• 
In the JUPITER trial, the investigators split the patients in the rosuvastatin group into two 
cohorts of achieved LDL-C <50 mg/dL (n=4154) and >50 mg/dL (n=4000) and compared 
them to the placebo group.  Those that had achieved LDL-C <50 mg/dL demonstrated 
significantly lower rates of CV events than either of the other two groups (14). 
In none of these three analyses there was evidence of an adverse safety signal observed with 
patients that achieved these lower levels of LDL-C. A recent communication compared patients 
who achieved a LDL-C ≤30 mg/dL (n=621) versus those with LDL-C >30 mg/dL (n=7533) (15). 
No differences in overall TEAEs and many other specific AEs were observed, with the exception 
of a greater incidence in insomnia (1.6/100 PY versus. 1.2/100 PY; p=0.031) and hematuria 
(1.8 /100 PY versus. 1.1/100 PY; p=0.0007) among patients with LDL-C ≤30 mg/dL. The rate of 
clinically relevant declines in eGFR (≥30%) tended to be lower among patients with lower 
reduction in LDL-C. 
Similar findings have been observed in a patient-level meta-analysis conducted by the Cholesterol 
Trialists Treatment Collaboration.  This examination of 26 large statin CV event trials 
encompassing approximately 170,000 patients has demonstrated that 20% reduction in major CV 
events can be derived for every 1 mmol/L (38.6 mg/dl) reduction in LDL-C, even in patients 
whose starting LDL-C levels are less than 2 mmol/L (77 mg/dl) (16).  This meta-analysis has also 
demonstrated no significant safety risks with long-term cholesterol reduction treatment, including 
cancer (17). 
These data provide strong support for the concept that high risk patients may derive further 
benefits of reductions in LDL-C to levels <50 mg/dl (1.29 mmol/L). A number of lipid and 
cardiovascular experts have begun to consider lower LDL-C values as the ideal level for humans 
with the concept that LDL-C levels of 30-50 mg/dL (0.78-1.29 mmol/L) represent the 
physiological ideal.  This is based upon the findings from both the observed LDL-C levels in 
human newborns as well as in humans with more primitive/paleolithic lifestyles (18) (19) (20). 
However, many high CV risk patients cannot achieve such levels with currently available lipid-
lowering drugs. Furthermore, a significant number of high-risk patients even fail to achieve their 
recommended LDL-C target levels (21) (22) and most CV events are actually not prevented, 
leaving a substantial “residual risk” for patients and thus additional pharmacologic therapies for 
the prevention of coronary heart disease (CHD) remains essential, particularly for high-risk 
patients with ACS. 
Introduction to proprotein convertase subtilisin kexin type 9 (PCSK9): 
Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the subtilisin family of serine 
proteases and is highly expressed in the liver. PCSK9 is involved in regulating the levels of the 
low-density lipoprotein receptor (LDL-R) protein (23) (24). Once PCSK9 is secreted into plasma 
it directly binds to the LDL-R and promotes its degradation. The increased degradation of LDLRs 
leads to a reduced LDL-C removal, and therefore higher LDL-C circulating levels. Experiments 
with mice have shown that increasing PCSK9 protein levels decreases levels of LDL-R protein in 
the liver while PCSK9 knockout mice have increased levels of LDL-R in the liver (25) (26). In 
humans, PCSK9 mutations have been identified: the gain-of-function mutations are rare and cause 
an autosomal dominant form of severe hypercholesterolemia and premature CHD, whereas 
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loss-of-function mutations are more common and are associated with reduced plasma levels of 
LDL-C and protection from CHD (27) (28). 
Therefore blocking PCSK9 binding to the LDL-R can potentially benefit patients with 
hypercholesterolemia by decreasing their plasma LDL-C levels. In addition, PCSK9 messenger 
ribonucleic acid (mRNA) and protein levels are increased in response to statins, potentially 
attenuating their cholesterol-lowering effect (29). 
Summary of selected clinical studies with alirocumab: 
Phase 1 studies 
Three Phase 1 studies have been conducted with alirocumab and evaluated the safety, tolerability 
and pharmacokinetics/pharmacodynamics (PK/PD) profile. Two studies were single dose 
administration (R727-CL-0902 study with intravenous (IV) administration of doses from 0.3 to 
12 mg/kg and R727-CL-0904 study with SC administration of doses from 50 to 250 mg) 
conducted in healthy volunteers with LDL-C >100 mg/dL for whom statin therapy was not 
indicated. The third study (R727-CL-1001 study) was conducted in hypercholesterolemic patients 
(familial or non-familial) with single to multiple subcutaneous (SC) administration of 50 mg, 
100 mg, 150 mg and 200 mg either as add-on to stable doses of atorvastatin from 10 to 40 mg/day 
or as monotherapy. 
Results of these Phase 1 studies showed that alirocumab administered to healthy volunteers and 
patients either by IV or SC administration was generally well tolerated at all doses; treatment 
emergent adverse events (TEAEs) did not display a dose relationship. No pattern of adverse 
events related to the drug was identified. In all these Phase 1 studies, administration of alirocumab 
induced rapid, substantial, and sustained reductions from baseline in LDL-C, up to 60%. The 
magnitude and duration of these reductions were positively related to the dose administered. It 
should also be noted that in the R727-CL-1001 study, results were similar in the familial and non-
familial hypercholesterolemic patients. 
Overall, a total of 109 subjects were exposed to at least one dose of alirocumab in these three 
Phases 1 studies. 
Phase 2 studies: 
Three Phase 2 studies have been conducted: 
• Two dose / dose regimen finding studies (DFI11565 and R727-CL-1003) with the main 
objective to assess, over a 12 week-treatment duration, the effects on LDL-C level 
reduction of several doses of alirocumab and 2 dose-regimens (50 mg, 100 mg and 150 mg 
every 2 weeks (Q2W), and 200 mg and 300 mg every 4 weeks (Q4W) for the DFI11565 
study and 150 mg Q2W, 150 mg, 200 mg, and 300 mg Q4W for the R727-CL-1003 
study). DFI11565 was conducted in hypercholesterolemic patients with elevated LDL-C 
(≥100 mg/dL or 2.59 mmol/L) despite stable atorvastatin therapy.  R727-CL-1003 study 
was conducted in patients with heterozygous familial hypercholesterolemia (heFH) and 
with elevated LDLC (≥100 mg/dL or 2.59 mmol/L) despite their current lipid lowering 
therapy (statin ± ezetimibe). 
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• The third Phase 2 study (DFI11566) aimed to evaluate in patients with 
hypercholesterolemia the efficacy and safety of the co-administration of alirocumab 
150 mg every 2 weeks and a high daily dose of atorvastatin (80 mg) in comparison to the 
co-administration of placebo and this high daily dose of atorvastatin (80 mg), in patients 
previously receiving a stable dose of atorvastatin 10 mg. This treatment scheme is 
anticipated to be used when a rapid decrease in LDLC level is needed, eg after an acute 
coronary syndrome. 
Overall, a total of 274 patients were exposed to at least one dose of alirocumab in these three 
Phases 2 studies. 
Efficacy results: 
In both dose finding studies, statistically significant decreases in percent change from baseline in 
LDL-C at 12 weeks were observed in all alirocumab groups compared to the placebo group.  In 
the DFI11565 study for the Q2W dose regimen, the greatest decrease was seen in the 150 mg 
Q2W group (-72.4%) compared with a small decrease in the placebo group (-5.1%) (LS mean 
difference versus placebo of -67.3%; p<0.0001). The decreases observed with the doses 
administered Q2W were maintained from the first injection throughout the study and more 
particularly throughout the interval period between the injections. A similar pattern with the dose 
of 150 mg Q2W was seen in the R727-CL-1003 study with a significant decrease from baseline 
of -67.9% versus -10.7% in the placebo group (LS mean difference versus. placebo of -57.3%; 
p<0.0001).  Large decreases in LDL-C from baseline to 12 weeks were also observed with doses 
administered Q4W; however, the treatment effect was not fully maintained over a 4-week period 
(ie, the time interval between the two injections). 
The same magnitude of effect was shown for the dose of 150 mg Q2W in the DFI11566 study, 
with a statistically significant decrease in LDL-C at 8 weeks in the alirocumab 150 mg 
+ atorvastatin 80 mg group (median reduction of – 70.6 %) compared with the placebo 
+ atorvastatin 80 mg group (median reduction of – 26.9 %). 
In all three studies, consistent results were seen for total-cholesterol (TC), ApoB, non-HDL-C and 
ApoB/ApoA-1 ratio. A favorable trend was also observed for high-density lipoprotein cholesterol 
(HDL-C), apolipoprotein A-1 (ApoA-1), triglycerides (TG) and lipoprotein a (Lp (a)). 
Safety results 
Alirocumab was well tolerated in all completed Phase 2 studies throughout the treatment period 
and for all treatment groups. Injection sites reactions were reported in patients including placebo-
treated patients; the reporting of these events was greatest in the R727-CL-1003 study (40.3% in 
alirocumab-treated patients versus 12.6% and 3.3% in DFI11565 and DFI 11566, 
respectively); however these events were generally transient with no dose relationship. Rare cases 
of hypersensitivity reactions were reported. Among all SAEs reported for all alirocumab studies, 
only one case, leucocytoclastic vasculitis (angiitis), was reported as being related to alirocumab 
(DFI11565 study). The patient developed one episode of diarrhea followed on the same evening 
by rash on arms, legs and abdomen, 9-days after the first administration of alirocumab 300 mg 
Q4W. The diagnosis was confirmed by skin biopsy. The patient was discontinued from study drug 
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but completed the study. The patient fully recovered from the rash after a course of tapering 
steroid administration.  A positive antidrug antibody (ADA) status was reported with a low titer of 
30 (corresponding to the minimum titer detected by the assay), only observed at the Week 20 
assessment (ie, between 2.5 and 3 months after the event) with a negative retest after 6 months. 
Additional tests also obtained 6 months after the event were unremarkable and included normal 
immunoglobulin levels, a negative antinuclear antibody test, and only a mild elevation of CRP. 
No particular signal was noted for TEAEs related to musculoskeletal or connective tissue 
disorders as well as there were no LFT elevations. Given the limited published data on the safety 
of LDL-C level <25 mg/dL, a prespecified statistical analysis was conducted in patients reaching 
LDL-C value <25mg/dL in all the Phase 2 studies with no specific safety signal identified over the 
study duration. In the two dose finding studies (DFI11565 and R727-CL-1003), the proportion of 
patients reaching an LDL-C <25 mg/dL in the 150 mg Q2W group was from 31.3% to 44.8%. In 
DFI11566, with atorvastatin 80mg the proportion in the 150 mg Q2W group was approximately 
50%. 
For detailed information, please refer to the CIB (1). 
Dose and regimen selection 
Based on the results of the above studies, the Q2W dosing regimen was selected as the most 
appropriate to maintain constant LDL-C lowering throughout the interdosing interval. Since the 
magnitude of effect observed with 150 mg Q2W may not be needed to achieve the LDL-C goal in 
all patients, a lower dose of 75 mg was selected as a starting dose. This selection is also based on 
the LDL-C reduction needed to provide the best benefit in terms of CVD reduction, and potential 
safety considerations regarding low LDL-C values. 
The current and most relevant evidence around the effects of achieved low LDL-C levels comes 
from examinations of large statin trials (12) (13) (14) as presented above, and patients with 
PCSK9 loss-of-function mutations (30).  The patients achieving the lower levels of LDL-C had 
the lower CV event rates. To date, there is no evidence that very low LDL-C levels result in 
significant adverse health effects based on these sources of information, though this conclusion is 
based on a relatively low number of patients with very low LDL-C who have been studied. 
Rationale for protocol design: 
The objective of the present study is to evaluate the ability of alirocumab to reduce CV events in 
patients who recently experienced an ACS event and despite intensive statin therapy or at 
maximally tolerated dose don’t reach the goal as defined in the guidelines for these very high risk 
patients. 
For this randomized, double-blind, placebo-controlled study it is estimated that approximately 
18,600 patients will be enrolled, of which about 18,000 will either have died or have had a 
minimum follow-up of approximately 24 months, supplemented by an additional subset of 
patients from China (~600) possibly followed for less than 24 months. Total study duration will 
be approximately 5 years. Randomization will occur within 52 weeks of the index ACS event and 
patients will enter a run-in period during which (if not already receiving such treatment before 
V1) they will have to be stabilized on an LMT that includes intensive statin therapy (defined as 
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atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) or maximally tolerated dose of either of 
these 2 agents in case of tolerability issues, and is optimized for long-term chronic use with non-
statin LMT (at Investigator’s discretion). Only patients not reaching goal, ie, LDL-C ≥70 mg/d L 
(≥1.81 mmol/L) or ApoB ≥80 mg/dL (≥ 0.8 g/L) or non HDL-C ≥100 mg/dL (≥2.59 mmol/L) 
under such treatment, will be randomized to either background LMT therapy + alirocumab or 
background LMT therapy + placebo. The choice to select eligible patients on two other lipid 
parameters, in addition to the traditional LDL-C target lipid parameter, is based on the acceptance 
that ApoB and non HDL-C can be considered to be equal to LDL-C in risk prediction (10) (11). 
Some adjustment in the lipid-modifying background therapy can occur during the run-in period, 
e.g., in case of poor tolerance to intensive statin therapy. 
The proposed primary efficacy endpoint is the effect of alirocumab compared to placebo on top of 
best evidence background therapy on the occurrence of the following composite endpoint: 
coronary heart disease (CHD) death, non-fatal myocardial infarction, non-fatal and fatal ischaemic 
stroke, and unstable angina requiring hospitalization with stringent criteria for the definition of 
this later endpoint. Based on other contemporary studies (31) (32), the primary endpoint event rate 
in the placebo group is assumed to be 11.4% at 48 months (3.8% at 12 months, 6.4% at 
24 months, 9.0% at 36 months). 
In this trial, all patients will be initially treated with 75 mg Q2W, and only those patients whose 
LDL-C levels remain equal or higher than 50 mg/dL (1.29 mmol/L) after 1 month of treatment 
will be up-titrated to 150 mg Q2W (at Month 2). 
With this treatment scheme, most patients can be expected to achieve their target LDL-C, as 
recommended by international guidelines committees (10) (11). Furthermore, the up-titration 
threshold set at 50 mg/dL (1.29 mmol/L), supported by findings from post-hoc analyses of the 
PROVE-IT, TNT and JUPITER trials, will promote the achievement of an LDL-C level within the 
‘physiologic ideal’ zone. 
Available data do not point to a lower limit of safe and effective cholesterol lowering (12) (13) 
(14). However, this conclusion is based on a relatively low number of patients with very low 
LDL-C who have been studied. In this trial, with the use of 75 mg as starting dose and a 
target-based up-titration scheme, it is anticipated that few patients will reach a LDL-C level below 
25 mg/dL (0.65 mmol/L).  For patients titrated-up to 150 mg Q2W who reach a LDL-C level 
below 25 mg/dL (0.65 mmol/L), a down-titration from 150 mg to 75 mg Q2W will be performed. 
For patients on 75 mg Q2W, two different rules will be applied depending on the level of LDL-C. 
In case of an LDL-C level below 25 mg/dL (0.65 mmol/L) but greater than or equal to 15 mg/dL 
(0.39 mmol/L), additional monitoring will be implemented to further confirm the safety of low 
LDL-C levels. Due to lack of available information at a LDL-C level below 15 mg/dL 
(0.39 mmol/L) (except in subjects with rare genetic mutations), patients reaching such low levels 
on 2 consecutive occasions will have their treatment discontinued. 
Addition to alirocumab in patients not yet at goal should derive to further benefits in terms of 
reductions in LDL-C. However a greater treatment effect in patients with higher LDL-C levels at 
baseline cannot be ruled out. For this reason, the distribution of LDL-C levels at baseline will be 
monitored to ensure that the initial assumption of a mean baseline LDL-C of 90-100 mg: dL 
(2.33-2.59 mmol/L) is fulfilled. In case it is observed that the distribution is shifted to lower 
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baseline levels of LDL-C, a capping of the number of patients with a baseline LDL-C between 
70-80 mg/dL may be considered. 
Conclusion on the benefit risk assessment with alirocumab 
Based on the clinical data available to date, treatment with alirocumab has demonstrated a 
significant LDL-C lowering effect and was generally well tolerated in a population of patients 
with non-familial hypercholesterolemia or with heterozygous familial hypercholesterolemia. The 
efficacy on LDL-C was associated with consistent results in total cholesterol, ApoB, non-HDL-C 
and ApoB/ApoA-1 ratio and a positive trend for HDL-C, TG and Lp (a).  There was no evidence 
that alirocumab adversely affects other cardiovascular risk factors, eg, body weight, blood 
pressure, glucose, or CRP. 
In terms of identified or potential risks with alirocumab, local injection site reactions were 
reported as well as rare cases of hypersensitivity reactions. Local injection site reactions were 
reported in both alirocumab and placebo treatment groups with no evidence of dose relationship. 
These AEs will be monitored in the Phase 3 program including this study. A substantial 
proportion of patients reached low LDL-C levels (<25 mg/dl [0.65 mmol/L]) with no safety signal 
identified to date. However, further monitoring for potential AEs associated with low LDL-C 
levels will be implemented. Although no particular signal related to CPK elevation and associated 
AEs (e.g., myalgia, rhabdomyolysis) was detected with the co-administration of alirocumab and 
statins over a maximum duration of 12 weeks, monitoring for such adverse events will continue 
for all the Phase 3 studies, including this study. An independent Data Monitoring Committee 
(DMC), dedicated to the EFC11570 study and identified as CV DMC, will meet periodically to 
review unblinded safety data. This CV DMC will have a close connection with the other 
independent DMC implemented for all Phase 3 studies evaluating the efficacy and safety of 
alirocumab on LDL-C (identified as Phase 3a DMC). 
This CV outcome study is undertaken to demonstrate in patients who recently experienced an 
ACS event and who are not at their LDL-C goal despite an intensive lipid-lowering therapy that 
alirocumab 75mg Q2W or 75 mg Q2W / 150 mg Q2W provides an additional benefit with the 
reduction of CV events. 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to compare the effect of alirocumab with placebo on the 
occurrence of cardiovascular events (composite endpoint of coronary heart disease (CHD) death, 
non-fatal myocardial infarction (MI), fatal and non-fatal ischemic stroke, unstable angina 
requiring hospitalization) in patients who have experienced an acute coronary syndrome (ACS) 
event 4 to 52 weeks prior to randomization and are treated with an LMT regimen that is statin-
intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg) or at maximally 
tolerated dose of these given statins, and optimized for long-term chronic use with other non-
statin LMT(s) at Investigator’s discretion. 
5.2 
SECONDARY 
The secondary objectives are: 
• To compare the efficacy of alirocumab versus placebo on secondary endpoints (any CHD 
event, major CHD event, any CV event, composite of all-cause mortality/non-fatal 
MI/non-fatal ischemic stroke, all-cause mortality) 
A Clinical Events Committee (CEC) will be established to adjudicate, in a blinded fashion, events 
corresponding to the primary and secondary cardiovascular endpoints as well as all causes of 
death. 
• To evaluate the safety and tolerability of alirocumab throughout the study 
• To evaluate the development of anti-alirocumab antibodies 
• To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) 
apolipoprotein B (ApoB), and non-high-density lipoprotein cholesterol (non-HDL-C) 
 
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6 
STUDY DESIGN 
This is a double-blind, randomized, placebo-controlled, balanced (1:1, alirocumab: placebo), 
parallel-group, multi-national, multicenter study. Randomization will take place between 4 weeks 
(28 days) and 52 weeks (+5 days) after the qualifying index ACS event and will be stratified 
according to country. 
Prior to this randomization, eligible patients will enter a run-in period of at least 2 weeks (14 
days) but no more than 16 weeks (+ 5 days), during which Investigator ensures that patient has 
received an LMT regimen that is: 
• statin-intensive (defined as atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) or 
maximal tolerated dose of one of these 2 statins, and 
• optimized for long-term chronic use (with other non-statin LMT(s) at Investigator’s 
discretion), and 
• well tolerated after at least 2 weeks of stable dose prior to V2. 
Following this run-in period, only patients not reaching goal, ie, LDL-C ≥70 mg/dL 
(≥1.81 mmol/L) or ApoB ≥ 80 mg/dL (≥ 0.8 g/L) or non-HDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) 
after > 2 weeks of such treatment, will be randomized to either background LMT + alirocumab, or 
background LMT + placebo. All patients randomized to alirocumab will initially receive 
alirocumab 75 mg Q2W. Patients on alirocumab not reaching the target LDL-C level (< 
50 mg/dL) at Month 1 will have their dose up-titrated to 150 mg Q2W at Month 2 in a blinded 
fashion. 
The double-blind treatment period will continue for 24 months after the closing of randomization 
ex-China (last date of randomization in all countries except China) or until the target number of 
events (1613) is reached whichever comes last. 
• Closing of randomization ex-China will occur shortly after a total of 18,000 patients have 
been randomized (these may or may not include some patients randomized in China). 
• Closing of randomization in China will occur shortly after a total of 600 patients have 
been randomized in China or at the common study end date (see Section 6.2.2), whichever 
comes first. 
NOTE 1: Throughout this document, ‘China’ refers to mainland China, excluding Hong Kong. 
NOTE 2: Continued enrolment of patients in China after the initial target of 18,000 randomized 
globally has been reached, and leading to an increase in sample size to about 18,600 patients, 
will be implemented only after appropriate local authorizations in China have been obtained. 
The corresponding estimated study duration is 64 months. All patients, even if they have achieved 
an endpoint or those who have prematurely discontinued the study treatment, will be asked to 
remain in the study until the common study end date (so that all suspected efficacy endpoints are 
collected until the end of study). 
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6.1 
DESCRIPTION OF THE PROTOCOL 
The study will comprise 2 periods: 
• A run-in period (~ 2 to 16 weeks) during which the background lipid-modifying therapy 
(LMT) will be adjusted as needed, to ascertain the patient is receiving the required 
intensive statin treatment (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 
40 mg) or the maximally tolerated doses of these given statins, or other non-statin LMTs 
prior to randomization, and to stabilize this treatment. 
• A double-blind treatment period (~ 2 to 5 years) during which the following should be  
emphasized and reinforced: 
- 
compliance with study visits and assessments: all randomized patients (including those 
who permanently discontinued treatment early) must remain in the study and be 
followed until the end of the study; sites should maintain a contact with the patient 
every 2 to 3 months (as per study assessments) throughout the study and contact 
information (for patient, family, GP/cardiologist) should be periodically updated as 
necessary; in addition, it is important to continuously remind patients (and their 
family) throughout the study that, in case of hospitalization, patient (or patient’s family 
member) should inform site (Investigator, Coordinator) as soon as possible and not 
wait until the next visit. 
- 
compliance with blinded study treatment (IMP): patients should be treated with 
blinded study treatment for as long as possible, unless safety concerns arise (in case of 
temporary interruption, blinded study treatment should be restarted, as best as possible, 
unless there are safety concerns; to be assessed by Investigator) 
- 
compliance with required background LMT regimen (as determined from run-in period 
see Section 6.1.1): intensive statin therapy (atorvastatin 40 or 80 mg or rosuvastatin 
20 or 40 mg) or maximal tolerated dose of one these 2 statins, optimized with addition 
of non-statin LMTs (at Investigator’s discretion) should be continued for as long as 
this regimen remains well tolerated. If tolerability concerns arise, LMT can be 
modified, based on clinical tolerability only (see Figure 2, Section 8.8.1) 
- 
compliance with requirement to not check cholesterol levels: every effort should be 
made to refrain from checking cholesterol levels during the entire duration of the study 
(to preserve double-blind nature of the study); Investigators are encouraged to 
communicate and explain this aspect to patient, patient’s family and patient’s family 
doctor/cardiologist at the time of informed consent and run-in period, and throughout 
the study (along with rationale that patient receives best possible LMT with intensive 
or maximal tolerated statin therapy with addition of non-statin LMTs, at Investigator’ s 
discretion). 
Patients should be on stable diet (NCEP-ATPIII TLC diet or equivalent) throughout the entire 
study duration from screening to the end of the study. 
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6.1.1 Run-in period 
6.1.1.1  Overview of run-in period 
The Run-in period starts with a screening visit (V1), continues with a qualifying visit (V2), and 
ends with a randomization visit (V3). V1 and V2 visits can be separate visits or, in some 
circumstances (described below), can be combined as one visit (V1/V2) 
The main goals of the run-in period are to ensure that: 
• 
the patient has received prior to the qualifying visit (V2), a required LMT regimen that is: 
- 
statin-intensive (defined as atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) or 
maximal tolerated dose of one these 2 statins, and 
- 
optimized for long-term chronic use with addition of non-statin LMTs (at 
Investigator’s discretion), and 
- 
well tolerated after at least 2 weeks of stable dose 
• 
lipid criteria outlined in the inclusion criteria are met at V2 
• 
patient (and his/her family) has been adequately informed and agrees to participate in a 
long-term study (up to ~ 5 years) with an injection every 2 weeks 
• 
patient has been trained on at least 2 occasions to self-administer study drug injections 
- 
at least 2 training injections are required on 2 different occasions. These can take place 
at V1, V2, Combined V1/V2, or V3 at the discretion of the study site.  If the second 
training injection is done at V3, the randomization study drug injection may be used as 
the second training injection 
• 
there are no exclusion criteria 
The run-in period should be planned carefully, keeping in mind 3 elements: 
• 
The visit and time interval requirements with respect to: 
- 
 Index ACS event 
- 
V1 (start of run-in period) 
- 
V2/V2b (collection of lipid qualifying labs) 
- 
V3 (randomization) 
• 
 The required background lipid-modifying therapy (LMT) 
• 
The coronary revascularization strategy 
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6.1.1.2 Visit and Time Intervals during Run-In Period 
6.1.1.2.1  From qualifying index ACS event to Start of Run-In Period (V1) 
Interval between index ACS event and V1 is flexible. V1 can be performed: 
• 
as early as on the day of the index ACS event 
• 
but no later than 50 weeks after the index ACS event if V1 and V2 are separate visits (or 
50 weeks + 5 days after ACS event, if combined V1/V2) 
NOTE: In case of several ACS before V1, the last ACS event fulfilling the inclusion criteria before 
V1 should be used as the index ACS event. In case of rescreening, see Section 6.1.3.2. 
Prior to V1, relevant information should be provided to the patient and his/her family about the 
study, before obtaining informed consent. Investigators are encouraged to assess and explain the 
following aspects to the patient and his/her family: 
• 
Willingness to participate in a long-term study (up to ~ 5 years) in which patient will 
receive an injection every 2 weeks 
• 
Willingness to come back periodically for study visits for several years (even if study 
treatment was discontinued early), and to remain in contact with Investigator/Coordinator 
during entire duration of the study, including in case of hospitalizations outside of 
enrolling site 
It is also advisable that the Investigator communicates with the patient’s general 
practitioner/family doctor/cardiologist about main aspects of the study requirements (e.g. 
background LMT during run-in, and requirement for blinding of lipid levels during the entire 
study). 
6.1.1.2.2 Run-In Period (from V1 to V3) 
The run-in period includes 2 time interval requirements (and both should be met): 
• 
Time from V1 to V3: this is the duration of overall run-in period. It should be between 
2 weeks (14 days) and 16 weeks (+5days) 
• 
Time from index ACS event to randomization (V3): this includes the run-in period plus 
time between index ACS event and V1. Randomization (V3) should occur no earlier than 
4 weeks (28days) and no later than 52 weeks (+ 5 days) after the index ACS event 
The run-in period can be conducted in one of 2 ways, depending on whether the required LMT 
regimen prior to V2 lipid qualifying labs (see below Section 6.1.1.3) was already administered for 
at least 2 weeks (and found well tolerated) prior to V1 or not. 
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If required LMT regimen was not already administered for at least 2 weeks prior to V1, then V1 
and V2 visits should be separate visits with an interval of at least 2 weeks: 
• 
Investigator will administer required LMT regimen at or after V1 
• 
V2 should occur after at least 2 weeks of treatment with the required LMT regimen (at 
stable doses), and no further LMT increase is planned (i.e. no addition of LMT treatment 
and/or no increase in doses of statin or non-statin is planned) 
• 
V3 (randomization) can occur as soon as the qualifying lipid lab results from V2 are 
obtained from the central lab (typically results are available within 2-5 days of collection) 
and it is determined that the patient meets the lipid eligibility criteria and all other 
eligibility criteria have been confirmed 
If it is documented that the required LMT regimen was already administered for at least 2 weeks 
prior to V1 (and found well tolerated), then V1 and V2 can be combined as one visit (combined 
V1/V2); this scenario can occur under the following circumstances: 
• 
patient has been on stable, well tolerated dose of atorvastatin 40/80 mg or rosuvastatin 
20/40 mg for at least 2 weeks prior to V1 
• 
patient has documented intolerance to the required high doses of atorvastatin or 
rosuvastatin, but has been on a stable well tolerated  low/moderate dose of atorvastatin or 
rosuvastatin for at least 2 weeks prior to V1 
• 
patient has documented intolerance to statin therapy (i.e. intolerance to 2 or more statins) 
and has been on at least 2 weeks of non-statin LMT prior to V1 
• 
patient has documented intolerance to statin therapy (i.e. intolerance to 2 or more statins), 
and Investigator has determined (after discussion with patient, his/her family and patient’s 
GP/cardiologist)  that best option for the long-term is to not administer any chronic LMT 
(statin or non-statin) to the patient 
NOTE: Prior to conducting a combined V1/V2, prior LMT treatments (and, if applicable, 
intolerance to statin) must be documented in a source document such as a discharge summary, 
history and physical, clinic note or consultation report to confirm treatment. 
In case of combined V1/V2 visit, after qualifying lipid labs are collected and if patient is eligible, 
V3 (randomization) should occur at least 2 weeks (14 days) after the combined V1/V2 visit. 
6.1.1.2.3 Optional V2b Visit 
An optional additional V2 visit with repeat central laboratory lipid assessments (V2b) may be 
scheduled in the following circumstance: 
• 
V2 labs indicate that lipid inclusion criteria are not met: Investigator has the option to keep 
patient in the study and continue the run-in period while monitoring tolerability of 
statin-intensive LMT regimen. If patient subsequently develops intolerance to 
statin-intensive LMT leading to lowering the statin dose (or to using the other statin or, if 
documented intolerance to 2 or more statins, to using no statin), Investigator can repeat V2 
labs after the new lower (and well tolerated) statin dose has been administered for at least 
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2 weeks (and ideally 4 weeks, in order for the V2b lipid labs to fully reflect the effect of 
the new lower dose rather than the previous higher statin dose) 
Below are 2 other scenarios, one in which V2b must be performed (i.e. not optional) and one in 
which V2b cannot be performed: 
• 
If V2 lipid labs inclusion criteria are met however statin dose (or non-statin LMT regimen) 
was subsequently increased after V2, then a V2b visit (i.e. with repeat central laboratory 
lipid qualifying assessments) must be performed to check if patient still qualifies with this 
higher dose. 
• 
If V2 lipid labs inclusion criteria were not met with a given statin regimen, a V2b visit (ie, 
with repeat central laboratory lipid qualifying assessments) cannot be performed when 
using the same statin regimen (ie, no ‘second chance’ regarding lipid inclusion critera is 
allowed, using same statin regimen). 
6.1.1.3 Required background LMT during the run-in period 
Since the study aims to evaluate whether alirocumab is beneficial in patients who do not meet 
desired lipid levels with high-dose statins, one of the main objectives of the run-in period is that 
the Investigator has identified prior to V2 (or combined V1/V2), a background LMT regimen that 
meets all following criteria: 
• 
statin-intensive (defined as atorvastatin 40 or 80 mg, or rosuvastatin 20 or 40 mg), or with 
maximally tolerated dose of these given statins 
• 
optimized for long-term chronic use (i.e. with the intent of administering such treatment, 
on a chronic basis, for several years) 
• 
well tolerated (after stable dose for at least 2 weeks) 
 
 
 
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 Figure 1 - Overview Adjustment Required Background LMT during Run-In Period 
 
  
   *   Atorvastatin high-dose (80, 40 mg daily), moderate/low dose (20, 10 mg daily) 
          
 
        Rosuvastatin high-dose (40, 20 mg daily), moderate/low dose (10, 5 mg daily) 
 **   In statin-intolerant patients (2 or more statins), after careful assessment (incl. after 
review of latest evidence and after discussion with the patient, his/her family and 
patient’s primary GP/cardiologist), Investigator may determine that no background 
chronic LMT is appropriate for the patient. 
6.1.1.3.1 Statin-intensive treatment 
Statin-intensive treatment is defined as high-dose atorvastatin (40 or 80 mg daily) or high-dose 
rosuvastatin (20 or 40 mg daily); these should be administered to all patients, including: 
• 
statin-naive patients (i.e. patients not receiving any LMT, or patients on non-statin LMT) 
• 
patients previously treated with other statins (statins other than atorvastatin or rosuvastatin 
are not allowed during the run-in period, and should be discontinued at V1) 
• 
patients treated with and tolerating moderate or low doses of atorvastatin or rosuvastatin 
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High-dose atorvastatin/rosuvastatin: 
• 
may have been administered prior to V1, and should then be continued at V1 and beyond, 
or 
• 
can be initiated at V1, or 
• 
can be reached  progressively during the interval between V1 and V2, starting with lower 
doses at V1 (such as in patients with known prior statin tolerability issues, or with 
advanced age, or low body mass index or other concerns) 
If high doses of atorvastatin/rosuvastatin are administered but not tolerated, then Investigator 
should administer the maximal tolerated dose of atorvastatin 10 or 20 mg, or rosuvastatin 5 or 
10 mg. 
In infrequent instances, when there is a valid reason as per Investigator’s best judgment (including 
but not limited to prior statin tolerability issues, advanced age, low body mass index or other 
concerns), it is acceptable to use during the run-in period, only a low or moderate dose of 
atorvastatin (10 or 20 mg) or rosuvastatin (5 or 10 mg), and not use high doses, as described 
above. In such instances however, the reasons for not treating the patient with high dose statin 
should be documented in source notes. 
Statin-intolerant patients: 
In statin-intolerant patients (defined as intolerance to at least 2 statins), LMT can be optimized 
with non-statins LMT only (e.g. ezetimibe, or other non-statin LMT). After careful assessment 
(and ideally after discussion with patient’s primary GP/cardiologist), Investigator may 
alternatively elect to not to administer any LMT at all (i.e. use of non-statin LMT is not 
mandatory in statin-intolerant patients – see Section 6.1.1.3.2 below). 
6.1.1.3.2 Optimized for long-term chronic use 
Prior to V2, LMT should be also optimized for long-term chronic use, as per Investigator’s 
discretion. 
This means that, in addition to being statin-intensive, Investigator may choose to administer 
(before V2) non-statin LMT that he/she deems beneficial for the patient for long-term chronic 
administration. Addition of non-statin LMT to chronic administration of atorvastatin or 
rosuvastatin however is not required, and should be determined by the Investigator, and after 
discussion with patient’s GP/cardiologist, and on the basis of available clinical evidence and 
clinical judgment to support such a strategy. 
During the run-in period, fibrates (other than fenofibrate or fenofibric acid) are prohibited, and 
should be discontinued at V1, if patient was receiving such treatments. 
6.1.1.3.3 Well tolerated LMT 
Well tolerated LMT is defined as an LMT that is well tolerated after at least 2 weeks of stable 
LMT doses (statin and/or non-statin LMT) prior to V2(or V2b). 
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6.1.2 Coronary revascularization strategy 
When indicated for the treatment of the qualifying index ACS event, a coronary revascularization 
(PCI, CABG) may have taken place before V1, but may also occur during the run-in period. 
If a PCI and/or CABG occurs during the run-in period, randomization should be scheduled to 
allow for a minimum 2 week interval between the last coronary procedure and the randomization 
visit V3 (see exclusion criterion E18). 
6.1.3 Screen failures and Rescreening 
6.1.3.1 Screen failure 
Screen failure may occur in (but is not limited to) the following circumstances: 
• 
Lipid inclusion criteria are not met on the V2/V2b qualifying labs 
• 
Presence of exclusionary non-lipid laboratory abnormalities (including on repeat labs) 
during run-in 
• 
New ACS event or coronary intervention occurring within 2 weeks prior to last possible 
randomization day (52 weeks + 5 days) after original index ACS event, in a patient who 
had not yet been randomized (See exclusion criteria) 
• 
Duration of run-in period has exceeded 16 weeks (+5 days) 
6.1.3.2 Rescreening 
A patient who failed screening and left the study may undergo rescreening and re-enter the study 
(only once) under the following scenarios: 
• 
If lipid inclusion criteria at V2/V2b (LDL-C, non-HDL-C, Apo B) were met during a (first 
initial) screening with a given statin dose and patient failed screening for a reason not 
related to these lipid inclusion criteria, then patient can be rescreened using the same statin 
at same dose or, if documented intolerance, with same statin at lower dose or other 
authorized statin or no statin (later option only if documented intolerance to 2 or more 
statins). Reasons include but are not limited to: correction of exclusionary labs other than 
lipid inclusion criteria (ie, other than LDL-C, non-HDL-C, Apo B) , patient and/or family 
changed their mind regarding trial participation 
• 
However, if lipid inclusion criteria at V2/V2b (LDL-C, non-HDL-C, Apo B) were not met 
during a (first) screening with a given statin dose, patient cannot be rescreened using the 
same statin at same dose (i.e. no ‘second chance’ regarding lipid inclusion critera is 
allowed, using same statin regimen). Such patient can only be rescreened if statin 
intolerance has developed subsequently (to be documented in source notes) leading to 
using same statin at lower dose, or using other authorized statin or no statin (later option 
only if documented intolerance to 2 or more statins). 
In such cases, the first screening will be referred to as ‘Screening 1’, and the rescreening as 
‘Screening 2’. 
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For the index ACS event relative to the rescreening, one should: 
• 
Use the original index ACS event (ie, from Screening 1) as the index ACS event for 
Screening 2, if the run-in period can be restarted and completed within 52 weeks (+5 days) 
of the original index ACS event 
• 
Otherwise, use a new (subsequent) qualifying ACS event as the index event 
6.1.4 Double-blind treatment period 
The double-blind treatment period will continue until 24 months after the closing of 
randomization ex-China (ie, last date of randomization in all countries except China) or until the 
target number of events (1613) is reached, whichever comes last (see beginning of Section 6). The 
corresponding estimated study duration is 64 months (as described in the sample size 
considerations – Section 11.1). 
During this double-blind treatment period, the dosing of alirocumab is intended to achieve LDL-C 
levels of 30-50 mg/dL (0.78-1.29 mmol/L) which is considered as the physiologic ideal level and 
to avoid levels of LDL-C that are clearly below the physiologic range (ie, <15 mg/dL). To achieve 
this goal the following up-titration or down-titration scheme (including discontinuation if needed) 
will be applied: 
• 
At randomization Visit (V3), the starting dose of alirocumab will be 75 mg every 2 weeks 
(Q2W). At Month 2 (V5),  patients randomized to alirocumab will, in a blinded manner, 
either: 
- 
Continue alirocumab 75 mg Q2W, if the Month 1 (V4) LDL-C is <50 mg/dL 
(1.29 mmol/L) OR 
- 
Be titrated-up to alirocumab 150 mg Q2W, if the Month 1 (V4) LDL-C is ≥50 mg/dL 
(1.29 mmol/L) 
NOTE: In case Month 1 (V4) LDL-C is not available or not valid (e.g. issue with blood sample) 
for potential up-titration at Month 2 (V5), the next available LDL-C sample at Month 2 (V5) will 
be used for potential up-titration at Month 4 (V6). 
• 
At subsequent visits, for patients on alirocumab, the following adjustments may be 
applied: 
- 
For patients receiving 150 mg Q2W: 
 
 
 
 
 
LDL-C<25mg/dL (0.65mmol/L), including LDL-C < 15mg/dL (0.39mmol/L) on 2 
consecutive values 
At the next visit: 
Down-titration to 75 mg Q2W / done in a blinded manner. 
Additional monitoring* until the 
down-titration done 
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- 
For patients receiving 75 mg Q2W: 
 
 
 
 
 
 
 
 
 
OR             
 
 
 
 
 
 
 
 
* NOTE: Additional monitoring includes: 
• 
Patient level listing for surveillance and review for patients who are managed by 
IVRS/IWRS (i.e with planned automatic down-titration from 150mg to 75mg, or switch 
from 75mg to placebo) 
• 
Individual patient profile monitoring for potential site alerts for patients on alirocumab 75 
mg and not managed by IVRS/IWRS (i.e. with no planned automatic down-titration or 
switch to placebo by IVRS/IWRS) 
     Further details are provided in Appendix A. 
As lipid values will not be communicated to investigators after randomization to maintain the 
blind, the continuation of the 75 mg dose, the up-titration to the 150 mg dose, the down-titration 
from 150 to 75 mg, or discontinuation will occur automatically, without site or patient awareness. 
Moreover, blinded dose adjustment will avoid the need for dummy titrations in the placebo group. 
Patients who achieve 2 consecutive LDL-C levels <25 mg/dL (0.65 mmol/L) during the study will 
be monitored and managed as per Appendix A . An independent external physician will be 
notified by the central laboratory of 2 consecutive LDL-C <25 mg/dL (0.65 mmol/L). The 
independent physician will review the unmasked LDL-C values and patient safety data, in close 
collaboration with the dedicated member of the Phase 3a DMC implemented for all Phase 3 
studies evaluating the efficacy and safety of alirocumab on LDL-C (called Phase 3a studies). This 
dedicated Phase 3a DMC member will then transmit any information as necessary to the common 
member involved in both DMCs (Phase 3a DMC and CV DMC). 
Atorvastatin or rosuvastatin daily dose as well as dose of other non-statin LMT (if applicable) 
should be stable from randomization up to the common study end date, unless safety reasons 
prompt dose reduction or discontinuation (see also Section 8.8.1 and Section 10.3). 
NOTE: all randomized patients, even those who have achieved an endpoint or prematurely 
discontinued the study treatment should be followed during the entire duration of the study 
(ie, from randomization until the common study end date visit V30) for collection of suspected 
efficacy endpoints (please refer to Section 10.3 for further details on handling of patients who 
discontinued treatment early). 
LDL-C < 25 mg/dL (0.65mmol/L) but ≥ 
15mg/dL (0.39mmol/L) on 2 consecutive 
values 
Dose of 75 mg Q2W is continued with 
additional monitoring * 
LDL-C < 15 mg/dL (0.39 mmol/L) on 2 
consecutive measurements 
Discontinuation of alirocumab with blinded 
substitution of placebo injections for the 
remaining study duration 
Additional monitoring* 
until discontinuation 
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6.2 
DURATION OF STUDY PARTICIPATION. 
6.2.1 Duration of study participation for each patient 
The duration of the run-in period (V1 to V3) must be between 2 weeks (14 days) and 16 weeks 
(+5 days). Randomization must occur no earlier than 4 weeks (28 days) and no later than 
52 weeks (+ 5 days) after the index ACS event. 
The double-blind treatment period will continue (for about 2 to 5 years) until 24 months after the 
closing of randomization ex-China (ie, after last date of randomization in all countries except 
China) or until the target number of events (1613) is reached, whichever comes last (see 
beginning of Section 6). 
The corresponding estimated study duration is 64 months (as described in the sample size 
considerations). 
6.2.2 Determination of end of clinical trial (all patients) - Common Study End Date 
All randomized patients will be followed up until the Common Study End Date (CSED) visit, 
which is the final study visit (and a clinic visit) to be scheduled for each patient within 30 days of 
the CSED (see Section 10.1.5.4). 
The CSED is defined as the date corresponding to 24 months after the closing of randomization 
ex-China (last date of randomization in all countries except China) or date when the target number 
of events (1613) is reached, whichever comes last. 
• Closing of randomization ex-China will occur shortly after a total of 18,000 patients have 
been randomized (these may or may not include some patients randomized in China). 
Closing of randomization in China will occur shortly after a total of 600 patients have been 
randomized in China or at the common study end date (see Section 6.2.2), whichever comes first. 
Therefore, at the end of the double-blind treatment period, the overall randomized population will 
include about 18,000 patients who have either died or been followed for a minimum of 24 months, 
supplemented with an additional subset of patients from China (~600) who may be followed for 
less than 24 months. 
NOTE:  Common study end date is not dependent on the situation in China, and therefore will 
apply, regardless of Clinical Trial Authorization status and randomization status in China. 
6.3 
INTERIM ANALYSIS 
Patients will be followed until 1,613 patients experience at least one primary endpoint event or for 
approximately 24 months after the last date of randomization ex-China, whichever comes last. 
Interim analyses for futility will be performed, under the supervision of the CV DMC, when 50% 
and 75% of events have occurred. 
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An interim analysis for efficacy will be performed when 75% of events have occurred. Control of 
the type I and type II error will be ensured using gamma (-5) spending function for Type II error 
(futility) and Gamma (-22) for Type I error (efficacy). Stopping rules details are further described 
in Section 11.5. 
6.4 
STUDY COMMITTEES 
Executive Steering Committee: 
The Executive Steering Committee is composed of university-based scientists (experts in 
cardiology field, and lipids) with clinical and methodological expertise, working in collaboration 
with Sponsor based scientists. The Steering Committee provides scientific and strategic direction 
for the trial and will have overall responsibility for its execution. The committee provides 
guidance on producing and conducting a scientifically sound design and ensuring accurate 
reporting of the study. In that capacity, the Steering Committee must address and resolve 
scientific issues encountered during the study. 
Among its responsibilities, the Steering Committee will receive blinded (aggregate) study status 
reports from the Sponsor.  The Steering Committee will also review the recommendations from 
the Data Monitoring Committee throughout the study. 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 are described in the Steering 
Committee charter. 
Data Monitoring Committee: 
An independent Data Monitoring Committee (DMC), composed of members independent from 
the Sponsor and the study Investigators, is implemented in order to monitor patient safety by 
conducting formal reviews of accumulated safety data that will be unblinded.  This DMC 
exclusively dedicated to this study will be identified as CV DMC.  The chairman of the DMC 
dedicated to the Phase 3a studies supporting the LDL-C reduction indication (Phase 3a DMC) will 
be also a member of this CV DMC and will serve as a liaison between the two DMCs.  Safety 
data review will include the cardiovascular outcomes adjudicated or not at the time of this review. 
The CV DMC will also supervise the two interim analyses for futility and efficacy conducted 
when 50% and 75% of events occur (see Section 6.3). The CV DMC will provide the Sponsor and 
the Steering Committee with appropriate recommendations on the conduct of the clinical trial to 
ensure the protection and safety of the patients enrolled in the study. In addition, the CV DMC 
will also institute any measures that may be required for ensuring the integrity of the study results 
during the study execution. 
Additionally, the CV DMC will thoroughly analyze the aggregate data for patients who achieve 
LDL-C <25 mg/dL during their periodic reviews throughout the study and more particularly, will 
review adverse events potentially associated with LDL-C <25 mg/dL (0.65 mmol/L) 
(see Section 10.6.3 and Appendix A). 
All activities and responsibilities of this CV DMC are described in the DMC charter. 
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Clinical Events Committee: 
The Clinical Events Committee (CEC), managed by the Duke Clinical Research Institute (DCRI), 
is composed of experts in the field of cardiovascular diseases, independent from the Sponsor and 
the Investigators. This committee will be responsible for defining, validating and classifying, in a 
blinded fashion, all components of the primary and secondary endpoints related to cardiovascular 
outcomes as well as validating the classification of the cause of all deaths. 
A CEC charter and an adjudication operational manual specify the procedures, criteria, and 
classification used for adjudication of these events. 
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7 
SELECTION OF PATIENTS 
NOTE: Qualifying visit (V2) as mentioned below in some inclusion / exclusion criteria refers to 
the latest visit where lipid labs are collected (before V3), and may correspond to a combined 
V1/V2, V2 or V2b visit. 
7.1 
INCLUSION CRITERIA 
I 01. (A6)  Patients hospitalized for ACS (ST-elevation MI, non-ST-elevation MI or high-risk 
unstable angina ) defined by: 
• 
Ischemic symptoms with unstable pattern, occurring at rest or minimal exertion within 
72 hrs of an unscheduled hospital admission, due to presumed or proven obstructive 
coronary disease AND at least one of the following (A and/or B): 
A) Elevated cardiac biomarkers (troponin I or T or CK-MB with at least one determination 
>99th percentile or upper limit of normal for the laboratory). 
OR 
B) Resting ECG changes consistent with ischemia or infarction (B1) AND additional 
evidence of obstructive coronary disease, based upon the following criteria (B2): 
B1. Resting ECG changes consistent with ischemia or infarction requires at least one of 
the following: 
a) new or presumed new ST depression 
b) new or presumed new ST elevation 
c) new or presumed new T wave inversion 
B2. Additional evidence of obstructive coronary disease requires at least one of the 
following: 
a) new or presumed new evidence of  myocardial ischemia or infarction by perfusion 
imaging 
b) new or presumed new regional wall motion abnormality 
c) current evidence of at least one epicardial coronary artery stenosis > 70% by coronary 
angiography 
a) need for revascularization (PCI or CABG) related to index ACS event 
NOTE: Latest ACS event occurring prior to V1 and meeting the ACS criteria as defined above 
will be the qualifying index ACS event. In case of rescreening, see Section 6.1.3.2 
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I 02. (A6) Patient lipid levels not adequately controlled at V2 (qualifying visit) despite 
evidence-based lipid lowering therapy (including intensive atorvastatin/rosuvastatin 
therapy or maximally tolerated dose of either of these 2 statins) or other non-statin LMTs. 
Inadequate lipid control means that patient must meet at least one of the following criteria 
at V2 to qualify: 
• 
LDL-C ≥ 70 mg/dL   [≥1.81 mmol/L], or 
• 
ApoB ≥ 80 mg/dL   [≥ 0.8 g/L], or 
• 
non-HDL-C ≥100 mg/dL [≥2.59 mmol/L] 
I 03. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. Age < 40 years. 
E 02. (A6) Uncontrolled hypertension (multiple readings with SBP > 180 mmHg or  
DBP > 110 mmHg) at V3. 
E 03. History of New York Heart Association (NYHA) class III or IV congestive heart failure 
persisting despite treatment or, if measured, LVEF < 25% at the most recent measurement. 
E 04. Known history of hemorrhagic stroke. 
E 05. History of cancer within the past 5 years, except for adequately treated basal cell skin 
cancer, squamous cell skin cancer, or in situ cervical cancer. 
E 06. (A6) Recent diagnosis of hypothyroidism for which treatment was initiated within 1 month 
prior to qualifying visit (V2). 
E 07. Patient who has been previously treated with at least one dose of alirocumab or any other 
anti-PCSK9 monoclonal antibody in other clinical trials. 
E 08. Patient who has taken other investigational drugs within 1 month or 5 half-lives, whichever 
is longer. 
E 09. (A6) Laboratory findings measured during screening and before randomization visit: 
• 
Positive test for hepatitis B surface antigen 
• 
Positive hepatitis C antibody confirmed with positive RNA testing ( indicative of active 
hepatitis C infection) 
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• 
Triglycerides (TG) > 400mg/dL (>4.52 mmol/L) (1 repeat lab allowed) 
• 
Positive serum or urine pregnancy test in females of childbearing potential 
• 
eGFR <30 mL/min/1.73 m² according to 4-variable MDRD Study equation (calculated by 
central lab) 
• 
ALT or AST >3 x ULN on most recent determination prior to randomization (1 repeat lab 
is allowed) 
• 
CPK >3 x ULN on most recent determination prior to randomization (1 repeat lab is 
allowed) 
E 10. Conditions/situations such as: 
• 
Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or any sub-Investigator would preclude safe completion of 
the study or constrain endpoints assessment such as major systemic diseases, patients with 
short life expectancy. 
• 
Patients considered by the Investigator or any sub-Investigator as inappropriate for this 
study for any reason, eg: 
- 
Those deemed unable to meet specific protocol requirements, such as scheduled visits 
- 
Investigator or any sub-Investigator, pharmacist, study coordinator, other study staff or 
relative thereof directly involved in the conduct of the protocol, etc 
- 
Presence of any other conditions (eg, geographic, social….) actual or anticipated, that 
the Investigator feels would restrict or limit the patient’s participation for the duration 
of the study 
For the entry into the double-blind treatment period (randomization): 
E 11. (A6) All of the 3 following criteria are concomitantly present at the qualifying visit (V2): 
• 
LDL-C <70 mg/dL (<1.81 mmol/L), and 
• 
ApoB <80 mg/dL (<0.8 g/L), and 
• 
non-HDL-C <100 mg/dL (<2.59 mmol/L) 
      NOTE: If not all 3 but only 1 or 2 criteria are present then the patient may qualify 
E 12. (A6) Patients in whom the qualifying index ACS event occurred less than 4 weeks 
(28 days) or more than 52 weeks (+ 5 days) prior to randomization visit (V3). 
E 13. (A6) Not on stable LMT doses (statin and/or non-statin LMT) for at least 2 weeks prior to 
qualifying visit (V2). 
E 14. (A6) Use of fibrates, other than fenofibrate or fenofibric acid, during the run-in period. 
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E 15. (A6) In patients who meet lipid eligibility criteria at qualifying visit (V2), any increase in 
dose of atorvastatin, rosuvastatin or non-statin LMT after V2 without subsequent 
requalification for lipid laboratory parameters. 
E 16. (A6) Use of red yeast rice products during the run-in period up to randomization Visit 
(V3). 
E 17. (A6) New ACS within 2 weeks prior to the randomization Visit (V3). 
E 18. (A6) Coronary revascularization (PCI or CABG) planned after randomization and/or 
performed within 2 weeks prior to the randomization Visit (V3). 
E 19. Patient who withdraws consent during the screening period (patient who is not willing to 
continue or fails to return). 
7.2.2 Exclusion criteria related to the background therapy 
E 20. All contraindications to atorvastatin, rosuvastatin or other LMTs or warning/precaution of 
use (when appropriate) as displayed in the respective National Product Labeling for these 
treatments. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab 
E 21. (A6) Known hypersensitivity to monoclonal antibody or any component of the drug 
product. 
E 22. Pregnant or breast-feeding women. 
E 23. Women of childbearing potential not protected by highly effective method(s) of birth 
control (as defined in the informed consent form and/or in a local protocol addendum) 
and/or who are unwilling or unable to be tested for pregnancy. 
NOTE: Women of childbearing potential must have a confirmed negative pregnancy test at 
screening and randomization visits. They must use a highly effective contraceptive method 
throughout the entire duration of the study while receiving blinded study treatment (IMP), and for 
10 weeks following the last injection of blinded study treatment (IMP) and agree to repeat urine 
pregnancy test at designated visits. The applied methods of contraception have to meet the criteria 
for a highly effective method of birth control according to the ‘Note for guidance on non-clinical 
safety studies for the conduct of human clinical trials for pharmaceuticals (CPMP/ICH/286/95)’ 
(33). 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 
both as 1 mL volume in an autoinjector. 
Sterile placebo for alirocumab will be prepared in the same formulation as alirocumab without the 
addition of protein as 1 mL volume in an autoinjector. 
 
NOTE: in order to ensure the continuity of the study treatment without interruption (only in the 
event the manufacturer faces any performance or supply issues of the auto-injector), contingency 
alternatives are: 
• 
in case of disruption of the 150 mg auto-injector only, if the use of 75 mg auto-injectors is 
maintained, patients will need to administer 2 injections as follows: 
- 
2 injections of 75 mg as 1 mL each in an auto-injector for patients receiving the 
150 mg dose 
- 
1 injection of 75 mg as 1 mL in an auto-injector plus 1 injection of placebo as 1mL in 
an auto-injector for patients receiving the 75mg dose 
- 
2 placebo injections as 1 mL each in an auto-injector for patients receiving placebo 
     OR 
• 
in case of disruption of either 75 mg or 150 mg or both auto-injectors, patients will be 
switched to the use of prefilled syringes of placebo, 75 mg and 150 mg, with one injection 
of 1 mL for each of these doses 
 
Should this occur, the alternative investigational medicinal product (IMP) will be maintained until 
the end of the study. 
 
8.1.1 Route and method of administration 
A manual for IMP administration (injection instruction manual) will be provided to patients 
containing detailed instructions on use. Also, an administration package containing gauze, alcohol 
swabs, band aids, etc will be provided to the patients. 
The IMP could be administered by self-injection or by another designated person (such as a 
spouse, relative, nurse etc…). The used autoinjector will be discarded in a sharps container which 
will be provided to patients. It is recommended that the IMP injections be rotated within an 
anatomical area (eg, right 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) during the study.  
It should be noted that if patients have problems activating the auto-injector by pressing the 
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needle cover against their belly (e.g. soft tissue), it is recommended to inject into the thigh, where 
the skin is firmer than the belly. 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. 
Patients will be asked to store the IMP in a refrigerator. Prior to administration, the IMP should be 
set outside in a safe location at room temperature for about 30 to 40 minutes. Thereafter, the IMP 
should be administered as soon as possible. 
Instructions as outlined above should be provided to the patient (or to another designated person 
[such as spouse, relative, nurse etc...] who will administer the injections) during the run-in period 
(training injections) and as needed during the course of the study. Close supervision and feedback 
should be given at the training visit, randomization visit, and other visits as needed. 
8.1.2 Timing of administration 
During the run-in period, at least 2 training injections are required on 2 different occasions. These 
can take place at V1, V2, Combined V1/V2, or V3 at the discretion of the study site.  First 
training injection (with placebo) must be done before V3. The initial IMP double-blind injection 
(active or placebo) performed at V3 may serve as second training injection. If needed, additional 
training injections (with placebo) are available. 
During the double-blind treatment period, alirocumab or placebo will be administered 
subcutaneously every 2 weeks, starting at randomization Visit (V3, Day 1, Month 0) continuing 
up to the common study end date. 
Further training with the scheduled double-blind IMP can be done at any time during the study as 
necessary. 
Double-blind IMP will start as soon as possible after the call for randomization using the 
treatment kit number provided by the IVRS. The first injection after randomization will be done at 
the investigational site by the patient or another designated person (such as spouse, relative, etc…) 
under direct site staff supervision.  Patients will be monitored at the investigational site for at least 
30 minutes after this first double-blind injection. 
IMP should ideally be administered every 2 weeks subcutaneously at approximately the same 
time of the day; however it is acceptable to have a window period of ± 3 days. The time of the day 
is based on patient’s preference. 
If by mistake or due to other circumstances an injection is delayed by more than 7 days or 
completely missed, then the patient should return to the original schedule of study treatment 
administration without administering delayed injections. On the other hand, if the delay is less 
than or equal to 7 days from the missed date, then the patient should administer the delayed 
injection and then resume the original schedule of study treatment administration. 
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8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as non-investigational medicinal products (NIMP) 
because the medication is a background therapy: 
• 
Statins (during run-in period: only atorvastatin or rosuvastatin are allowed; after 
randomization: every effort should be made to continue atorvastatin / rosuvastatin until 
end of study; alternative, including other statin,  allowed in case intolerance to lowest dose 
of atorvastatin/rosuvastatin has developed post-randomization – see Figure 2, 
Section 8.8.2) 
• 
Cholesterol absorption inhibitors (ezetimibe) 
• 
Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam) 
• 
Nicotinic acid (niacin) 
• 
Fenofibrate, fenofibric acid 
• 
Omega-3 fatty acids 
Please see Section 8.8 for further information. 
8.3 
BLINDING PROCEDURES 
8.3.1 Methods of blinding 
Alirocumab and placebo will be provided in identically matched auto injector and packaged 
identically which includes labeling to protect the blind. 
Each double-blind treatment kit will be labeled with a number, which will be generated by a 
computer program from Sanofi. The treatment kit numbers will be obtained by the Investigator at 
the time of patient randomization and subsequent patient visits scheduled via a centralized 
treatment allocation system that will be available 24 hours-a-day, 7 days-a-week. 
In accordance with the double-blind design, study patients, Investigators and study site personnel 
will remain blinded to study treatment and will not have access to the randomization (treatment 
codes) except under circumstances described in Section 8.3.6. 
8.3.2 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 after randomization and until after the final database lock has occurred. 
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For patients who achieve 2 consecutive LDL-C <25 mg/dL (0.65mmol/L) on alirocumab and 
depending on the dose received, the following will be applied: 
• 
If the dose is 150 mg Q2W: 
 
 
 
 
 
 
• 
If the dose is 75 mg Q2W: 
 
 
 
 
 
 
 
 
 
OR             
 
 
 
 
 
 
 
* NOTE: Additional monitoring includes: 
• 
Patient level listing for surveillance and review for patients who are managed by 
IVRS/IWRS (i.e with planned automatic down-titration from 150 mg to 75 mg, or switch 
from 75mg to placebo) 
• 
Individual patient profile monitoring for potential site alerts for patients on alirocumab 
75 mg and not managed by IVRS/IWRS (i.e. with no planned automatic down-titration or 
switch to placebo by IVRS/IWRS) 
     Further details are provided in Appendix A. 
As described above, in case of LDL-C <25 mg/dL (0.65 mmol/L) on 2 consecutive values and 
until specific actions are undertaken, patients will be monitored according to process outlined in 
Section 10.6.3 and Appendix A. In order to maintain the integrity of the blind as much as possible 
with this monitoring process, the following points will be undertaken: 
• 
Specific steps will be in place to ensure that the work which will be carried out by the 
central lab group and the communication with the independent external physician(s) (also 
known as independent physician), who is responsible for closely monitoring patients with 
these 2 consecutive LDL-C levels, will be in strict confidence. 
LDL-C<25mg/dL (0.65mmol/L), including LDL-C < 15mg/dL (0.39mmol/L) on 2 
consecutive values. 
At the next visit: 
Down-titration to 75 mg Q2W / done in a blinded manner. 
Additional monitoring* until the 
down- titration done 
LDL-C < 25 mg/dL (0.65mmol/L) but ≥ 
15mg/dL (0.39mmol/L) on 2 consecutive  
values 
Dose of 75 mg Q2W is continued with 
additional monitoring * 
LDL-C < 15 mg/dL (0.39 mmol/L) on 2 
consecutive measurements 
Discontinuation of alirocumba with blinded 
substitution of placebo injections for the 
remaining study duration 
Additional monitoring* 
until discontinuation 
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• 
The independent physician(s) and the dedicated member of the Phase 3a DMC 
(implemented for all Phase 3 studies evaluating the efficacy and safety of alirocumab on 
LDL-C) will work in close collaboration and independently from the clinical team and the 
sites. This dedicated Phase 3a DMC member will then transmit any information as 
necessary to the common member involved in both DMCs (CV DMC and Phase 3a DMC) 
• 
The actual LDL-C levels will not be reported to the sites 
• 
Monitoring will be discontinued when specific actions are undertaken as described above, 
unless patients still display a LDL-C <25 mg/dL 
8.3.3 Anti-alirocumab antibodies 
Patients’ anti-alirocumab antibody results will not be communicated to the sites during the study. 
The sponsor’s operational team will not have access to anti- alirocumab antibodies associated 
with patient identification until after the final database lock has occurred. 
The lab technicians involved in the determination of patients’ anti- alirocumab antibodies are 
excluded from the operational team and a process will be set up to prevent any potential 
unblinding. 
Patients who have titers at or above 240 for anti- alirocumab antibodies at the common study end 
date will have an additional antibody sample between 6 to 12 months after this date. 
In patients who permanently discontinued treatment early, blood sample for anti- alirocumab 
antibodies should be drawn at the early end-of-treatment visit (V70) and when the patient 
returns for an on-site clinic visit where this assessment was planned, i.e. annually 
(see also Section 10.3.4). 
8.3.4 Committees 
The independent Clinical Events Committee (CEC) will review and adjudicate events in a blinded 
manner. 
The Data Monitoring Committee will receive blinded by treatment group or unblinded (if 
necessary) confidential reports from an independent statistician for review (Section 6.4). 
8.3.5 Data Analysis 
Regular DMC safety analyses and both Interim Analyses will be performed by the external 
independent CV DMC Statistician and will be reviewed under the supervision of the CV DMC. 
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8.3.6 Randomization code breaking during the study 
In case of an Adverse Event (AE), the code must be broken by the site only in exceptional 
circumstances when knowledge of the IMP is essential for treating the patient. If possible, a 
contact should be initiated with the Monitoring Team/Medical Monitor before breaking the code. 
All calls will be documented by the Monitoring Team as appropriate to include date and time of 
the call, name of the person contacted within the Monitoring Team, patient ID, documentation of 
the request, and decision for unblinding or not. 
Code breaking can be performed at any time by using the proper module of the centralized 
treatment allocation system and/or by calling any other phone number provided by the Sponsor 
for that purpose. However, it is preferable to contact the Medical Monitor to discuss the case 
before unblinding the case. If the blind is broken, the Investigator should document the date, time 
of day, and reason for code breaking, and report this information (or “relevant information as 
required by”) on the appropriate page of the electronic case report from (eCRF). 
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 can also be performed by contacting the "24 hour alert system"; but this 
system should be used in very exceptional cases only (ie, unavailability of a centralized treatment 
allocation system or inability to contact Investigator and/or site staff). However, the preferred 
option is to unblind using a centralized treatment allocation system. The Investigators will be 
informed by the clinical monitoring team about the availability of the local code-breaking details 
(through an emergency centralized 24 hour telephone system for use with e-SMS). A patient card, 
including the relevant “24 hour alert system” telephone number will be provided to every patient 
who will participate in the study. 
Unblinding may also be performed by the Sponsor for some Serious Adverse Events that are both 
related and unexpected in order to conform to regulatory reporting requirements. 
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 kit (75 mg or 150 mg), or placebo kit] will be packaged in accordance with this list. 
The Project Demand manager will provide the randomized list of treatment kit numbers and the 
Study Biostatistician will provide the randomization scheme to the centralized treatment 
allocation system provider. Then, this centralized treatment allocation system provider will 
generate the patient randomization list according to which it will allocate the treatment kits to the 
patients. 
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Patients will be randomized to receive either placebo or alirocumab during the double-blind study 
treatment period using a ratio 1:1, with permuted-block randomization. Randomization will be 
stratified according to country. 
The treatment kit numbers will be allocated using the centralized treatment allocation system on 
randomization visit (Day 1, Month 0), Month 2, Month 4, every 4 months up to Month 24, and 
then every 6 months up to Month 64. 
For patients in the alirocumab treatment arm, the treatment kit allocated at Month 2 (V5) will be 
based on their Month 1 (V4) LDL-C level following the up-titration rules (see Section 6.1.4). 
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 “patient will be considered as not 
randomized and withdrawn from the study. 
Two types of centralized treatment allocation system will be used, the Interactive Voice Response 
System (IVRS) and the Interactive Web Response System (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, will be prepared to contain 6 autoinjectors in a child-resistant package. 
In order to protect the blind, all double-blind treatment kit boxes will have the same look and feel 
and therefore will be labeled with a double-blind label. 
In addition to the double-blind treatment kits, a training kit containing 1 placebo autoinjector  
each will be prepared for the purpose of instructing patients on injection administration which is 
to be performed prior to randomization. These training injections should be performed on site at 
screening Visit (V1, Week-16 to Week-4) and qualifying Visit (V2, Week-2), respectively. A 
third training injection can be performed at an additional visit such as the optional visit V2b. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
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8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP (alirocumab or placebo) will be stored in a refrigerator between +2°C and +8°C 
(36°- 46° F) by the site. The temperature of the site refrigerator should be checked every working 
day 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 as necessary 
will be in place for transportation of the IMP kits from the study site to the patient’s refrigerator. 
NOTE: Exceptionally, after discussion between site and sponsor (eg, patient unable to attend a 
clinic visit due to special circumstances) some IMP kits could be supplied, when feasible, directly 
from site to patient via a sponsor-approved courier company. This process (which requires 
maintenance of the cold chain) would be implemented only at selected sites/countries (where 
certain conditions would be fulfilled, and where permitted locally) and for selected patients (who 
could handle and would consent to such a process). This direct-to-patient process will be 
described in detail in a separate document and would be implemented after appropriate training 
of monitoring teams and investigational sites. 
8.7 
RESPONSIBILITIES 
The Investigator, the Pharmacist, or other personnel allowed to store and dispense 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 the applicable regulatory requirements. 
All IMP shall be dispensed after IVRS contact in accordance with the Clinical Trial Protocol and 
it is the Investigator's responsibility to ensure that an accurate record of IMP issued and returned 
is maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure (ie, Product 
Technical Complaint [PTC] form). 
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, allows the IMP to be 
used other than as directed by this Clinical Trial Protocol, or dispose of IMP in any other manner. 
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8.7.1 Treatment accountability and compliance 
IMP administration data will be recorded by the patients onto a patient’s diary. 
Measures taken to ensure and document IMP compliance and accountability are described below: 
• 
The Investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) and 
he/she will dispense the treatment kit(s) to the patient. 
• 
The accountability is to be performed at IMP kit re-supply visits only (see Section 10.1.5). 
The used and unused kit(s) should be brought back to such visits for accountability 
purposes. 
• 
The Investigator or designee will complete the corresponding treatment log form from 
patient’s diary. 
NOTES: 
At every opportunity (clinic visit or phone call), Investigator should remind patient to 
complete the diary and to bring the diary at the next clinic visit. 
If patient forgets to bring the diary at a clinic visit, site should come up with an alternative 
solution to obtain as soon as possible information contained in the diary in order to be 
able to complete IMP information in eCRF in a timely manner. 
If patient dies, site should make every possible effort to obtain patient diary from the 
family (in addition to collecting detailed information about the circumstances of patient 
death). 
• 
The Investigator/study coordinator will enter data in the appropriate eCRF pages, 
according to data recorded in the treatment log form. 
• 
The monitor will check the data consistency between eCRF pages, treatment log forms 
using patient’s diary, and returned unused IMPs of a corresponding kit. 
8.7.2 Return and/or destruction of treatments 
Destruction of IMP kits (i.e., used, unused or expired) can be performed during the course of the 
study in addition to the end of the study. 
Destruction at site is strongly encouraged and can be performed provided that the following 
requirements are met: 
• 
Site has the appropriate facilities to destroy IMP and 
• 
Site has procedures to allow traceability of the batches and quantities destroyed and 
delivers the corresponding destruction documentation/certificate, 
• 
Sanofi provides the appropriate authorization. 
In case the above requirements are not satisfied and the site cannot safely destroy IMP, the 
treatments will be returned to the local depot for destruction. 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. 
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8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study 
(until the common study end date). 
8.8.1 Background Lipid-Modifying Therapy 
During the run-in period, all LMTs are authorized with the exception of fibrates (other than 
fenofibrate and fenofibric acid), and statins other than atorvastatin, and rosuvastatin. 
These include but are not limited to: 
• 
Statins (atorvastatin, rosuvastatin only; other statins are not allowed during run-in period) 
• 
Cholesterol absorption inhibitors (ezetimibe) 
• 
Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam) 
• 
Nicotinic acid (niacin) 
• 
Fenofibrate, fenofibric acid 
• 
Omega-3 fatty acids 
After randomization, the required background LMT regimen, as determined from the run-in 
period, with intensive statin therapy (atorvastatin 40 or 80 mg or rosuvastatin 20 or 40 mg) or 
maximal tolerated dose of one these 2 statins, and optimized with addition of non-statin LMTs (at  
the Investigator’s discretion) should be continued, for as long as this regimen remains well 
tolerated. 
If, during the course of the study, significant tolerability concerns arise and patient is found 
intolerant to any dose of atorvastatin or rosuvastatin, other statins (i.e. other than atorvastatin or 
rosuvastatin) as well as non-statin LMTs are authorized. A proposed algorithm for modification of 
LMT post-randomization is provided in Figure 2. 
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Figure 2 - Proposed algorithm for adjusting LMT post-randomization, in case tolerability concerns 
arise (e.g. myalgia) 
High-dose statin 1 (atorva / rosuva)
Find new maximal tolerated dose statin 1
Discontinue statin 1 
Start statin 2 (rosuva / atorva) 
(find maximal tolerated dose statin 2)
Give any other statin and/or non-statin LMT (e.g. ezetimibe) at 
Investigator’s discretion
If lowest dose statin 2  not  tolerated
If lowest dose statin 1 not 
tolerated
reduce dose statin 1
 
NOTE: If statin 1 is atorvastatin, statin 2 is rosuvastatin; if statin 1 is rosuvastatin, statin 2 is 
atorvastatin. 
For background LMT, including statins, sites must follow the national product label for the safety 
monitoring and management of patients. 
LMT (whether administered as prescription drugs or over the counter) will be recorded in the 
CRF and source data. However, detailed use of nutraceutical products (such as plant stanols found 
in Benecol, flax seed oil, psyllium or LMT found in multivitamins) will not be collected in the 
CRF but should be maintained in source documents. 
8.8.2 Other Concomitant Medications 
All other concomitant medication(s) are allowed. 
All patients should receive contemporary evidence-based treatment for ACS and chronic CHD as 
described in regional professional guidelines, including, but not limited to anti-platelet agents, 
beta blockers, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers 
(ARBs), and treatments for diabetes, hypertension, and smoking. 
Concomitant medications (from a prescription or over-the-counter) that are administered 
chronically, as well as those that are administered during hospitalizations and considered relevant 
(i.e. pertaining to the patient’s background or current medical history, or related to an 
AE/AESI/SAE, and as determined by Investigator’s best judgment) are allowed and will be 
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recorded in the e–CRF and source data.  Use of some medications related to efficacy may be 
collected only in (cardiovascular) efficacy endpoint eCRF pages (e.g. use of diuretics for CHF). 
Other medications administered during hospitalizations and considered not relevant [including but 
not limited to: PRN (i.e. as needed) medications, anesthetic agents, medications given related to 
the performance of a procedure, IV fluids] as well use of multivitamins or nutraceuticals will not 
be recorded in the eCRF, however should be maintained in the source documents. 
8.9 
MITIGATION PLAN IN CASE OF IMP ISSUE 
In the exceptional case of a major IMP issue, the following mitigation plan may be implemented 
in order to achieve the dual goal of optimizing IMP inventory at all sites, while maintaining 
patient treatment continuity with IMP: 
From M24 (V16) and at all subsequent clinic visits (M30, M36, M42, M48, M54, and M60), a 
reduced number of IMP autoinjectors would be dispensed (12 instead of 18) covering 24 weeks of 
treatment. As a consequence, subsequent clinic visits would need to be scheduled in a more 
tightly manner and at a slightly shorter interval, ie, every 22 to 24 weeks (161d  ±7d), instead of 
every 26w ±14d. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
EFFICACY ENDPOINTS 
Any suspected cardiovascular event suggestive of an endpoint as well as all deaths will be 
submitted to the Clinical Events Committee (CEC). The CEC will review the data of the reported 
cases in a blinded manner for adjudication purpose and will validate if the event should be 
considered as an endpoint. The cardiovascular events adjudicated and validated by the CEC will 
be used for the analyses. 
Events that the CEC could not classify as well as suspected event according to investigator but not 
confirmed by the CEC will not be part of the outcomes. 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint is the time from randomization to first occurrence of one of the 
following clinical events, as determined by the CEC: 
• 
CHD death (including “undetermined causes of death” as per the CEC) 
• 
Any non-fatal MI 
• 
Fatal and non-fatal ischemic stroke (including “stroke not otherwise specified” as per the 
CEC) 
• 
Unstable angina requiring hospitalization 
If none of these events is observed at the time of the analysis cut-off date (final or interim, 
depending of the analysis, see Section 11.4.2.1 for details), the patient will be censored at the date 
of last contact, at the date of death, or at the date of cut-off, whichever comes first. 
Of note, suspected event according to the investigator but not confirmed by the CEC will not be 
part of the primary efficacy outcome; their description will be provided separately. 
9.1.2 Secondary efficacy endpoints 
Time-to-event secondary endpoints will be censored using the same methodology as for the 
primary efficacy endpoint. 
9.1.3 Main Secondary Efficacy Endpoint(s): 
• 
Time from randomization to first occurrence of any CHD event (major CHD event, 
unstable angina requiring hospitalization, ischemia-driven coronary revascularization 
procedure) 
• 
Time from randomization to first occurrence of any major CHD event (CHD death, non-
fatal MI) 
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• 
Time from randomization to first occurrence of any CV event defined as follows: any non- 
fatal CHD event, any CV death, and non-fatal ischemic stroke 
• 
Time from randomization to first occurrence of all-cause mortality, non-fatal MI, non-fatal 
ischemic stroke 
• 
Time from randomization to death (all-cause mortality) 
9.1.4 Other Secondary Efficacy Endpoint(s): 
• 
Component of the primary endpoint considered individually: 
- 
Time from randomization to CHD death 
- 
Time from randomization to first occurrence of any non-fatal MI 
- 
Time from randomization to first occurrence of fatal or any non-fatal ischemic stroke 
- 
Time from randomization to first occurrence of any unstable angina requiring 
hospitalization 
• 
Time from randomization to first occurrence of any ischemia-driven coronary 
revascularization procedure 
• 
Time from randomization to first occurrence of any congestive heart failure requiring 
hospitalization 
9.1.5 Efficacy assessment methods 
Definitions of the primary and secondary efficacy endpoints related to CV events and death are 
based on FDA/CDISC Standardized Definitions for End Point Events in Cardiovascular Trials, 
and on the Thygesen Universal Definition for the definition of myocardial infarction (34) (35) 
(36). 
9.1.6 Definitions of components of the composite primary efficacy endpoint 
9.1.6.1 Coronary Heart Disease (CHD) Death 
Coronary Heart Disease Death is defined as the subset of Cardiovascular deaths for which there is 
a clear relationship to underlying coronary heart disease, including death secondary to acute MI, 
sudden death, heart failure, complication of a coronary revascularization procedure performed for 
symptoms, coronary disease progression, or new myocardial ischemia where the cause of death is 
clearly related to the procedure, unobserved and unexpected death, and other death that cannot 
definitely be attributed to a nonvascular cause (see Section 9.1.7.1  for the different definitions). 
9.1.6.1.1 Death due to acute myocardial infarction 
Death by any mechanism (arrhythmia, heart failure, low output) within 30 days after a myocardial 
infarction (MI) related to the immediate consequences of the myocardial infarction, such as 
progressive congestive heart failure (CHF), inadequate cardiac output, or refractory arrhythmia. If 
these events occur after a “break” (eg, a CHF and arrhythmia free period of at least a week), they 
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should be designated by the immediate cause, even though the MI may have increased the risk of 
that event (eg, late arrhythmic death becomes more likely after an acute myocardial infarction 
(AMI)). The acute myocardial infarction should be verified to the extent possible by the 
diagnostic criteria outlined for acute myocardial infarction or by autopsy findings showing recent 
myocardial infarction or recent coronary thrombus. 
Sudden cardiac death, if accompanied by symptoms suggestive of myocardial ischemia, new ST 
elevation, new LBBB, or evidence of fresh thrombus by coronary angiography and/or at autopsy 
should be considered death resulting from an acute myocardial infarction, even if death occurs 
before blood samples or 12-lead electrocardiogram (ECG) could be obtained, or at a time before 
the appearance of cardiac biomarkers in the blood. 
Death resulting from a procedure to treat a myocardial infarction such as percutaneous coronary 
intervention (PCI), coronary artery bypass graft surgery (CABG), or to treat a complication 
resulting from myocardial infarction, should also be considered death due to acute MI. 
Death resulting from an elective coronary procedure to treat myocardial ischemia (ie, chronic 
stable angina) or death due to a MI that occurs as a direct consequence of a CV 
investigation/procedure/operation should be considered as a death due to a CV procedure. 
9.1.6.1.2 Sudden cardiac death 
Death that occurs unexpectedly, not following an acute MI, and includes the following deaths: 
a) Death witnessed and occurring without new or worsening symptoms 
b) Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless documented (ie by ECG or other objective) to be due to acute 
myocardial infarction 
c) Death witnessed and attributed to an identified arrhythmia (eg, captured on an 
electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but 
found on implantable cardioverter-defibrillator review) 
d) Death after unsuccessful resuscitation from cardiac arrest 
e) Death after successful resuscitation from cardiac arrest and without identification of a 
non-cardiac etiology 
f) 
Unwitnessed death without other cause of death (information regarding the patient’s 
clinical status preceding death should be provided, if available) 
General considerations 
A subject seen alive and clinically stable 24 hours prior to being found dead without any evidence 
or information of a specific cause of death should be classified as “sudden cardiac death.” 
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Typical scenarios include: 
• 
Subject well the previous day but found dead in bed the next day 
• 
Subject found dead at home on the couch with the television on 
Deaths for which there is no information beyond ‘Patient found dead at home’ may be classified 
as ‘Death due to other cardiovascular causes’. 
9.1.6.2 Non-fatal myocardial infarction (MI) 
Definition for myocardial infarction is based on the most recent Thygesen Universal Definition 
(37): 
9.1.6.2.1 Acute myocardial infarction 
The term acute myocardial infarction (MI) refers to evidence of myocardial necrosis in a clinical 
setting consistent with acute myocardial ischemia. Under these conditions any one of the 
following criteria meets the diagnosis for MI: 
a) Detection of a rise and/or fall of cardiac biomarker values [preferably cardiac troponin 
(cTn)] with at least one value above the upper reference limit (URL) and with at least one 
of the following: 
• Symptoms of ischemia 
• New or presumed new significant ST-segment–T wave (ST–T) changes or new left 
bundle branch block (LBBB). 
• Development of pathological Q waves in the ECG 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
• Identification of an intracoronary thrombus by angiography or autopsy 
b) Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new 
ischemic ECG changes or new LBBB, but death occurred before cardiac biomarkers were 
obtained, or before cardiac biomarker values would be increased. 
c) Percutaneous coronary intervention (PCI) related MI is defined by elevation of cTn values 
(>5 x URL) occurring within 48h of the procedure in patients with normal baseline values 
(≤URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or 
falling. In addition, at least one of the following is required: 
• Symptoms suggestive of myocardial ischemia 
• New ischemic ECG changes 
• Angiographic findings consistent with a procedural complication 
• Imaging demonstration of new loss of viable myocardium or new regional wall 
motion abnormality 
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d) Stent thrombosis associated with MI when detected by coronary angiography or autopsy in 
the setting of evidence of myocardial ischemia and with a rise and/or fall of cardiac 
biomarker values with at least one value above the URL. 
e) Coronary artery bypass grafting (CABG) related MI is defined by elevation of troponin 
values (>10 x URL) occurring within 48h of the procedure in patients with normal 
baseline cTn values (≤URL). In addition at least one of the following is required: 
• New pathological Q waves or new LBBB 
• Angiographic documented new graft or new native coronary artery occlusion 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
Cardiac troponin is the preferred biomarker for diagnosis of MI. In absence of troponin, CK-MB 
will be used. 
9.1.6.2.2 Silent myocardial infarction 
Silent MI is not considered part of the primary endpoint. 
Asymptomatic patients who develop new pathologic Q wave criteria for MI detected during 
routine ECG follow-up, or reveal evidence of MI by cardiac imaging, that cannot be directly 
attributed to a coronary revascularization procedure, are termed ‘silent MI”. Any one of the 
following criteria meets the diagnosis: 
• 
Pathological Q waves with or without symptoms in the absence of non-ischemic causes 
• 
Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract, in the absence of a non-ischemic cause 
• 
Pathological findings of a prior MI 
9.1.6.2.3 Classification according to Universal MI definition subtypes 
All MI events will be classified by Universal MI definition subtypes as follows: 
• 
Type 1 
Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, 
erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries 
leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte 
necrosis. The patient may have underlying severe coronary artery disease (CAD) but on occasion 
non-obstructive or no CAD. 
• 
Type 2 
In instances of myocardial injury with necrosis where a condition other than CAD contributes to 
an imbalance between myocardial oxygen supply and/or demand, eg, coronary endothelial 
dysfunction, coronary artery spasm, coronary embolism, tachy/brady-arrhythmias, anemia, 
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respiratory failure, hypotension, and hypertension with or without left ventricular hypertrophy 
(LVH). 
• 
Type 3 
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic 
ECG changes or new LBBB, but death occurring before blood samples could be obtained, before 
cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected. 
• 
Type 4a 
Myocardial infarction associated with PCI. 
• 
Type 4b 
Myocardial infarction associated with stent thrombosis. 
• 
Type 4c 
Myocardial infarction associated with restenosis (restenosis is the only angiographic explanation) 
• 
Type 5 
Myocardial infarction associated with CABG. 
9.1.6.2.4 Sub-classifications 
a) Sub-classifications into STEMI versus NSTEMI 
All MI events will be sub-classified into STEMI versus NSTEMI as follows: 
• STEMI: new ST elevation at the J point in two contiguous leads with the cut-points: 
≥0.1 mV in all leads other than leads V2–V3 where the following cut points apply: 
≥0.2 mV in men ≥40 years; ≥0.25 mV in men <40 years, or ≥0.15 mV in women. 
• NSTEMI: if ECG does not meet STEMI criteria will be classified as NSTEMI 
• If ECGs are unavailable or uninterpretable the MI will be classified as unknown 
b) Sub-classifications into Q wave versus Non Q wave MI 
MI events will be sub-classified into Q wave vs. Non Q wave MI as follows: 
Criteria for abnormal Q-waves are any one of: 
• Any Q wave in leadsV2–V3 ≥0.02 sec or QS complex in leads V2 and V3 
• Q wave ≥0.03 sec and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF or V4–V6 in 
any two leads of a contiguous lead grouping (I, aVL; V1–V6; II, III, aVF)a 
a The same criteria are used for supplemental leads V7-V9. 
• R wave ≥0.04 sec in V1–V2 and R/S ≥1 with a concordant positive T wave in absence of 
conduction defect 
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• If Q-waves criteria are not met, MI is classified as non-Q-wave MI 
• If ECGs are unavailable or uninterpretable the MI will be classified as unknown 
9.1.6.3 Fatal and Non-fatal stroke 
Stroke is defined as an acute episode of focal or global neurological dysfunction caused by central 
nervous system (CNS) vascular injury as a result of hemorrhage or infarction. CNS includes brain, 
spinal cord and retina. 
Classification: 
a) Ischemic Stroke 
Ischemic stroke is defined as an acute episode of focal cerebral, spinal, or retinal dysfunction 
caused by CNS infarction. Evidence of infarction is defined as: 
• Pathological, imaging, or other objective evidence of acute cerebral, spinal cord, or retinal 
focal ischemic injury in a defined vascular distribution; or 
• In the absence of the above (i.e. imaging or autopsy unavailable), clinical evidence of 
cerebral, spinal cord, or retinal focal ischemic injury is based on symptoms persisting 
≥24 hours or until death, and other etiologies excluded 
NOTE: Hemorrhagic infarction, defined as parenchymal hemorrhage after CNS infarction, is 
considered an ischemic stroke (i.e. hemorrhagic conversion of infarction) and is part of the 
primary endpoint. 
Ischemic strokes may be further classified according to most likely etiology (example large 
artery atherosclerosis, cardio-embolic, etc.) 
b) Cerebral Hemorrhage 
Hemorrhages in the CNS are classified as stroke if they are nontraumatic, caused by a vascular 
event, and result in injury to the CNS. In contrast, traumatic hemorrhages will not be 
characterized as stroke. Subdural hematoma will not be classified as a stroke. 
The diagnoses included in this section are intracerebral hemorrhage (intraparenchymal and 
intraventricular) and subarachnoid hemorrhage (both aneurysmal and nonaneurysmal). 
Diagnoses included in this section are not part of the primary endpoint. 
• Stroke caused by intracerebral hemorrhage 
Rapidly developing clinical signs of neurological dysfunction (focal or global) attributable 
to a focal collection of blood within the brain parenchyma or ventricular system that is not 
caused by trauma. 
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• Stroke caused by subarachnoid hemorrhage 
Rapidly developing signs of neurological dysfunction (focal or global) and/or headache 
because of bleeding into the subarachnoid space (the space between the arachnoid 
membrane and the pia mater of the brain or spinal cord), which is not caused by trauma. 
Hemorrhages may be further classified according to location (example, supratentorial, 
subtentorial, intraparenchymal etc.) 
c) Stroke not otherwise specified 
An episode of acute neurological dysfunction presumed to be caused by ischemia or 
hemorrhage, persisting ≥24 hours or until death, but without sufficient evidence to be 
classified as one of the above. 
Strokes not otherwise specified are part of the primary endpoint. 
A functional disability assessment will be performed for strokes after 3 to 6 months following the 
start date of the event (see Appendix I). 
Fatal stroke 
Death due to Stroke refers to death after a stroke that is either a direct consequence of the stroke 
or a complication of the stroke. Acute stroke should be verified to the extent possible by the 
diagnostic criteria outlined for stroke. 
9.1.6.4 Unstable angina requiring hospitalization 
A diagnosis of unstable angina (new ACS event without elevations in cardiac biomarkers) that 
meets the primary endpoint requires the following: 
• Admission to hospital or emergency room (until at least next calendar day) with symptoms 
presumed to be caused by myocardial ischemia with an accelerating tempo in the prior 
48 hrs and/or prolonged (at least 20 min) rest chest discomfort 
AND 
• New high-risk ECG findings consistent with ischemia or infarction (or presumed new if no 
prior ECG available) as defined below: 
- 
New or presumed new ST depression >0.5mm in 2 contiguous leads or T wave 
inversion >1mm in leads with prominent R wave or R/S >1 in 2 contiguous leads, OR 
- 
New or presumed new ST elevation at the J point in > 2 contiguous leads >0.2mV in 
V2 or V3 in men or >0.15 mV in women in V2 or V3 or >0.1mV in other leads. 
- 
LBBB (new or presumed new) 
AND 
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• Definite contemporary evidence (defined below) of angiographically significant coronary 
disease as demonstrated by: 
- 
Need for coronary revascularization procedure (PCI or CABG) excluding those 
performed to treat only restenosis lesion(s) at previous PCI site(s) OR 
- 
Angiographic evidence of at least one significant (≥ 70%) epicardial coronary stenosis 
not due to restenosis at previous PCI site 
The coronary revascularization procedure or the diagnostic angiography must have been 
performed during the hospitalization for that event. 
9.1.7 Definitions of the secondary efficacy endpoints 
9.1.7.1 Death 
All deaths will be categorized as Cardiovascular, non-Cardiovascular or Undetermined based on 
the definitions below. In addition, all deaths will also be categorized as Coronary Heart Disease 
Death and further sub-typed based on the specific Cardiovascular and non-Cardiovascular 
categories defined below. 
9.1.7.1.1 Definition of Cardiovascular Death 
Cardiovascular Death is defined as death resulting from an acute myocardial infarction, sudden 
cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular (CV) 
procedures, death due to CV hemorrhage, and death due to other cardiovascular causes. 
9.1.7.1.1.1 Coronary Heart Disease (CHD) Death 
Definition of CHD death is described in Section 9.1.6.1. 
9.1.7.1.1.2 Other Cardiovascular Deaths 
Death due to Heart Failure or Cardiogenic Shock: 
Death due to Congestive Heart Failure refers to a death in association with clinically worsening 
symptoms and/or signs of heart failure not following an acute MI. Deaths due to heart failure can 
have various etiologies, including single or recurrent myocardial infarctions, ischemic or non-
ischemic cardiomyopathy, hypertension, or valvular disease. 
Cardiogenic shock not occurring in the context of an acute myocardial infarction or as the 
consequence of an arrhythmia occurring in the absence of worsening heart failure. 
Cardiogenic shock is defined as systolic blood pressure (SBP) <90 mm Hg for greater than 1 hour, 
not responsive to fluid resuscitation and/or heart rate correction, and felt to be secondary to 
cardiac dysfunction and associated with at least one of the following signs of hypoperfusion: 
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• 
Cool, clammy skin or 
• 
Oliguria (urine output <30 mL/hour) or 
• 
Altered sensorium or 
• 
Cardiac index <2.2 L/min/m² 
Cardiogenic shock can also be defined if SBP <90 mm Hg and increases to ≥90 mm Hg in less 
than 1 hour with positive inotropic or vasopressor agents alone and/or with mechanical support. 
Death due to Stroke (see Section 9.1.6.3 for the definition of fatal stroke). 
Death due to Cardiovascular Procedures 
Death due to Cardiovascular Procedures refers to death caused by the immediate complications of 
a cardiac procedure and excludes death resulting from procedures to treat an acute MI or the 
complications resulting from an acute MI. 
Death due to Cardiovascular Hemorrhage 
Death due to Cardiovascular Hemorrhage refers to death related to hemorrhage such as a non-
stroke intracranial hemorrhage, non-procedural or non-traumatic vascular rupture (eg, aortic 
aneurysm), or hemorrhage causing cardiac tamponade. 
Death due to Other Cardiovascular Causes: 
Death due to Other Cardiovascular Causes refers to a cardiovascular death not included in the 
above categories (e.g., pulmonary embolism or peripheral arterial disease). 
9.1.7.1.2 Definition of Non-Cardiovascular Death 
Non-cardiovascular death is defined as any death that is not thought to be due to a cardiovascular 
(CV) cause. The following categories may be collected. 
9.1.7.1.2.1 Non-Malignant Causes 
• 
Pulmonary 
• 
Renal 
• 
Gastrointestinal 
• 
Hepatobiliary 
• 
Pancreatic 
• 
Infection (includes sepsis) 
• 
Non-infectious (eg, systemic inflammatory response syndrome [SIRS]) 
• 
Hemorrhage* excluding hemorrhagic strokes and bleeding in the setting of coronary 
revascularization 
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• 
Non-cardiovascular procedure or surgery 
• 
Accidental (e.g. physical accidents or drug overdose) or Trauma 
• 
Suicide 
• 
Prescription drug error (e.g. prescribed drug overdose, use of inappropriate drug, or drug-
drug interaction) 
• 
Neurological process that is not a stroke or hemorrhage 
• 
Other non-cardiovascular, specify: _________________ 
*Examples:  
Death due to GI bleeding is not considered a CV death. Death due to retroperitoneal hematoma 
following PCI is considered CV death. Death due to intracerebral hemorrhage is considered CV 
death. 
9.1.7.1.2.2 Malignant Causes 
 
• 
Death results directly from the cancer; OR 
• 
Death results from a complication of the cancer (e.g., infection, complication of  surgery / 
chemotherapy / radiotherapy); OR 
• 
Death results from withdrawal of other therapies because of concerns relating to the poor 
prognosis associated with the cancer 
Cancer deaths may arise from cancers that were present prior to randomization or which 
developed subsequently. Those cancer deaths should be further classified (worsening prior 
malignancy; new malignancy). 
9.1.7.1.3 Definition of Undetermined Cause of Death 
Undetermined cause of death refers to a death not attributable to one of the above categories of 
cardiovascular death or to a non-cardiovascular cause, due to absence of any information (eg, the 
only available information is “patient died”).  The use of this category of death is discouraged and 
should apply to a minimal number of cases when no information at all on the circumstances of 
death is available (ie, found on obituary of local newspaper). In all circumstances the reviewer 
will use all available information to attribute to one of the categories based on best clinical 
judgment. 
9.1.7.2 Ischemia-driven coronary revascularization procedure 
‘Ischemia-driven coronary revascularization’ includes all coronary revascularization procedures 
(PCI/CABG) performed during the study, and driven by new or presumed new myocardial 
ischemia since randomization (categories 1 and 2 described below), and excluding procedures 
performed only to treat restenosis lesion(s) at prior PCI site(s). 
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Reasons for the PCI/CABG will be collected in the CRF as follows: 
1. driven by acute ischemia (ACS). 
2. driven by new/progressive (i.e. not present at randomization or with indication of 
progression since randomization), chronic (ie not in context of ACS) ischemia, evidenced 
by new/progressive symptoms (angina or equivalent) or new/progressive functional testing 
abnormalities (e.g. stress test, imaging). 
3. other (i.e. not driven by ACS event, or by new/progressive chronic ischemia). 
PCI involves a catheter-based tool (eg, balloon catheters, cutting balloons, atherectomy devices, 
lasers, bare metal stents, and drug-eluting stents) that improves myocardial blood flow by 
increasing the luminal area at a site of an obstructive coronary lesion. Coronary artery bypass 
grafting (CABG) is an open surgical procedure designed to improve myocardial blood flow by 
providing a conduit (arterial, venous, or synthetic) for blood flow distal to an obstructive coronary 
lesion. Insertion of a guidewire through a coronary guide catheter into a coronary vessel or 
aortocoronary bypass graft for the purpose of percutaneous coronary intervention (PCI) is 
considered as a PCI (since there is an intention to perform a PCI). However, insertion of a 
guidewire in order to assess the severity of intermediate lesions with the use of intravascular 
ultrasound, Doppler flow velocity, or fractional flow reserve, will NOT be considered PCI. 
9.1.7.3 Congestive Heart Failure requiring hospitalization. 
Congestive Heart Failure (CHF) requiring hospitalization is defined as an event that meets ALL of 
the following criteria: 
1) The patient is admitted to the hospital or emergency room (until at least next calendar day) 
with a primary diagnosis of CHF 
2) The patient exhibits documented new or worsening symptoms due to CHF on presentation, 
including at least ONE of the following: 
a) Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal 
dyspnea) 
b) Decreased exercise tolerance 
c) Fatigue 
d) Other symptoms of worsened end-organ perfusion or volume overload 
3) The patient has objective evidence of new or worsening CHF, consisting of at least TWO 
physical examination findings OR one physical examination finding and at least ONE 
laboratory/imaging/hemodynamic criterion), including: 
a) Physical examination findings considered to be due to heart failure, including new or 
worsened: 
• Peripheral edema. 
• Increasing abdominal distension or ascites (in the absence of primary hepatic disease) 
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• Pulmonary rales/crackles/crepitations 
• Increased jugular venous pressure and/or hepatojugular reflux 
• S3 gallop 
• Clinically significant or rapid weight gain thought to be related to fluid retention 
b) Laboratory, imaging or hemodynamic evidence of new or worsening CHF, including: 
• Increased B-type natriuretic peptide (BNP)/ N-terminal pro-BNP (NT-proBNP) 
concentrations consistent with decompensation of heart failure. In patients with 
chronically elevated natriuretic peptides, a significant increase should be noted above 
baseline 
• Radiological evidence of pulmonary congestion 
• Hemodynamic evidence from right-heart catheterization (e.g. elevated pulmonary 
capillary wedge pressure, elevated central venous pressure, or low cardiac index) or 
from left heart catheterization (elevated left ventricular end-diastolic pressure) 
4) The patient receives initiation or intensification of treatment specifically for HF, including at 
least ONE of the following: 
a) Significant augmentation in oral diuretic therapy 
b) Intravenous diuretic, inotrope, or vasodilator therapy 
c) Mechanical or surgical intervention, including: 
• Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device) 
• Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis) 
9.2 
SAFETY ENDPOINT(S): 
Observation period 
The observation of safety data will be as follows: 
• 
PRE-TREATMENT period: The PRE-TREATMENT observation period is defined from 
the signed informed consent up to the first dose of double-blind IMP injection 
• 
Treatment Emergent Adverse Event (TEAE) period: The TEAE observation 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 
• 
POST-TREATMENT period: The POST-TREATMENT observation period is defined as 
the time starting the day after the end of the TEAE period up to the end of the study 
Rationale for TEAE period definition is detailed in Section 4. 
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9.2.1 Adverse event 
All adverse events diagnosed by the Investigator, irrespective of the result of the adjudication for 
cardiovascular events, 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. 
AEs of special interest include, but are not limited to, the following: 
• 
Allergic events (using special eCRF pages, see Section 10.6.2) 
• 
Local injection site reactions (using special eCRF pages, see Section 10.6.1) 
• 
Hemolytic anemia (using special eCRF pages, see Section 10.4.7.1) 
Adverse event observation period 
The AE observations are per the observation periods defined above. 
Death observation period 
The death observations are per the observation periods defined above. 
9.2.2 Safety laboratory 
The clinical laboratory data consist of hematology (red blood cell count, reticulocyte count, 
hemoglobin, hematocrit, platelets, white blood cell count [WBC] with differential blood count),  
standard chemistry (glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, γ Glutamyl Transferase [γGT]), 
Hepatitis C antibody, liver panel (ALT, AST, alkaline phosphatase [ALP], and total bilirubin), 
and CPK. 
Some additional safety laboratory parameters may be reflexively measured, based on actual data 
(please refer to Section 10.4.7). 
Clinical laboratory values will be analyzed after conversion into standard international units. 
Standard international units will be used in all listings and tables. 
9.2.3 Vital signs measurement 
Vital signs include: weight, heart rate, systolic and diastolic blood pressure in sitting position. 
9.2.4 Electrocardiogram measurement 
Electrocardiogram (ECG) assessments will be described as normal or abnormal. 
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9.3 
OTHER ENDPOINT(S): 
9.3.1 Anti-alirocumab antibody assessments 
Anti-alirocumab antibodies include the antibody status (positive/negative) and antibody titers. 
9.3.1.1 Sampling time 
Serum samples for anti-alirocumab antibody determination will be drawn periodically throughout 
the study as per schedule noted in the study flowchart – Section 1.2. The first scheduled sample at 
randomization visit will be obtained before IMP injection (pre-dose). 
Patients who have titers at or above 240 for anti-alirocumab antibodies at the common study end 
date will have an additional antibody sample between 6 to 12 months after this date. 
In patients who permanently discontinued blinded study treatment early, anti-alirocumab antibody 
assessments will be performed at the early end-of-treatment visit (V70) and at every subsequent 
clinic visit, where this assessment was planned. 
9.3.1.2 Sampling procedure 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Five (5) ml blood volume is to be collected for 
each anti-alirocumab antibody sample. 
9.3.1.3 Bioanalytical method 
All anti-alirocumab antibody samples will be analyzed by the Regeneron Sample Analysis group. 
Anti- alirocumab antibody samples will be analyzed using a validated, non-quantitative, titer-
based bridging immunoassay. It involves an initial screen, a confirmation assay based on drug 
specificity, and a measurement of the titer of anti-alirocumab antibodies in the sample. 
 
Samples that are positive in the ADA assay will be assessed for neutralizing antibodies using a 
validated, non-quantitative, competitive ligand binding assay 
 
 
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9.3.2 Lipid parameters 
9.3.2.1 Endpoints 
The percent changes from baseline to Month 4, to Month 24, and to the final analysis cutoff date 
for the following parameters: 
• 
Calculated LDL-C 
• 
ApoB 
• 
Non-HDL-C 
All measurements (scheduled or unscheduled, fasting or not fasting) may be used to provide a 
value for the endpoint considered, even if assessed after patient’s discontinuation to the study 
treatment (Intent-To-Treat [ITT] approach). The analysis windows used to allocate a time point to 
a measurement will be defined in the Statistical Analysis Plan (SAP). 
9.3.2.2 Assessment method 
LDL-C will be calculated using the Friedewald formula (38). In case of calculated  
LDL-C <15 mg/dL (0.39 mmol/L), LDL-C value will be confirmed with direct measurement. If 
the TG values exceed 400 mg/dL (4.52 mmol/L), the central lab will reflexively measure the 
LDL-C rather than calculating it. Direct LDL-C measurement will be done via the beta 
quantification method. Apo B will be directly measured by the Central Laboratory. Non-HDL-C 
will be calculated by subtracting HDL-C from the total-C. Detailed procedures of sample 
preparation, storage and shipment will be described in the specific laboratory manual which will 
be provided to sites. Lipids parameters will be assessed from screening to common study end 
date. 
9.3.3 hs-CRP 
The percent change in hs-CRP from baseline up to the common study end date. 
9.3.4 HbA1C 
The absolute change in HbA1c (%) from baseline up to the common study end date. 
9.3.5 EQ-5D Patient Questionnaire 
EQ-5D is a standardized measure of health status developed by the EuroQol Group in order to 
provide a simple, generic measure of health for clinical and economic appraisal. The EQ-5D as a 
measure of health-related quality of life, defines health in terms of 5 dimensions: mobility, self-
care, usual activities, pain/discomfort, anxiety/depression. Each dimension can take one of three 
responses (3 ordinal levels of severity): 'no problem’ (1). “some problems” (2). “severe problems” 
(3). Overall health state is defined as a 5-digit number. Health states defined by the 5-dimensional 
classification can be converted into corresponding index scores that quantify health status, where 
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0 represents 'death' and 1 represents “perfect health” (See Appendix G). If response to one or 
more dimension is missing, the index score will be missing.) 
EQ-5D variables include response of each EQ-5D items, index score and change of index score 
from baseline Week (39). 
This questionnaire will only be administered in patients receiving the double-blind treatment. 
Patients who will prematurely discontinue will be asked to fill in this questionnaire until the early 
end of treatment visit (V70) to be performed at the time of discontinuation. 
9.3.6 Pharmacogenomic Samples 
An optional pharmacogenomic sub-study will be conducted to identify genetic associations with 
clinical or biomarker response to PCSK9 inhibition, hyperlipidemia, or cardiovascular disease.  If 
needed, samples may also be used to identify markers associated with toxicity. 
Randomized patients who agree to participate in the genomics sub-study will be required to sign a 
separate genomics sub-study informed consent form (ICF) prior to collection of the DNA sample. 
Blood for DNA extraction should be collected before IMP injection (pre-dose) on randomization 
visit; however, it could be collected at any time during the study. Patients who choose not to 
enroll in the genomics sub-study are still eligible to enroll in the primary study. 
Special procedures for storage and shipping of pharmacogenomic samples are summarized below 
(Table 1) and are described in detail in Appendix B. 
Table 1 - Summary of handling procedures for DNA storage samples 
Sample Type(s) 
Pharmacogenetics 
Blood Sample 
Volume 
6 mL  
Tube Type 
6 mL Becton Dickinson K2 EDTA VACUTAINER™ Plus tubes with HEMOGARD™ closure 
(PN367863/4) sterile tubes 
Anticoagulant 
K2 EDTA 
Blood Handling 
Procedures 
Keep blood on ice or frozen at -20°C (or colder) within 30 min of sampling time.  DO NOT 
CENTRIFUGE. 
Storage Conditions 
In collection tube at approximately -20°C (or colder) 
 
The Sponsor has included safeguards for protecting patient confidentiality. The blood sample and 
DNA that is extracted from it will be assigned a second number, a Genetic ID (de-identification 
code) that is different from the Subject ID. This “double coding” is performed to separate a 
patient’s medical information and DNA data. The clinical study data (coded by Subject ID) will 
be stored in a distinct database at a different location from the database containing the 
pharmacogenomic data (coded by Genetic ID). The key linking Subject ID and Genetic ID will be 
maintained by a third party, under appropriate access control. The matching of clinical data and 
pharmacogenomic data, for the purpose of data analysis, will be possible only by using this key, 
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which will be under strict access control. All data will be reported only in coded form in order to 
maintain confidentiality. 
DNA may be stored and used for analyses for up to 15 years from the completion of the Clinical 
Study Report (CSR).  Analyses may include sequence determination or single nucleotide 
polymorphisms (SNP) from candidate genes. Candidate genes may include (but are not limited to) 
PCSK9, Apo B and LDL-R. Genome-wide studies, including (but not limited to) SNP analyses 
and/or genomic sequencing may also be performed. 
9.3.7 Cardiovascular events of interest (other than efficacy endpoints) 
Clinically significant complications or procedures (not planned at the time of randomization) 
related to peripheral arterial disease (such as critical limb ischemia, amputation, peripheral 
revascularization) as well as venous thromboembolic events (deep vein thrombosis, pulmonary 
embolism) will be collected on the case report form. 
 
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10 
STUDY PROCEDURES 
The study consists of a run-in period of at least 2 weeks with randomization no earlier than 
4 weeks (28 days) and no later than 52 weeks (+ 5 days) after the index ACS event. The 
double-blind, placebo-controlled treatment period will continue for 24 months after the closing of 
randomization ex-China or until the target number of events (1613) is reached whichever comes 
last (see beginning of Section 6). The corresponding estimated study duration is approximately 
64 months. All randomized patients (whether they are still receving IMP at the end of the study, 
or had earlier permanent treatment discontinuation) should have a final visit (CSED visit) between 
the CSED and CSED + 30 days. 
For all visits after Day 1/Month 0 (randomization visit), a timeframe of a certain number of days 
will be allowed.  The window period for visits at Months 1 and 2 are ± 7 days, and for all other 
subsequent visits it is ± 14 days during the double-blind treatment period (NOTE: in case of major 
IMP issue, please refer to Section 8.9). 
For all visits after Day 1/randomization visit, if one visit date is changed, then the next visit 
should take place according to the original schedule as outlined Section 1.2. 
Ideally all the visits should take place in the morning approximately at the same time. However 
after randomization in case there is no other possibility for the patient, visits can be arranged later 
in the day. 
For the phone calls/contacts via internet to be performed in between on-site/clinic visits, they 
should be scheduled with the goal of maintaining a contact with the patient about every 2 months 
during first 24 months, and about every 3 months thereafter. Having no phone or email contact 
with a patient for a prolonged period (>4 months) should be avoided as much as possible. 
Blood samplings: 
The blood sampling for determination of lipid parameters (eg, LDL-C, Apo B, and non-HDL-C) 
should be preferably performed in the morning, in fasting condition (ie overnight, at least 8 hours 
fast) for all site visits throughout the study. 
Laboratory tests: 
The laboratory data are collected in accordance with the study schedule in Section 1.2  and 
forwarded to the central laboratory: 
• Hematology 
NOTE: At selected sites with a longer transit time to Central Lab, a duplicate 
hematology sample will be collected for local assessment of reticulocyte count, 
• Chemistry 
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• Liver panel: in case of total bilirubin values above the normal range, differentiation 
into conjugated and non-conjugated bilirubin will occur automatically 
• Lipids 
• Creatine Phosphokinase (CPK). 
• Hepatitis B surface antigen 
• Hepatitis C antibody 
NOTE: In case of positive hepatitis C antibody test, a blood sample will be collected at 
a subsequent visit and sent to Covance Central Lab for further confirmatory testing 
• Serum pregnancy test 
Central Laboratory results will be provided to sites (with the exception of lipid levels collected 
post-randomization in order to maintain the double-blind nature of the study). An alert will be 
provided by the Central Laboratory to sites in case of 2 consecutive significant elevations of 
triglyceride levels.  Table 2 summarizes the management of selected blood samples during the 
study. 
Table 2 - Overview of selected blood samples during study 
Blood 
samples 
Collection 
Results 
Comment 
Blood samples 
described above 
(other than 
lipids) 
Collected periodically at 
study visits during run-in and 
post-randomization and sent 
to Central Laboratory 
Results provided 
to sites 
         During run-in period, results used for qualification 
 
 
Collected at study visits 
during run-in period and sent 
to Central Laboratory 
Results provided 
to sites 
            Results at V2/V2b used for qualification 
            (run-in period) 
Blood sample 
for lipids  
Collected                       post-
randomization periodically at 
study visits throughout the 
study and sent to Central 
Laboratory 
Results not 
provided to sites 
(in order to 
maintain the 
blind)  
- 
Results will be analyzed at the end of the trial 
- 
Alert provided to sites by Central Laboratory for 
significant elevation of triglycerides (2 
consecutive values) 
- 
Low cholesterol values (and associated clinical 
safety) reviewed in unblinded manner by 
Independent Physician with oversight by DMC 
members (who may determine upon individual 
circumstances that a site should be alerted) 
- 
No alert provided for high or elevation of 
cholesterol levels (see below) 
 
Additional lipid level assessments (at a local 
laboratory) should not be performed during entire 
study 
 
  
- 
Rationale is that patient is already treated with 
maximal LMT regimen (statin-intensive and 
optimized for long-term chronic use) since study 
start 
- 
Compliance to required background LMT 
regimen should be emphasized throughout 
study; LMT may be modified based on clinical 
tolerability considerations only – see Section 
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Blood 
samples 
Collection 
Results 
Comment 
8.8.1 
- 
Investigator should periodically remind and 
educate GP/cardiologist of study requirements 
(i.e. during entire study, GP/cardiologist should 
refrain from checking lipid levels at a local 
laboratory, and should not modify LMT regimen 
without discussing with Investigator) 
Cardiac 
biomarkers  
To be collected and analyzed locally, as 
needed(for assessment of suspected cardiac 
events), with results provided to sites  
                Results used for efficacy endpoints 
Urine samplings: 
• Urinalysis will be performed periodically (yearly) throughout the study in about 750 
randomized patients, at selected sites. A urine sample will be sent to Covance Central 
Labs for macroscopic analysis (presence of blood, protein, glucose, ketones, nitrates, 
leukocyte esterase, uro-bilinogen and bilirubin). In case of abnormalities, Covance 
Central Lab will perform a microscopic analysis. 
• Urine pregnancy test – dipstick will be performed on site. 
NOTE: Any clinically relevant abnormal laboratory value should be immediately rechecked 
(whenever possible using the central laboratory) for confirmation before making any decision for 
the concerned patient. It should be documented as an AE/SAE as applicable. Please also refer to 
Section 10.4.4 and Section 10.4.7. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C and Appendix D 
Other endpoints assessment methods 
All other blood parameters will also be measured by a Central Laboratory during the study (as per 
the schedule in Section 1.2, on blood samples taken preferably in the morning in fasting condition 
(at least 8 hours fast). 
• 
Glycemic parameters (HbA1c) and serum glucose will be measured by a Central 
laboratory, periodically throughout the study as per the schedule in Section 1.2. 
• 
The blood sampling for inflammatory parameter, hs-CRP will be collected periodically 
throughout the study as per the schedule in Section 1.2. 
NOTE: In case of high HbA1c values at screening, the Investigator is responsible for the 
optimization of the patient’s treatment to achieve HbA1c targets as defined by local guidelines or 
the Standards of Medical Care in Diabetes-2012 by the American Diabetes Association (40). 
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Library samples 
Library (plasma and serum) samples should be collected, as permitted by local regulatory policies. 
They will be collected periodically throughout the study as per schedule noted in the study 
flowchart - Section 1.2. The first scheduled sample at randomization visit will be obtained before 
IMP injection (pre-dose). 
Library samples will be coded to maintain patient confidentiality and may be stored for up to 
10 years or as permitted by local regulatory policies, whichever is shorter, for exploratory 
research of PCSK9 levels, PCSK9 function, effect(s) of PCSK9 inhibition with a monoclonal 
antibody, lipoprotein sub-fraction, inflammation, and cardiovascular risk markers (eg, 
lipoprotein–associated phospholipase A2). If needed, samples may also be used to identify 
markers associated with toxicity.  The library samples will never be used for genomic analysis. 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Library samples will be sent to a central 
laboratory (only for randomized patients) for long-term storage between –70°C to –85°C. 
• Plasma samples: 8.5 mL blood volume to be collected as specified in the specific 
laboratory manual 
• Serum samples:  2.5 mL blood volume to be collected as specified in the specific 
laboratory manual 
Physical examination: 
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart in Section 1.2.  If a new clinically significant abnormality or worsening from 
baseline is detected after randomization, then an AE should be reported and the patient should be 
considered for further clinical investigations and/or specialist consultation as per the 
Investigator’s medical judgment. 
Blood pressure (BP)/heart rate: 
BP should be measured in sitting position under standardized conditions. 
Heart rate will be measured at the time of the measurement of blood pressure. 
NOTE: In case of high BP values at screening the Investigator is responsible for the optimization 
of the patient’s treatment to achieve BP targets as defined by local guidelines or the Seventh 
Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure (JNC 7) (41). 
ECG: 
The ECGs will be interpreted locally by the Investigator.  Any clinically significant abnormality 
should be documented as an AE/SAE as applicable (see Section 10.4.4). All ECG traces will be 
kept as source data. 
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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. 
Height needs to be measured as self-reported heights are not acceptable. 
10.1 
VISIT SCHEDULE 
10.1.1 Screening visit - Visit 1 (at least 2 weeks prior to randomization visit) and entry in 
the run-in period 
Visit 1 (V1) and Visit 2 (V2) can be separate visits or can be combined (see Section 6.1.1. -  Run-
in period. 
• If V1 and V2 are separate visits, V1 should be scheduled between 0 and 50 weeks post 
index ACS event 
• If V1 and V2 are combined, the combined V1/V2 visit should be scheduled between 0 and 
50 weeks + 5 days post index ACS event 
The patient will receive verbal information concerning the aims and methods of the study, its 
constraints and risks and the study duration. A written summary in the form of an information 
leaflet will be given to the patient. The written informed consent must be signed by the patient and 
the Investigator prior to any investigations. Only patients who meet the inclusion criteria as noted 
in Section 7 may be screened. Women of childbearing potential will be requested to use a 
medically approved contraceptive method during the entire study. 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 the first injection-training done at this visit V1. 
This visit will include: 
• 
Complete informed consent 
• 
Assessment of inclusion and exclusion criteria 
• 
Demographic (age, gender, race, ethnicity) 
• 
Collect contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
Patient’s medical and surgical history (including menopausal status and cardiovascular 
history, and relevant family history e.g. allergy), alcohol habits, and smoking habits 
• 
Patient’s cardiovascular history 
• 
Index ACS event: type of event and date of onset 
• 
Record of previous LMT medications (related to statins, and non-statin LMTs) from 
prescription or over-the-counter within 1 month prior to screening; use of chronic statin 
treatment or not prior to index ACS event 
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• 
Record of concomitant medications, especially lipid-modifying treatments (statins and 
non-statin LMTs from prescription or over-the counter therapies as above), and 
cardiovascular medications 
• 
Βody weight and height measurements 
• 
Physical examination including vital signs: sitting systolic and diastolic blood pressure 
(SBP and DBP), heart rate 
• 
Collection of adverse events from this point onward: 
All adverse events and serious adverse events will be collected from the time of informed consent 
signature and throughout the study until the common study end-date visit (V30). 
• 
IVRS/IWRS contact for notification of screening and entry in the run-in period: 
- 
Patients meeting the inclusion/exclusion criteria for eligibility at screening will enter 
the run-in period of the study. IVRS/IWRS is to be contacted for notification of 
screening and for patient number allocation (please note that it is important to have the 
IVRS/IWRS contact before any blood sample is drawn because the patient number is 
given by IVRS/IWRS and it must be reported on the requisition forms). This patient 
number is composed of a 9-digit number containing the 3-digit country code, the 
3-digit center code and the 3-digit patient chronological number (the 3-digit patient 
chronological number is 001 for the first patient screened in a center, 002 for the 
second patient screened in the same center...). 
- 
Allocation of a batch number for training kit 
• 
Fasting blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB 
- 
Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count,  
white blood cell count with differential count and platelets 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin). 
- 
HbA1c 
- 
CPK 
- 
Hepatitis B surface antigen and hepatitis C antibody tests 
NOTE: In case of positive hepatitis C antibody test, a blood sample will be collected at 
a subsequent visit and sent to Covance Central Lab for further confirmatory testing 
- 
Serum pregnancy test (females of childbearing potential only) 
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• 
First potential injection-training on site (see also Section 8.1.2): 
- 
Injection-training should be provided as outlined in Section 8.1.2 
- 
The 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 
- 
Record batch number allocated in eCRF 
• 
An appointment will be given for the next visit V2 after required LMT regimen (statin-
intensive, and optimized for long-term chronic use with addition of non-statin LMT, at 
Investigator’s discretion) has been administered for at least two weeks, was found well 
tolerated and no further increase in LMT regimen is planned. 
If necessary one additional visit (V2b) and central laboratory assessments may occur during the 
run-in period (see Section 6.1.1.2.3) 
The patient should be seen for the next visit in the morning and preferably in fasting condition 
(ie, overnight, at least 8 hours fast). 
10.1.2 Qualifying visit - Visit 2 
V2 should be scheduled after required LMT regimen was administered at stable dose for at least 
2 weeks and found well tolerated (see Section 6.1.1.3). 
• 
If V1 and V2 are separate visits, the interval between V1 and V2 should be at least 
2 weeks (14 days) 
• 
Alternatively, V1 and V2 may be combined in one visit (see Section 10.1.3) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
Assessment of inclusion and exclusion criteria 
• 
Record of concomitant medication (including but not limited to LMT regimen used during 
the 2 weeks prior to V2) 
NOTE: In case of rescreening, reason for potential different statin dose/regimen used 
during the 2 weeks prior to V2/Screening 2 (as compared  to the 2 weeks prior to 
V2/Screening 1) will be recorded 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of adverse events 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Fasting blood sample for qualifying lipid labs: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB 
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• 
Potential injection-training on site: 
- 
IVRS/IWRS contact for allocation of a batch number for training kit 
- 
Injection-training should be provided as outlined in Section 8.1.2 
- 
The 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 
- 
Record batch number allocated in eCRF 
• 
An appointment will be given for the next visit (V3 randomization) in 2 to 5 days, after 
results of V2 labs are obtained 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next 
visit 
- 
The patient will be instructed to continue the LMT at the same dose 
10.1.3 Combined V1/V2 Visit 
If required LMT regimen (see Section 6.1.1.3) was already administered at stable dose prior to V1 
for > 2 weeks and found well tolerated, V1 and V2 visits can be combined as one visit (combined 
V1/V2 visit), with all assessments of V1 and V2 visits to be performed at this combined visit. 
NOTE: Prior to conducting a combined V1/V2 visit, prior LMT (and, if applicable, intolerance to 
statin) must be adequately documented in a source document such as a discharge summary, 
history and physical, clinic note or consultation report to confirm treatment. 
10.1.4 Optional qualifying visit - Visit 2b 
See Section 6.1.1.2.3 for circumstances in which this visit should be performed. 
This visit is similar to the Visit V2, and a training injection can be performed. 
• 
Third (potential) training injection as necessary 
- 
IVRS/IWRS contact for allocation of a batch number for training kit 
- 
Injection-training should be provided as outlined in Section 8.1.2 
- 
The 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 
- 
Record batch number allocated in eCRF 
• 
An appointment will be given for the next visit V3 (randomization) – See 
Section 10.1.5.1.1 
- 
Remind patient to be in fasting conditions (ie overnight, at least 8 hours fast) for next 
visit 
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10.1.5 Double-blind treatment period 
10.1.5.1  Study site visits from Visit 3 (Month 0, D1) to Visit 30 (Month 64) 
10.1.5.1.1 Baseline (randomization) visit - Visit 3 (Month 0, D1) 
V3 should be scheduled as follows: 
• 
If V1 and V2 are separate visits (≥ 2 weeks between V1 and V2): V3 (randomization) can 
occur as soon as the qualifying lipid lab results from V2 are obtained from the central lab 
(typically final results are available within 2-5 days of collection) 
• 
In case of combined V1/V2 visit, after qualifying lipid labs are collected and if patient is 
eligible, V3 (randomization) should occur at least 2 weeks (14 days) after the combined 
V1/V2 visit 
• 
In all cases, V3 (randomization) should occur no earlier than 4 weeks (28 days) and no 
later than 52 weeks (+ 5 days) post index ACS event 
• 
Also, there should be no new ACS event or coronary intervention within 2 weeks prior to 
V3. 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
Assessment of inclusion and exclusion Criteria 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Physical examination including vital signs: SBP and DBP, heart rate 
• 
Collection of adverse events 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, ± 
other LMT) 
• 
Informed consent form proposal for the optional genomic sub-study, and if patient agrees 
to participate then obtain written consent 
- 
If patient declines participation in the genomic sub-study then this has no 
consequences for participation in the study otherwise 
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 
• 
12-lead ECG 
• 
Urinalysis (at selected sites), with urine sample sent to Central Lab 
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• 
Urine pregnancy test (females of childbearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB, ApoA-1, ratio ApoB/ApoA-1, 
and Lp (a) 
- 
Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count, 
reticulocyte count, white blood cell count with differential count and platelets 
NOTE: At selected sites with a longer transit time to Central Lab, a second 
hematology sample will be collected for local assessment of reticulocyte count 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
HbA1c 
- 
CPK 
- 
hs-CRP 
- 
Hepatitis C antibody test 
NOTE: In case of positive hepatitis C antibody test, a blood sample will be collected at 
a subsequent visit and sent to Covance Central Lab for further confirmatory testing 
- 
Library samples 
- 
Anti- alirocumab antibodies 
- 
Genomic specimen collection (for specifically consented patients only) 
NOTE: Collection of all blood and urine samples at V3 should be performed before first 
double-blind IMP injection. 
• 
EQ-5D patient questionnaire: to be completed by the patient on site and data will be 
reported onto the eCRF by site staff. 
• 
Double-blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder.  The patient injection instruction manual and treatment 
administration package should be provided.  The patient diary should be given and 
instructions on its completion should be reviewed. 
• 
The first double-blind IMP injection will take place at the study site, but only after the 
collection of the fasting blood samples and after the assessment of all evaluations planned 
at that visit. Close supervision, feedback and further training to be provided for IMP 
administration. The patient should be stay in observation for at least 30 minutes after the 
injection. 
NOTE: This first injection of double-blind IMP injection can serve as second training 
injection. 
• 
Provide ODYSSEY Outcomes card (or equivalent) to patient (and family) mentioning 
patient participation in the study and site contact information. 
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• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie overnight, at least 8 hours fast) for next 
study site visit, if applicable 
- 
Remind patient to bring 3 items at the next study visit: 
o the diary, 
o used and unused IMP kits, 
o the ODYSSEY Outcomes card (or equivalent) containing site contact 
information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
10.1.5.1.2 Visit 4 (Month 1, ± 7 days) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance checked by review of diary 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
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• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
• 
The patient diary should be given and instructions on its completion should be reviewed. 
• 
Reminders: 
- 
An appointment will be given for the next study site visit. 
- 
Remind patient to be in fasting conditions (ie overnight, at least 8 hours fast) for next 
study site visit, if applicable. 
- 
Remind patient to bring 3 items at the next study visit: 
o the diary, 
o used and unused IMP kits, 
o the ODYSSEY Outcomes card (or equivalent) containing site contact 
information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
10.1.5.1.3 Visit 5 (Month 2, ± 7 days) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
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• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C 
- 
Anti-alirocumab antibodies. 
• 
EQ-5D patient questionnaire 
• 
Double blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder and the treatment administration package should be provided.  The 
patient injection instruction manual and diary may be given, as needed 
• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie overnight, at least 8 hours fast) for next 
study site visit, if applicable 
- 
Remind patient to bring 3 items at the next study visit: 
o the diary, 
o used and unused IMP kits, 
o the ODYSSEY Outcomes card (or equivalent) containing site contact 
information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
10.1.5.1.4 Visit 6 (Month 4, ± 14 days) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Body weight measurement 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 100 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB, ApoA-1, ratio ApoB/ApoA-1, 
and Lp (a) 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
- 
hs-CRP 
- 
Library samples 
- 
Anti- alirocumab antibodies 
• 
EQ-5D patient questionnaire 
• 
Double blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder and the treatment administration package should be provided.  The 
patient injection instruction manual and diary may be given, as needed 
• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next 
study site visit, if applicable 
- 
Remind patient to bring 3 items at the next study visit: 
• the diary, 
• used and unused IMP kits, 
• the ODYSSEY Outcomes card (or equivalent) containing site contact information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 101 
10.1.5.1.5 Visit 8 (Month 8, ± 14 days) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Urine pregnancy test (females of child-bearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C 
• 
EQ-5D patient questionnaire 
• 
Double blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder and the treatment administration package should be provided.  The 
patient injection instruction manual and diary may be given, as needed 
• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next 
study site visit, if applicable 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 102 
- 
Remind patient to bring 3 items at the next study visit: 
o the diary, 
o used and unused IMP kits, 
o the ODYSSEY Outcomes card (or equivalent) containing site contact 
information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
10.1.5.1.6 Visit 10 (Month 12, ± 14 days) 
This visit will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Physical examination including vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Urinalysis (at selected sites), with urine sample sent to Central Lab 
• 
Urine pregnancy test (females of childbearing potential only) 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 103 
•
Blood sample for:
-
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB, ApoA-1, ratio ApoB/ApoA-1,
and Lp (a)
-
Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count,
reticulocyte count, white blood cell count with differential count and platelets
NOTE: At selected sites with a longer transit time to Central Lab, a duplicate
hematology sample will be collected for local assessment of reticulocyte count
-
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous,
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT
-
Liver panel (ALT, AST, ALP, and total bilirubin)
-
HbA1c
-
CPK
-
hs-CRP
-
Library samples
-
Anti- alirocumab antibodies
•
EQ-5D patient questionnaire
•
Double-blind IMP kit dispensation as per treatment kit number provided by IVRS along
with schedule reminder.  The patient injection instruction manual and treatment
administration package should be provided.  The patient diary should be given and
instructions on its completion should be reviewed
•
Reminders:
-
An appointment will be given for the next study site visit
-
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next
study site visit, if applicable
-
Remind patient to bring 3 items at the next study visit:
o
the diary,
o
used and unused IMP kits,
o
the ODYSSEY Outcomes card (or equivalent) containing site contact
information.
-
Remind patient (and family) that, in case patient is hospitalized, they should contact
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the
next visit.
(electronic 1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 104 
10.1.5.1.7 Visit 12 (Month 16)/ Visit 14 (Month 20)/ Visit 18 (Month 30)/ Visit 22 (Month 42)/ Visit 
26 (Month 54) (± 14 days) 
These visits will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, 
± other LMT) 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
CPK 
• 
EQ-5D patient questionnaire 
• 
Double-blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder.  In case an extra kit for the patient is needed, it should be done by 
contacting the IVRS/IWRS. The patient injection instruction manual and treatment 
administration package should be provided.  The patient diary should be given and 
instructions on its completion should be reviewed 
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 105 
• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next 
study site visit, if applicable 
- 
Remind patient to bring 3 items at the next study visit: 
o the diary, 
o used and unused IMP kits, 
o the ODYSSEY Outcomes card (or equivalent) containing site contact 
information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
10.1.5.1.8 Visit 16 (Month 24)/ Visit 20 (Month 36)/ Visit 24 (Month 48)/ Visit 28 (Month 60) 
(± 14 days) 
These visits will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Physical examination including vital signs: SBP and DBP, heart rate 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE:  In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete IMP information in eCRF in a timely manner. 
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 106 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, ± 
other LMT) 
• 
Urinalysis (at selected sites), with urine sample sent to Central Lab 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C (in addition, at Month 24 only, ApoB 
will be collected) 
- 
Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count, 
reticulocyte count, white blood cell count with differential count and platelets 
NOTE: at selected sites with a longer transit time to Central Lab, a second hematology 
sample will be collected for local assessment of reticulocyte count 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
HbA1c 
- 
CPK 
- 
Anti- alirocumab antibodies 
• 
EQ-5D patient questionnaire 
• 
Double-blind IMP kit dispensation as per treatment kit number provided by IVRS along 
with schedule reminder.  In case an extra kit for the patient is needed, it should be done by 
contacting the IVRS/IWRS. The patient injection instruction manual and treatment 
administration package should be provided.  The patient diary should be given and 
instructions on its completion should be reviewed 
• 
Reminders: 
- 
An appointment will be given for the next study site visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast) for next 
study site visit, if applicable 
- 
Remind patient to bring 3 items at the next study visit: 
• the diary, 
• used and unused IMP kits, 
• the ODYSSEY Outcomes card (or equivalent) containing site contact information. 
- 
Remind patient (and family) that, in case patient is hospitalized, they should contact 
the site (Investigator, Research Coordinator) as soon as possible, and not wait until the 
next visit. 
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 107 
10.1.5.2 Contacts (phone calls, text messages or contacts via internet) from randomization 
Contacts should be scheduled in between on-sites visits as follows:  Visit 7 (Month 6)/ Visit 9 
(Month 10)/ Visit 11 (Month 14)/ Visit 13 (Month 18)/ Visit 15 (Month 22)/ Visit 17 (Month 27)/ 
Visit 19 (Month 33)/ Visit 21 (Month 39)/ Visit 23 (Month 45)/ Visit 25 (Month 51)/ Visit 27 
(Month 57)/ Visit 29 (Month 62). 
Although flexibility is allowed in the timing of phone call in between the on-site/clinic visits, it 
should be scheduled with the goal of maintaining a contact with the patient about every 2 months 
during first 24 months, and about every 3 months thereafter. Having no phone or email contact 
with a patient for a prolonged period (>4 months) should be avoided as much as possible. Some 
additional instructions for scheduling phone call may be provided at time of interim analysis. 
This contact will include: 
• 
Update contact information (address, e mail, home and cell phone number) for patient, 
patient’s family and patient’s GP/cardiologist 
• 
Review compliance with background LMT (including statin, ezetimibe) 
• 
Collection of information on IMP administration (and remind patient to complete diary) 
• 
Collection of information on suspected efficacy endpoints (and remind patient to call site 
in case of hospitalization and not wait until next visit) 
• 
Reminders: as applicable for IMP administration schedule, timing of next visit, fasting 
conditions for next lab assessment, to bring the diary and used and unused kits at the next 
study site visit 
In addition to the contacts detailed above, a SMS/text messaging vendor (EXCO InTouch) has 
been engaged to send appointment and injection reminders to any patient who wishes to and is 
able to receive them.  This service is optional and each study site will have the opportunity to 
participate or refuse as per their policies. 
These contacts will conform to privacy regulations at each site. 
10.1.5.3 Early end of treatment visit – Visit 70 
For patients who will have prematurely permanently discontinued IMP (see Section 10.3.2 for 
more details on when to consider that a patient has permanently discontinued treatment), an end of 
treatment visit called Visit 70 (early end of treatment visit) will be performed as soon as 
practically possible (within 1 month) after IMP discontinuation is considered permanent by the 
Investigator. Assessments done at this visit will be similar to those planned for the study 
completers at the final visit (Visit 30, Month 64) (see Section 1.2). 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 108 
In addition: 
• 
Update contact information (address, email, home and cell phone number) for patient, 
patient’s family, and patient’s GP/cardiologist 
• 
ODYSSEY Outcomes card (or equivalent) mentioning patient participation in the study 
and site contact information: 
- 
Verify that patient has the card; if unsure, provide new cards to patient (and family). 
- 
Verify that site contact information (Investigator, Study Coordinator) provided to the 
patient is correct (update as necessary). 
Then those patients must continue to remain in the study and will be strongly encouraged to 
complete all the remaining study visits as originally scheduled (as described in Section 1.2), until 
the common study end date (ie, final visit, Visit 30, Month 64). Complete usual study assessments 
(with the exception of IMP administration and its associated procedures) will be performed for 
6 months following V70. Thereafter, study assessments are reduced (see Section 10.3.4 for more 
details). Patients who will not be able to attend any particular study visit will be invited to attend a 
subsequent visit. 
Finally, the Investigator will make every effort to contact participants who are lost to follow-up. 
Attempts to contact such participants must be documented in the participant’s records. 
10.1.5.4 Common study end date visit (Final Visit) – Visit 30 (~Month 64, between CSED 
and CSED + 30 days) 
This final CSED visit should be scheduled and be performed on or shortly after the actual 
occurrence of the CSED (see also Section 6.2.2). CSED is scheduled to occur at around Month 64, 
and will be announced by the sponsor in advance in order for sites to be able to plan this final 
visit. 
This final CSED visit (Visit 30, Month 64): 
• should be a clinic visit, 
• should be performed for all randomized patients regardless of the patient status (still 
receiving IMP or having prematurely discontinued IMP permanently), 
• however there are some differences on how to plan the visit (and last IMP injection, when 
applicable) and in assessments to be performed at that final visit, depending on patient 
status. 
For patients still receiving IMP (study completers), both CSED visit and last IMP injection should 
be determined taking into account the following: 
• CSED visit should take place between CSED and CSED + 30 days 
• CSED visit should occur 14 days (±3 days) after last IMP injection 
• Site has clearly communicated and agreed in advance with patient (and family) on date of 
last IMP injection and date of CSED visit 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 109 
• In order to ensure compliance with these critical final study procedures, sites should: 
- 
contact patients a few days prior to the agreed-upon date of last IMP injection, 
- 
remind patient about the final IMP injection and final CSED visit, and 
- 
ask patient to return to the investigational site in the morning preferably in fasting 
condition (ie, overnight, at least 8 hours fast) and to bring the used and unused kits 
and the diary. 
Assessments to be performed at the CSED visit for study completers are described in 
Section 10.1.5.4.1. 
For patients who had previously permanently discontinued IMP: 
• CSED visit should take place between CSED and CSED + 30 days. 
• Site has communicated and agreed in advance with patient (and family) on date of CSED 
visit. 
• In order to ensure compliance with these critical final study procedures, sites should: 
- 
contact patients a few days prior to the final CSED visit, and 
- 
ask patient to return to the investigational site in the morning preferably in fasting 
condition (ie, overnight, at least 8 hours fast). 
- 
If IMP permanent discontinuation occurred after the prior most recent clinic visit 
and/or if patient still has IMP kits at home, patient should bring the used and unused 
kits and the diary. 
Assessments to be performed at the CSED visit for patients who had permanently discontinued 
IMP are described in Section 10.1.5.4.2. 
10.1.5.4.1 Final Visit - Visit 30 for study completers 
This visit will include: 
• 
Record of concomitant medication 
• 
Βody weight measurement 
• 
Physical examination including vital signs: SBP and DBP, heart rate 
• 
Collect information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of adverse events 
(electronic 
 
 
 
1.0)

Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 110 
• 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit accountability (used and unused kits) 
NOTE: In case patient forgets to bring back diary at the visit, site should come up with an 
alternative solution to obtain as soon as possible information contained in patient diary in 
order to be able to complete final IMP information in eCRF. 
• 
Check of the compliance and stability of the dose of the LMT (atorvastatin, rosuvastatin, ± 
other LMT) 
• 
12-lead ECG 
• 
Urinalysis (at selected sites), with urine sample sent to Central Lab 
• 
Urine pregnancy test (females of childbearing potential only) 
• 
Blood sample for: 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB, ApoA-1, ratio ApoB/ApoA-1, 
and Lp (a) 
- 
Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count, 
reticulocyte count, white blood cell count with differential count and platelets 
NOTE: At selected sites with a longer transit time to Central Lab, a second 
hematology sample will be collected for local assessment of reticulocyte count 
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, LDH, total protein, albumin, and γGT 
- 
Liver panel (ALT, AST, ALP, and total bilirubin) 
- 
HbA1c 
- 
CPK 
- 
hs-CRP 
- 
Hepatitis C antibody test 
NOTE: In case of positive hepatitis C antibody test at V30, patient should be 
recontacted as soon as possible after the site has been informed by Central Lab of this 
positive test, and a subsequent visit should be scheduled also as soon as possible, for 
collection of a confirmatory blood sample to be sent to Covance Central Lab. 
- 
Library samples 
- 
Anti-alirocumab antibodies 
• 
EQ-5D patient questionnaire 
• 
IVRS/IWRS contact for notification of the date of this final visit; for patients still on 
treatment this will also be the end of treatment visit 
This will be the final study visit for the patient. New or ongoing related or serious AE (as well as 
new or ongoing AESI) at this CSED visit should continue to be followed until resolution, 
stabilization, or death (whichever comes first) and related data will be collected (see 
Section 6.2.1). 
(electronic 
 
 
 
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Amended Clinical Trial Protocol No. 11  
25-Feb-2016 
ODYSSEY Outcomes (EFC11570) - alirocumab (SAR236553) 
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Page 111 
10.1.5.4.2 Final Visit - Visit 30 for prematurely discontinued patients 
This visit will include: 
• 
Collection of information on suspected efficacy endpoints 
• 
Collection of cardiovascular events of interest other than efficacy endpoints (peripheral 
arterial disease, venous thromboembolic events) 
• 
Collection of related and/or serious AEs 
• 
Selected concomitant medications (statin, ezetimibe) 
• 
Blood sample for 
- 
Lipids: TC, LDL-C, HDL-C, TG, non-HDL-C, ApoB 
- 
HbA1c 
- 
Anti-alirocumab antibodies 
• 
IVRS/IWRS contact for notification of the date of this final visit 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the eCRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
• Agreement, date, and signature of informed consent mentioning the study identification 
• Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology 
• Contraception methods for women of childbearing potential 
• Previous and concomitant medication (including the lipid modifying therapy) 
• Study identification 
• Treatment number, dates of administration 
• Dates of visits and assessments including the examination report 
• Vital signs, height, body weigh. 
• Faxed central lab reports (dated and signed by the Principal Investigator or Sub-
Investigator) 
• IVRS/IWRS confirmation fax (screening, screen failure, training kit allocation, 
randomization, treatment reallocation, discontinuation, end of double blind treatment 
period, end of study, unblinding if applicable) 
• ECG records signed and dated 
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• Adverse events and follow-up 
- 
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the follow 
up of the SAE 
• Date of premature study discontinuation (if any) and reason 
Source documentation may be found in the following: 
• Patient’s identity 
• Medical history 
• Hospital records 
• Nursing notes 
• Physician’s notes 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
All randomized patients should be treated with blinded study treatment (IMP) for as long as 
possible. 
As a general rule, any IMP treatment discontinuation should be initially considered temporary, 
and Investigator should make best effort to resume IMP treatment as early as practically possible, 
after several weeks or months (pending there are no safety concerns), and perform all study visits 
and assessments as usual. 
Permanent IMP discontinuation should be a last resort. Any IMP discontinuation should be fully 
documented in the eCRF and source notes. 
Pregnancy will lead to permanent treatment discontinuation in all cases. 
All randomized patients should be followed-up (and suspected efficacy endpoints collected) until 
the end of the study (common study end date visit), even if treatment was permanently 
discontinued early. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation (also referred to as treatment interruption) may be 
considered by the Investigator in case of AEs/SAEs or for other reasons. In general, every effort 
should be made to resume treatment with blinded study drug (IMP) following a temporary 
interruption. In case of AEs/SAEs, resuming treatment with the IMP will be done under close and 
appropriate clinical and/or laboratory monitoring once the Investigator has considered according 
to his/her best medical judgment that the responsibility of the IMP in the occurrence of the 
concerned event was unlikely and patient does not meet any permanent discontinuation criteria. 
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All treatment interruption duration should be recorded by the Investigator in the appropriate eCRF 
screens when considered as confirmed. 
Treatment interruption is defined as one or more scheduled injections that are not administered to 
the patient, and typically as decided by the Investigator. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation (also referred to as treatment discontinuation) is any 
treatment discontinuation associated with the definitive decision from the Investigator or the 
patient not to re-expose the patient to the IMP at any time. 
Investigator is strongly encouraged to discuss with monitoring team before considering any 
treatment discontinuation as permanent. A discussion with National Coordinator may occur 
regarding other possible options. 
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 eCRF. 
Patients should discontinue the Investigational Medicinal Product (IMP) for the following 
reasons: 
• 
Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females only) 
• 
Acute injection reaction of clinical concern 
• 
Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to IMP 
• 
At patient request 
• 
If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's safety or well-being (NOTE: please refer to Section 10.4.7, 
Appendix C and Appendix D, for management and follow-up of selected laboratory 
abnormalities, including guidance for treatment discontinuation) 
• 
At the specific request of the Sponsor 
• 
Any code breaking requested by the Investigator 
• 
Patient receives double-blind treatment prior to randomization 
Patient withdrawal from the study treatment or study should be avoided as much as possible. If 
this occurs, every attempt should be made to restart study drug if medically appropriate, whatever 
the duration of discontinuation. In case of permanent study treatment discontinuation, the 
appropriate follow-up until the common study end date visit should still be continued. 
All efforts should be made to document the reasons for treatment discontinuation and this should 
be documented in the eCRF. 
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10.3.4 Handling of patients after permanent treatment discontinuation 
Patients in whom IMP treatment discontinuation is considered permanent by Investigator should 
come for an extra visit (early end-of-treatment visit V70) as soon as practically possible (within 1 
month) after IMP discontinuation is considered permanent by Investigator. V70 is similar to the 
common end of study visit (Visit 30, Month 64) for study treatment completers, and should 
include similar procedures. 
Such patients must continue to remain in the study and will be strongly encouraged to complete 
all the remaining study visits as originally scheduled in Section 1.2, until the common study 
end-date visit. Therefore, a contact should be maintained with these patients every 2 to 3 months 
(as per study assessments), and a clinic visit performed every 4 to 6 months until the common 
study end-date visit (V30). 
• Over the 6 months following V70, all assessments (other than IMP administration and its 
associated procedures) should be performed as originally planned. These include but are 
not limited to collection of suspected efficacy endpoints, AE/AESI/SAE, concomitant 
medications, hematology and chemistry labs, lipid labs and anti- alirocumab antibodies. 
• From 6 months post V70 until common study end date visit (V30), assessment at visits are 
simplified and will include updating patient contact information (as well as patients’ 
family and patient’s GP/cardiologist) and the collection of: 
- 
suspected efficacy endpoints 
- 
cardiovascular events of interest other than efficacy endpoints (peripheral arterial 
disease and venous thromboembolic events) 
- 
related and/or serious AEs 
- 
selected concomitant medications (statins, ezetimibe) 
- 
selected labs: 
o anti alirocumab antibodies, lipid panel and HbA1c: annually (at M12, M24, 
M36, M48, M60) and at common study end-date 
o ApoB at month 24 and at common study end-date. 
Previously observed AEs/AESIs/SAEs that had not resolved should be followed-up until 
an outcome (e.g. resolution, stabilization) has been determined. 
• In case of difficulty to comply with the 4 to 6-month clinic visit periodicity in patients who 
discontinued treatment early, every effort should be made to have an actual clinic visit at 
least annually (with periodic phone/internet contacts every 3 months in between) and a 
final visit V30. During that annual visit and at V30, selected blood samples as described 
above should be collected. 
In rare cases of written withdrawal of consent (WOC) for follow-up visits (i.e. patient does not 
wish to come back even for an annual visit), and unless otherwise stated by the patient in the 
informed consent form, Investigators will be encouraged to get information from the general 
practitioner, any other physician, or other medical-care provider, in order to follow the medical 
status of the patients (especially when they withdraw their consent after having experienced an 
AE/SAE or a cardiovascular event [efficacy endpoint]). Investigators will also be expected to try 
as much as possible to re-contact those patients at the end of the trial, in order to obtain at least 
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their vital status (dead or alive), as well as their cardiovascular status if possible, and thus avoid 
lost to follow-up for the efficacy assessment. 
If the patient exercises his right of opposition to transmission of the data to the sponsor or removal 
of data from the database, the investigator will inform, in writing, the clinical trial sponsor, and 
the sponsor will decide how to handle the subject data and samples based on local regulations and 
data privacy requirements. 
All definitive discontinuation of study treatment should be recorded by the Investigator in the 
appropriate screens of the eCRF and in the patient’s medical records 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 or this may be the Investigator’s decision: 
• 
All study withdrawals should be recorded by the Investigator in the appropriate screens of 
the eCRF and in the patient’s medical records when considered as confirmed (at least date 
of withdrawal and reason for). IVRS/IWRS should be notified when a patient prematurely 
discontinues study 
• 
The patients should be assessed using the procedure normally planned for the visit V70 
which corresponds to the early end of treatment visit. (see Section 10.3.4) 
However, all randomized patients should be followed-up (and suspected efficacy endpoints as 
well as related and/or serious AEs collected) until the end of the study (common study end date 
visit), even if treatment was permanently discontinued early. 
In case of study treatment discontinuation (temporary or permanent) due to an adverse event, such 
patients will be closely monitored until the resolution or stabilization of this adverse event. This 
may mean that follow-up will continue after the patients have completed the study. 
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, review available registries or 
health care database), and to determine his/her health status, including at least his/her vital status 
dead or alive at minimum, preferably also stroke or MI status). Attempts to contact such patients 
must be documented in the patient’s records (e.g., times and dates of attempted telephone contact, 
receipt for sending a registered letter). This will be clearly stated in the informed consent form. 
For patients considered lost to follow-up, the eCRF must be completed up to the last visit 
performed. The statistical analysis plan will provide the details concerning the analysis of these 
patients. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment number must not be reused. 
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
Please refer to Appendix E for Adverse Event (AE) reporting requirements. 
10.4.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect 
• 
Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require 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 dependency 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 
10.4.2 Adverse event of special interest 
Adverse Events of Special Interest (AESI) are AEs (serious or non-serious) that need to be 
monitored, documented, and managed in a pre-specified manner described in the protocol.   
Please see Section 10.4.6.2 and Appendix E for additional information. 
10.4.3 Serious adverse events waived from expedited regulatory reporting to health 
authorities 
Unlike most studies where the primary efficacy variable is the resolution or improvement of an 
existing condition, in this study efficacy outcomes include the occurrence of life-threatening 
events. Indeed, participants to this study are recruited precisely because they are at high risk for 
these life threatening events. They are therefore expected to have at least one cardiovascular 
efficacy endpoint during the course of the study. 
In light of the above, (primary and secondary) suspected cardiovascular efficacy endpoints as 
specified in this protocol will not be considered as AEs and are waived from regulatory reporting 
to Health Authorities except if the Investigator according to his/her best medical judgment 
considers these events as unexpected in the context of the underlying disease condition. In that 
case, the Investigator will complete an AE/SAE form (in addition to eCRF efficacy endpoint page 
– see below) including causality assessment within 24 hours. 
For this study, all suspected cardiovascular efficacy endpoints will be reported (within 24 hours) 
in the specific eCRF efficacy endpoint pages; the system will automatically send the notification 
to the Clinical Event Committee Coordination Center at DCRI. This automatic notification will 
occur after the Investigator has approved the eCRF screens or after a standard time interval has 
elapsed, whichever comes first. 
Expedited reporting to Health Authorities for the following cardiovascular outcomes will be 
waived: 
• 
CV death including CHD death 
• 
All other causes of death 
• 
Non-fatal MI 
• 
Non-fatal stroke 
• 
Unstable angina requiring hospitalization 
• 
Ischemia-driven coronary revascularization procedure 
• 
Congestive heart failure requiring hospitalization 
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10.4.4 General guidelines for reporting adverse events 
• AEs are to be recorded in corresponding screen(s) included in the eCRF. 
• The reporting requirement of AEs depends on patient status (study completer or patient 
who had premature permanent discontinuation of IMP) 
- 
In patients who receive IMP until the end of the study (study completer), all AEs, 
regardless of seriousness or relationship to IMP/NIMP, spanning from the signature of 
the informed consent form until the CSED visit are to be recorded in the eCRF. 
Patients who experience a new or ongoing related or serious AE or a new or ongoing 
AESI (see Section 10.4.2) at the CSED visit should be followed beyond the CSED 
visit until resolution, stabilization, or death (whichever comes first) and related data 
will be collected (see Section 10.1.5.4.1). 
- 
In patients who have permanent premature IMP discontinuation: 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until 6 months following V70 (end of 
treatment visit) are to be recorded in the eCRF. 
• From 6 months following V70 until the CSED visit, related and/or serious AEs 
should be recorded in the eCRF. 
NOTE: Reporting requirement for suspected efficacy endpoints is the same regardless of 
patient status (study completers or patients who had premature permanent discontinuation 
of IMP); suspected efficacy endpoinsts should be reported in all randomized patients until 
the end of the study (CSED). 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP. 
• When treatment is prematurely discontinued, the patient will be maintained in the study 
and the patient’s observations will continue until the common study end date visit (see 
Section 10.3.4). 
• Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if: 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or 
- 
Leading to IMP discontinuation or modification of dosing (with exception of LDL-C 
levels which may lead to IMP dosing modification, but in a blinded manner), and/or 
- 
Considered as clinically relevant (such as for ECG a prolonged QTcB > 500 ms or an 
increase in QTcB of > 60 msec compared to baseline), and/or 
- 
Fulfilling a seriousness criterion, and/or 
- 
Defined as an AE of special interest with immediate notification 
See Appendix E for a summary of AE and efficacy endpoint reporting guidelines. 
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10.4.5 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send a notification to a representative of the 
pharmacovigilance team after approval of the Investigator within the eCRF or after a 
standard time has elapsed, whichever comes first. Transmission to the pharmacovigilance 
team of information related to the SAE will be done either by fax or with an electronic 
solution. 
• 
SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to a representative of the 
pharmacovigilance team whose name, fax number, and email address will be provided for 
each region in a separate document. 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. 
• 
All further data updates should be recorded in the eCRF 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 a representative of the 
pharmacovigilance team within 24 hours of knowledge of the SAE. In addition, every 
effort should be made to further document any SAE that is fatal or life threatening within a 
week (7 days) of the initial notification. 
• 
A back-up plan (using a paper CRF process) is available and should be used when the 
eCRF system does not work. 
10.4.6 Guidelines for reporting adverse events of special interest 
10.4.6.1 Reporting of adverse events of special interest with immediate notification 
For these AEs, the Sponsor will be informed immediately (ie within 24 hours), as per SAEs 
notification described in Section 10.4.5, even if not fulfilling a seriousness criterion, using the 
corresponding screens in the eCRF. 
• 
ALT ≥3 ULN (if baseline ALT < ULN) Or ALT ≥2 times the baseline value (if baseline 
ALT ≥ ULN) (Please refer to related flowchart in Appendix C). 
• 
Allergic events 
- 
Allergic drug reactions and/or local injection site reactions deemed to be allergic (or 
have an allergic component) that require consultation with another physician for 
further evaluation of hypersensitivity/allergy, as per the investigator's medical 
judgment or as per Section 10.6.2, should be reported as an AESI with immediate 
notification. 
- 
All allergic events, and all injection site reactions having an allergic component or 
deemed to be allergic, require completion of the specific eCRF screen (see 
Section 10.6.2), regardless of requirements for immediate reporting. 
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• 
Hemolytic anemia (see Section 10.4.7.1 and Appendix D) 
- 
If there is a decrease in hemoglobin and reflexive testing as per Appendix D 
suggesting hemolysis, then report this as an AESI with immediate notification.  Special 
eCRF screen will need to be completed 
• 
Pregnancy 
- 
Pregnancy occurring in a female patient enrolled in the study will be recorded as a 
pre-specified AE with immediate notification in all cases, and IMP should be 
discontinued in all cases. It will be qualified as an SAE only if it fulfills the SAE 
criteria. The follow-up of the pregnancy will be mandatory until the outcome of the 
pregnancy has been determined. 
- 
Pregnancy occurring in the female partner of a male patient included in the clinical 
trial: if permitted by the female partner and by local regulatory policies, it will be 
recorded as a pre-specified AE with immediate notification (SAE if it fulfills the SAE 
criteria), and pregnancy should be followed-up until the outcome has been determined. 
• 
Symptomatic Overdose with IMP 
- 
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic injection counts) and 
defined as at least twice of the intended dose within the intended therapeutic interval 
(ie, 2 or more injections from the double-blind treatment kit are administered in 
<7 calendar days); to be reported using the corresponding screens in the eCRF using 
the Term “symptomatic OVERDOSE (accidental [or intentional])”. The patient should 
be monitored and appropriate symptomatic treatment instituted 
- 
The circumstances of the overdose should be clearly specified in the verbatim 
• 
Neurologic and Neurocognitive Events 
- 
Neurologic and Neurocognitive Events that require additional 
examinations/procedures and/or referral to a specialist should be reported as an 
AESI with immediate notification (see also Appendix E for reporting 
requirements). 
10.4.6.2 Reporting of adverse events of special interest without immediate notification 
See Appendix E. 
For these AEs, the Sponsor does not have to be informed immediately, unless meeting seriousness 
criterion. 
• Asymptomatic 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 from the double-blind treatment kit are administered in 
<7 calendar days); to be reported using the corresponding screens in the eCRF using 
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the Term “asymptomatic OVERDOSE (accidental [or intentional])”  The patient 
should be monitored for any AEs and treated, as needed 
• Local injection site reactions (see Section 10.6.1) 
- 
Local injection site reactions related to IMP that are considered as non-allergic events 
should be further characterized by evaluating the related symptoms that comprise an 
injection site reaction such as but not limited to redness, pain, etc (See Appendix F). 
Special eCRF screens will need to be completed.  If such an AE was to occur, then do 
not report the individual components of the reaction but rather the term “local injection 
site reaction”, the individual components being described in the specific eCRF screen 
• Allergic events not referred for consultation with another physician (see Section 10.4.6.1) 
- 
All allergic events will need to have allergy specific eCRF screens completed (see 
Section 10.6.2), regardless of requirements for immediate reporting. 
• Neurologic and Neurocognitive events 
- 
AEs related to neurologic or neurocognitive abnormalities with the exception of those 
requiring additional examinations/procedures and/or referral to a specialist (as 
mentioned in Section 10.4.6.1) should be reported in accordance with Appendix E. 
10.4.7 Guidelines for management of specific laboratory abnormalities 
Laboratory abnormalities with pre-specified monitoring should be monitored, documented, and 
managed according to the related flowchart in protocol Appendix C  and Appendix D 
• 
Neutropenia 
• 
Thrombocytopenia 
• 
Increase in ALT 
• 
Acute renal insufficiency 
• 
Decrease in hemoglobin (defined as ≥1.5 g/dL decrease from pre-randomization baseline 
value) 
• 
Increase in CPK (other than cardiac-related) and suspicion of rhabdomyolysis. 
Investigators are strongly encouraged to follow these algorithms in Appendix C  and Appendix D, 
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 
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: 
• patients with known stable low or borderline neutrophil or platelet count or impaired renal 
function at baseline; Investigator should attempt to have a diagnosis for the observed 
finding and should use his/her best judgment whether or not to enroll these patients, and if 
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patient is enrolled, on how to best monitor these baseline abormalities throughout the 
study 
• patients with ALT increase or elevated CK for which the abnormality resolves following 
statin dose reduction or statin discontinuation 
• patients with elevated CK 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. 
10.4.7.1 Hemoglobin decrease 
See Appendix D. 
At the first post-randomization study visit with occurrence of a hemoglobin (Hb) measurement 
decrease by ≥1.5 g/dL as compared to the randomization visit hemoglobin measurement, then the 
Central Lab will reflexively measure haptoglobin using specimens already obtained at the same 
time point for which the hemoglobin decrease was detected.  The Central Lab will then provide 
the results of the reticulocyte count, haptoglobin, LDH and indirect bilirubin (reflexively 
measured only if the total bilirubin > ULN) to the Investigator. 
NOTE: At selected sites with a longer transit time to Central Lab where reticulocyte count cannot 
be measured by Central Lab, a second hematology sample will be collected for local assessment 
of reticulocyte count, 
• 
If the following pattern of abnormalities is noted: 
- 
Reticulocyte count > Central Lab (or if applicable, local lab) upper limit of the 
reference range (also referred to as ULN) AND 
- 
Haptoglobin < Central Lab’s lower limit of the reference range (also referred to as 
LLN) AND 
- 
LDH > ULN AND 
- 
Indirect bilirubin > ULN (only if the total bilirubin > ULN) 
The patient should be referred to a hematologist. The hematologist should obtain a 
peripheral blood smear and anti-erythrocyte antibodies (direct and indirect) by Coombs 
test.  Further investigations are at the discretion of the hematologist. 
• 
If the results are normal or the pattern of abnormality is something other than that 
described above, then the Investigator should exercise his/her medical judgment in the 
interpretation of the results, necessity for workup of the decrease in hemoglobin or referral 
to a hematologist 
If a second hemoglobin measurement demonstrating a further decrease of ≥1 g/dL from the last 
available value is observed, even if the previous work-up was negative, the same investigations 
can be repeated and a hematology consultation can be requested at the discretion of the 
Investigator or at the Sponsor's request. 
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10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the IMP (Suspected Unexpected Serious 
Adverse Reaction[SUSAR]), to the Health Authorities, IECs/IRBs as appropriate and to the 
Investigators. 
In addition, the Sponsor will report in an expedited manner all SAEs that are expected and at least 
reasonably related to the IMP to the Health Authorities, according to local regulations. 
In this study, cardiovascular efficacy endpoints specified (primary and secondary efficacy 
endpoints) are waived from expedited reporting to Health Authorities providing an agreement has 
been reached with them. 
Also some other AEs may be considered related to the underlying condition and thus will not be 
considered unexpected as given 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 as unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Local tolerability (Local Injection Site Reactions) 
In case the Investigator or the patient recognizes any signs of local intolerability, then this should 
be treated and followed up as per the Investigator’s medical judgment. See Section 10.4.6.2 and 
Appendix F for further information. 
10.6.2 Allergic adverse events (See Section 10.4.6.1 and Section 10.4.6.2) 
Specific eCRF screens are to be filled in to assess allergic reactions or allergic-like reactions that 
may occur during the clinical studies conducted with alirocumab. 
Sometimes transient injection site reactions, irritant in nature, may occur, requiring no 
intervention and being of dubious significance. These reactions would not be considered to be 
allergic reactions. 
Adverse events that may constitute an allergic reaction (eg, generalized itch, nasal itch, swelling at 
injection site, flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, 
difficulty to swallow, hoarseness, change in pitch of voice, incapacity to speak, wheezing, chest 
tightness, stridor, etc) should be considered to be reported on the General Allergic Reaction and/or 
Local Injection Site Reaction Complementary Form. 
Adverse events that are obviously not of allergic origin (eg, local injection site reactions related to 
IMP and with no allergic component) should only be recorded on the Local Injection Site 
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Reaction Complementary Form.  However, injection site reactions which 
progress/expand/worsen/etc should be evaluated as recommended in Section 10.6.2.1 and General 
Allergic Reaction Complementary form should be completed. 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP.  See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.2 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 
extra-cutaneous symptoms and signs.  An unscheduled Central Laboratory assessment for 
hematology, chemistry, liver panel, and ADA should be obtained. If it is possible, the site will 
take pictures of the skin lesions in order to provide the patient with them for the dermatologist’s 
visit.  If the photos are obtained, then copies should be kept as source documents which may later 
be collected by the sponsor.  The investigator will provide a summary of the patient's case, reason 
for consultation, and information being requested to the consulting dermatologist. 
A full consultation report should be sent by the dermatologist to the investigator.  The full report 
should contain, at a minimum, the following information; a detailed description of the rash (such 
as the morphology [lesion type], shape of individual lesions, arrangement of multiple lesions [eg, 
scattered, grouped, linear, etc], distribution, color, consistency, presence of pruritus or pain, and 
other clinical signs) and in case a skin biopsy (including histopathology and immunofluorescence) 
was done (if it was deemed necessary as per the dermatologist’s or investigator’s medical 
judgment), the results of this investigation with, if applicable, a specific diagnosis of the AE. The 
investigator will fax the full report and the corrected AE form if necessary, to the Monitoring 
Team Representative within 24 hours. 
10.6.2.2 Acute allergic injection reactions (Section 10.4.6.2) 
Acute allergic injection reaction (which are considered under the category of general allergic 
reactions) is defined as any AE that occurs during or shortly after injection of the IMP 
(characterized by but not limited to hypotension, bronchoconstriction, urticaria, edema, 
angioedema, nausea, vomiting). The investigator should ascertain that patient can be rapidly 
managed with emergency equipment and medication for the treatment of these potential adverse 
effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, acetaminophen, and 
epinephrine) for the injections at the training, and randomization visits. 
Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the randomization visit. Patients should be treated symptomatically if any AEs 
are observed. Patients are to remain on observation until any acute injection reaction is assessed as 
stable, per the Investigator’s or emergency team’s discretion.  General Allergic Reaction and/or 
Local Injection Site Reaction Complementary Form will have to be completed. 
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10.6.3 Monitoring related to two consecutive LDL-C <25 mg/dL (0.65 mmol/L) 
Patients who achieve 2 consecutive LDL-C levels <25 mg/dL (0.65 mmol/L) during the study will 
be monitored and managed as per Appendix A (any time after randomization) as the lower limit of 
safe and effective LDL-C lowering has not yet been established. An independent external 
physician(s) (also known as independent physician) will be notified by the central laboratory of 
2consecutive LDL-C <25 mg/dL (0.65 mmol/L). The independent physician will review the 
unmasked LDL-C values and patient safety data, in close collaboration with the dedicated 
member of the Phase 3a DMC (implemented for all Phase 3 studies evaluating the efficacy and 
safety of alirocumab on LDL-C). This dedicated Phase 3a DMC member will then transmit any 
information as necessary to the common member involved in both DMCs (CV DMC and Phase 3a 
DMC). 
Please see Appendix A for an outline of the process. 
Then at subsequent visits, specific actions can be undertaken depending on the alirocumab dose 
(down-titration or discontinuation) as follows: 
• 
On dose of 150 mg Q2W: if LDL-C <25 mg/dL (including LDL-C <15 mg/dL) on 
2 consecutive values, down-titration to 75 mg Q2W will be done in a blinded manner at 
the next visit. The patient will remain at the down titrated dose of 75 mg Q2W for the 
remaining duration of the study, unless patient meets criteria below. As described above, 
specific monitoring consisting of review of patient level listing will be implemented. 
• 
On dose of 75 mg Q2W: 
- 
If LDL-C <25 mg/dL on 2 consecutive values but there are no 2 consecutive 
measurements < 15 mg/dL (i.e. no measurement < 15 mg/dL or only one occasional 
measurement < 15 mg/dL):  study treatment with 75 mg Q2W will be continued but 
additional monitoring with review of individual patient profiles will be implemented, 
to further confirm the safety of low LDL-C levels. A site alert related to 2 consecutive 
LDL-C < 25 mg/dL (0.65 mmol/L) may be requested by the independent physician 
(after consultation with dedicated phase 3a DMC member) 
- 
If measured LDL-C <15 mg/dL on 2 consecutive measurements: study treatment with 
75 mg Q2W will be discontinued at the next visit.  In order to maintain the blind there 
will be blinded substitution to placebo injections for the remaining duration of the 
study 
As lipid values will not be communicated to investigators after randomization to maintain the 
blind, the continuation of the 75 mg dose, the up-titration to the 150 mg dose, the down-titration 
from 150 to 75 mg, or discontinuation will all occur automatically, without site or patient 
awareness. Moreover, blinded dose adjustment will avoid the need for dummy titrations in the 
placebo group. 
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 
The sample size calculations are based on the primary efficacy variable, with the following 
assumptions: 
• 
Primary efficacy endpoint is the time from randomization to the date of first occurrence of 
one of the following Clinical Events, as determined by the CEC: CHD death, any non-fatal 
MI, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization. Based 
on PROVE-IT results (8) and considering adjustment based on the study design and 
endpoints definition, the following Kaplan-Meier probabilities of event in the placebo 
group have been considered: 3.8% at 12 months, 6.4% at 24 months, 9.0% at 36 months, 
11.4% at 48 months. Probability of event at different time points are estimated using a 
piece-wise exponential model. The primary efficacy endpoint will be analyzed on an 
intent-to-treat basis (all randomized patients, including those who discontinue study 
medication are followed for any efficacy event until the termination of the study) 
• 
Hazard ratio of 0.85 in test group relative to placebo (corresponding to a 15% risk 
reduction). Constant hazard ratio assumption is used 
• 
A log-rank test at a 1-sided 2.5% significance level with 90% power 
• 
Two interim analyses, according to a group sequential design, using for efficacy Gamma  
(-22) α-spending function, and for futility a Gamma (-5) β-spending function. Non-
binding spending functions are used. See Section 11.5 for interim analysis details 
• 
1% lost-to-follow rate at 24 months in both arms 
• 
Enrolment rate: sample size of about 18,600 patients enrolled in 1400 sites (these sites 
should be active within 12 months). The table below describes the expected enrolment rate 
per month; these assumptions are based on internal experience to enroll this patient 
population 
Table 3 - Enrolment rate assumptions per month 
Month 
1 to 3 
4 
5 
6 
7 
8 
9 
10 
11 
12 to 40 
No. pts per 
month 
32 
64 
80 
104 
160 
240 
320 
420 
520 
560 
Cumulative 
no. patients  
96 
160 
240 
344 
504 
744 
1064 
1484 
2004 
2564 at M12, 
18000 at M40 
 
Based on the above assumptions, 1613 events are needed for 90% power. In order to achieve the 
1613 targeted events, about 18000 patients (~9000 per group) will need to be randomized over a 
period of about 40 months. However, taking into account the situation in China (target of about 
600 randomized patients in China based on local regulatory considerations, and local delayed 
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study start), the total number of patients randomized will be increased to approximately 
18,600 patients (~9,300 per group). At the end of the study, the overall population will include 
about 18,000 randomized patients who have either died or been followed for a minimum of 
24 months, supplemented with an additional subset of patients from China (~600) who may be 
followed for less than 24 months. 
NOTE:  Continued enrolment of patients in China after the initial target of 18,000 randomized 
globally has been reached, and leading to an increase in sample size to about 18,600 patients, 
will be implemented only after appropriate local authorizations in China have been obtained. 
Calculations were made using East 5.4 software. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the qualifying ACS 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 these patients will be reported separately, and they 
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 
11.3.1.1 Intent–to-treat population 
The primary efficacy analysis population will be the intent-to-treat (ITT) population, consisting of 
all randomized patients as defined above. Patients in the ITT population will be analyzed 
according to the treatment group allocated by randomization. 
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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). 
In addition: 
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
• 
For patients receiving double-blind IMP from more than 1 treatment group during the trial, 
the treatment group allocation for as-treated analysis will be the one to which the patient 
was treated with the longest duration 
• 
In case of two consecutive LDL-C values <15 mg/dL, placebo injections will be given to 
patients randomized in the alirocumab group in order to maintain the blind. Those placebo 
injections will not be considered as double-blind IMP 
11.3.3 Other analysis populations 
The anti- alirocumab antibody analysis will be performed on all treated patients (safety 
population) with a blood sample on D1 (baseline) and at least one evaluable blood sample for 
antibodies post double-blind IMP injection. 
Analysis populations for pharmacogenomics will be defined in a specific Statistical Analysis Plan 
(SAP). 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
In order to ensure the continuity of the investigational treatment for the patients without 
interruption (only in case a disruption occurs in the availability of device components or during 
production of the auto injectors), back-up plans may be implemented as described in Section 8.1. 
In that case, exposure to initial device and back-up device, if applicable, will be summarized and 
impact on study results will be assessed. More details will be provided in the SAP, if applicable. 
Double-blind IMP injections are those administered from randomization to discontinuation of the 
study treatment, that is: 
• 
Containing placebo for the ones administered to patients randomized in the placebo group 
• 
Containing 75 or 150 mg of  alirocumab 
Placebo injections given to patients randomized to alirocumab following 2 consecutive  
LDL-C <15 mg/dL will not be considered as double-blind IMP in the statistical analyses. 
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11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
• 
Duration of IMP exposure in months defined as: (last dose of double-blind IMP injection 
date +14 – first dose of double-blind IMP injection date)/30.4375, regardless of unplanned 
intermittent discontinuations 
• 
The total number of double-blind IMP injections by patient 
• 
Duration of observation period (months), defined as: (last contact date – first dose 
date+1)/30.4375. Non-integer values will be rounded to one decimal place 
The number (n) and percentage (%) of patients with an up-titration in the alirocumab group will 
be described. 
The number (n) and percentage (%) of patients with an up-titration followed by a down-titration 
in the alirocumab group will be also described. 
11.4.1.2 Compliance 
Compliance will be assessed using the following parameters: 
• 
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) 
• 
The overall compliance will be defined for each patient as: 100-(% days with under-
planned dosing + % days with above-planned dosing).Under-planned and above-planned 
dosing will be defined as follows, considering that injections should be performed every 2 
weeks (+/- 3 days allowed time window): 
- 
The % days with under-planned dosing will be defined for each patient as the number 
of days with no injection administered within the previous 17 days divided by the 
duration of IMP injection exposure in days. 
- 
The % days with above-planned dosing will be defined for each patient as the number 
of days with more than one injection administered within the 11 days before/duration 
of IMP exposure in days. 
These parameters will be summarized descriptively (N, Mean, standard deviation [SD], Median, 
Min and Max) at 6 months, by year, and on the overall study period. 
Cases of overdose (ie, 2 or more injections from the double-blind treatment kit are administered in 
<7 calendar days) will be summarized by treatment group. 
11.4.2 Analyses of efficacy endpoints 
All efficacy analyses will be performed based on intent-to-treat (ITT) approach that included 
events occurring or assessments performed from randomization to the analysis cut-off date, even 
after the patient has discontinued the study treatment. 
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11.4.2.1 Analysis of primary efficacy endpoint(s) 
The analysis of primary efficacy endpoint will be the comparison between the two treatments 
using the log-rank test procedure stratified by region (North America, South America, Western 
Europe, Eastern Europe, Asia, Other). As the number of events per individual country is expected 
to be low (about 50 countries), the analysis will be stratified according to a grouping of countries 
into regions. 
This primary comparison is the test of the following hypotheses on the hazard ratio (HR), 
applying a one-sided nominal type I error of 0.0249 at the final analysis: 
H0: HR ≥1 versus H1: HR <1 
The estimates of the HR and corresponding confidence interval at (1-2α) % level (α being the one-
sided nominal significance level: α=0.249 at final analysis, α=0.0001 at second interim analysis) 
will be provided using a Cox Proportional Hazard Model stratified by region as for the log-rank 
test described above. 
Consistency of the treatment effect across regions will be assessed. 
Underlying assumptions of the Cox Proportional Hazard Model will be checked using graphical 
methods. If proportionality is not observed, some ad-hoc sensitivity analyses will be performed 
depending on the data (data-driven). 
The survival curves will be estimated using Kaplan-Meier estimates: cumulative incidence of 
events at 6 months and by year, and appropriate confidence interval will be presented by treatment 
arm using Kaplan-Meier estimates. Kaplan-Meier curves will be displayed by treatment arm. 
Two interim analyses will be performed See Section 11.5 for description of these analyses. The 
cut-off dates of final and interim analyses are expected to be: 
• 
First interim analysis (futility): when  807 patients have been experienced at least one 
primary efficacy event (50% fraction information) 
• 
Second interim analysis (futility and efficacy): when  1210 patients have been experienced 
at least one primary efficacy event (75% fraction information) 
• 
Final analysis: when 1613 patients have experienced at least one primary efficacy event or 
24 months after the last date of randomization ex-China, whichever comes last 
Subgroup analyses 
For the primary endpoint, the treatment effects across the following subgroup factors will be 
examined: 
• 
Gender 
• 
Age group (<65, ≥65) 
• 
Race (Caucasian, Black, Asian/Oriental, and Other, as appropriate) 
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• 
Country (IVRS stratum, depending on the size of subgroups) 
• 
Region (USA/Non-USA, and North America/South America/Eastern Europe/Western 
Europe/Asia/Rest of world) 
• 
Time from ACS event to randomization (eg, 4-24 weeks, > 24 weeks) 
For each parameter, a Cox proportional hazard model will be used for the overall population, 
including the parameter and the treatment by parameter interaction. In addition, Kaplan-Meier 
curves and summary statistics showing number of patients, number (%) of primary efficacy 
outcome events, cumulative incidence of events at 6 month and by year, and appropriate 
confidence interval may be provided for each treatment arm in previously selected subgroups 
defined by the baseline characteristic/prognostic factors. 
In addition, the effect of the time from ACS event to randomization (weeks) will be assessed 
using a Cox proportional hazard model including the time from ACS event to randomization 
(continuous) as a covariate, the treatment group and the interaction. 
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. 
Time to events secondary endpoints will be analyzed using the same statistical methodology as for 
the primary endpoint. 
The percent change from baseline in calculated LDL-C at Month 4, at Month 24 and at the end of 
the study will be analyzed in the ITT population using an analysis of covariance (ANCOVA) 
model with treatment group and region as fixed effects, and the baseline calculated LDL-C as 
covariate. 
Similar analyses will be performed for ApoB and non-HDL. 
Based on previous experiences and published data on these endpoints, the assumptions of 
normality of the residuals, homogeneity of slopes and homoscedasticity underlying these models 
are usually valid. 
Throughout the ANCOVA models, the alirocumab group will be compared to placebo using an 
appropriate contrast tested at the two-sided 0.05 level, and providing the 95% confidence interval 
(CI) of the difference. 
For patients without calculated LDL-C, ApoB, or non-HDL-C value in the time window analyzed, 
the percent change from baseline will not be calculated. 
11.4.2.3 Multiplicity consideration 
In order to handle multiple main secondary endpoints, the overall Type-I error will be controlled 
by the use of a sequential inferential approach. Statistical significance of the primary parameter is 
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required before drawing inferential conclusions about first key secondary parameter (at the 0.0001 
one-sided alpha level at the second interim analysis or at the 0.0249 one-sided alpha level at the 
final analysis). The order of tests is detailed in Section 9.1.3. Inferential conclusions about 
successive main 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 
required one-sided level (0.0001 for the second interim analysis and 0.0249 at the final analysis). 
No further adjustments will be made for other secondary endpoints or subgroup analyses 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 last available value 
before first double-blind IMP injection as baseline definition. 
The following definitions will be applied to laboratory parameters, and vital signs. 
• 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, and vital signs. 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the PCSA percentage. 
AE definition: 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the PRE-
TREATMENT period; 
• 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious 
during the TEAE period; 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
POST-TREATMENT period. 
Possible drug-induced liver injury 
The liver function tests, namely ALT, AST, alkaline phosphatase and total bilirubin, are used to 
assess possible drug induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
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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. 
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 need further characterization or for adverse event of clinical 
interest (eg, injection site reaction, allergic reaction), 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. 
Local injection site reaction could be further described in terms of time pattern (time to first 
occurrence, duration, recurrence) and intensity. 
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 and by year of exposure 
will be presented and Kaplan-Meier curves will be provided. 
LDL-C <25 mg/dL: 
Summaries of adverse events will be also provided on the safety subgroup population of patients 
with two consecutive LDL-C <25mg/dL in the alirocumab group. Only adverse events, for which 
it will be confirmed or unclear that they occurred, worsened or became serious after the first level 
of LDL-C <25mg/dL will be considered. 
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Death: 
The following deaths summaries will be generated: 
• 
Number (%) of patients who died by study period (TEAE, on-study) and adjudicated 
reasons, summarized on the safety population by treatment received; 
• 
Death in non randomized patients or randomized and not treated patients; 
• 
TEAE leading to death (death as an outcome on the AE eCRF 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, standard error, minimum and 
maximum) of all laboratory variables, all vital signs parameters (raw data and changes from 
baseline) will be calculated for each visit, last and worst value assessed during the treatment 
period and presented by treatment group. For selected parameters, mean changes from baseline 
with the corresponding standard error will be plotted over time (at same time points) in each 
treatment group. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and/or according to the following baseline categories: 
• 
Normal/missing; 
• 
Abnormal according to PCSA criterion or criteria. 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
Hepatitis C antibody: 
The number and percentage of patients with an observed seroconversion for Hepatitis C Test will 
be provided by treatment group. 
11.4.4 Other endpoints: 
11.4.4.1 Cardiovascular events of interest (other than efficacy endpoints) 
Clinically significant complications or procedures (not planned at the time of randomization) 
related to peripheral arterial disease, and venous thromboembolic events (see Section 9.3.7) will 
be analyzed using a time-to-event approach (Kaplan-Meier methodology) in the ITT population. 
Time from randomization to the first occurrence of the event will be calculated. Patients without 
any event will be censored using the same methodology as for the primary efficacy endpoint. 
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11.4.4.2 Other endpoints 
All analyses for other endpoints (not already described above) will be performed on the Safety 
population. The baseline value is defined as the last available value before first double-blind IMP 
injection. 
The number and percentage of patients with calculated LDL-C <25 mg/dL (respectively, LDL-C 
<15 mg/dL) will be provided by treatment group and visit. 
Exploratory variables defined in Section 9.3 will be summarized by time points using number of 
available data, mean, SD, median, minimum, and maximum for each treatment group (for 
hs-CRP, Q1 and Q3 will be also provided). The time profile of each parameter will be also plotted 
by treatment group with the corresponding standard errors. For hs-CRP, the incidence of PCSA at 
any time during the TEAE period will be also summarized by treatment group using descriptive 
statistics. 
The anti-alirocumab antibody status (positive/negative) and antibody titers will be summarized by 
treatment group and visit using descriptive statistics. Anti- alirocumab antibody will be further 
described in terms of time-to-onset, persistence (transient/persistent anti- alirocumab antibodies). 
Correlations between antibody titers, safety and/or efficacy endpoints could be also provided by 
graphical methods. Further details will be provided in SAP. 
11.5 
INTERIM ANALYSIS 
Two interim analyses (IA) are planned, when 50% and 75% of the total number of expected 
events have occurred: 
• 
Interim analysis for futility will be conducted, when approximately 807 events (50% of the 
targeted number of primary endpoint events) have occurred. 
• 
Interim analysis for futility and overwhelming efficacy will be conducted, when 
approximately 1210 events (75% of the targeted number of primary endpoint events) have 
occurred. 
Both IA will be performed by the external independent CV DMC Statistician and will be 
reviewed under the supervision of the CV DMC. The CV DMC will also review secondary 
efficacy endpoints and safety data (AEs, laboratory data, vital signs) available at the time of the 
IA. 
Control of the type I and type II error will be ensured using gamma (-5) spending function for 
Type II error (futility) and Gamma (-22) for Type I error (efficacy) at each IA (the Type I error 
spending function is also applied at the first IA, even if the objective of this first IA is only 
futility). It has to be noted that, in order to protect the global type one error in case the decision is 
taken to overrule the futility rule, non binding boundaries were used. 
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The following table shows the stopping rules at each interim analysis (using the sample size 
assumptions described in Section 11.1): 
Table 4 - Interim Analyses stopping boundaries corresponding to Gamma (-22) type I error and 
Gamma (-5) type II error spending functions  
Stopping boundaries 
(one-sided p-value and Hazard ratio) 
Timing of analyses 
Futility 
Overwhelming efficacy 
First IA : 50% of targeted events 
p > 0.548 
(Ù HR > 1.008) 
NA 
 
Second IA: 75% of targeted events 
p > 0.19 
(Ù HR > 0.951) 
p < 0.0001* 
(Ù HR < 0.802) 
Calculations done using EAST 5.4 
*Should the second interim analysis be triggered just before or after 1210 events have been reached, the exact nominal 
significance level to be used at the second IA would be re-computed based on a Gamma(-22) spending function. 
The CV DMC could consider early stopping of the study for overwhelming efficacy at the second 
IA, if the following conditions are met: 
• Stopping boundaries for overwhelming efficacy are crossed 
• Positive trend observed for secondary efficacy endpoints, including all cause mortality, 
and no excess of non-CV mortality 
• Consistency of the treatment effect on the primary efficacy endpoint across subgroups and 
regions 
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12 
ETHICAL AND REGULATORY STANDARDS 
12.1 
ETHICAL PRINCIPLES 
This clinical trial will be conducted in accordance with the principles laid down by the 18th World 
Medical Assembly (Helsinki, 1964) and all applicable amendments laid down by the World 
Medical Assemblies, and the International Conference on Harmonization [ICH] guidelines for 
good clinical practice (GCP). 
In compliance with Sanofi public disclosure commitments, this clinical trial will be recorded in 
the public registry website clinicaltrials.gov before the enrollment of the first patient. The registry 
will contain basic information about the trial sufficient to inform interested patients (and their 
healthcare practitioners) how to enroll in the trial. 
12.2 
LAWS AND REGULATIONS 
This clinical trial will be conducted in compliance with all international guidelines, and national 
laws and regulations of the country(ies) in which the clinical trial is performed, as well as any 
applicable guidelines. Please see Section 13.1 
12.3 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient. 
The Informed Consent Form and the optional written Informed Consent Form for 
pharmacogenetics used by the Investigator for obtaining the patient's informed consent must be 
reviewed and approved by the Sponsor prior to submission to the appropriate Ethics Committee 
(IRB/IEC) for approval/favorable opinion. 
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic informed consent 
form (written) should be signed, name filled in, and personally dated by the patient or by the 
subject’s legally acceptable representative, and by the person who conducted the consent 
discussion. A copy of the signed and dated written optional informed consent form will be 
provided to the subject. 
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12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate Ethics Committee (IRB/IEC), and is required to forward to the 
respective other party  a copy of the written and dated approval/favorable opinion signed by the 
Chairman with Ethics Committee (IRB/IEC) composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the Ethics Committee (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 Ethics Committee (IRB/IEC). 
A progress report is sent to the Ethics Committee (IRB/IEC) at least annually and a summary of 
the clinical trial’s outcome at the end of the clinical trial. 
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator(s) and delegated Investigator staff undertake(s) to perform the clinical trial in 
accordance with this clinical trial protocol, ICH guidelines for Good Clinical Practice and the 
applicable regulatory requirements. 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to health authorities for taking all reasonable steps 
to ensure the proper conduct of the clinical trial protocol as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-s. 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. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH guidelines for Good Clinical Practice, and in accordance with the Sponsor’s 
guidelines and policies for source document verification, the monitoring team will check the 
eCRF entries against the source documents. This does not include pre-identified source data 
directly recorded in the eCRF. The informed consent form will include a statement by which the 
patient allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the 
regulatory authorities to have direct access to original medical records  which support the data on 
the eCRFs (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 (eCRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (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 eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF 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 eCRF. 
The computerized handling of the data by the Sponsor when available in the eCRF 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 
eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
Computerized systems used during the different steps of the study are: 
• For data management activities, Medidata RAVE version 5.6.4 (Covance) 
• For statistical activities, nQuery Advisor 6.01, SAS, EAST 5.4 
• For pharmacovigilance activities, AWARE , Business Objects XI 
• For monitoring activities, CTMS of each involved institution (DCRI, Covance, and Sanofi, 
as applicable). 
• For medical writing activities, DOMASYS 
External data loading is planned for this clinical trial. 
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14 
ADMINISTRATIVE EXPECTATIONS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, the CRFs, the Investigator's Brochure and the results obtained during the course of the 
clinical trial, is confidential, prior to the publication of results. The Investigator and any person 
under his/her authority agree to undertake to keep confidential and not to disclose the information 
to any third party without the prior written approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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Furthermore, the Investigator and the Sponsor agree to adhere to the principles of personal data 
confidentiality in relation to the patients, Investigator and its collaborators involved in the study. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not mention any information or the Product in any application for a patent 
or for any other intellectual property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
The patient's personal data, which are included in the Sponsor’s database, shall be treated in 
compliance with all applicable laws and regulations. 
When archiving or processing personal data pertaining to the Investigator and/or to the patients, 
the Sponsor shall take all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
The Sponsor also collects specific data regarding Investigator as well as personal data from any 
person involved in the study which may be included in the Sponsor’s databases, shall be treated 
by both the Sponsor and the Investigator in compliance with all applicable laws and regulations. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from 
maintaining their own liability insurance policy. An insurance certificate will be provided to the 
Ethics Committees (IECs/IRBs) or health authorities in countries requiring this document. 
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 Decided by the Sponsor 
Decided by the Sponsor in the following cases 
• 
If the information on the product leads to doubt as to the benefit/risk ratio 
• 
If 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 
• 
In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the clinical trial protocol, breach of the 
applicable laws and regulations or breach of the ICH guidelines on Good Clinical Practice 
• 
If the total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 Decided by the Investigator 
The Investigator must notify (30 days' prior notice) the Sponsor of his/her decision and give the 
reason in writing. 
In all cases (decided by the Sponsor or by the Investigator), the appropriate Ethics Committee(s) 
(IRB/IEC) and Health Authorities should be informed according to applicable regulatory 
requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
During the course of the study, the Executive Steering Committee co-Chairs will form a 
Publications Subcommittee, which will include all ESC members, and Sponsor representatives 
and to which selected National Leaders may be invited.  The role of the Publication Sub-
Committee will be to oversee the publications from the Study, assign authorship, assure that 
authorship requirements are met, and that the publications which are created are of the highest 
scientific quality. 
The Publications Subcommittee will review and approve all manuscripts of Study results prior to 
publication. 
All study participants (Investigators and Committee members) give full authority to the ESC for 
primary presentation and/or primary publication of results. No other publication is allowed before 
the primary publication. Any subsequent presentation or publication by a study participant must 
be approved by this Publications Committee and/or ESC and make reference to the study and the 
primary publication. 
As the study is being conducted at multiple sites, the Sponsor and the Publications Subcommittee 
agree that, consistent with scientific standards, first presentation or publication of the results of the 
study shall be made only as part of a publication of the results obtained by all sites performing the 
protocol. However, if no multicenter publication has occurred within twelve (12) months of the 
completion of this study at all sites, the Investigator shall have the right to publish or present 
independently the results of this study to the review procedure set forth herein.   The Investigator 
shall provide the Sponsor and the Publications Subcommittee with a copy of any such 
presentation or publication derived from the study for review and comment at least 30 days in 
advance of any presentation or submission for publication.  In addition, if requested by the 
Sponsor, any presentation or submission for publication shall be delayed for a limited time, not to 
exceed 90 days, to allow for filing of a patent application or such other measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights. 
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The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial Patients, or when the change(s) involves only logistical or administrative aspects 
of the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
Ethics Committee (IRB/IEC) prior to its implementation, unless there are overriding safety 
reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
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