Open-Label Extension Study of EFC12492, R727-CL-1112, EFC12732 and LTS11717 Studies to Assess the Long-Term Safety and Efficacy of Alirocumab in Patients With Heterozygous Familial Hypercholesterolemia
Phase: PHASE3
Conditions: Hypercholesterolemia
Sponsor: Sanofi

According to template: QSD-002579 VERSION N°8.0 (16-AUG-2012) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 2 
COMPOUND: alirocumab 
Open-Label Extension Study of EFC12492, R727-CL-1112, EFC12732, & LTS11717 
Studies to Assess the Long-Term Safety and Efficacy of Alirocumab in Patients 
with Heterozygous Familial Hypercholesterolemia  
STUDY NUMBER: LTS13463  
STUDY NAME: ODYSSEY OLE 
VERSION DATE / STATUS: 10 July 2015 / Approved 
CLINICAL STUDY DIRECTOR:
Protocol Amendment 7 
Version number: 1 
Date: 10-Jul-2015 
Amended Protocol 2 (USA/Canada) 
Version number: 1 
Dare: 09-Oct-2014 
Protocol Amendment 6 (USA/Canada) 
Version number: 1 
Date: 09-Oct-2014 
Amended Protocol 1  
Version number: 1 
Date: 30-Jul-2014 
Protocol Amendment 5 
Version number: 1 
Date: 30-Jul-2014 
Amended Protocol 2 (Denmark) 
Version number: 1 
Dare: 05-May-2014 
Protocol Amendment 4 (Denmark) 
Version number: 1 
Date: 05-May-2014 
Amended Protocol 1 (Denmark) 
Version number: 1 
Dare: 14-Mar-2014 
Protocol Amendment 3 (Denmark) 
Version number: 1 
Date: 14-Mar-2014 
Amended Protocol 1 (Sweden) 
Version number: 1 
Date: 04-Mar-2014 
Protocol Amendment 2 (Sweden) 
Version number: 1 
Date: 04-Mar-2014 
Amended Protocol 1 (UK) 
Version number: 1 
Date: 11-Oct-2013 
Protocol Amendment 1 (UK) 
Version number: 1 
Date: 11-Oct-2013 
Clinical Trial Protocol 
Version number: 1 
Date: 12-Jul-2013 
EudraCT number:  
IND number:  
UTN number:  
2013-002572-40 
IND105574 
U1111-1143-3810 
Date: 
10-Jul-2015
Total number of pages: 
95 
(electronic 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
NCT01954394

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND: alirocumab 
STUDY No: LTS13463 / ODYSSEY OLE 
TITLE 
Open-Label Extension Study of EFC12492, R727-CL-1112, EFC12732, & 
LTS11717 Studies to Assess the Long-Term Safety and Efficacy of 
Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia 
INVESTIGATOR/TRIAL LOCATION 
Multinational - Multicenter 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVES 
Primary objective 
x 
To assess the long-term safety of alirocumab when added to 
currently available lipid-modifying drug therapy in patients with 
heterozygous familial hypercholesterolemia (heFH) who have 
completed one of the following studies: EFC12492, R727-CL-1112, 
EFC12732 & LTS11717. 
Secondary objectives 
x 
To evaluate the long-term efficacy of alirocumab on lipid 
parameters.  
x 
To evaluate the long term immunogenicity of alirocumab. 
STUDY DESIGN 
This is a Phase 3, open-label extension (OLE), uncontrolled study. 
Patients must have been diagnosed with heFH in the parent study and have 
completed one of the four randomized, double-blind, 18-month parent studies. 
Patients who missed the last injection or who performed the end of treatment 
visit outside the expected timelines can also be enrolled. 
The end of treatment visit of the Double-Blind Treatment Period of the parent 
study corresponds to the visit 1 (Day 1) of the OLE study, except for the 
patients having participated in the LTS11717. These latter patients will have 
the opportunity to enter the OLE study, after they have completed the parent 
study, including the 8 week follow-up period. Patients who meet eligibility 
criteria at the visit 1 (Day 1) will receive a first SC injection of alirocumab on 
that day.  
All patients will receive 75 mg Q2W at entry into the OLE, with the exception 
of patients from EFC12732 (ODYSSEY High-FH). These latter patients, who 
had a screening LDL-C ≥160 mg/dL in the parent study, will hence receive 
150 mg Q2W at entry into the OLE, as in the parent study. 
At entry in the OLE (at visit 1 on Day 1): 
x 
All eligible patients from EFC12732 will get the alirocumab dose 
150 mg at Day 1.  
x 
All eligible patients from EFC12492, R727-CL-1112 and LTS11717 
will get 75 mg alirocumab.  
The first SC injection of alirocumab will be administered in the clinic (Day 1, 
Visit 1). Patients from the LTS11717 will have the possibility to perform a 
placebo self-injection training before the first alirocumab administration using 
an auto-injector on that same day (Day 1), as they used a different device (a 
prefilled syringe) in the parent study.  
From Visit 1, patients have the option to self-administer or have the study 
drug injection administered by another designated person (such as spouse, 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 4 
relative, etc.).  
From Day 1 (Visit 1) until Week 8 (first unblinded LDL-C value), neither the 
treatment received at the end of the double-blind treatment period in the 
parent study, nor the lipid parameters level, will be known by the Investigator, 
and by the patient, in order to prevent any potential blinding breaking of the 
parent clinical study. However, from Week 8 (Visit 3) in the OLE, the lipid 
values will be communicated to the investigator in real time.  
From Week 12 (Visit 4), the Investigator will be responsible, based on his/her 
own judgment and the patients’ LDL levels, to manage alirocumab dose (up-
titration from 75 to 150 mg every 2 weeks, down-titration from 150 to 75 mg 
every 2 weeks or maintenance of the dose, will be possible).  
Daily dose of statin or of other lipid-modifying therapy (LMT) (if applicable) 
can be modified based on the Investigator’s judgment throughout the study.  
After Week 24 (visit 5), visits will be scheduled every 24 weeks 
(approximately 6 months) and a dispensation visit will be scheduled in 
between the 24 weeks visits interval. This dispensation visit will allow to 
supply IMP for the next 3 months, and will also allow to check the treatment 
compliance, the concomitant medications, and occurrence of any adverse 
event. 
Patients should be on a stable diet (NCEP-ATPIII TLC diet or equivalent) 
throughout the entire study duration from visit 1 (V1) to the end of OLE 
treatment period (OLETP) (V17). 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
x 
Eligible patients for this OLE study will be men and women 
diagnosed with heFH in the parent study and who have completed 
one of the following studies, EFC12492, R727-CL-1112, EFC12732 
or LTS11717. Patients who missed the last injection or who 
performed the end of treatment visit outside the expected timelines 
can also be enrolled. 
 
Exclusion criteria 
x 
Significant protocol deviation in the parent study based on the 
Investigator judgment, such as non-compliance by the patient. 
x 
Adverse event leading to permanent discontinuation from parent 
study. 
x 
Have any new condition or worsening of existing condition which in 
the opinion of the Investigator would make the patient unsuitable for 
enrollment, or could interfere with the patient participating in or 
completing the study.   
x 
Positive pregnancy test at the end of treatment visit or end of study 
visit, according to the parent study the patient was originating from.  
x 
Women of childbearing potential not willing to continue highly-
effective method of birth control and/or who are unwilling or unable 
to be tested for pregnancy. 
Total expected number of patients 
Up to approximately 1,200 patients may be enrolled in the study. 
Expected number of sites 
Approximately 200 sites worldwide 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 5 
STUDY TREATMENT(s) 
 
Investigational medicinal product: 
alirocumab 
Formulation 
Sterile alirocumab drug product supplied at a concentration of 75 mg/mL and 
150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose, both as 1 mL 
volume in an auto-injector. 
Route of administration 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper 
arm. 
Dose regimen 
 
Injection for training: 
Formulation 
 
Route of administration 
75 mg every 2 weeks OR 
150 mg every 2 weeks 
Placebo  
Sterile solution consisting of histidine, pH 6.0, polysorbate 20, and sucrose, 
as 1 mL volume in an auto-injector. 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper 
arm 
ENDPOINTS 
The primary endpoint of this study is safety.  
Safety Endpoints: 
x 
Safety parameters (adverse events, laboratory data, vital signs) 
assessed throughout the OLE study. 
Efficacy Endpoints of interest include: 
x 
Calculated serum LDL-C values and percent changes from baseline 
of the parent study (EFC 12492, R727-CL-1112, EFC 12732 or 
LTS11717) over time in this study.  
x 
Proportion of patients achieving an LDL-C < 100 mg/dL (2.59 
mmol/l) over time in this study.  
x 
Proportion of patients achieving an LDL-C < 70 mg/dL (1.81 
mmol/L) over time in this study. 
 
x 
Proportion of patients with LDL-C <70 mg/dL (1.81 mmol/L) and/or 
≥50% reduction from baseline of the parent study in LDL-C (if LDL-
C ≥70 mg/dL [1.81 mmol/L]) over time in this study. 
x 
Values and percent changes from baseline of the parent study in 
other lipids and other lipoproteins, including total cholesterol, non-
high-density lipoprotein cholesterol (non-HDL-C), HDL-C, 
triglycerides (TGs), apolipoprotein (Apo) B, ApoA-1, ApoB/ApoA-1 
ratio and Lp(a) over time in this study.  
Other Endpoints: 
x 
Anti-alirocumab antibodies assessed throughout the study. 
x 
Proportion of patients who were up-titrated to 150 mg of alirocumab 
based on Investigator’s judgment.  
x 
Proportion of patients who were down-titrated to 75 mg of 
alirocumab based on Investigator’s judgment.  
x 
Reasons (ie, LDL-C threshold, AE) that trigger a down-titration or an 
up-titration of alirocumab. 
x 
EQ-5D summary scores.  
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 6 
ASSESSMENT SCHEDULE 
Patient assessments in the OLE period 
x 
Day 1 / Week 0 (End of treatment visit of the parent double-blind 
study = OLE Visit 1, except for the patients having participated in 
the LTS11717). 
x 
Complete study visits: Patients will be assessed in the clinic at 
Weeks 4 (Visit 2), 8 (Visit 3), 12 (Visit 4), 24 (Visit 5), and then 
every 24 weeks until EOT Visit (Visit 17), or early termination.  
x 
IMP dispensing visits: From Week 24, until study completion IMP 
dispensing visits will be scheduled every 12 weeks, in-between the 
clinic visits in order to allow for dispensing IMP. 
Patient assessments in the FU period 
x 
A follow up call, Visit 18, will be planned 10 weeks after the last IMP 
injection, ie 8 weeks after the EOT visit, for the patients who will 
complete the study and for the patients who will early discontinue 
whatever the reason. 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
As this study is an open-label extension planning to include patients from 
previous studies, no calculation for sample size was performed. It is expected 
to enroll up to 1,200 heFH patients based on the number of patients already 
enrolled in the parent studies.  
Analysis Population: 
Safety analyses will be performed on Safety population which consists of 
patients receiving at least one dose or partial dose of IMP in the current study. 
Efficacy analyses will be performed on patients receiving at least one dose or 
partial dose of IMP in the current study, with a baseline (from parent study) 
LDL-C available and with at least one LDL-C value available in the period 
from first IMP injection in the current study to last IMP injection + 21 days.  
Analysis of safety endpoints: 
Safety analysis (Adverse events, laboratory, vital signs) will be descriptive, 
based on the safety population. The safety analysis will focus on the 
Treatment Emergent Adverse Events (TEAE) period defined as the time from 
the first dose of the current study to the last dose of IMP + 70 days (10 
weeks).  
For analyses of changes from baseline for laboratory and vital signs 
parameters, baseline of the parent study or of the current study may be 
considered. 
Efficacy parameters: 
As secondary objectives of the study, efficacy variables will be explored 
through descriptive statistics at each scheduled visit of the current study. 
Formal statistical testing is not planned and alpha adjustments not needed. 
95% confidence intervals will be provided for percent changes from baseline 
and success rate to reach targets.  
In addition, percent changes from baseline of the parent study and success 
rate to reach targets from the week 8 time point will also be analyzed in all 
groups combined as the influence of treatment received during the parent 
study should be offset by the treatment received during the current study after 
8 weeks of treatment. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 7 
DURATION OF STUDY PERIOD (per 
patient)  
Study will end in second quarter 2017 or until the drug is commercially 
available for the patient in the respective country, whatever comes first.  
The study duration includes up to 168 weeks of treatment, ie approximately 
3.5 years, for the first patients enrolled, and an additional 8 week follow up 
safety period for the patients who will complete the study and for the patients 
who will early discontinue whatever the reason. For patients in the UK, the 
study will last a maximum of 176 weeks. 
STUDY COMMITTEES 
Data Monitoring Committee: 
 Yes    
 No 
The independent Data Monitoring Committee (DMC) is implemented in order 
to monitor patient safety by conducting formal reviews of accumulated safety 
data.  The DMC will provide the Sponsor with appropriate recommendations 
on the conduct of the clinical trial to ensure the protection and the safety of 
the enrolled patients in the study.   
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 8 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
(electronic 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 9 
1.2 
STUDY FLOW CHART   
 
Day (D)/Week (W)/ Month (M)  
W0    (End of 
DB 
treatment 
visit parent 
study)c (D1) 
W 4 
W 8  
W 
12 
W 
24 
W 
36 
W 
48  
W 
60 
W 
72 
M18 
W 
84 
W 
96 
M24 
W 
108 
W 120 
M30 
W 
132 
W 
144 
M36 
W 
156 
W 168 
EOT 2Q 
2017 
M40 
W176 
EOS 
Call***  
Visit Number 
1 
2 
3 
4 
5 
6* 
7 
8* 
9 
10* 
11 
12* 
13 
14* 
15 
16* 
17 
18 
Visit Window (days) 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demography  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Body weight 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
IVRS/IWRS contact 
Xa 
 
 
X 
 X 
X 
X 
X 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection at site 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of diet 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
Investigational Medicinal 
Product (IMP) kit dispensation 
Xa 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Compliance check of IMP 
(review patient diary e and 
treatment kit) and data 
collection on IMP administration 
X 
(diary a)  
X 
(diary 
only) 
X 
(diary 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 10 
Day (D)/Week (W)/ Month (M)  
W0    (End of 
DB 
treatment 
visit parent 
study)c (D1) 
W 4 
W 8  
W 
12 
W 
24 
W 
36 
W 
48  
W 
60 
W 
72 
M18 
W 
84 
W 
96 
M24 
W 
108 
W 120 
M30 
W 
132 
W 
144 
M36 
W 
156 
W 168 
EOT 2Q 
2017 
M40 
W176 
EOS 
Call***  
Visit Number 
1 
2 
3 
4 
5 
6* 
7 
8* 
9 
10* 
11 
12* 
13 
14* 
15 
16* 
17 
18 
Visit Window (days) 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Vital signs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Heart rate, blood pressure 
X 
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 
X 
X 
X 
X 
X 
X 
Central Laboratory Testing – 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total-C, calculated LDL-C, 
HDL-C, TG, non-HDL-C 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Apo B, Apo A-1, ratio Apo B / 
Apo A-1, and Lp (a) 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Laboratory Testing – Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Hematology and 
chemistry 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Central Creatine phosphokinase 
(CPK) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Central Liver panel 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Local Urine pregnancy test 
Xb 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
(electronic 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 11 
Day (D)/Week (W)/ Month (M)  
W0    (End of 
DB 
treatment 
visit parent 
study)c (D1) 
W 4 
W 8  
W 
12 
W 
24 
W 
36 
W 
48  
W 
60 
W 
72 
M18 
W 
84 
W 
96 
M24 
W 
108 
W 120 
M30 
W 
132 
W 
144 
M36 
W 
156 
W 168 
EOT 2Q 
2017 
M40 
W176 
EOS 
Call***  
Visit Number 
1 
2 
3 
4 
5 
6* 
7 
8* 
9 
10* 
11 
12* 
13 
14* 
15 
16* 
17 
18 
Visit Window (days) 
 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
±7 
Laboratory Testing – Other 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central Anti-alirocumab 
antibodies** 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Quality of Life Variables 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EQ-5D patient questionnaire  
Xa 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
a. 
Investigations to be performed specifically for the entry in OLE at Day 1 (Visit 1) in addition to all investigations planned to be performed during the End of Double-Blind treatment visit of the parent study or 
for patients from the LTS11717, the visit V1 (Day 1) of the OLE study can occur at the time of the end of study visit, after the 8-week follow-up period. 
b. 
Pregnancy status should be checked by urine pregnancy testing on the Day 1 at visit 1 and during the OLE period. 
c. 
The end of treatment period visit of the Double-Blind parent study corresponds to the visit V1 (Day 1) of the OLE study, except for patient having participated in the LTS11717. These latter patients will have 
the opportunity to enter in the OLE study, after they have completed the parent study, including the 8-week follow-up period. For these patients, the visit V1 (Day 1) of the OLE study can occur at the time of 
the end of study visit, after the 8-week follow-up period. 
d. 
 
e. 
It is recommended a new diary to be dispensed to the patient at each visit starting from week 24, so that the compliance could be effectively checked at each visit 
*  
These visits are mainly dispensing visits 
**  Anti-alirocumab antibodies collections are to be done prior to the IMP injection, except for the EOT visit where no IMP injection is done.  
*** A follow-up safety call will be done 10 weeks after the last injection of alirocumab in case of premature discontinuation and for the patients who complete the study (see section 10.3.4). 
 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 12 
2 
TABLE OF CONTENTS 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART ....................................................................................................................9 
2 
TABLE OF CONTENTS ................................................................................................................12 
3 
LIST OF ABBREVIATIONS ..........................................................................................................17 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
5 
STUDY OBJECTIVES ...................................................................................................................24 
5.1 
PRIMARY.......................................................................................................................................24 
5.2 
SECONDARY ................................................................................................................................24 
6 
STUDY DESIGN ............................................................................................................................25 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................25 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................26 
6.2.1 
Duration of study participation for each patient .............................................................................26 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................27 
6.3 
INTERIM ANALYSIS......................................................................................................................27 
6.4 
STUDY COMMITTEE ....................................................................................................................27 
7 
SELECTION OF PATIENTS..........................................................................................................28 
7.1 
INCLUSION CRITERIA..................................................................................................................28 
7.2 
EXCLUSION CRITERIA ................................................................................................................28 
7.2.1 
Exclusion criteria related to study methodology ............................................................................28 
7.2.2 
Exclusion criteria related to the background therapies..................................................................28 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................28 
8 
STUDY TREATMENTS .................................................................................................................30 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................30 
8.1.1 
Route and method of administration..............................................................................................30 
8.1.2 
Timing of administration.................................................................................................................31 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS....................................................................32 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 13 
8.3 
BLINDING PROCEDURES............................................................................................................32 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................32 
8.5 
PACKAGING AND LABELING ......................................................................................................32 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................33 
8.7 
RESPONSIBILITIES ......................................................................................................................33 
8.7.1 
Treatment accountability and compliance......................................................................................33 
8.7.2 
Return and/or destruction of treatments ........................................................................................34 
8.8 
CONCOMITANT MEDICATION.....................................................................................................34 
8.8.1 
Management of background lipid-modifying therapy.....................................................................34 
8.8.2 
Contraception.................................................................................................................................35 
8.8.3 
Prohibited concomitant medications ..............................................................................................35 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................36 
9.1 
PRIMARY SAFETY ENDPOINTS..................................................................................................36 
9.1.1 
Adverse events ..............................................................................................................................36 
9.1.2 
Safety laboratory............................................................................................................................37 
9.1.3 
Vital signs measurement................................................................................................................37 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................37 
9.2.1 
Efficacy endpoints..........................................................................................................................37 
9.2.2 
Efficacy assessment method .........................................................................................................38 
9.3 
OTHER ENDPOINTS.....................................................................................................................38 
9.3.1 
Anti-alirocumab antibody assessment ...........................................................................................38 
9.3.1.1 
Sampling time ................................................................................................................................38 
9.3.1.2 
Sampling procedure.......................................................................................................................38 
9.3.1.3 
Bioanalytical method......................................................................................................................38 
9.3.2 
EQ-5D patient questionnaire..........................................................................................................39 
9.3.3 
Other exploratory endpoints...........................................................................................................39 
9.3.3.1 
Up-titration assessment .................................................................................................................39 
9.3.3.2 
Down-titration assessment.............................................................................................................39 
10 
STUDY PROCEDURES ................................................................................................................40 
10.1 
VISIT SCHEDULE..........................................................................................................................42 
10.1.1 
Open-label Treatment Period.........................................................................................................42 
10.1.1.1 Initial Visit: Visit 1 (Visit 1/Week 0/Day 1) ......................................................................................42 
10.1.1.2 Visit 2/ Week 4 (Day 29 ± 7) ..........................................................................................................45 
10.1.1.3 Visit 3/ Week 8 (Day 57 ± 7) ..........................................................................................................46 
10.1.1.4 Visit 4/ Week 12 (Day 85 ± 7) ........................................................................................................46 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 14 
10.1.1.5 Visit 5/ Week 24 (Day 169 ± 7) ......................................................................................................47 
10.1.1.6 Visit 6/ Week 36 (Day 253 ± 7) ......................................................................................................48 
10.1.1.7 Visit 7/ Week 48 (Day 337 ± 7) ......................................................................................................48 
10.1.1.8 Visit 8/ Week 60 (Day 421 ± 7) ......................................................................................................49 
10.1.1.9 Visit 9/ Week 72/ Month 18 (Day 505 ± 7) .....................................................................................49 
10.1.1.10 Visit 10/ Week 84 (Day 589 ± 7) ....................................................................................................50 
10.1.1.11 Visit 11/ Week 96 / Month 24 (Day 673 ± 7) ..................................................................................51 
10.1.1.12 Visit 12/ Week 108 (Day 757 ± 7) ..................................................................................................51 
10.1.1.13 Visit 13/ Week 120/ Month 30 (Day 841 ± 7) .................................................................................52 
10.1.1.14 Visit 14/ Week 132 (Day 925 ± 7) ..................................................................................................52 
10.1.1.15 Visit 15/ Week 144/ Month 36 (Day 1009 ± 7) ...............................................................................53 
10.1.1.16 Visit 16/ Week 156 (Day 1093 ± 7) ................................................................................................54 
10.1.1.17 End-of-treatment visit: Visit 17/ Week 168/ Month 40 (Day 1177± 7)............................................54 
10.1.2 
Post-treatment Follow up period.....................................................................................................55 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................55 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................56 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................56 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................57 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................57 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................57 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................58 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................58 
10.4.1 
Definitions of adverse events.........................................................................................................58 
10.4.1.1 Adverse event ................................................................................................................................58 
10.4.1.2 Serious adverse event ...................................................................................................................58 
10.4.1.3 Adverse event of special interest...................................................................................................59 
10.4.2 
General guidelines for reporting adverse events ...........................................................................59 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................60 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................61 
10.4.4.1 AESI with immediate notification:...................................................................................................61 
10.4.4.2 AESI without immediate notification:..............................................................................................62 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................63 
10.4.5.1 Hemoglobin decrease ....................................................................................................................63 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................64 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................64 
10.6.1 
Local tolerability (Local Injection Site Reactions) ..........................................................................64 
10.6.2 
Allergic adverse events..................................................................................................................64 
10.6.2.1 Allergic events with cutaneous involvement ..................................................................................65 
10.6.2.2 Acute allergic Injection Reactions..................................................................................................66 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 15 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................66 
11 
STATISTICAL CONSIDERATIONS..............................................................................................67 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................67 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................67 
11.3 
ANALYSIS POPULATIONS...........................................................................................................67 
11.3.1 
Safety population ...........................................................................................................................67 
11.3.2 
Efficacy population.........................................................................................................................67 
11.3.2.1 Modified Intent–to-treat population ................................................................................................67 
11.3.3 
Other analysis population ..............................................................................................................67 
11.4 
STATISTICAL METHODS .............................................................................................................68 
11.4.1 
Extent of alirocumab exposure and compliance ............................................................................68 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................68 
11.4.1.2 Compliance ....................................................................................................................................68 
11.4.2 
Analyses of safety endpoints .........................................................................................................69 
11.4.2.1 Adverse events ..............................................................................................................................70 
11.4.2.2 Laboratory data and vital signs......................................................................................................70 
11.4.3 
Analyses of efficacy data ...............................................................................................................71 
11.4.4 
Analyses of other endpoints...........................................................................................................71 
11.4.4.1 Analyses of quality of life/health economics variables...................................................................72 
11.5 
INTERIM ANALYSIS......................................................................................................................72 
12 
ETHICAL AND REGULATORY STANDARDS.............................................................................73 
12.1 
ETHICAL PRINCIPLES .................................................................................................................73 
12.2 
LAWS AND REGULATIONS .........................................................................................................73 
12.3 
INFORMED CONSENT .................................................................................................................73 
12.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............73 
13 
STUDY MONITORING...................................................................................................................75 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................75 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................75 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................76 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................76 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................76 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 16 
14 
ADMINISTRATIVE EXPECTATIONS ...........................................................................................77 
14.1 
CURRICULUM VITAE....................................................................................................................77 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................77 
14.3 
CONFIDENTIALITY .......................................................................................................................77 
14.4 
PROPERTY RIGHTS.....................................................................................................................78 
14.5 
DATA PROTECTION.....................................................................................................................78 
14.6 
INSURANCE COMPENSATION....................................................................................................79 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................79 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................79 
14.8.1 
Decided by the Sponsor.................................................................................................................79 
14.8.2 
Decided by the Investigator ...........................................................................................................80 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................80 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................80 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................81 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................82 
17 
APPENDICES................................................................................................................................84 
APPENDIX A 
SUMMARY OF TLC DIET FOR HIGH CHOLESTEROL.....................................................85 
APPENDIX B 
SUMMARY OF ADVERSE EVENT REPORTING INSTRUCTIONS ..................................86 
APPENDIX C GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................88 
APPENDIX D GUIDELINES FOR HEMOGLOBIN (HB) DECREASE 1.5 G/DL......................................93 
APPENDIX E 
EQ-5D PATIENT QUESTIONNAIRE...................................................................................94 
APPENDIX F ASSESSMENT OF LOCAL INJECTION SITE REACTIONS ..............................................95 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 17 
3 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AI 
auto-injector 
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 
CBC 
complete blood count 
CHD 
coronary heart disease  
CI 
confidence interval 
CIB 
clinical Investigator's brochure 
CPK 
creatine phosphokinase 
CRO 
contract research organization 
CSR 
clinical study report  
CT 
computed tomography  
CVD 
cardiovascular disease 
DBTP 
double blind treatment period 
DM 
diabetes mellitus 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DRF 
discrepancy resolution form 
ECG 
electrocardiogram 
eg 
exempli gratia = for example 
e-SMS 
emergency scientific & medical services  
e-CRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate  
EDTA 
ethylene diamine tetra-acetic acid  
ELISA 
enzyme linked immuno-sorbent assay  
EOS 
end of Study 
EOT 
end of Treatment 
FH 
familial hypercholesterolemia 
FPI 
first patient in 
FU 
follow-up 
GCP 
good clinical practice 
ȖGT 
gamma-glutamyl transferase 
Hb 
hemoglobin  
HDL-C 
high density lipoprotein cholesterol 
heFH 
heterozygous familial hypercholesterolemia 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 18 
HLGT 
high level group term 
HLT 
high level term 
HR 
heart rate 
HRQoL 
health-related quality of life 
hs-CRP 
high-sensitivity C-reactive protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonization  
ie 
id est = that is 
IEC 
independent ethics committee 
INN 
international nonproprietary name  
IMP 
investigational medicinal product  
IRB 
institutional review board 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS 
interactive voice response system  
IWRS 
interactive web response system  
Kg 
kilogram 
LDH 
lactate dehydrogenase 
LDL-C 
low-density lipoprotein cholesterol  
LDL-R  
low-density lipoprotein receptor  
LLN 
lower limit of normal range 
LLT 
lowest Level Term 
LMT 
lipid-modifying therapy 
LPI 
last patient in 
LOCF 
last-observation-carried-forward 
Lp(a) 
lipoprotein a 
MDRD 
modification of diet in renal disease 
MedDRA 
medical dictionary for regulatory activities 
μg 
microgram 
mITT 
modified intent-to-treat  
mmHg 
millimeter of mercury 
MTD 
maximally tolerated dose 
NCEP-ATPIII 
National Cholesterol Education Program Adult Treatment Panel III  
NIMP 
non investigational medicinal product 
OLE 
open label extension 
OLETP 
open label extension treatment period 
PAD 
peripheral arterial disease 
PCSA 
potentially clinically significant abnormality 
PCSK9 
proprotein convertase subtilisin/kexin type 9 
PD 
pharmacodynamics 
PDM 
project demand manager 
PT 
preferred term 
PTC 
product technical complaint 
Q2W 
every 2 weeks 
RDW 
red blood cell distribution width 
SAE 
serious adverse event  
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 19 
SAP 
statistical analysis plan  
SC 
subcutaneous 
SD 
standard deviation 
SMQ 
standardized MedDRA query 
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 
ULN 
upper limit of normal range  
WBC 
white blood cell 
WHO-DD 
World Health Organization-Drug Dictionary 
WOCBP 
women of childbearing potential 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 20 
4 
INTRODUCTION AND RATIONALE 
SAR236553 is a fully human monoclonal antibody that binds with high affinity to PCSK9. Its 
International Nonproprietary Name (INN) is alirocumab. Alirocumab was previously referred as 
SAR236553 or REGN727. All relevant information concerning the compound is available in the 
latest version of the Clinical Investigator’s Brochure (CIB). 
Background on patient populations: 
This open-label extension study will include patients diagnosed with heterozygous familial 
hypercholesterolemia (heFH) who have completed EFC12492, R727-CL-1112, EFC12732 or 
LTS11717.  
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism that predisposes a 
person to premature severe cardiovascular disease (CVD).  Familial hypercholesterolemia has a 
high prevalence in Caucasian populations, where an estimated 1 in 500 individuals are affected.  
Defects in at least 3 different genes that code for proteins involved in hepatic clearance of low 
density lipoprotein-cholesterol (LDL-C) can cause FH.  These include mutations in the gene 
coding for the LDL receptor (LDL-R) that removes LDL-C from the circulation, and less 
commonly, in the gene for Apo B, which is the major protein of the LDL particle.  In rare cases, 
the gene coding for proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme involved in 
degrading the LDL-R (gain of function mutation), is mutated.  In all cases, this results in an 
accumulation of LDL-C in the plasma from birth, and subsequent development of tendon 
xanthomas, xanthelasmas, atheromata, and premature CVD. 
In the heterozygous form of FH (heFH), the cumulative risk of experiencing a coronary event by 
the age of 60 years without effective treatment is at least 50% in men and approximately 30% in 
women (coronary disease occurs approximately 10 years later in women than in men, with a 
marked increase in post-menopausal women).  Before effective treatment with 3-hydroxy-3-
methyl-glutaryl-CoA reductase inhibitors (commonly referred to as statins) became available, 
mortality from coronary disease was increased by nearly 100 fold in young FH adults aged 20 to 
39 years, and approximately 4 fold for FH patients aged 40 to 59 years (1). 
In the real world, a large proportion of patients with FH do not reach treatment goals and, by 
consequence, remain at increased risk of CVD (2). In a recent large cross-sectional study 
conducted in the Netherlands, nearly all heterozygous FH patients (96%) were on statin treatment. 
Only 21% of patients achieved the LDL-C goal of less than 100 mg/dL (less than 2.59 mmol/L) 
and about 5% of patients still had an LDL-C concentration greater than 200 mg/dL. Among those 
not at goal, 27% were on combination therapy of maximum statin dose and ezetimibe (3). These 
data emphasize the need for new LDL-lowering therapies. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 21 
Introduction to proprotein convertase subtilisin kexin type 9 (PCSK9) and alirocumab: 
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 (4) (5). Once PCSK9 is secreted into plasma, it 
directly binds to the LDL-R and promotes its degradation. The increased degradation of LDL-Rs 
leads to a reduced removal of LDL particles -C and therefore, higher circulating levels of LDL-
C.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 (6), (7). 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 
coronary heart disease (CHD), whereas loss-of-function mutations are more common and are 
associated with reduced plasma levels of LDL-C and protection from CHD (8) (9).  
Therefore, blocking PCSK9 from 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 (10). 
Rationale for study design: 
The objective of the present study is to provide additional long term safety and efficacy 
experience with alirocumab in a closer to real life setting than a double-blind design study, in 
patients with heFH receiving lipid-modifying drug therapy including statins.  
Patients with heFH who cannot attain LDL-C goal despite lipid-modifying therapy, including a 
statin at maximally tolerated dose, present a high unmet need regarding their life-long increased 
cardiovascular risk.  This study gives these heFH patients, who already participated in one of the 
double-blind 18-month ODYSSEY Phase 3 studies, the possibility to start or continue treatment 
with alirocumab after the end of the parent study. All patients will receive alirocumab at entry in 
the open-label extension study regardless of the study treatment they received during the 18-
month double-blind treatment period of the parent study, provided they fulfill the eligibility 
criteria of the open-label extension study. 
Description of the parent studies: 
The study design of the four concerned parent studies was similar: Phase 3, 18-month treatment 
duration, randomized, double-blind, placebo controlled, parallel-group, multi-national, multi-
center study. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 22 
They are briefly described in the table below. 
 
Studies 
EFC12492 
ODYSSEY FH I  
R727-CL-1112 
ODYSSEY FH II  
EFC12732 
ODYSSEY High FH  
LTS11717 
ODYSSEY Long Term  
Patient population 
enrolled 
Patients diagnosed with heFH, not adequately controlled with a maximally tolerated daily dose 
(MTD) of statin, stable for at least 4 weeks prior to the screening visit, with or without other lipid 
modifying therapy (LMT) 
Screening LDL-C at 
entry 
(mg/dL)  
≥ 70 with a history of documented 
cardiovascular disease  
≥ 100 without history of documented 
cardiovascular disease 
≥ 160  
≥ 100 
(then ≥ 70, as per 
amendment 3, for 
about 10% of the heFH 
enrolled patients) 
With or without 
documented 
cardiovascular disease 
Sample size  
(heFH patients 
actually randomized 
in the parent study) 
486 
249 
107 
385 
(about 20% of all 
enrolled patients) 
Placebo or 
alirocumab dose at 
entry in parent study 
Q2W 
75 mg  
150 mg 
Double-blind 
treatment period 
duration 
18 months 
Background LMT 
MTD* statin (atorvastatin, rosuvastatin, simvastatin) 
+/- other LMT 
*  Definition of Maximally Tolerated Dose (any of the following are acceptable): 
-  Rosuvastatin 20 mg or 40 mg daily 
-  Atorvastatin 40 mg or 80 mg daily 
-  Simvastatin 80 mg daily (if already on this dose for >1 year) 
-  Patients not able to be on any of the above statin doses should be treated with the daily dose of atorvastatin, 
rosuvastatin or simvastatin which is considered appropriate for the patient as per the investigator's judgment 
or concerns. Some examples of acceptable reasons for a patient taking a lower statin dose include, but are 
not limited to: adverse effects on higher doses, advanced age, low body mass index, regional practices, local 
prescribing information, concomitant medications, co-morbid conditions such as impaired glucose 
tolerance/impaired fasting glucose. The reason(s) will need to be documented in the case report form. 
Rationale for dose selection: 
Two doses of alirocumab are currently being evaluated in the ODYSSEY Phase 3 program: 75 mg 
and 150 mg, to be administered subcutaneously every 2 weeks (Q2W), based on data from the 
Phase 1 and 2 programs. However, for many patients, the magnitude of effect observed with the 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 23 
150 mg Q2W dose may not be needed to achieve the target LDL-C goal, and starting with a lower 
dose may be undertaken.  
From the range of Q2W doses tested in the alirocumab Phase 2 program, 75 mg Q2W has been 
selected to be investigated in the Phase 3 program by employing the use of a dose response model. 
Most patients participating in the double-blind Phase 3 trials have initially been treated with 75 
mg Q2W and only those patients whose LDL-C levels remain above goal after 8 weeks of 
treatment are up-titrated to 150 mg Q2W (at week 12) in this initial double-blind treatment period.  
Only patients who are participating in two studies, LTS11717 and EFC12732 were initiated with 
150 mg Q2W. In the LTS11717 study, the aim was to provide the highest systemic exposure to 
alirocumab, in order to gather adequate safety and tolerability information at this dose; EFC12732 
only included patients with a LDL-C level above 160 mg/dL (4.14 mmol/L) while receiving 
maximal tolerated statin: the aim was to assess the benefit from starting directly at the most 
effective dose in this specific population of patients who need large LDL-C decrease.  
In the OLE study, patients will start treatment with 75 mg Q2W, regardless of the treatment / dose 
they received at the end of the parent study, except patients from EFC12732. These latter patients, 
who had a screening LDL-C  160 mg/dL in the parent study, will receive 150 mg Q2W at entry 
into the OLE. Based on LDL-C value that will be unblinded from Week 8, the treatment dose can 
be up-titrated to 150 mg Q2W for patients receiving 75 mg Q2W or down-titrated to 75 mg Q2W 
for patients receiving 150 mg Q2W from Week 12 as needed. In order to maintain the blind in the 
parent study, which will still be ongoing at the time the first patients are included in the OLE, no 
information will be available on the treatment / dose received at the end of the parent study, nor 
on LDL-C level at the end of the parent study / baseline of the OLE.  
Brief description of the OLE study: 
Depending on the parent study the patient participated in, either 75 mg or 150 mg every 2 weeks 
will be administered at the entry in the OLE study.   
From Week 12 (Visit 4), based on the Investigator judgment and the LDL-C level unblinded from 
Week 8, dose adjustment, such as up-titration to 150 mg Q2W or down-titration to 75 mg Q2W of 
alirocumab, will be possible. It is anticipated that in real life, after initial up-titration, subsequent 
dose adjustment over time may include down-titration. This will be allowed in this study, and the 
Investigator will be asked to report the reason for down-titration from 150 to 75 mg Q2W and for 
up-titration from 75 mg to 150 mg Q2W. 
Taking into consideration the current number of patients enrolled in the four parent studies, it is 
estimated that up to approximately 1,200 patients could be enrolled. 
This open-label extension study will be conducted for approximately three additional years or 
more, depending on the inclusion date in the current study, after the 18-month double-blind 
treatment period of the parent studies.  
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 24 
5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to assess the long-term safety of alirocumab when added to 
currently available lipid-modifying drug therapy, in patients diagnosed with heterozygous 
Familial Hypercholesterolemia who have completed one of the four parent studies. 
5.2 
SECONDARY 
The secondary objectives of this study are 
x 
To evaluate the long-term efficacy of alirocumab on lipid parameters 
x 
To evaluate the long-term immunogenicity of alirocumab 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 25 
6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a multicenter, multinational, Phase 3, open-label extension, uncontrolled study to assess 
the long-term safety and efficacy of alirocumab, when added to currently available LMT, in heFH 
patients previously participating in the ODYSSEY FH I, ODYSSEY FH II, ODYSSEY High FH 
or ODYSSEY Long Term studies.  
Patients must have been diagnosed with heFH in the parent study, have completed one of the 
above parent studies, and be willing to participate in the ODYSSEY OLE study. Patients who 
missed the last injection or who performed the end of treatment visit outside the expected 
timelines can also be enrolled. 
The visit 1 (Day 1) of the ODYSSEY OLE study corresponds to: 
x the end of treatment visit of the Double-Blind Treatment Period for the patients enrolled in 
one of the three following parent studies ODYSSEY FH I, ODYSSEY FH II, ODYSSEY 
High FH. 
x the end of study visit, after the 8 week follow-up period, for the patients having 
participated in the ODYSSEY Long Term study. 
Patients who meet eligibility criteria at the visit 1 (Day 1) will receive the first SC injection of 
alirocumab in the clinic on the same day.  
In addition, patients from the ODYSSEY Long Term study will have the possibility to perform a 
placebo, self-injection training, before the first alirocumab administration using an auto-injector 
on that same day (Day 1), as they used a different device (a prefilled syringe) in the parent study.  
At entry in the ODYSSEY OLE study, visit 1 on Day 1: 
x All eligible patients from ODYSSEY High FH will get the alirocumab 150 mg dose. 
x All eligible patients from ODYSSEY FH I, ODYSSEY FH II and ODYSSEY Long Term 
will get alirocumab 75 mg.  
From Week 12 (Visit 4), the Investigator will manage, based on his/her own judgment and LDL-C 
values, adjustment of alirocumab doses (either up-titration from 75 to 150 mg every 2 weeks or 
down-titration from 150 to 75 mg every 2 weeks, or maintenance of the dose, will be possible).   
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 26 
The study consists of: 
x 
An open-label treatment period with alirocumab of up to 168 weeks, ie approximately 3.5 
years, for the first patients enrolled, or until the product becomes commercially available 
for the patient in the country, whatever comes first. 
x 
A post-treatment safety follow up period of 10 week-duration after last IMP injection for 
all the patients, the patients who will complete the study and the patients who will early 
discontinue whatever the reason.  
Although the background therapies, statin at MTD or other LMT (if applicable), should be 
maintained stable if possible, they might be adjusted based on Investigator judgment, in particular 
in case of tolerability issue. The reasons of any adjustment should be documented and recorded in 
the e-CRF. 
For adjustments based on LDL-C values, simultaneous adjustments in alirocumab dose and any 
LMT should be avoided.   
Patients will be asked to continue to follow a stable diet (equivalent to the National Cholesterol 
Education Program Adult Treatment Panel III Therapeutic Lifestyle Changes (NCEP ATP III 
TLC) during the study.  
Patients will return for regular on site visits according to the flow chart for additional laboratory 
testing, questionnaires, clinical examination and IMP dispensation. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The OLE study is planned to be completed in second quarter 2017 which corresponds to a study 
duration of approximately 168 weeks for the first patients enrolled or until the drug is 
commercially available for the patient in the respective country, whatever comes first. For patients 
in the UK, the study will last a maximum of 176 weeks.  
The study duration includes up to approximately 3.5 years of treatment for the first patients 
enrolled, and 10 weeks of follow up after the last IMP injection for all the patients, those who will 
complete the study and those who will early discontinue whatever the reason. 
The study will be considered as completed for a patient in the following situations: 
x 
When the alirocumab is commercially available in the patient’s country 
x 
In second quarter 2017, if alirocumab is not yet commercially available in the patient’s 
country  
An EOT visit will be done 2 weeks after the last IMP injection and a safety follow up call 10 
weeks after the last IMP injection. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 27 
The following situations will be considered as premature discontinuation of the patient from the 
study: 
x 
Any withdrawal from the study to switch to an anti-PCSK9 inhibitor different from 
commercial alirocumab 
x 
Any other reason 
An unscheduled visit should take place within 5 days after the last IMP administration if possible, 
with assessments normally planned at the EOT visit, and a safety follow up call performed 10 
weeks after the last IMP injection (see section 10.3.4). 
The end of study per patient is the last protocol planned call. Patients with a Serious Adverse 
Events (SAEs) or an Adverse Event of Special Interest (AESI) should be followed until 
resolution, stabilization, or death.  
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is scheduled to be in second quarter 2017, including in the UK, which 
corresponds to the last protocol planned call of the last patient.  
6.3 
INTERIM ANALYSIS 
Interim analyses might be performed if requested by Health Authorities or if needed for the 
purpose of scientific communication. 
6.4 
STUDY COMMITTEE 
Data Monitoring Committee: 
An independent Data Monitoring Committee (DMC), composed of members who are independent 
from the Sponsor and the study Investigators, is implemented in order to monitor patient safety by 
conducting formal reviews of accumulated safety data. The DMC will provide the Sponsor with 
appropriate recommendations on the conduct of the clinical trial to ensure the protection and 
safety of the patients enrolled in the study.  
All activities and responsibilities of the DMC are described in the DMC charter. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 28 
7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Eligible patients for this OLE study will be patients diagnosed with heFH in the parent 
study and who have completed one of them: ODYSSEY FH I, ODYSSEY FH II, 
ODYSSEY High FH or ODYSSEY Long Term studies. Patients who missed the last 
injection or who performed the end of treatment visit outside the expected timelines can 
also be enrolled. 
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted into the following 3 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. Significant protocol deviation in the parent study based on the Investigator judgment, such 
as non-compliance by the patient 
E 02. Any patient who experienced an adverse event leading to permanent discontinuation from 
parent study 
E 03. Patients having any new condition or worsening of existing condition which in the opinion 
of the Investigator would make the patient unsuitable for enrollment, or could interfere 
with the patient participating in or completing the study   
E 04. Patients who will be prescribed fibrates, other than fenofibrate 
7.2.2 Exclusion criteria related to the background therapies  
E 05. All contraindications to the background therapies or warnings/precautions of use (when 
appropriate) as displayed in the respective National Product Labeling 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab   
E 06. Known hypersensitivity to monoclonal antibody or any component of the drug product 
E 07. Positive pregnancy test at last visit of the parent double-blind study (Day 1, Visit 1) 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 29 
E 08. Women of childbearing potential not willing to continue 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 Visit 1 
at entry in the OLE. They must use an effective contraceptive method throughout the entire 
duration of the study treatment, and for 10 weeks after the last injection of IMP, and agree to 
repeat urine pregnancy test at designated visits. The applied methods of contraception have to 
meet the criteria for a highly effective method of birth control according to the “Note for guidance 
on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals 
(CPMP/ICH/286/95)” (11).  
Postmenopausal women must be amenorrheic for at least 12 months. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 30 
8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
Sterile alirocumab drug product will be supplied at a concentration of 75 mg/mL and 150 mg/mL 
in histidine, pH 6.0, polysorbate 20, and sucrose, both as 1 mL volume in an auto-injector (AI). 
Unlike the patients from the other studies, the patients from the ODYSSEY Long Term study used 
a different device (a prefilled syringe) in the parent study, and thus will have the possibility to 
perform on Visit 1 (Day 1) a placebo, self-injection training, using an auto-injector, before the 
first alirocumab administration.  
Injection for training: Sterile placebo for alirocumab will be prepared in the same formulation as 
alirocumab without the addition of protein as 1 mL volume in an auto-injector, for those patients 
willing to perform injection training. 
Note: Only in the event the manufacturer faces any performance or supply issues of the auto-
injector, contingency alternatives are the following ones, in order to ensure the continuity of the 
study treatment without interruption: 
x In case of disruption of the 150 mg auto-injector, and the use of 75 mg auto-injectors is 
maintained: 
- 
patients receiving the 150 mg dose will need to administer 2 injections of 75 mg as 1 
mL each in an auto-injector, 
OR 
- 
patients will be switched to the use of prefilled syringes of 150 mg, with one injection 
of 1 mL.  
x In case of disruption of either 75 mg or both auto-injectors, patients will be switched to the 
use of prefilled syringes of 75 mg and 150 mg, with one injection of 1 mL for each of 
these doses. 
Should this occur, the alternative investigational medicinal product 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, in particular for the patients having participated in the 
ODYSSEY Long Term study, for which the device was a prefilled syringe. Also, an 
administration package containing gauzes, alcohol swabs, band aids, etc. will be provided to the 
patients. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 31 
The IMP could be administered by self-injection or by another designated person (such as a 
spouse, relative, etc…). The used auto-injector will be discarded in a sharps container which will 
be provided to patients. It is recommended that the subcutaneous IMP injections be rotated within 
an anatomical area (eg, right thigh then left thigh or right abdomen then left abdomen). Patients 
also have the option to inject in a different anatomical area (eg, thigh then abdomen) during the 
study. 
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 another designated person 
[such as spouse, relative, etc...] that will administer the injections) at training and as needed 
during the course of the study. Close supervision and feedback should be given at the first visit, 
and other visits as needed. Anyone that plans to administer the IMP must be trained by the study 
staff. 
8.1.2 Timing of administration 
On Day 1, visit 1, patients from the ODYSSEY Long Term study will have the possibility to 
perform a placebo, self-injection training using an auto-injector, before the first alirocumab 
injection. 
On the same day, the first alirocumab injection will be done at the site by the patient or another 
designated person (such as spouse, relative, etc) under direct site staff supervision. Patients will be 
monitored at the investigational site for at least 30 minutes after this first injection in this study. 
Alirocumab subcutaneous injections will then be performed outside of the clinic, every two weeks 
up to the last injection planned in the protocol. If the injection is scheduled to take place on the 
same date as the site visit, then the IMP should be administered after the blood sampling has been 
completed. 
Alirocumab should ideally be administered subcutaneously every two weeks at approximately the 
same time of the day. The time of the day is based upon patient’s preference; however it is 
acceptable to have a window period of ± 3 days.  
If by mistake or due to other circumstances an injection is delayed: 
x 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.  
x by less than or equal to 7 days from the missed date, then the patient should administer the 
delayed injection and then resume the original schedule of study treatment administration. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 32 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
The following classes of drugs are identified as non-IMP because the medication is either a 
background therapy or a potential rescue medication: 
x Statins  
x Cholesterol absorption inhibitors (ezetimibe) 
x Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam) 
x Nicotinic acid 
x Fenofibrate 
x Omega-3 fatty acids (1000 mg daily) 
Please see Section 8.8 for further information. 
8.3 
BLINDING PROCEDURES 
From Day 1 (visit 1) until Week 8 (first unblinded LDL-C value),  
x neither the treatment received during the double-blind treatment period of the parent study, 
x nor the lipid parameters levels,  
will be known by the Investigator and by the patient, in order to prevent any potential to 
jeopardize the blinding of the parent clinical study. 
From Week 8 (visit 3), the lipid parameters values will be communicated to the Investigator in 
real time. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is an open-label study and every patient will receive alirocumab. Treatment kit numbers will 
be allocated via interactive voice/web response system (IVRS/IWRS). Patients will keep the same 
identification number that they were allocated in the parent study. 
From Week 12 (Visit 4), the Investigator will manage, based on his/her own judgment and LDL-C 
value from sample obtained at the previous scheduled visit, adjustment of alirocumab doses 
(either up-titration from 75 mg to 150 mg every 2 weeks or down-titration  from  150 mg to 75 mg 
every 2 weeks, or maintenance of the dose, will be possible).  For adjustments based on LDL-C 
values, simultaneous adjustments in alirocumab dose and any LMT should be avoided. 
8.5 
PACKAGING AND LABELING 
Each alirocumab treatment kit will be prepared to contain 6 auto-injectors in a child-resistant 
package. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 33 
In addition to the alirocumab treatment kits, a training kit containing 1 placebo auto-injector will 
be prepared for the purpose of instructing patients on injection administration, in particular for 
patients originating from the ODYSSEY Long Term study. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements.  
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP will be stored in a refrigerator between +2°C and + 8°C (36°F to 46° F) by the site. The 
temperature of the site refrigerator should be checked daily and recorded on a log sheet. 
The IMP that will be stored at the investigational site should be kept in an appropriate locked 
room, under the responsibility of the Investigator or designee or other authorized person in 
accordance with the storage conditions indicated on the label. 
After the supply of IMP kits to patients at the study site visits, appropriate provisions will be in 
place for transportation of the IMP kits from the study site to the patient’s refrigerator. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
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: 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 34 
x The Investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) and 
he/she will dispense the treatment kit(s) to the patient. 
x 
The accountability is to be performed at IMP kit re-supply visits only (see Section 10.1.1). 
The used kit(s) and unused auto-injector(s) should be brought back to such visits for 
accountability purposes. 
x The Investigator or designee will complete the corresponding treatment log form from 
patient’s diary. 
x The Investigator/study coordinator will enter data in the appropriate e-CRF pages, 
according to data recorded in the treatment log form. 
x The monitor will check the data consistency between e-CRF pages, treatment log forms 
using patient’s diary, and returned unused auto-injectors of a corresponding kit. 
8.7.2 Return and/or destruction of treatments 
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the 
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will 
not destroy the unused IMP unless the Sponsor provides written authorization. 
If the site is not able to destroy or destruction of IMPs are not allowed in the country, all 
treatments kits will be retrieved by the Sponsor. A detailed treatment log of the returned IMP will 
be established with the Investigator or designee and countersigned by the Investigator and the 
Monitoring Team. 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to the study 
drug until the end of the patient’s participation in the study. 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient’s welfare and are unlikely to interfere with the IMP, they may 
be given at the discretion of the Investigator, with a stable dose (when possible). Besides the 
specific information related to concomitant medications provided in this section, any other 
concomitant medication(s) will be allowed and will have to be recorded in the e-CRF and source 
data. 
8.8.1 Management of background lipid-modifying therapy 
Throughout the whole treatment period, the patients should stay, as far as possible, on the stable 
maximally tolerated registered daily dose of statins, with or without other LMT, that was received 
during the parent study.  
Background LMT may be adjusted as per the Investigator’s judgment, for example in case of 
tolerability issue. Any adjustment will be documented in the e-CRF. For adjustments based on 
LDL-C values, simultaneous adjustments in alirocumab dose and any LMT should be avoided.   
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 35 
For background LMT, including statins, sites must follow the national product label for the safety 
monitoring and management of patients. 
Lipid profile values from samples obtained after inclusion will be blinded until week 8.  
8.8.2 Contraception 
Women of childbearing potential must use an effective contraceptive method throughout the study 
treatment, and for 10 weeks after the last IMP injection for those patients who discontinue 
prematurely. 
8.8.3 Prohibited concomitant medications 
Forbidden concomitant medications from the initial visit until the last visit include the following: 
x Fibrates, other than fenofibrate. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 36 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY SAFETY ENDPOINTS 
The safety parameters (adverse events, laboratory data, vital signs) will be assessed throughout 
the study. 
The definition and reporting procedures of Adverse Events (AE), Adverse Events of Special 
Interest (AESI) and Serious Adverse Events (SAE) and management of specific laboratory 
abnormalities are described in sections 10.4 to 10.6.  
Adverse event observation period: 
The observation of safety data will be as follows: 
x 
Pre-treatment observation period is defined as the time from signing the informed consent 
to the time of first dose of alirocumab in the current study. The adverse events occurring 
during this period will be reported and recorded in the parent study data base. 
x 
TEAE period: the TEAE (Treatment Emergent Adverse Event) observation period is 
defined as the time from first dose of alirocumab in the OLE up to 70 days (10 weeks) 
after the last dose of alirocumab received in the OLE study for the patients who will either 
complete the study or who will prematurely discontinue, as residual effect of treatment is 
expected until 10 weeks after the stop of alirocumab. 
x 
Post-treatment period: the post-treatment observation period is defined as the time starting 
the day after the end of the TEAE period up to the end of the study (see definition in 
section 6.2.1). 
Death observation period: 
The death observations are per the observation period defined above. In addition, “post-study” 
death includes all deaths reported after the end of the study (see definition of end of study period 
per patient in Section 6.2.1). 
9.1.1 Adverse events 
All adverse events diagnosed by the investigator will be reported and described. 
All AEs will be coded to a “Lowest Level Term (LLT)”, “Preferred Term (PT)”, “High Level 
Term (HLT)”, “High Level Group Term (HLGT)” and associated primary “System Organ Class 
(SOC)” using the version of MedDRA (Medical Dictionary for Regulatory Activities) currently in 
effect at Sanofi at the time of the considered database lock. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 37 
9.1.2 Safety laboratory 
The clinical laboratory data consist of hematology (red blood cell count, hemoglobin, red blood 
cell distribution width (RDW), reticulocyte count, hematocrit, platelets, white blood cell count 
with differential blood count), standard chemistry (glucose, sodium, potassium, chloride, 
bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, total protein, LDH, 
albumin, Ȗ Glutamyl Transferase [ȖGT]), liver panel (ALT, AST, ALP, and total bilirubin), and 
CPK. 
Some additional safety laboratory parameters may be reflexively measured based on actual data 
(see Section 10.4.5.1). 
Clinical laboratory values will be analyzed after conversion into standard international units. 
Standard international units will be used in all listings and tables. 
9.1.3 Vital signs measurement 
Vital signs include: heart rate, systolic and diastolic blood pressure in sitting position. 
The study-specific and general safety criteria are developed in Section 10.4. 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Efficacy endpoints 
Efficacy will be assessed on the following parameters during the efficacy period. The efficacy 
period is defined as the time from the first alirocumab dose in the current study up to 21 days after 
the last dose of alirocumab. 
x Percent change in calculated LDL-C from baseline of the parent study over time in this study  
Percent change at Week X is defined as: 100 x (calculated LDL-C value at Week X -
calculated LDL-C value at baseline) / calculated LDL-C value at baseline 
x The absolute change in calculated LDL-C (mg/dL and mmol/L) from baseline of the parent 
study over time in this study  
x Proportion of patients achieving an LDL-C<100 mg/dL (2.59 mmol/L) over time in this 
study  
x Proportion of patients achieving an LDL-C<70 mg/dL (1.81 mmol/L) over time in this study  
x Proportion of patients with calculated LDL-C<70 mg/dL (1.81 mmol/L) and/or 50% 
reduction in calculated LDL-C from baseline of the parent study (if LDL-C 70 mg/dL) 
over time in this study  
x Values and percent changes from baseline of the parent study over time in this study for 
the following parameters:  
- 
total cholesterol,  
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 38 
- 
non-high-density lipoprotein cholesterol (non-HDL-C),  
- 
HDL-C,  
- 
Fasting triglycerides (TGs),  
- 
lipoproteins:  apolipoprotein (Apo) B, ApoA-1, ApoB/ApoA-1 ratio (for this parameter 
only absolute changes) and Lp(a)  
The analysis windows used to allocate a time point to a measurement will be defined in the 
Statistical Analysis Plan (SAP). 
9.2.2 Efficacy assessment method 
Total-C, HDL-C, TG, Apo B, Apo A-1, and Lp (a) will be directly measured by the Central 
Laboratory as per the schedule in Section 1.2. LDL-C will be calculated using the Friedewald 
formula (12) at all visits. If TG values exceed 400 mg/dL (4.52 mmol/L) then the central lab will 
reflexively measure (via the beta quantification method) the LDL-C rather than calculating it. 
Non-HDL-C will be calculated by subtracting HDL-C from the total-C. Ratio Apo B/Apo A-1 
will be calculated. Detailed procedures of sample preparation, storage and shipment will be 
described in the specific laboratory manual which will be provided to sites. Information on the 
processing, methodology and other relevant information will be available upon request, in The 
Medpace Reference Laboratory Manual. 
Efficacy endpoints will not be considered as Adverse Events, such as those involving 
abnormalities in lipid levels, unless meeting the criteria in Section 10.4.2. 
9.3 
OTHER ENDPOINTS 
9.3.1 Anti-alirocumab antibody assessment  
9.3.1.1 Sampling time 
Serum samples for anti-alirocumab antibody determination will be drawn periodically throughout 
the study as per schedule noted in the study flowchart of Section 1.2. All scheduled samples will 
be obtained before IMP injection (predose). 
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 
 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 39 
 
 
9.3.2 EQ-5D patient questionnaire 
EQ-5D™ (13) is a standardized and generic instrument for measuring patient’s health status and 
health-related quality of life (HRQoL) for clinical and economic assessments (See Appendix E).  
EQ-5D™ instrument includes 5 items corresponding to the following domains: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression.  
Each item can take one of three responses: (1) “no problems”, (2) “some problems”, and (3) 
“severe problems”.  
Response to items can be converted to a standard utility score ranging between -0.594 
representing “severe problems” and 1 representing “no problem”.  
EQ-5D endpoints include: 
x 
Change in proportion of patients within each domain and response categories from 
baseline to Weeks 12, 24, 48, and End of OLETP. 
x 
Change in mean EQ-5D utility scores from baseline to Weeks 12, 24, 48, and End of 
OLETP. 
9.3.3 Other exploratory endpoints 
9.3.3.1 Up-titration assessment 
x Proportion of patients who were up-titrated to 150 mg of alirocumab based on 
Investigator’s judgment. 
x Reasons that trigger an up-titration of alirocumab will be documented in the e-CRF. 
9.3.3.2 Down-titration assessment 
x Proportion of patients who were down-titrated to 75 mg of alirocumab based on 
Investigator’s judgment. 
x Reasons that trigger a down-titration of alirocumab will be documented in the e-CRF. 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 40 
10 
STUDY PROCEDURES 
For all visits after Day 1/Week 0 (first visit), a time window of ± 7 days during the whole 
treatment period, including the follow-up call as applicable) will be allowed.  
For all visits after Day 1/first visit, if one visit date is changed, then the next visit should take 
place according to the original schedule as outlined Section 1.2. 
Blood samplings: 
The blood sampling for determination of lipid parameters (ie, total-C, LDL-C, HDL-C, TG, non- 
HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp [a]) should be performed in the morning, in 
fasting condition (ie overnight, at least 10-12 hours fast and refrain from smoking) for all site 
visits requiring blood sampling throughout the study. Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. 
Note: if the patient is not in fasting conditions, the blood sample will not be collected and a new 
appointment will be given the closest as possible to the date of this visit) to the patient with 
instruction to be fasted (see above conditions). 
Laboratory tests: 
The laboratory data are collected in accordance with the study schedule in Section 1.2 and 
forwarded to the central laboratory: 
x Hematology: blood cell count including hematocrit, hemoglobin, red blood cell count, red 
blood cell distribution width, reticulocyte count, white blood cell count with differential 
count and platelets 
x Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea 
nitrogen, creatinine, uric acid, total protein, LDH, albumin, and ȖGT 
x Liver panel: ALT, AST, ALP, and total bilirubin; in case of total bilirubin values above 
the normal range, differentiation into conjugated and non-conjugated bilirubin will occur 
automatically. 
x Creatine Phosphokinase (CPK). 
x Local urine pregnancy test. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C and Appendix D. 
Anti-alirocumab antibody samples: see section 9.3.1. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 41 
 
 
 
 
 
 
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 informed consent signed, 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, approximately at the 
same time of the day, on the same arm, with the same apparatus (after the patient has rested 
comfortably in sitting position for at least five minutes). Values are to be recorded in the e-CRF; 
both systolic blood pressure and diastolic blood pressure should be recorded.  
Throughout the OLE study, blood pressure should be measured on the same arm as the one used 
in the parent study. 
Heart rate will be measured at the time of the measurement of blood pressure. 
Notes: in case of high BP values at first visit 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) (14). 
Body weight: 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study. 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 42 
Calibrated balance scales should be used to guarantee accuracy of patients’ weight. Self-reported 
weights are not acceptable; patients must not read the scales themselves. 
10.1 VISIT SCHEDULE 
10.1.1 Open-label Treatment Period 
10.1.1.1 Initial Visit: Visit 1 (Visit 1/Week 0/Day 1) 
Only patients who meet the inclusion criteria as noted in Section 7.1 should be asked for 
participation of this extension study.  
The first visit will take place:  
x At the end of treatment (EOT) visit of the double-blind treatment period for the patients 
enrolled in the following parent studies: ODYSSEY FH I, ODYSSEY FH II and 
ODYSSEY High FH. A minimal interval of 11 days between the last injection of IMP in 
the parent study and the parent EOT visit/OLE first visit should be kept in order to avoid 
any possible overdose. 
x At the end of study (EOS) visit, after the 8-week follow up period, for the patients enrolled 
in the ODYSSEY Long Term study. 
For the patients having participated to one of these studies: ODYSSEY FH I, ODYSSEY FH 
II and ODYSSEY High FH. 
Perform the investigations already planned in the EOT visit of the parent study:  
Only the investigations scheduled in the EOT of the parent studies and which are necessary at the 
inclusion in OLE are listed below: 
x Collect adverse events 
x Record concomitant medication 
x Get body weight measurement 
x Take vital signs including heart rate and blood pressure 
x Perform physical examination 
x Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent. 
x Completion of EQ-5D questionnaire by patient 
x Urine pregnancy test (females of childbearing potential only) 
x Obtain fasting blood sample for: 
- 
Lipid parameters: measure and/or calculation  
- 
 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 43 
- 
Hematology 
- 
Chemistry 
- 
Liver panel  
- 
CPK 
- 
Anti-alirocumab antibodies 
In addition, perform the investigations scheduled for the current OLE study: 
x Complete informed consent - the patient will receive complete information about the study 
both verbally and in writing. Written informed consent for the study must be obtained 
prior to any study-related investigations. 
x Assess inclusion/exclusion criteria 
x If the patient is confirmed eligible, the Investigator will start the next study procedures: 
- 
IVRS/IWRS contact for allocation of a 7-digit treatment kit number according to the 
list. Investigators should never allocate a treatment kit number to a patient without 
contacting IVRS/IWRS. 
x 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. 
x The first 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, if necessary, to be provided for IMP 
administration. The patient should be observed for at least 30 minutes after the injection. 
x Collect 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 last planned protocol 
visit. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary at the next visit. 
For the patients having participated to the ODYSSEY Long Term study 
Perform the investigations already planned in the EOS visit of the parent study:  
Only the investigations scheduled in the EOS of the parent study and which are necessary at the 
inclusion in OLE are listed below: 
x Collect adverse events 
x Record concomitant medication 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 44 
x Get body weight measurement 
x Take vital signs including heart rate and blood pressure. 
x Perform physical examination (including neurological exam) 
x Urine pregnancy test (females of childbearing potential only) 
x Obtain fasting blood sample for: 
- 
Anti-alirocumab antibodies.  
- 
In case of clinically relevant abnormal values of the following parameters at the  EOT 
visit, fasting blood sample will be obtained at this EOS visit for: 
 
Hematology 
 
Chemistry 
 
Liver panel  
 
CPK. 
Note: if the patient is not in fasting conditions, the blood sample will not be collected and a new 
appointment will be given the day after (or as close as possible to this date) to the patient with 
instruction to be fasted (at least 10 to 12 hours fasting). Alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the blood sampling are discouraged. 
In addition, perform the investigations scheduled for the current OLE study: 
x Complete informed consent - the patient will receive complete information about the study 
both verbally and in writing. Written informed consent for the study must be obtained 
prior to any study-related investigations. 
x Assess inclusion/exclusion criteria 
x Completion of EQ-5D questionnaire by patient 
x Obtain fasting blood sample for: 
- 
Lipid parameters 
- 
 
- 
If not done at the EOS visit: 
 
Hematology 
 
Chemistry 
 
Liver panel 
 
CPK. 
If the patient is confirmed eligible, the Investigator will start the next study procedures: 
x A training placebo injection with an auto-injector will be proposed: 
- 
IVRS/IWRS contact for allocation of a batch number for training kit 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 45 
- 
Record batch number allocated in e-CRF. 
- 
Injection training should be provided as outlined in Section 8.1.1 
- 
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. 
- 
IVRS/IWRS contact for allocation of a 7-digit treatment kit number according to the 
list. Investigators should never allocate a treatment kit number to a patient without 
contacting IVRS/IWRS. 
- 
IMP kit dispensation as per treatment kit number provided by IVRS along with 
schedule reminder. The patient injection instruction manual and treatment 
administration package should be provided. The patient diary should be given and 
instructions on its completion should be reviewed. 
- 
The first 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 observed for at least 30 minutes after the 
injection. 
x Collect 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 last planned protocol visit. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary at the next visit. 
10.1.1.2 Visit 2/ Week 4 (Day 29 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Data collection on IMP administration and IMP compliance check by review of diary  
x Obtain blood sample for: 
- 
Liver panel  
x Local urine pregnancy test (females of childbearing potential only). 
x Reminders 
- 
An appointment will be given for the next visit. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 46 
- 
Patient to bring the diary at the next visit. 
- 
Remind patient to be in fasting conditions (ie overnight, at least 10-12 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 48 
hours and intense physical exercise within 24 hours preceding the next visit are 
discouraged. 
10.1.1.3 Visit 3/ Week 8 (Day 57 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Data collection on IMP administration and IMP compliance check by review of diary  
x Obtain fasting blood sample for: 
- 
Lipids: measure or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology  
- 
Chemistry 
- 
CPK 
- 
Liver panel  
x From week 8 onwards, lipid parameters will be unblinded and communicated to the 
investigator in real time.  
x Local urine pregnancy test (females of childbearing potential only). 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Also, alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.4 Visit 4/ Week 12 (Day 85 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 47 
x Obtain blood sample for: 
- 
Liver panel  
x Local urine pregnancy test (females of childbearing potential only). 
x Completion of EQ-5D questionnaire by patient 
x IVRS/IWRS contact for allocation of a batch number for treatment kit, in accordance with 
dosage adjustment decided by the investigator 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. From week 12 onwards, 
the Investigator will have the possibility to up or down-titrate the alirocumab dosage 
according to the lipid values and his/her clinical judgment. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Also, alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.5 Visit 5/ Week 24 (Day 169 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x Obtain fasting blood sample for: 
- 
Lipids: measure or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel  
- 
Anti-alirocumab antibodies 
- 
 
x Local urine pregnancy test (females of childbearing potential only). 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 48 
x Completion of EQ-5D questionnaire by patient 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.6 Visit 6/ Week 36 (Day 253 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit.  
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.7 Visit 7/ Week 48 (Day 337 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent. 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C, Apo 
B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 49 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel  
- 
Anti-alirocumab antibodies 
x Local urine pregnancy test (females of childbearing potential only). 
x Completion of EQ-5D questionnaire by patient 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.8 Visit 8/ Week 60 (Day 421 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit.  
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.9 Visit 9/ Week 72/ Month 18 (Day 505 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 50 
x Physical examination 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x Obtain fasting blood sample for: 
- 
Lipids: measure or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel  
- 
Anti-alirocumab antibodies 
x Local urine pregnancy test (females of childbearing potential only). 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.10 Visit 10/ Week 84 (Day 589 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit.  
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 51 
10.1.1.11 Visit 11/ Week 96 / Month 24 (Day 673 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent. 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C, Apo 
B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel  
- 
Anti-alirocumab antibodies 
- 
x Local urine pregnancy test (females of childbearing potential only). 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.12 Visit 12/ Week 108 (Day 757 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x IVRS/IWRS contact for allocation of a batch number for treatment kit 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 52 
x IMP kit dispensation and treatment administration package should be provided. The patient 
injection instruction manual and diary may be given, as needed. 
x Reminders 
- 
An appointment will be given for the next visit.  
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.13 Visit 13/ Week 120/ Month 30 (Day 841 ± 7) 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel  
- 
Anti-alirocumab antibodies 
x Local urine pregnancy test (females of childbearing potential only). 
x 
IVRS/IWRS contact for allocation of a batch number for treatment kit 
x 
IMP kit dispensation and treatment administration package should be provided. The 
patient injection instruction manual and diary may be given, as needed. 
x 
Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.14 Visit 14/ Week 132 (Day 925 ± 7)  
x 
Collect adverse events 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 53 
x 
Record concomitant medication 
x 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x 
IVRS/IWRS contact for allocation of a batch number for treatment kit 
x 
IMP kit dispensation and treatment administration package should be provided. The 
patient injection instruction manual and diary may be given, as needed. 
x 
Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.15 Visit 15/ Week 144/ Month 36 (Day 1009 ± 7)  
x 
Collect adverse events 
x 
Record concomitant medication 
x 
Take vital signs including heart rate and blood pressure 
x 
Get body weight measurement 
x 
Physical examination 
x 
Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent. 
x 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x 
Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C, Apo 
B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel 
- 
Anti-alirocumab antibodies 
x 
Local urine pregnancy test (females of childbearing potential only). 
x 
IVRS/IWRS contact for allocation of a batch number for treatment kit 
x 
IMP kit dispensation and treatment administration package should be provided. The 
patient injection instruction manual and diary may be given, as needed. 
x 
Reminders 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 54 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit. 
10.1.1.16 Visit 16/ Week 156 (Day 1093 ± 7)  
x 
Collect adverse events 
x 
Record concomitant medication 
x 
Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit. 
x 
IVRS/IWRS contact for allocation of a batch number for treatment kit 
x 
IMP kit dispensation and treatment administration package should be provided. The 
patient injection instruction manual and diary may be given, as needed. 
x 
Reminders 
- 
An appointment will be given for the next visit. 
- 
Patient to bring the diary and used kits and unused auto-injectors at the next visit 
- 
Remind patient to be in fasting conditions (ie, overnight, at least 10-12 hours fast and 
refrain from smoking) for next visit. Alcohol consumption within 48 hours and intense 
physical exercise within 24 hours preceding the next visit are discouraged. 
10.1.1.17 End-of-treatment visit: Visit 17/ Week 168/ Month 40 (Day 1177± 7) 
The end of study is scheduled to be in second quarter 2017 or when the drug will become 
commercially available for the patient in the respective country whatever comes first. Thus, the 
End-of-treatment visit might be performed earlier than on Week 168 according to the date of 
inclusion of each patient in the OLE study, or if the patient early discontinues the study. 
x Collect adverse events 
x Record concomitant medication 
x Take vital signs including heart rate and blood pressure 
x Get body weight measurement 
x Physical examination 
x Review patient’s diet. Patient should be on a NCEP-ATPIII TLC diet or equivalent.  
x Data collection on IMP administration and IMP compliance check by review of diary and 
treatment kit 
x IVRS/IWRS contact to document the end of treatment  
x 
Obtain fasting blood sample for: 
- 
Lipids: measure and/or calculation of total-C, LDL-C, HDL-C, TG, non-HDL-C, Apo 
B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 55 
- 
Hematology 
- 
Chemistry 
- 
CPK 
- 
Liver panel 
- 
Anti-alirocumab antibodies 
- 
x Local urine pregnancy test (females of childbearing potential only). 
x Completion of EQ-5D questionnaire by patient. 
x 
Reminders 
- 
For all the patients, those who prematurely discontinue the treatment irrespective of 
the reason and those who will complete the study, an appointment will be given for the 
Follow up call. This phone call will have to be scheduled 10 weeks after last injection 
(+/- 7 days). 
10.1.2 Post-treatment Follow up period 
End of Study Phone call: Visit 18/ Week 176 (± 7 days) 
This phone call is to be done for all the patients, those who discontinue the treatment prematurely, 
whatever the reason, and those who will complete the study, and will take place approximately 10 
weeks after the last injection of alirocumab. 
x Collect adverse events 
x Record concomitant medication, including any commercially available PCSK9 inhibitor 
different from alirocumab 
x IVRS/IWRS contact to document the end of study 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
x Agreement, date, and signature of informed consent mentioning the study identification. 
x Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology. 
x Contraception methods for women of childbearing potential. 
x Previous and concomitant medication (including the lipid modifying therapy). 
x Study identification. 
x Treatment number, dates of administration. 
(electronic 

Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 56 
x Dates of visits and assessments including the examination report. 
x Vital signs, height, body weight. 
x Faxed central lab reports (dated and signed by the Principal Investigator or Sub-
Investigator). 
x IVRS/IWRS confirmation fax (training kit allocation, treatment reallocation, 
discontinuation, end of open label extension period, end of study). 
x 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. 
x Date of premature study discontinuation (if any) and reason. 
Source documentation may be found in the following: 
x Patient’s identity. 
x Medical history. 
x Hospital records. 
x Nursing notes. 
x Physician’s notes. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily or permanently according to the context. 
Any IMP discontinuation should be fully documented in the e-CRF and source notes.  
Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation (also referred to as treatment interruption) may be 
considered by the Investigator because of suspected AEs. Reinitiating of treatment with the IMP 
will be done under close and appropriate clinical and/or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the 
responsibility of the IMP in the occurrence of the concerned event was unlikely and if the 
selection criteria for the study are still met (refer to Section 7.1 and Section 7.2). 
All treatment interruption duration should be recorded by the Investigator in the appropriate e-
CRF screens when considered as confirmed. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 57 
Treatment interruption is defined as one or more scheduled injections that are not administered to 
the patient as decided by the Investigator. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation (also referred to as treatment discontinuation) is any 
treatment discontinuation associated with the definitive decision from the Investigator or the 
patient not to re-expose the patient to the IMP at any time. 
Patient withdrawal from the study treatment or study should be avoided as much as possible. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Patients should discontinue the IMP for the following reasons: 
x Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females only). 
x Acute injection reaction of clinical concern. 
x Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to IMP. 
x At patient request. 
x If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being. 
x 
Intercurrent condition that requires discontinuation of the IMP (eg, laboratory 
abnormalities, please refer to decision tree Appendix C). 
x 
Any abnormal laboratory value will be immediately rechecked for confirmation before 
making a decision of permanent discontinuation of the IMP for the concerned patient 
x At the specific request of the Sponsor. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients who prematurely discontinue study treatment (regardless of the reason) should undergo 
an unscheduled visit with assessments normally planned at the end of treatment visit (it should 
take place within 5 days of treatment discontinuation, if possible).  
The patient, at a minimum, should then be followed up for at least 10 weeks from last study 
treatment administration or up to recovery or stabilization of any AE to be followed-up as 
specified in this protocol, whichever comes last.  
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 58 
A final End of Study phone call will take place with assessments at 10 weeks after the premature 
treatment discontinuation. 
All definitive discontinuation of study treatment should be recorded by the Investigator in the 
appropriate screens of the e-CRF and in the patient’s medical records when considered as 
confirmed. IVRS/IWRS should be notified when a patient prematurely discontinues study 
treatment. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. If possible, the patients should be assessed using the 
procedure defined above. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the e-
CRF and in the patient’s medical records (with, in this medical records, at least date of withdrawal 
and reason for) when considered as confirmed. 
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, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter)  
Patients who have withdrawn from the study cannot be included in the study again. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
Please refer to Appendix B 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: 
x Results in death, or 
x Is life-threatening, or 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 59 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
x Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x Results in persistent or significant disability/incapacity, or 
x Is a congenital anomaly/birth defect 
x Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require 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 
- 
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. 
10.4.1.3 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 10.4.4 for additional information. 
10.4.2 General guidelines for reporting adverse events 
x All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form of the current study until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding screen(s) of the e-CRF. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 60 
x 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.  
x The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor.  
x When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
x Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI  
See Appendix B for a summary of AE reporting guidelines. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
x ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
x SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
x All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge. 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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 61 
x A back-up plan (using paper flow) is available and should be used when the e-CRF system 
does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest   
10.4.4.1 AESI with immediate notification: 
For these AEs, the Sponsor will be informed immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.3, even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF. 
x 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). Baseline to be considered 
is the baseline of the current study. 
x 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 e-CRF screen (see Section 
10.6.2), regardless of requirements for immediate reporting. 
x Hemolytic anemia (See Section 10.4.5.1 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 
e-CRF screen will need to be completed. 
x 
Pregnancy 
- 
Pregnancy occurring in a female patient included in the clinical trial. 
  
Pregnancy will be recorded as a pre-specified AE with immediate notification in 
all cases. It will be qualified as an SAE only if it fulfills the SAE criteria. 
  
IMP should be discontinued. 
  
The follow-up of the pregnancy will be mandatory until the outcome has been 
determined. 
- 
Pregnancy occurring in the partner of a male patient included in the clinical trial. If 
permitted by the female partner and by local regulatory policies, 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 62 
  
Pregnancy will be recorded as a pre-specified AE with immediate notification in 
all cases. It will be qualified as an SAE only if it fulfills the SAE criteria. 
  
The follow-up of the pregnancy will be mandatory until the outcome has been 
determined. 
x Symptomatic Overdose with IMP 
- 
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic injection counts) and 
defined as at least twice of the intended dose within the intended therapeutic interval 
(ie, 2 or more injections from the treatment kit are administered in <7 calendar days); 
to be reported using the corresponding screens in the e-CRF using the Term 
‘Symptomatic OVERDOSE (accidental [or intentional])’. The patient should be 
monitored and appropriate symptomatic treatment instituted. 
- 
The circumstances of the overdose should be clearly specified in the verbatim. 
x Neurologic Events 
- 
Neurologic Events that require additional examinations/procedures and/or referral to a 
specialist should be reported immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.1.3, even if not fulfilling a seriousness criterion. 
x Ophthalmologic Events 
- 
Ophthalmologic Events that require additional examinations/procedures and/or referral 
to a specialist should be reported immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.1.3, even if not fulfilling a seriousness criterion. 
10.4.4.2 AESI without immediate notification: 
x Asymptomatic Overdose with IMP 
An overdose is defined in the above section. 
In case of an asymptomatic overdose with IMP, the event should be reported using the 
corresponding screens in the e-CRF using the Term “Asymptomatic OVERDOSE (accidental 
[or intentional])”. The patient should be monitored for any adverse events and treated, as 
needed 
x Local injection site reactions (see section 10.6.1) 
Local injection site reactions that are considered as non-allergic events and that are related to 
the IMP injection, as opposed to another injectable agent, should be further characterized by 
evaluating the related symptoms that comprise an injection site reaction such as but not 
limited to redness, pain, etc (See Appendix F). Special e-CRF screens will need to be 
completed. If such an AE were to occur, then do not report the individual components of the 
reaction but rather the term “local injection site reaction”, with the individual components 
being described in the specific e-CRF screen. 
x Allergic events not referred for consultation with another physician (see above section) 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 63 
- 
All allergic events will need to have allergy specific e-CRF screens completed (see 
Section 10.6.2), regardless of requirements for immediate reporting. 
x Neurologic Events 
- 
Any AEs related to neurologic abnormalities with the exception of those requiring 
additional examinations/procedures and/or referral to a specialist should be reported. 
x Ophthalmologic Events 
- 
Any AEs related to ophthalmologic abnormalities with the exception of those requiring 
additional examinations/procedures and/or referral to a specialist should be reported. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Laboratory abnormalities with pre-specified monitoring should be monitored, documented, and 
managed according to the related flowchart in protocol Appendix C and Appendix D. 
Where it is applicable in the flowchart, baseline is defined as baseline in the current study. 
x Neutropenia 
x Thrombocytopenia 
x Increase in ALT 
x Acute renal insufficiency 
x Decrease in hemoglobin (defined as 1.5 g/dL) 
x Increase in CPK and suspicion of rhabdomyolysis. 
10.4.5.1 Hemoglobin decrease 
At the first post-inclusion occurrence of a hemoglobin (Hb) measurement decrease by 1.5 g/dL 
as compared to the first visit (in the current study) 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 provide the results of the 
reticulocyte count, haptoglobin, LDH and indirect bilirubin [reflexively measured only if the total 
bilirubin >ULN] to the investigator (see Appendix D). 
x If the following pattern of abnormalities is noted: 
- 
Reticulocyte count >Central Lab’s upper limit of the reference range (also referred to 
as ULN) AND 
- 
Haptoglobin <Central Lab’s lower limit of the reference range (also referred to as 
LLN) AND 
- 
LDH>ULN AND 
- 
Indirect bilirubin >ULN (only if the total bilirubin >ULN), 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 64 
- 
The patient should be referred to a hematologist. The hematologist should obtain a 
peripheral blood smear and anti-erythrocyte antibodies (direct and indirect) by Coombs 
test. Further investigations are at the discretion of the hematologist. 
x If the results are normal or the pattern of abnormality is something other than that 
described above, then 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.  
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x all SAEs that are both unexpected and at least reasonably related to the IMP (Suspected 
Unexpected Serious Adverse Reaction; SUSAR), to the Health Authorities, IECs/IRBs as 
appropriate and to the Investigators.  
x all SAEs that are expected and at least reasonably related to the IMPs to the Health 
Authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected, as given in the Investigator’s Brochure. 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (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 Appendix F for further 
information. 
10.6.2 Allergic adverse events  
Specific e-CRF screens are to be filled in to assess allergic reactions or allergic-like reactions that 
may occur during the clinical studies conducted with alirocumab. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 65 
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 (see Section 10.4.4). 
Adverse events that are obviously not of allergic origin (eg, local injection site reactions) should 
only be recorded on the Local Injection Site Reaction Complementary Form. However, injection 
site reactions which progress/expand/worsen/etc should be evaluated as recommended in 10.6.2.1 
and General Allergic Reaction Complementary form should be completed. (See Sections 10.4.4) 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP.  See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.3 for criteria for permanent treatment discontinuation. 
10.6.2.1 Allergic events 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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 66 
10.6.2.2 Acute allergic Injection Reactions  
Acute allergic injection reaction (which are considered under the category of general allergic 
reactions) is defined as any AE that occurs during or shortly after injection of the IMP 
(characterized by but not limited to hypotension, bronchoconstriction, urticaria, edema, 
angioedema, nausea, vomiting). Emergency equipment and medication for the treatment of these 
potential adverse effects (eg, antihistamines, bronchodilators, IV saline, corticosteroids, 
acetaminophen, and epinephrine) must be available for immediate use for the injections at the 
training, and randomization visits. (See Section 10.4.2) 
Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the randomization visit. Patients should be treated symptomatically if any AEs 
are observed. Patients are to remain at the site until any acute injection reaction is assessed as 
stable, per the Investigator’s discretion. General Allergic Reaction and/or Local Injection Site 
Reaction Complementary Form will have to be completed. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 67 
11 
STATISTICAL CONSIDERATIONS  
11.1 
DETERMINATION OF SAMPLE SIZE 
Taking into consideration the current number of patients enrolled in the four parent studies, it is 
estimated that up to approximately 1,200 patients could be enrolled. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who originally met the inclusion criteria and signed 
the informed consent form. 
Enrolled patients consist of all screened patients, with a treatment kit number allocated and 
recorded in the IVRS/IWRS database, regardless of whether treatment kit was used or not. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Safety population 
The Safety population considered for safety analyses will be the population who did actually 
receive at least one dose or partial dose of IMP in the current study. 
11.3.2 Efficacy population 
11.3.2.1 Modified Intent–to-treat population 
The efficacy population considered for efficacy analyses will be the population of patients who 
received at least one dose or partial dose of IMP in the current study, with a baseline (from parent 
study) LDL-C available and with at least one LDL-C value available in the period from first IMP 
injection in the current study to last IMP injection + 21 days.  
11.3.3 Other analysis population 
The anti-alirocumab antibody analysis will be performed on all treated patients (safety population) 
with a blood sample on Week 0 (baseline from parent study) and at least one evaluable blood 
sample for antibodies post IMP injection in the current study. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 68 
11.4 
STATISTICAL METHODS 
11.4.1 Extent of alirocumab exposure and compliance 
The alirocumab extent exposure and compliance will be assessed and summarized within the 
safety population. 
In order to ensure the continuity of the investigational treatment for the patients without 
interruption (only in the event the manufacturer faces any performance or supply issues of the 
auto-injector), back-up plans may be implemented as described in Section 8.1. In that case, 
exposure to initial device and back-up device will be summarized and impact on study results will 
be assessed. More details will be provided in the SAP, if applicable. 
11.4.1.1 Extent of investigational medicinal product exposure 
The total exposure will be assessed by: 
x Duration of alirocumab exposure in weeks defined as: (last alirocumab injection date 
+ 14 -first alirocumab injection date) / 7, regardless of unplanned intermittent 
discontinuations. 
x The total number of injections by patient. 
11.4.1.2 Compliance 
Compliance will be assessed using the following parameters: 
x The mean injection frequency will be defined for each patient as the average number of 
days between 2 consecutive injections, that is: (last dose date – first dose date)/(number of 
injections -1). 
This parameter will be summarized descriptively (N, Mean, SD, Median, Min and Max). 
x 
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): 
x 
The %days with under-planned dosing will be defined for each patient as the number 
of days with no injection administered within the previous 17 days divided by the 
duration of IMP injection exposure in days. For example, if a patient takes a dose 
18 days after his/her previous injection, then 1 day is counted as a day under-planned 
dosing. 
x 
The %days with above-planned dosing will be defined for each patient as the number 
of days with more than one injection administered within the 11 days before divided 
by the duration of IMP injection exposure in days. For example, if a patient takes a 
dose 9 days after his/her previous injection, then 2 days are counted as a days above-
planned dosing. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 69 
11.4.2 Analyses of safety endpoints 
All safety analyses will be performed on the Safety population using the following common rule:  
The baseline value is defined generally as the last available value before first injection. For 
analyses of changes from baseline for laboratory and vital signs parameters, baseline of the parent 
study or of the current study (ie value at visit 1 before the first injection) may be considered. 
The safety analysis will focus on the Treatment Emergent Adverse Events (TEAE) period defined 
as the time from the first dose of the current study to the last dose of IMP + 70 days (10 weeks).  
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.   
Treatment period: the treatment period used for quantitative analysis is defined as the time from 
first dose of IMP injection to the last dose of IMP injection + 21 days.  
AE definition: 
x Pre-treatment AEs are AEs that developed or worsened or became serious during the 
PRE-TREATMENT period; 
x Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious 
during the TEAE period; 
x Post-treatment AEs are AEs that developed or worsened or became serious during the 
POST-TREATMENT period. 
Drug-induced liver injury: 
Liver function tests, namely ALT, AST, alkaline phosphatase and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. A 
graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 70 
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. 
11.4.2.1 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, 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. 
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all treatment 
emergent AESI, all treatment emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
If any clinically significant signal is detected and need further characterization or for adverse 
event of clinical interest, exploration of time to onset could be performed for these selected 
TEAEs as described below to account for the differential exposure time in all patients. 
Selected TEAEs will be also analyzed using time-to-event approach (Kaplan-Meier 
methodology). Time from the first dose of IMP injection to the first occurrence of the event will 
be calculated (only the first event will be counted). Patients without any event will be censored 
at the end of the TEAE period. Incidence rates at different time points of exposure will be 
presented and Kaplan-Meier curves will be provided. 
Death: 
The following deaths summaries will be generated: 
x Number (%) of patients who died by study period (TEAE, on-study, post-study) 
summarized on the safety population  
x TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC , HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 
11.4.2.2 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. For selected parameters, mean changes from baseline with the corresponding standard 
error will be plotted over time (at same time points). 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 71 
The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized whatever the baseline level and/or according to the following baseline categories: 
x Normal/missing 
x Abnormal according to PCSA criterion or criteria 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
11.4.3 Analyses of efficacy data 
Efficacy variables will be explored through descriptive statistics at each scheduled visit of the 
current study. 
Percent changes from baseline of the parent study and success rate to reach targets from week 8 
time point will be analyzed all groups combined as influence of treatment received during the 
parent study should be offset by the treatment received during the current study after 8 weeks of 
treatment. 
Percent changes, and when appropriate absolute change, from baseline of the parent study in 
calculated LDL-C, total-C, HDL-C, TG, and non-HDL-C will be summarized at each time point 
in the efficacy population using number of available data, mean, SD, median, minimum, and 
maximum. For percent change, 95% confidence intervals of the mean will also be provided. All 
measurements, scheduled or unscheduled, collected from week 8 up to 21days after the last IMP 
injection, will be assigned to analysis windows defined in the SAP in order to provide an 
assessment for these time points. Laboratory assessments other than the ones provided by the 
central laboratory will be excluded. For TG, measurements on not fasting patients will be 
excluded. 
Same kind of tables (with either percent change from baseline or absolute change from baseline) 
will be provided for other efficacy parameters: Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp(a). 
For TG and Lp(a), summary statistics will include Q1 and Q3. 
Success rate to reach the different targets defined for LDL-C in Section 9.2.1 will be provided 
with corresponding 95% confidence intervals.  
11.4.4 Analyses of other endpoints 
The antibody status (positive/negative) and antibody titers will be summarized by visit using 
descriptive statistics. If appropriate, correlations between antibody titers, safety and/or efficacy 
endpoints will be provided by graphical methods. 
The number (n) and percentage (%) of patients with an up-titration to 150 mg of alirocumab will 
be described as well as the detailed reasons that trigger the up-titration for patients for whom the 
parent study was not ODYSSEY High FH. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 72 
The number (n) and percentage (%) of patients with a down-titration to 75 mg of alirocumab will 
be described as well as the detailed reasons that trigger the down-titration. 
Further details will be provided in SAP. 
11.4.4.1 Analyses of quality of life/health economics variables 
The analysis of data from EQ-5D instrument will be performed on efficacy population. 
Descriptive summaries for individual EQ-5D items. 
x 
Frequency and proportion of patients within each EQ-5D domain and response categories 
will be summarized by visits on which EQ-5D is assessed (Weeks 0,12, 24, 48, and End of 
OLETP) 
Descriptive summaries for EQ-5D utility scores. 
x 
Response from individual items will be converted into a single EQ-5D utility score by 
means of a standard regression model. Summary statistics for the utility score (number, 
mean, median, Q1, Q3, standard deviation, minimum and maximum) will be calculated by 
visits on which EQ-5D is assessed (Weeks 0, 12, 24, 48, and End of OLETP). Change in 
mean EQ-5D utility scores from baseline (Week 0) to Weeks 12, 24, 48, and End of 
OLETP, will be calculated. 
Further details will be provided in SAP. 
11.5 
INTERIM ANALYSIS 
Interim analyses might be performed if requested by Health Authorities or if needed for the 
purpose of scientific communication. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 73 
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 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 (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 used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
12.4 
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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 74 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the 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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 75 
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 CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to 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 CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 76 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH guidelines for Good Clinical Practice, the monitoring team must check the 
CRF entries against the source documents, except for the pre-identified source data directly 
recorded in the CRF. The informed consent form will include a statement by which the patient 
allows the Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the 
regulatory authorities to have direct access to original medical records  which support the data on 
the CRFs (eg, patient's medical file, appointment books, original laboratory records, etc). These 
personnel, bound by professional secrecy, must maintain the confidentiality of all personal 
identity or personal medical information (according to confidentiality and personal data protection 
rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor when available in the 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 e-
CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
Computerized systems used during the different steps of the study are: 
x 
For data management activities, Inform 4.6 
x 
For statistical activities, SAS 
x 
For pharmacovigilance activities, AWARE, Business Object XI 
x 
For monitoring activities, MedPace Clintrack and IMPACT (SANOFI) 
x 
For medical writing activities, DOMASYS. 
External data loading is planned for this clinical trial. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 77 
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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 78 
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 
x 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
x 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
x 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
x 
Subject race will be collected in this study in the Covance laboratory requisition form, for 
clearance creatinine calculation purpose. 
x 
The data will not be captured in the eCRF, however it is part of data transfer between the 
Sponsor and the Central Lab Covance. 
x 
The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). 
They may be further processed if they have been anonymized. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 79 
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. 
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 
x 
If the information on the product leads to doubt as to the benefit/risk ratio; 
x 
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; 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 80 
x 
In the event of breach by the Investigator of a fundamental obligation under this 
agreement, including but not limited to breach of the clinical trial protocol, breach of the 
applicable laws and regulations or breach of the ICH guidelines on Good Clinical Practice; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, 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 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.  
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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 81 
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. 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 82 
16 
BIBLIOGRAPHIC REFERENCES 
1. Neil A, Cooper H, Betteridge J. Reduction in all-cause, cancer, and coronary mortality in 
statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective 
registry study. Eur Heart J. 2008;29:2625-38. 
2. Farnier M, Bruckert E. Review: Severe familial hypercholesterolaemia: Current and future 
management. Arch of Cardiovasc Disease. 2012;105:656-65 
3. Pijlman AH, Huijgen R, Verhagen SN, Imholzc AH, Liemd JJP, Kasteleinb EJ, et al. 
Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a 
large cross-sectional study in The Netherlands. Atherosclerosis. 2010;209:189-94. 
4. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism. 
Trends Biochem Sci. 2007;32(2):71-7. 
5. Benjannet S, Rhainds D, Essalmani R, Mayne J, Wickham L, Jin W, et al. NARC-1/PCSK9 
and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) 
receptor and LDL cholesterol. J Biol Chem. 2004;279:48865-75. 
6. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein 
receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem. 
2004;279:50630-8. 
7. Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, et al. Decreased plasma 
cholesterol and hypersensitivity to statins in mice lacking PCSK9. Proc Natl Acad Sci USA 
2005;102:5374-9. 
8. Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, et al. Mutations in 
PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-6. 
9. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL, 
and protection against coronary heart disease. N Engl J Med. 2006;354:34-42. 
10. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci USA. 2009;106(24):9546-7. 
11. Note for guidance on non-clinical safety studies for the conduct of human clinical trials and 
marketing authorization for pharmaceuticals (CPMP/ICH/286/95). Available at 
http://www.ema.europa.eu/pdfs/human/ich/028695en.pdf. 
12. Friedewald W.T, Levy R. I., Fredrickson D.S. Estimation of the concentration of Low-Density 
Lipoprotein Cholesterol in Plasma, without use of the preparative ultracentrifuge. Clinical 
chemistry. 1972;18(6):499-502. 
13. Dolan P. Modeling valuations for EuroQol health states. Medical Care 1997;35(11):1095-108 
(electronic 
 
 
 


Amended Clinical Trial Protocol 2  
10-Jul-2015 
alirocumab - LTS13463 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 83 
14. Chobanian AV, Bakris GL, Black HR, et al, and the National High Blood Pressure Education 
Program Coordinating Committee. The Seventh Report of the Joint National Committee on 
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. 
JAMA. 2003;289:2560-72. 
(electronic 
 
 
 
