An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia Followed by an Extension Phase
Phase: PHASE2
Conditions: Hypercholesterolaemia
Sponsor: Sanofi

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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
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According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016)
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AMENDED CLINICAL TRIAL PROTOCOL NO. 02 
COMPOUND: alirocumab 
An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the 
Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous 
Familial Hypercholesterolemia Followed by an Extension Phase 
STUDY NUMBER: DFI14223 
STUDY NAME: ODYSSEY KIDS 
VERSION DATE / STATUS: 11-Dec-2017 / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date : 11-Dec-2017 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 3.0) 
Date : 11-Aug-2016 
Protocol Amendment 01 
Version number: 1 (electronic 3.0) 
Date : 11-Aug-2016 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 30-Mar-2016 
EudraCT Number: 
2015-003766-85 
IND Number: 
105574 
BLA Number: 
125559 
UTN Number: 
U1111-1178-4764 
Version Number: 
1 
WHO universal trial number: 
NA 
Date: 
11-Dec-2017 
Total number of pages: 
137 
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NCT Number: NCT02890992

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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: alirocumab 
STUDY No: DFI14223 
TITLE 
An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the 
Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous 
Familial Hypercholesterolemia Followed by an Extension Phase. 
INVESTIGATOR/TRIAL 
LOCATION 
Multi-center, multi-national. 
PHASE OF DEVELOPMENT 
Phase 2. 
STUDY OBJECTIVE(S) 
Primary objective: 
• 
To evaluate the effect of alirocumab administered every 2 weeks (Q2W) or 
every 4 weeks (Q4W) on low-density lipoprotein cholesterol (LDL-C) levels 
after 8 weeks of treatment in heterozygous familial hypercholesterolemia 
(heFH) patients aged of 8 to 17 years, with LDL-C ≥130 mg/dL  
(3.37 mmol/L) on optimal stable daily dose of statin therapy ± other lipid 
modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of 
intolerance to statins, for at least 4 weeks prior to the screening period.  
Secondary objective(s): 
• 
To evaluate the safety and tolerability of alirocumab. 
• 
To evaluate the pharmacokinetics profile of alirocumab. 
• 
To evaluate the effects of alirocumab on other lipid parameters  
(eg, Apolipoprotein B (Apo B), non-high density lipoprotein cholesterol 
(non-HDL-C), Total-Cholesterol (Total-C), high-density lipoprotein 
cholesterol (HDL-C), Lipoprotein (a) (Lp[a]), Triglycerides (TGs), 
Apolipoprotein A-1 (Apo A-1) levels after 8 weeks of treatment.  
• 
To evaluate the development of anti- alirocumab antibodies. 
STUDY DESIGN 
This study is an open-label, dose-finding, sequential group, multi-national, multi-
center study with repeated dose of subcutaneous (SC) alirocumab injections 
administered every 2 weeks (Q2W) or every 4 weeks (Q4W) in children and 
adolescents aged of 8 to 17 years with heFH having LDL-C ≥130 mg/dL 
(3.37 mmol/L) despite optimal stable daily dose of statin therapy ± other lipid 
modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of 
intolerance to statins, for at least 4 weeks prior to the screening period. There will be 
a sequential enrollment into the 4 separate and independent cohorts, Cohorts 1 to 
4.The duration of this open-label, dose-finding treatment period will be 8 weeks for 
the first 3 cohorts, and 12 weeks for Cohort 4. Each independent cohort below will 
include approximately 10 patients with no less than 4 patients in each body weight 
(BW) category: 
• 
Cohort 1 will receive 30 mg Q2W for BW <50 kg and 50 mg Q2W for BW 
≥50 kg. 
• 
Cohort 2 will receive 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW 
≥50 kg. 
• 
Cohort 3 will receive 75 mg Q4W for BW <50kg and 150 mg Q4W for BW 
≥50 kg. 
• 
Cohort 4 will receive 150 mg Q4W for BW<50 kg and 300 mg Q4W for BW 
>50kg. 
For each cohort, the study consists of a main phase and an optional extension 
phase.  The main phase is comprised of 3 periods: screening (including run-in, 
if applicable), open-label dose finding treatment, and follow-up only for Cohorts 1, 2, 
and 3, and 2 periods: screening (including run-in, if applicable), open-label dose 
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finding treatment, but no follow-up period for Cohort 4. The extension period is an 
open-label extension period that will be offered to all patients, whatever the cohort. 
STUDY DESIGN 
MAIN PHASE 
Screening Period: 
• 
An up to 6 week (+1 week) screening period to allow eligibility to be 
established. 
Patients already on a stable LMT(s) (ie, stable optimal dose of statin ± 
other stable LMTs or stable dose of non-statin LMTs in statin-intolerant 
patients for at least 4 weeks prior to screening LDL-C being obtained) and 
with heFH diagnosis confirmed by previous genetic testing or meeting 
Simon Broome criteria can be enrolled within 2 weeks if meeting all other 
eligibility criteria.   
The optimal dose of statin is defined as the dose prescribed based on 
regional practice or local guidelines or is the dose that is maximally 
tolerated due to adverse effects on higher doses. For patients not 
receiving maximally tolerated dose of statin, statin intensification should 
be carefully considered prior to inclusion in this study in order to ensure 
that the addition of a non-statin LDL-C lowering therapy (ie, alirocumab) 
would be the next appropriate step in the management of the patient’s 
hypercholesterolemia.  The highest dose of statin should not exceed the 
maximum labeled dose of statin for pediatric patients as per the local 
prescribing information.    
Patients not already on a stable LMT(s), as defined above, for at least  
4 weeks, will perform a “run-in” period as required to meet this eligibility 
criterion.  Patients eligible for the run-in period are expected to fulfill the 
LDL-C eligibility criterion at the end of the run-in period.  It is not 
authorized to select patients treated with statin de novo to avoid unstable 
LMT treatment during the screening period. 
Patients with suspected heFH but without confirmation by previous genetic 
testing and not meeting Simon Broome criteria will be asked to undergo 
genetic testing.  If they do not consent to this testing, they will not be 
eligible to participate in this study. 
Laboratory testing and other assessments will be performed during this 
period, but not all assessments need to be completed at the same visit.     
• 
Of note, all patients who are successfully  screened for Cohort 1 and are 
not included in Cohort 1, due to the appropriate Cohort 1 weight group 
being fully enrolled, may participate in Cohort 2, but only after eligibility, 
including all safety assessments, is reconfirmed. Patients who are 
successfully screened for Cohort 2 but are not enrolled, due to the 
appropriate Cohort 2 weight group being fully enrolled, may participate in 
Cohort 3, without the need to repeat the run-in/screening period.  In such a 
circumstance, the run-in/screening period from Cohort 2 will substitute for 
the run-in/screening period for Cohort 3 if there is no more than 3 months 
between eligibility confirmation and inclusion. 
Open-Label Dose Finding Treatment Period: 
• 
An open-label dose finding treatment period of 8 weeks with alirocumab 
for Cohorts 1, 2 and 3, but 12 weeks for Cohort 4. Four independent 
cohorts (as described above) will be administered SC alirocumab 
injections Q2W or Q4W in a sequential enrollment. The DMC will review 
data on a regular basis during the dose finding treatment period. After 
Cohort 1 completes the open-label dose finding treatment period, the DMC 
will continue to review the safety data and make a recommendation on 
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dose escalation to Cohorts 2 and 3.  Cohort 2 will initially begin enrollment.  
Once enrollment is completed for Cohort 2, then this will immediately be 
followed by enrollment into Cohort 3 (ie, sequential enrollment).  Cohort 4 
is an independent cohort with a later start date.  
• 
Cohorts 1 and 2 (Q2W): Alirocumab injections will be prepared from vials 
by the pharmacist (or equivalent).  Alirocumab injections will be 
administered at Weeks 0, 2, 4, and 6.  The Weeks 0 and 4 alirocumab 
injections will be administered at the clinical site by the site staff.  The 
Weeks 2 and 6 alirocumab injections will be administered at the clinical 
site by the site staff or at the patient’s home by a health care professional, 
depending upon local arrangements and preferences of the 
investigator/patient.   
• 
Cohort 3 (Q4W): Alirocumab injections will be prepared from vials by the 
pharmacist (or equivalent).  Alirocumab injections will be administered at 
Weeks 0 and 4 at the clinical site by the site staff.   
• 
Cohort 4 (Q4W): Alirocumab injections will be administered with pre-filled 
syringes by the site staff. Alirocumab injections will be administered at 
Week 0, Week 4, and Week 8 at the clinical site by the site staff. 
• 
The lipid results from specimens obtained during the open-label dose 
finding treatment period will be masked for the clinical site/Investigator and 
patients.  No attempts should be made by the investigator or patient to 
routinely have the patient’s lipid values independently evaluated after entry 
into the open-label dose finding treatment period and until the final  
follow-up visit for Cohorts 1 to 3, and the entry into the OLE period for 
Cohort 4 
Follow-Up Period, only for Cohort 1 to Cohort 3: 
• 
A follow-up period (off treatment) of 6 (Cohort 3) or 8 weeks  
(Cohorts 1 & 2) after the end of open-label dose finding treatment period 
visit.  For the first 3 cohorts, the final follow-up visit corresponds to 10 
weeks after the last alirocumab injection administered during the open-
label dose finding treatment period, since the last injection for Cohorts 1 & 
2 is Week 6 and for Cohort 3 it is Week 4.   
The daily optimal dose of statin therapy or of other LMT (if applicable) should be 
stable from screening through the end of the follow-up visit unless there is a safety 
concern, as per the Investigator’s judgment.   
At the end of the follow-up period of the main phase, patients enrolled in Cohorts 1-3 
and who successfully completed the main phase will be offered entry into an optional 
extension phase. 
For Cohort 4, patients who successfully completed the open-label dose-finding 
treatment period will be offered entry into an optional extension phase with latest 
end date of December 2018 or direct entry into the Phase 3 study, depending on the 
time of site initiation.   
STUDY DESIGN 
EXTENSION PHASE 
Open-label extension period: 
• 
For Cohorts 1- 3, all doses / dose regimens of alirocumab administered 
during the open-label dose finding treatment period of the main phase are 
expected to be efficacious.  Thus, the initial dose of alirocumab that will be 
administered Q2W or Q4W during the OLE period, will be a continuation of 
the same doses / dose regimens administered during the open-label dose 
finding treatment period of the main phase.  However, once the final 
optimal doses of alirocumab for the Phase 3 study are selected and device 
is available, treatment will be adjusted as needed to these final optimal 
doses, based on each patient’s body weight at the time of the dose 
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change.   
• 
For Cohort 4: If patients enter the OLE phase, patients will continue on 
their doses from the main phase. If patients decline entry into the OLE 
phase, their treatment will stop. 
• 
For Cohorts 1 to 3, alirocumab injections may be prepared from vials by 
the pharmacist (or equivalent) or supplied as prefilled syringes (PFS) 
depending on availability and additional considerations. Vials used for 
extension phase will be switched to PFS when available.  
- 
If the PFS is available in the extension phase, then patients may 
either switch from alirocumab injections prepared from vials to PFS or 
directly initiate PFS (depending on patient’s date of entry into the 
extension phase).  After appropriate training, the parent/guardian or 
patient (if appropriate) will administer the PFS at home or another 
preferred location. In certain cases, alternative arrangements may be 
made for the administration of the PFS.   
- 
If the PFS is not available in the extension phase, then alirocumab 
injections prepared from vials will be administered at the clinical site 
(by the site staff) or at the patient’s home or another preferred 
location contingent upon alternative arrangements being made for 
such an administration.   
• 
The alirocumab administration during the OLE period will continue until at 
least 10 weeks (corresponding to the wash out period) before initiation of 
the pediatric Phase 3 study in the site where the patient is potentially 
participating. Therefore, patients who consent to participate in the pediatric 
phase 3 study could have their alirocumab injection in the OLE period up 
to December 2018, depending on the time of initiation of the phase 3 study 
planned to be done no later than December 2018. All other patients 
enrolled in the OLE period who decline the participation in phase 3 study 
will have their last alirocumab injection in December 2018. 
• 
The lipid levels will be communicated to the investigator during the OLE 
period. If there is a need to adjust the degree of LDL-C lowering, the daily 
dose of statin should NOT be decreased, except in case of medical 
reason. The investigator has the option to discontinue alirocumab, or to 
adjust other LMT (if applicable). Increases in dose of any background LMT 
are allowed throughout the OLE, if needed. 
Patients will be instructed to follow a diet in accordance with the American Academy 
of Pediatrics (AAP) guidelines (1) or equivalent throughout the entire study (ie, both 
phases). 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
I 01. 
Children and adolescent male and female patients aged 8**** to 17 years 
at the time of signed informed consent.  
For Russia only: 
Male and female patients aged ≥12 and ≤17 years at the time of signed 
informed consent 
I 02. 
Patients with a diagnosis of heterozygous familial hypercholesterolemia 
(he FH) through genotyping or clinical criteria.* 
I 03. 
Patients treated with an optimal dose of statin** with or without other 
LMT(s) or non-statin LMT(s) if statin intolerant*** at stable dose for at least 
4 weeks prior to screening lipid sampling.  
I 04. 
Patients with calculated LDL-C greater than or equal to 130 mg/dL 
(≥3.37 mmol/L) obtained during the screening period after the patient has 
been on stable LMT (ie, stable optimal dose of statin ± other stable LMTs, 
or stable non-statin LMTs in statin intolerant patients) treatment for at least 
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4 weeks. 
I 05. 
Patients with body weight greater than or equal to 25 kg.   
I 06. 
Patients aged of 8 to 9 years to be at Tanner stage1 and patients aged of 
10 to 17 years to be at least at Tanner stage 2 in their development. 
I 07. 
A signed informed consent indicating parental permission with or without 
patient assent, depending on capacity for understanding based on 
developmental maturity. In cases involving emancipated or mature minors 
with adequate decision-making capacity, or when otherwise permitted by 
law, a signed informed consent directly from patients. 
* Diagnosis of heFH must be made either by previous genotyping, current 
genotyping, or by clinical criteria according to Simon Broome criteria.  
Previous genotyping refers to documented results that are available from 
prior genotyping testing supporting a diagnosis of heFH. Current 
centralized genotyping refers to patients electing to undergo genotyping 
during the screening period with results supporting a diagnosis of heFH. 
The clinical diagnosis should be based on the Simon Broome criteria for 
possible or definite FH (see Appendix F). Once eligibility is confirmed 
based on prior genetic testing or Simon Broome criteria, results of elective 
genetic testing will not impact patient’s eligibility.   
** The optimal dose of statin is defined as the stable daily dose prescribed 
based on regional practice or local guidelines or is the stable daily dose 
that is maximally tolerated due to adverse effects on higher doses. For 
patients not receiving the maximally tolerated dose of statin, statin 
intensification should be carefully considered prior to inclusion in this study 
in order to ensure that the addition of a non-statin LDL-C lowering therapy 
(ie, alirocumab) would be the next appropriate step in the management of 
the patient’s hypercholesterolemia.  The highest dose of statin should not 
exceed the maximum labeled dose of statin for pediatric patients as per 
the local prescribing information.       
***Statin intolerant patient is defined as the inability to tolerate at least  
2 statins: one statin at the lowest daily starting dose, AND another statin at 
any dose, due to skeletal muscle-related symptoms, other than those due 
to strain or trauma, such as pain, aches, weakness, or cramping, that 
began or increased during statin therapy and stopped when statin therapy 
was discontinued. Patients not receiving a daily regimen of a statin (eg, 1 
to 3 times weekly) are also considered as not able to tolerate a daily dose. 
****Patients aged of 8 to less than 10 years have had other available 
interventions to lower calculated LDL-C but these have been insufficient. 
Key Exclusion criteria: 
• 
Patient with secondary hyperlipidemia. 
• 
Diagnosis of homozygous familial hypercholesterolemia. 
• 
Patient who has received lipid apheresis treatment within 2 months prior to 
the screening period, or has plans to receive it during the study. 
• 
Known history of type 1 or type 2 diabetes mellitus. 
• 
Known history of thyroid disease.  
• 
Known history of hypertension. 
• 
Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening visit. 
• 
Severe renal impairment (ie, eGFR <30 mL/min/1.73 m2 at the screening 
visit. 
• 
ALT or AST >2 x ULN (1 repeat lab is allowed). 
• 
CPK >3 x ULN (1 repeat lab is allowed). 
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Total expected number of 
patients 
40 patients 
Cohort 1 – 10 patients; no less than 4 patients with BW <50 kg and no less than  
4 patients with BW ≥50 kg. 
Cohort 2 – 10 patients; no less than 4 patients with BW <50 kg and no less than  
4 patients with BW ≥50 kg. 
Cohort 3 – 10 patients; no less than 4 patients with BW <50 kg and no less than  
4 patients with BW ≥50 kg. 
Cohort 4 – 10 patients: no less than 4 patients with BW <50 kg and no less than  
4 patients with BW ≥50 kg. 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
Formulation: 
Alirocumab: 
For Cohort 1 to Cohort 3, vials (during the dose finding treatment period and 
extension period if PFS not available): sterile alirocumab drug product supplied at a 
concentration of 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose. 
Cohorts 1 & 2 (Q2W): Prefilled syringes (if available during the extension period): 
sterile alirocumab drug product supplied at a concentration of 30, 40, 50 or 
75 mg/ 0.5 mL in histidine, pH 6.0, polysorbate 20, and sucrose. 
Cohort 3 (Q4W): Prefilled syringes (if available during the extension period): sterile 
alirocumab drug product supplied at a concentration of 75 mg/1.0 mL or 
150 mg/1.0 mL in histidine, pH 6.0, polysorbate 20, and sucrose. 
For Cohort 4 (Q4W): Prefilled syringes: sterile alirocumab drug product supplied at a 
concentration of 150 mg/1.0 mL in histidine, pH 6.0, polysorbate 20, and sucrose, 
with 1 injection of 1 mL for the 150 mg dose, and 2 injections of 1mL 
containing150 mg each to provide a total 300 mg dose. 
Formulation for dilution: 
Solvent for alirocumab vials (during the dose finding treatment period and extension 
period if PFS not available): sterile solution consisting of 10 mM histidine, pH 6.0, 
polysorbate 20, and sucrose. 
Route(s) of administration: 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of upper arm. 
Dose regimen: 
Cohort 1: 30 mg Q2W for BW <50 kg and 50 mg Q2W for BW ≥50 kg; with possible 
change during the OLE period.   
Cohort 2: 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW ≥50 kg; with possible 
change during the OLE period. 
Cohort 3: 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg; with 
possible change during the OLE period. 
Cohort 4: 150 mg Q4W for BW<50 kg and 300 mg Q4W for BW ≥50 kg throughout 
the entire study. 
ENDPOINT(S) 
Primary endpoint: 
Percent change in calculated LDL-C from baseline to Week 8. 
Secondary endpoint(s): 
• 
Absolute change in calculated LDL-C from baseline to Week 8. 
• 
Proportion of patients achieving a calculated LDL-C level lower than  
130 mg/dL (3.37 mmol/L) at Week 8. 
• 
Proportion of patients achieving a calculated LDL-C level lower than  
110 mg/dL (2.84 mmol/L) at Week 8. 
• 
Percent change in LDL-C from baseline to Week 12 only for Cohort 4. 
• 
Percent change in Apo B, non-HDL-C, Total-C, Lp(a), TG, HDL-C,  
Apo A-1 from baseline to Week 8. 
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• 
Absolute change in Apo B, non-HDL-C, Total-C, Lp(a), TG, HDL-C,   
Apo A-1, ratio Apo B/Apo A-1 from baseline to Week 8. 
 
Safety endpoint(s): 
• 
Safety parameters: adverse events (AE)s, serious AEs (SAE), AESIs, 
laboratory data, vital signs, body weight, height, and Tanner stage 
assessed throughout the study. 
Other endpoint(s): 
• 
Anti- alirocumab antibodies assessed throughout the study. 
• 
Alirocumab and PCSK9 concentrations assessed throughout the study. 
• 
To evaluate the long-term efficacy and safety of alirocumab during the 
extension phase. 
ASSESSMENT SCHEDULE 
MAIN PHASE 
Screening period: 
The screening period is up to 6 weeks (+ 1 week), with 1 to 2 visits that are 
anticipated, depending on the duration of stable LMT dosing and the need for 
mandatory heFH genetic testing. 
Patients can be enrolled during this period as soon as eligibility is confirmed.   
Open-label dose finding treatment period: 
For Cohorts 1 to 3, visits schedule from entry into the open-label dose finding 
treatment period: baseline Visit (V2, Week 0) and then every 2 weeks (ie, Weeks 2, 
4, 6) until the end of the open-label dose finding period (Week 8). The visits at Week 
2 and Week 6 will take place either at the clinical site or patient’s home, depending 
upon local arrangements and preferences of the investigator/patient. 
For Cohort 4, visits schedule from entry into the open-label dose finding treatment 
period: baseline, Visit (V2, Week 0), and then every 4 weeks (ie, Weeks 0, 4, and 8) 
until the end of the open-label dose finding period (Week 12) will take place at the 
clinical site. Visits at Week 2 and Week 6 will be a phone call and at Week 10 will be 
at the clinical site. 
Follow-up period, only for Cohort 1 to Cohort 3: 
Follow-up visits will take place 6 and 10 weeks after the last alirocumab injection 
administered during the open-label dose-finding treatment period.  This corresponds 
to Week 12 and Week 16 for Cohorts 1 & 2 or Week 10 and Week 14 for Cohort 3.  
The Week 10 or Week 12 visit will be conducted through a phone call if there is no 
safety concern by the investigator. 
EXTENSION PHASE 
Open-label extension (OLE) period: 
After successful completion of Week 16 visit for Cohorts 1 & 2 or Week 14 visit for 
Cohort 3, patients will be offered entry into an optional OLE period.  The first visit of 
the OLE period will overlap with the final follow-up visit of the main phase.  Visits will 
take place at Week 20, Week 24, Week 28 and then every 12 weeks thereafter for 
assessments for Cohorts 1 & 2.  Visits will take place at Week 18, Week 22,  
Week 26 and then every 12 weeks thereafter for assessments for Cohort 3.  
Depending on the clinical supplies and/or alternative contingency plans, more 
frequent visits such as every 2 weeks (for Cohorts 1 & 2) or every 4 weeks (for 
Cohort 3) may be required. Visits will continue until visit end of OLE at least 2 or  
4 weeks after last alirocumab injection (with a follow-up phone call at least 10 weeks 
after the last alirocumab administration) before the initiation of the pediatric Phase 3 
study in the site where the patient is potentially participating or December 2018, 
whichever comes first.  A follow-up phone call will takes place at least 10 weeks 
after the last IMP of each cohort. 
All patients enrolled in Cohort 4 who successfully complete the open-label dose-
finding treatment period will also be offered either entry into the extension phase at 
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Week 12 or direct entry into the phase 3 study, depending on the start date of phase 
3 study in the site where patient is potentially participating. 
STATISTICAL 
CONSIDERATIONS 
Sample size determination: 
No power sample size calculations were performed for the main phase. A sample 
size of 10 patients per cohort is empirical and based on the sample size of the 
Phase 1 studies (R727-CL-904 and R727-CL-1001) conducted in adults. No less 
than 4 patients with BW <50 kg and no less than 4 patients with BW ≥50 kg will be 
enrolled in 4 independent cohorts (Cohort 1, Cohort 2, Cohort 3, and Cohort 4), 
which will allow the evaluation of the pharmacokinetics/pharmacodynamics (PK/PD) 
profile and safety of different alirocumab doses/dose regimen in each BW category 
and to compare with PK/PD profile and safety observed in adult patients. 
Analysis population: 
Efficacy analyses will be performed on the modified intent-to-treat (mITT) population 
defined as all patients receiving at least one dose or partial dose of alirocumab, with 
a baseline LDL-C available and with at least one LDL-C value available in the period 
from first alirocumab injection to last alirocumab injection + 21 days (for Cohorts 1 
and 2) or + 35 days (for Cohorts 3 and 4) during the main phase. 
Safety analyses will be performed on Safety population which consists of patients 
receiving at least one dose or partial dose of alirocumab. 
Primary analysis: 
There will be no formal statistical test for the primary endpoint, efficacy analyses will 
be descriptive. 
The primary analysis will be based on an on-treatment approach, and will use LDL-C 
values collected during the efficacy treatment period. The efficacy treatment period 
is defined as the period from first alirocumab injection to last alirocumab injection + 
21 days (for Cohorts 1 & 2) or + 35 days (for Cohorts 3 and 4) during the open-label 
dose finding treatment period. 
The percent change from baseline in calculated LDL-C at Week 8 will be analyzed in 
the mITT population using a mixed effect model with repeated measures (MMRM) 
approach. All on-treatment data available at Week 4 and Week 8 will be used and 
missing data will be accounted for by the MMRM model. The model will include the 
fixed categorical effects of alirocumab dose/dose regimen 30 mg Q2W (<50 kg), 
40 mg Q2W (<50 kg), 50 mg Q2W (≥50 kg), 75 mg Q2W (≥50 kg), 75 mg Q4W 
(<50 kg) ,150 mg Q4W (≥50 kg), 150 mg Q4W (<50 kg) and 300 mg Q4W (≥50 kg), 
time point (Week 4, Week 8), dose-by-time point interaction, as well as, the 
continuous fixed covariates of baseline LDL-C value and baseline value-by-time 
point interaction. 
LS mean with 95% confidence intervals will be provided for each alirocumab dose. 
In addition, LS mean with 95% confidence intervals will be provided for each cohort 
using appropriate contrasts. 
Additionally, for Cohort 4 only, the percent change from baseline in calculated LDL-C 
at Week 12 will be analyzed in the mITT population using the same MMRM model 
as for the primary endpoint but including all on-treatment corresponding data 
available at Week 4, Week 8, Week 10, and Week 12. 
Analysis of secondary endpoints: 
Secondary endpoints will be analyzed using the same MMRM model as for the 
primary endpoint. 
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Page 11 
DURATION OF STUDY 
PERIOD (per patient)  
MAIN PHASE 
For Cohorts 1 to 3, a study duration of approximately 16-23 weeks (screening 
period: up to 6 [+1] weeks, open-label dose finding treatment period: 8 weeks, 
follow-up period: 6-8 weeks). 
For Cohort 4, a study duration of approximately 14 -19 weeks (screening period: up 
to 6 [+1] weeks, open-label dose finding treatment period: 12 weeks). 
EXTENSION PHASE 
Patients who enroll in the open-label extension period will continue alirocumab 
administration until at least 10 weeks before the initiation of the pediatric  
Phase 3 study in the site where the patient is potentially participating. Therefore, 
patients who consent to participate to the pediatric phase 3 study could have their 
last alirocumab injection in the OLE period up to December 2018, depending on the 
timing of the phase 3 study. All other patients, enrolled in the OLE period, who 
decline participation in the phase 3 study, will have their last alirocumab injection in 
December 2018.  
For Cohorts 1 to 3, this corresponds to a maximum of approximately 24 months for 
first patients enrolled. 
For Cohort 4, this corresponds to a maximum of approximately 7 months for the first 
patients enrolled. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN (MAIN PHASE) 
1.1.1 COHORTS 1 TO 3 
 
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1.1.2 COHORT 4 
 
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1.2 
GRAPHICAL STUDY DESIGN (OPTIONAL EXTENSION PHASE) 
1.2.1 COHORTS 1 TO 3 
 
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1.2.2 COHORT 4 
 
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1.3 
STUDY FLOWCHART (MAIN PHASE) 
1.3.1 COHORTS 1 TO 3 
 Main Phase Cohorts 1 to 3 
Screening 
Period 
(including run-in 
if applicable) 
Open-Label Dose Finding Treatment Period 
Follow-Up Period 
VISIT 
1c 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1 
W2 
W4 
W6 
W8 
W10 (Cohort 3) 
or W12 
(Cohorts 1 & 2)  
W14 (Cohort 3) or 
W16 (Cohorts 1 & 
2) 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Clinical Site 
or Patient’s 
Homea 
Clinical Site 
Clinical Site or 
Patient’s 
Homea 
Clinical Site 
Clinical site or 
Phone Calla 
Clinical Site 
Informed Consent 
X 
 
 
 
 
 
 
 
heFH Genotyping Informed Consent (if 
needed) 
X 
 
 
 
 
 
 
 
Inclusion Criteria  
X 
X 
 
 
 
 
 
 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
 
 
Medical/Surgical/ Family medical History 
X 
 
 
 
 
 
 
 
Alcohol/Smoking habits 
X 
 
 
 
 
 
 
 
Prior Medication Historyr 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
Xd 
Xd 
 
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 Main Phase Cohorts 1 to 3 
Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose Finding Treatment Period 
Follow-Up Period 
VISIT 
1c 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1 
W2 
W4 
W6 
W8 
W10 (Cohort 3) 
or W12 
(Cohorts 1 & 2)  
W14 (Cohort 3) or 
W16 (Cohorts 1 & 
2) 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Clinical Site 
or Patient’s 
Homea 
Clinical Site 
Clinical Site or 
Patient’s 
Homea 
Clinical Site 
Clinical site or 
Phone Calla 
Clinical Site 
Measured Body Weight 
X 
X 
 
X 
 
X 
 
X 
Measured Height 
X 
 
 
 
 
 
 
X 
Tanner Stagesp 
X 
 
 
 
 
 
 
X 
IVRS/IWRS contact 
X 
X 
X 
X 
X 
 
 
X 
Inclusion  
 
X 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
Alirocumab Administration Q2W (Cohorts 1 & 
2)e 
 
X 
X 
X 
X 
 
 
 
Alirocumab Administration Q4W (Cohort 3 
only)e  
 
X 
 
X 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Review of diets 
X 
X 
 
X 
 
X 
 
 
Check of stability of background LMT  
X 
X 
X 
X 
X 
X 
 
 
 
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Page 18 
 Main Phase Cohorts 1 to 3 
Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose Finding Treatment Period 
Follow-Up Period 
VISIT 
1c 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1 
W2 
W4 
W6 
W8 
W10 (Cohort 3) 
or W12 
(Cohorts 1 & 2)  
W14 (Cohort 3) or 
W16 (Cohorts 1 & 
2) 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Clinical Site 
or Patient’s 
Homea 
Clinical Site 
Clinical Site or 
Patient’s 
Homea 
Clinical Site 
Clinical site or 
Phone Calla 
Clinical Site 
Efficacy: 
 
 
 
 
 
 
 
 
Total-C, calculated LDL-C, HDL-C, TG, non-
HDL-Cf 
X 
X 
 
X 
 
X 
 
 
Apo B, Apo A-1, ratio Apo B / Apo A-1, and 
Lp(a)f 
X 
X 
 
 
 
X 
 
 
Safety: 
 
 
 
 
 
 
 
 
AE /SAE  recording (if any) 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signst 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
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Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose Finding Treatment Period 
Follow-Up Period 
VISIT 
1c 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1 
W2 
W4 
W6 
W8 
W10 (Cohort 3) 
or W12 
(Cohorts 1 & 2)  
W14 (Cohort 3) or 
W16 (Cohorts 1 & 
2) 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Clinical Site 
or Patient’s 
Homea 
Clinical Site 
Clinical Site or 
Patient’s 
Homea 
Clinical Site 
Clinical site or 
Phone Callb 
Clinical Site 
Laboratory Testingf: 
 
 
 
 
 
 
 
 
heFH genotyping (Mandatory for consenting 
patients without documented heFH diagnosis; 
optional for documented heFH diagnosis 
patients wishing to undergo genotyping)g 
X 
X 
X 
X 
X 
X 
 
 
Hematology and chemistryh 
X 
 
 
X 
 
X 
 
Xq 
Creatine phosphokinase (CPK)  
X 
 
 
X 
 
X 
 
Xq 
Liver paneli 
X 
 
 
X 
 
X 
 
Xq 
Adrenal gland hormonesj 
 
X 
 
 
 
X 
 
 
Gonadal and pituitary hormonesk  
 
X 
 
 
 
X 
 
 
Fat soluble vitaminsl 
 
X 
 
 
 
X 
 
 
Pregnancy testm 
X 
X 
 
 
 
X 
 
X 
Anti-alirocumab antibodies (ADA)n  o 
 
X 
 
 
 
X 
 
Xo 
PCSK9 levels (free and total)/serum alirocumab 
concentration (PK) n 
 
X 
 
X 
 
X 
 
X 
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Page 20 
a The Week 2 and Week 6 visits will take place either at the clinical site or patient’s home, depending upon local arrangements and preferences of the Investigator/patient.  For Cohort 3, a phone call may be done 
instead of a home or office visit. 
b The Week 10 or Week 12 visit will be conducted at clinical site or through a phone call if no safety concerns by the investigator 
c Two site visits may be needed to complete eligibility confirmation.    
d Physical examination at the follow-up visits should be performed only in case of clinically relevant abnormality at Week 8 visit.   
e Alirocumab injections will be prepared from vials by the pharmacist (or equivalent).  For Cohorts 1 & 2 the Weeks 0 and 4 alirocumab injections will be administered at the clinical site by the site staff.  The Weeks 2 
and 6 alirocumab injections will be administered at the clinical site by the site staff or at the patient’s home by a health care professional, depending upon local arrangements and preferences of the 
Investigator/patient. For Cohort 3 the Weeks 0 and 4 alirocumab injections will be administered at the clinical site by the site staff, the Week 2 and  
Week 6 visits could be done at the patient’s home by a health care professional but without injections.  Prior to each alirocumab administration, a local topical anesthetic may be utilized as per the Investigator.   
f 
Prior to any laboratory testing, the site may utilize a local topical anesthetic as per the Investigator. In case only a limited amount of blood can be drawn, specific tests performed for each sample obtained will be 
prioritized. 
g Genotyping for heFH will be conducted from a specimen of whole blood, saliva, or buccal swab in patients consenting to undergo genotyping testing. This test will be recommended for all patients but will be 
mandatory only for patients without clinical diagnosis or no previous documented genotyping. In case of non-mandatory genotyping the sample could be taken preferentially during the screening period but could 
be done at any visit during the 8-week dose-finding part of the trial.   
h Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell count, white blood cell count with differential count, and platelets. Chemistry includes: glucose, sodium, 
potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate dehydrogenase (LDH), total protein, albumin, and γGT.   
i 
Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin.   
j 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN) and dehyroepiandrosterone sulfate (DHEAS).   
k Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  Gonadal hormones: testosterone [males] and estradiol [females].   
l 
Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone).   
m Pregnancy test should be done on females of childbearing potential who are sexually active or females who have experienced menarche.  The Screening (Week -2) pregnancy test should be a blood test.  All other 
pregnancy tests will be with a local urine pregnancy test.   
n ADA and PK samples should be collected before alirocumab administration.   
o Only patients who prematurely discontinue the main phase or do not enter the optional extension phase and have a titer at or above 240 for ADA at follow-up visit will have additional ADA samples, at 6 to 12 
months after the last alirocumab administration and thereafter, about every 3 to 6 months until titer returns below 240.   
p See Appendix E for Tanner stages evaluation.   
q Only in case of clinically relevant abnormal values at the end of the treatment visit (Week 8).   
r 
Document prior medication history within the previous 12 weeks, especially for lipid modifying therapy (including statin) and nutraceutical products that may affect lipids (eg, omega-3 fatty acids, plant stanols such 
as found in Benecol, flax seed oil, psyllium).   
s Patients will be instructed to follow a diet in accordance with the American Academy of Pediatrics guidelines or equivalent throughout the entire study.   
t 
Vital signs include: heart rate, systolic and diastolic BP in sitting position.   
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Page 21 
1.3.2 COHORT 4  
 Main Phase Cohort 4 
Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose-finding Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1b 
W2 
W4 
W6 
W8 
W10  
W12 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Phone Call 
Clinical Site 
Phone Call 
Clinical Site 
Clinical sitea 
Clinical Site 
Informed Consent 
X 
 
 
 
 
 
 
 
heFH Genotyping Informed Consent (if needed) 
X 
 
 
 
 
 
 
 
Inclusion Criteria  
X 
X 
 
 
 
 
 
 
Exclusion Criteria 
X 
X 
 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
 
 
Medical/Surgical/ Family medical History 
X 
 
 
 
 
 
 
 
Alcohol/Smoking habits 
X 
 
 
 
 
 
 
 
Prior Medication Historyo 
X 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
X 
 
 
Measured Body Weight 
X 
X 
 
X 
 
X 
 
X 
Measured Height 
X 
 
 
 
 
 
 
X 
Tanner Stagesn 
X 
 
 
 
 
 
 
X 
IVRS/IWRS contact 
X 
X 
 
 
 
 
 
X 
Inclusion  
 
X 
 
 
 
 
 
 
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Main Phase Cohort 4 
Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose-finding Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1b 
W2 
W4 
W6 
W8 
W10  
W12 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Phone Call 
Clinical Site  
Phone Call 
Clinical Site  
Clinical sitea 
Clinical Site 
Treatment: 
 
 
 
 
 
 
 
 
Alirocumab Administration Q4Wc 
 
X 
 
X 
 
X  
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
Review of dietp 
X 
X 
 
X 
 
X 
 
X 
Check of stability of background LMT  
X 
X 
X 
X 
X 
X 
 
X 
Efficacy: 
 
 
 
 
 
 
 
 
Total-C, calculated LDL-C, HDL-C, TG, non-HDL-Cd 
X 
X 
 
X 
 
X 
X 
X 
Apo B, Apo A-1, ratio Apo B / Apo A-1, and Lp(a)d  
X 
X 
 
 
 
X 
 
 
Safety: 
 
 
 
 
 
 
 
 
AE /SAE recording (if any) 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs q 
X 
X 
 
X 
 
X 
 
X 
 
 
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Page 23 
 Main Phase Cohort 4 
Screening 
Period 
(including run-
in if applicable) 
Open-Label Dose-finding Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
Week (W) 
Up to W-6 
W0/D1b 
W2 
W4 
W6 
W8 
W10  
W12 
Visit Window (+/- days) 
+7 
 
±3 
±3 
±3 
±3 
±7 
±7 
Visit Type 
Clinical Site 
Clinical Site 
Phone Call 
Clinical Site 
Phone Call 
Clinical Site  
Clinical Sitea 
Clinical Site 
Laboratory Testingd: 
 
 
 
 
 
 
 
 
heFH genotyping (Mandatory for consenting patients 
without documented heFH diagnosis; optional for 
documented heFH diagnosis patients wishing to 
undergo genotyping)e 
X 
X 
 
X 
 
X 
 
 
Hematology and chemistryf 
X 
 
 
X 
 
X 
 
 
Creatine phosphokinase (CPK)  
X 
 
 
X 
 
X 
 
 
Liver panelg 
X 
 
 
X 
 
X 
 
 
Adrenal gland hormonesh 
 
X 
 
 
 
X 
 
 
Gonadal and pituitary hormonesi 
 
X 
 
 
 
X 
 
 
Fat soluble vitaminsj 
 
X 
 
 
 
X 
 
 
Pregnancy testk 
X 
X 
 
 
 
X 
 
X 
Anti-alirocumab antibodies (ADA)l m 
 
X 
 
 
 
X 
 
 
PCSK9 levels (free and total)/serum alirocumab 
concentration (PK) l 
 
X 
 
X 
 
X 
X 
X 
a The Week 0, 4, 8, 10 and 12 visits will take place at the clinical site. For Week 2 and Week 6, a phone call may be done instead of a home or office visit. 
b Two site visits may be needed to complete eligibility confirmation.  
c The Week 0, 4 and 8 alirocumab injections will be administered at the clinical site by the site staff. Prior to each alirocumab administration, a local topical anesthetic may be utilized as per the Investigator, if at 
clinical site  
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d Prior to any laboratory testing, the site may utilize a local topical anesthetic as per the Investigator. In case only a limited amount of blood can be drawn, specific tests performed for each sample obtained will be 
prioritized. 
e Genotyping for heFH will be conducted from a specimen of whole blood, saliva, or buccal swab in patients consenting to undergo genotyping testing. This test will be recommended for all patients but will be 
mandatory only for patients without clinical diagnosis or no previous documented genotyping. In case of non-mandatory genotyping the sample could be taken preferentially during the screening period but could 
be done at any visit during the 8-week dose-finding part of the trial.   
f 
Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell count, white blood cell count with differential count, and platelets. Chemistry includes: glucose, sodium, 
potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate dehydrogenase (LDH), total protein, albumin, and γGT.   
g Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin.   
h Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN) and dehyroepiandrosterone sulfate (DHEAS).   
i 
Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  Gonadal hormones: testosterone [males] and estradiol [females].   
j 
Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone).   
k Pregnancy test should be done on females of childbearing potential who are sexually active or females who have experienced menarche.  The Screening (Week -2) pregnancy test should be a blood test.  All other 
pregnancy tests will be with a local urine pregnancy test.   
l 
ADA and PK samples should be collected before alirocumab administration.   
m Only patients who prematurely discontinue the main phase or do not enter the optional extension phase and have a titer at or above 240 for ADA at follow-up visit will have additional ADA samples, at 6 to 12 
months after the last alirocumab administration and thereafter, about every 3 to 6 months until titer returns below 240.   
n See Appendix E for Tanner stages evaluation.   
o Document prior medication history within the previous 12 weeks, especially for lipid modifying therapy (including statin) and nutraceutical products that may affect lipids (eg, omega-3 fatty acids, plant stanols such 
as found in Benecol, flax seed oil, psyllium).   
p Patients will be instructed to follow a diet in accordance with the American Academy of Pediatrics guidelines or equivalent throughout the entire study.   
q Vital signs include: heart rate, systolic and diastolic BP in sitting position.   
 
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Page 25 
1.4 
STUDY FLOW CHART (EXTENSION PHASE) 
1.4.1 COHORTS 1 TO 3 
 
Open-Label Extension (OLE) Perioda 
 Extension Phase Cohorts 1 to 3 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
ALL 
Cohorts 
Week (W) 
W14 
W16 
W18, 
W22 
W20,  
W24 
W26, 
W50, 
W74, 
W98, 
W120 
W28, 
W52, 
W76, 
W100, 
W124 + 
W38, 
W62, 
W86, 
W110 + 
W40, 
W64, 
W88, 
W112+ 
W130 
(End of 
OLEc) 
Visit Number 
8b 
9, 10 
11, 13, 15, 17, 19 
12, 14, 16, 18 
20 
ALL Cohorts 
Follow-up 
Phone contact 
at least 
10 weeks after 
last IMP for 
each cohort 
Visit Window (+/- days) 
 
±7 
 
±7 
±14 
±14 
±7 
±7 
Eligibility requirementd 
X 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
X 
X 
 
Body Weight 
 
 
 
 
 
 
X 
X 
 
Height 
 
 
 
 
 
 
X 
X 
 
Tanner Stagesq 
X 
 
 
 
 
X 
X 
 
IVRS/IWRS contact 
X 
 
 
X 
X 
X 
X 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
Alirocumab Injection - VIALS (If Applicable)e 
 
 
 
Injection Training (If Applicable)f 
X 
 
 
Alirocumab Kit Dispensation (If Applicable)g 
X 
 
 
X 
X 
 
 
Alirocumab Injection – PREFILLED SYRINGE (If Applicable)h 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
Review of diet 
X 
X 
X 
X 
X 
 
Compliance check of alirocumab injections (prefilled syringe – 
if applicable) 
 
 
X 
X 
X 
X 
 
Diary r 
X 
X 
X 
X 
X 
 
Check of stability of background LMT  
X 
X 
X 
X 
X 
 
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Page 26 
 
Open-Label Extension (OLE) Perioda 
 Extension Phase Cohorts 1 to 3 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
Cohort 3 
Cohort 1 
& 2 
ALL 
Cohorts 
Week (W) 
W14 
W16 
W18, 
W22 
W20,  
W24 
W26, 
W50, 
W74, 
W98, 
W120 
W28, 
W52, 
W76, 
W100, 
W124 + 
W38, 
W62, 
W86, 
W110 + 
W40, 
W64, 
W88, 
W112+ 
W130 
(End of 
OLEc) 
Visit Number 
8b 
9, 10 
11, 13, 15, 17, 19 
12, 14, 16, 18 
20 
ALL Cohorts 
Follow-up 
Phone contact 
at least 
10 weeks after 
last IMP for 
each cohort 
Visit Window (+/- days) 
 
±7 
 
±7 
±14 
±14 
±7 
±7 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
Total-C, calculated LDL-C, HDL-C, TG, non-HDL-Ci 
X 
 
 
X 
X 
X 
 
Apo B, Apo A-1, ratio Apo B / Apo A-1, and Lp(a)i 
X 
 
 
X 
X 
X 
 
Safety: 
 
 
 
 
 
 
 
 
 
 
AE /SAE recording (if any) 
 
 
X 
X 
X 
X 
X 
Vital Signs 
 
 
 
 
 
 
X 
X 
 
Laboratory Testingi: 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistryj 
 
 
 
 
X 
 
 
X 
 
Creatine phosphokinase (CPK)  
 
 
 
 
X 
 
 
X 
 
Liver panelk 
 
 
 
 
X 
 
 
X 
 
Anti-alirocumab antibodies (ADA) 
 
 
 
 
X 
 
 
X 
 
Adrenal gland hormonesm 
 
 
 
 
X 
 
 
Xl 
 
Gonadal and pituitary hormonesn 
 
 
 
 
X 
 
 
X 
 
Fat soluble vitaminso 
 
 
 
 
X 
 
 
X 
 
Pregnancy testp 
X 
 
 
X 
X 
X 
 
a Alirocumab injections may be prepared from vials by the pharmacist (or equivalent) or supplied as prefilled syringes (PFS) depending on availability and additional considerations. If the PFS is available in the 
extension phase, then patients may either switch from vials to PFS or directly initiate PFS (depending on patient’s date of entry into the extension phase).  If the PFS is not available in the extension phase, then 
alirocumab injections prepared from vials will be administered at the site (by the site staff) or at the patient’s home or another preferred location contingent upon alternative arrangements being made for such an 
administration. Depending on the clinical supplies and/or alternative contingency plans, more frequent clinic visits such as every 2 weeks or every 4 weeks may be required for alirocumab administration in addition 
to the scheduled visits noted in the flowchart.    
b The first visit of the OLE period from the extension phase will overlap with the final visit of the follow-up period from the main phase. 
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c The end of open-label extension period visit will take place at least 2 or 4 weeks after the last alirocumab administration (with a follow-up phone call at least 10 weeks after the last alirocumab administration) 
before the initiation of the pediatric Phase 3 study in the site where the patient is potentially participating or December 2018, whichever comes first.  
d In order to enter into the extension phase, the patient must successfully complete the main phase including the 8 week open-label dose finding treatment period. 
e Alirocumab administration will occur every 2 weeks or every 4 weeks.  Prior to each alirocumab administration, a local anesthetic may be utilized (as per the Investigator). Alirocumab injections prepared from vials 
by the pharmacist (or equivalent) will be administered at the clinical site (by the site staff) or at the patient’s home or another preferred location contingent upon alternative arrangements being made for such an 
administration. The last scheduled injection will take place 2 weeks or 4 weeks before the end-of-OLE visit for the Q2W regimen or Q4W regimen, respectively.   
f 
Patients who will switch to or directly initiate prefilled syringes, will undergo training prior to alirocumab administration. The parent/guardian or patient (if appropriate) will be trained to administer the injections with 
the use of open-label alirocumab injection. Additional visits for training can take place at the discretion of the Investigator or parent/guardian. Other relevant training information will also be provided such as storage 
of device, etc. Patients will also have the option of dose administration at home by a health care professional, depending on local arrangements and preferences of the investigator/patient. 
g Patients who will switch to or directly initiate prefilled syringes (PFS), should have a kit(s) dispensed containing alirocumab PFS.  Along with kit dispensation, the treatment administration package should be given 
as well as the patient diary and injection instruction manual, as needed. 
h Patients who will switch to or directly initiate prefilled syringes, will have alirocumab administration every 2 weeks or every 4 weeks at home or another preferred location.  Prior to each alirocumab administration, a 
local anesthetic may be utilized that has been provided by the site.  
i 
Prior to any laboratory testing, the site may utilize a local anesthetic as per the Investigator. 
j 
Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell count, white blood cell count with differential count, and platelets. Chemistry includes: glucose, sodium, 
potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate dehydrogenase (LDH), total protein, albumin, and γGT. 
k Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin. 
l 
Only patients who prematurely discontinue the extension phase or decide not to proceed to the Phase 3 study and have a titer at or above 240 for ADA at end-of-OLE visit will have additional ADA samples, at 6 to 
12 months after the last alirocumab administration and thereafter, about every 3 to 6 months until titer returns below 240. 
m Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol<LLN) and dehyroepiandrosterone sulfate (DHEAS). 
n Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  Gonadal hormones: testosterone [males] and estradiol [females]. 
o Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone). 
p Pregnancy test with a local urine pregnancy test should be done on females of childbearing potential who are sexually active or females who have experienced menarche. 
q See Appendix E for Tanner stages evaluation. 
r 
Diary completion starts from Pre-filled Syringe dispensation. 
 
 
 
 
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1.4.2 COHORT 4 
Extension Phase Cohort 4 
Open-Label Extension (OLE) Period 
Week (W) 
W12 
W16,  
W20 o 
W24 
W36  
W48 
(EOS/End of 
OLEb) 
Follow-up Phone 
contact at least 
10 weeks after 
last IMP 
Visit Number 
8 a 
9, 10 
11 
12 
13 (or Visit 20 
for eCRF) 
14 
Visit Window (+/- days) 
 
±7 
±14 
±14 
±7 
±7 
Eligibility requirement c 
X 
 
 
 
 
 
Physical Examination 
 
 
 
X 
X 
 
Body Weight 
X 
 
 
X 
X 
 
Height 
X 
 
 
X 
X 
 
Tanner Stages m 
X 
 
 
X 
X 
 
IVRS/IWRS contact 
X 
 
X 
X 
X 
 
Treatment: 
 
 
 
 
 
 
Alirocumab Injection – PREFILLED SYRINGEd 
X 
X 
X 
X 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
Review of diet 
X 
X 
X 
X 
X 
 
Compliance check of alirocumab injections (prefilled syringe 
– if applicable) 
 
X 
X 
X 
X 
 
Diaryn 
X 
Xo 
X 
X 
X 
 
Check of stability of background LMT  
X 
X 
X 
X 
X 
 
Efficacy: 
 
 
 
 
 
 
Total-C, calculated LDL-C, HDL-C, TG, non-HDL-Ce 
X 
 
X 
X 
X 
 
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Extension Phase Cohort 4 
Open-Label Extension (OLE) Period 
Week (W) 
W12 
W16,  
W20 o 
W24 
W36  
W48 
(EOS/End of 
OLEb) 
Follow-up Phone 
contact at least 
10 weeks after 
last IMP 
Visit Number 
8 a 
9, 10 
11 
12 
13 (or Visit 20 
for eCRF) 
14 
Visit Window (+/- days) 
 
±7 
±14 
±14 
±7 
±7 
Safety: 
 
 
 
 
 
 
AE /SAE recording (if any) 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
X 
X 
 
Laboratory Testing e: 
 
 
 
 
 
 
Hematology and chemistryf 
 
 
X 
 
X 
 
Creatine phosphokinase (CPK)  
 
 
X 
 
X 
 
Liver panel g 
 
 
X 
 
X 
 
Anti-alirocumab antibodies (ADA) h 
X 
 
X 
 
X 
 
Adrenal gland hormones i 
 
 
X 
 
Xh 
 
Gonadal and pituitary hormones j 
 
 
X 
 
X 
 
Fat soluble vitamins k 
 
 
X 
 
X 
 
Pregnancy test l 
X 
 
X 
X 
X 
 
a The first visit of the OLE period from the extension phase will overlap with the final visit of the 12-week dose-finding treatment period. 
b The end of open-label extension period visit will take place at least 4 weeks after the last alirocumab administration (with a follow-up phone call at least 10 weeks after the last alirocumab administration) before the 
initiation of the pediatric Phase 3 study in the site where the patient is potentially participating or December 2018 at the latest.  
c In order to enter into the extension phase, the patient must successfully complete the 12-week open-label dose-finding treatment period. 
d Alirocumab administration will occur every 4 weeks.  Prior to each alirocumab administration, a local anesthetic may be utilized (as per the Investigator). Alirocumab injections through PFS will be administered at 
the clinical site (by the site staff). The last scheduled injection will take place 4 weeks before the end-of-OLE visit.   
e Prior to any laboratory testing, the site may utilize a local anesthetic as per the Investigator. 
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f 
Hematology includes: complete blood cell count (CBC) including hematocrit, hemoglobin, red blood cell count, white blood cell count with differential count, and platelets. Chemistry includes: glucose, sodium, 
potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen, creatinine, uric acid, lactate dehydrogenase (LDH), total protein, albumin, and γGT. 
g Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin. 
h Only patients who prematurely discontinue the extension phase or decide not to proceed to the Phase 3 study and have a titer at or above 240 for ADA at end-of-OLE visit will have additional ADA samples, at 6 to 
12 months after the last alirocumab administration and thereafter, about every 3 to 6 months until titer returns below 240. 
i 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol<LLN) and dehyroepiandrosterone sulfate (DHEAS). 
j 
Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH).  Gonadal hormones: testosterone [males] and estradiol [females]. 
k Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone). 
l 
Pregnancy test with a local urine pregnancy test should be done on females of childbearing potential who are sexually active or females who have experienced menarche. 
m See Appendix E for Tanner stages evaluation. 
n Diary completion. 
o Phone Call Option 
 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................12 
1.1 
GRAPHICAL STUDY DESIGN (MAIN PHASE) ............................................................................12 
1.1.1 
COHORTS 1 TO 3 .........................................................................................................................12 
1.1.2 
COHORT 4.....................................................................................................................................13 
1.2 
GRAPHICAL STUDY DESIGN (OPTIONAL EXTENSION PHASE) .............................................14 
1.2.1 
COHORTS 1 TO 3 .........................................................................................................................14 
1.2.2 
COHORT 4.....................................................................................................................................15 
1.3 
STUDY FLOWCHART (MAIN PHASE) .........................................................................................16 
1.3.1 
COHORTS 1 TO 3 .........................................................................................................................16 
1.3.2 
COHORT 4.....................................................................................................................................21 
1.4 
STUDY FLOW CHART (EXTENSION PHASE) ............................................................................25 
1.4.1 
COHORTS 1 TO 3 .........................................................................................................................25 
1.4.2 
COHORT 4.....................................................................................................................................28 
2 
TABLE OF CONTENTS ................................................................................................................31 
3 
LIST OF ABBREVIATIONS ..........................................................................................................38 
4 
INTRODUCTION AND RATIONALE.............................................................................................40 
5 
STUDY OBJECTIVES ...................................................................................................................49 
5.1 
PRIMARY.......................................................................................................................................49 
5.2 
SECONDARY ................................................................................................................................49 
6 
STUDY DESIGN ............................................................................................................................50 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................50 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................54 
6.2.1 
Duration of study participation for each patient .............................................................................54 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................55 
6.3 
INTERIM ANALYSIS......................................................................................................................55 
6.4 
STUDY COMMITTEES..................................................................................................................55 
7 
SELECTION OF PATIENTS..........................................................................................................57 
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7.1 
INCLUSION CRITERIA..................................................................................................................57 
7.2 
EXCLUSION CRITERIA ................................................................................................................58 
7.2.1 
Exclusion criteria related to study methodology ............................................................................58 
7.2.2 
Exclusion criteria related to mandatory background therapies......................................................59 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................59 
7.2.4 
Additional exclusion criteria during or at the end of screening or run-in phase before 
inclusion .........................................................................................................................................60 
7.3 
EXCLUSION CRITERIA FOR THE OPEN-LABEL EXTENSION TREATMENT PERIOD............60 
7.3.1 
Exclusion criteria related to study methodology ............................................................................60 
7.3.2 
Exclusion criteria related to the current knowledge of alirocumab ................................................60 
8 
STUDY TREATMENTS .................................................................................................................61 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................61 
8.1.1 
Route and method of administration..............................................................................................63 
8.1.2 
Timing of administration.................................................................................................................64 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................65 
8.3 
BLINDING PROCEDURES............................................................................................................65 
8.3.1 
IMP.................................................................................................................................................65 
8.3.2 
Lipid parameters ............................................................................................................................65 
8.3.3 
Anti-alirocumab antibodies.............................................................................................................66 
8.3.4 
Committee......................................................................................................................................66 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................66 
8.5 
PACKAGING AND LABELING ......................................................................................................67 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................68 
8.7 
RESPONSIBILITIES ......................................................................................................................68 
8.7.1 
Treatment accountability and compliance .....................................................................................69 
8.7.2 
Return and/or destruction of treatments ........................................................................................69 
8.8 
CONCOMITANT MEDICATION.....................................................................................................70 
8.8.1 
Management of background lipid modifying therapy .....................................................................70 
8.8.2 
Contraception:................................................................................................................................71 
8.8.3 
Prohibited concomitant medications ..............................................................................................71 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................72 
9.1 
PRIMARY ENDPOINT ...................................................................................................................72 
9.1.1 
Primary efficacy endpoint...............................................................................................................72 
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9.2 
SECONDARY ENDPOINTS ..........................................................................................................72 
9.2.1 
Secondary efficacy endpoint(s)......................................................................................................72 
9.2.2 
Efficacy assessment method .........................................................................................................73 
9.2.2.1 
Lipid parameters ............................................................................................................................73 
9.2.3 
Safety endpoints ............................................................................................................................73 
9.2.3.1 
Observation period.........................................................................................................................73 
9.2.3.2 
Adverse event ................................................................................................................................74 
9.2.3.3 
Safety laboratory............................................................................................................................75 
9.2.4 
Vital signs measurement................................................................................................................75 
9.2.5 
Tanner stages measurement.........................................................................................................75 
9.3 
OTHER ENDPOINTS ....................................................................................................................75 
9.3.1 
ANTI-ALIROCUMAB ANTIBODY ASSESSMENTS ......................................................................75 
9.3.1.1 
Sampling time ................................................................................................................................75 
9.3.1.2 
Sampling procedure.......................................................................................................................76 
9.3.1.3 
Bioanalytical method......................................................................................................................76 
9.4 
OTHER ENDPOINTS ....................................................................................................................76 
9.4.1 
Pharmacokinetics...........................................................................................................................76 
9.4.1.1 
Sampling time ................................................................................................................................76 
9.4.1.2 
Pharmacokinetics handling procedure...........................................................................................76 
9.4.1.3 
Bioanalytical method......................................................................................................................77 
9.4.2 
Pharmacogenetic assessment.......................................................................................................77 
9.4.3 
Pharmacodynamic variables..........................................................................................................77 
9.4.4 
Efficacy and safety during the extension phase ............................................................................77 
9.5 
FUTURE USE OF SAMPLES........................................................................................................77 
9.6 
APPROPRIATENESS OF MEASUREMENTS..............................................................................77 
10 
STUDY PROCEDURES ................................................................................................................78 
10.1 
VISITS SCHEDULE .......................................................................................................................80 
10.1.1 
Screening period............................................................................................................................80 
10.1.2 
Dose finding Treatment Period ......................................................................................................82 
10.1.2.1 Inclusion visit (Visit 2/Week 0/Day 1) at clinical site ......................................................................83 
10.1.2.2 Visit 3/Week 2, (Day 14 ±3) at clinical site or nurse visit at patient’s home.  For Cohort 3 
and Cohort 4, a phone call may be done instead. .........................................................................84 
10.1.2.3 Visit 4/Week 4 (Day 28 ±3) at clinical site......................................................................................84 
10.1.2.4 Visit 5/Week 6 (Day 42 ±3) at clinical site or nurse visit at patient’s home. For Cohorts 3 
and 4, a phone call may be done instead......................................................................................85 
10.1.2.5 Visit 6/Week 8 (Day 56 ±3)/ at clinical site (end of the OL dose finding treatment period) ...........85 
10.1.2.6 Visit 7/Week 10 (Day 70 ±7) at clinical site (Cohort 4 Only):.........................................................86 
10.1.2.7 Visit 8/Week 12 (end of the OL dose finding treatment period) (Cohort 4 only)............................86 
10.1.3 
Follow-Up Period............................................................................................................................87 
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10.1.3.1 First Follow-Up Visit (Visit 7 / Week 10/Day 70 ±7 [Cohort 3] / Week 12/Day 84 ±7 [Cohorts 
1 & 2]) at clinical site or phone call if no safety concerns by the investigator at the previous 
visit or between the 2 visits “visit 6” and “visit 7”............................................................................87 
10.1.3.2 Second Follow-Up Visit (Visit 8 / Week 14 for Cohort 3/Day 98 ±7/ Week 16 for Cohorts 1 
& 2 / Day 112 ±7) at clinical site (end of the main study period). ..................................................87 
10.1.4 
Open label extension treatment period (OLETP, optional)............................................................88 
10.1.4.1 Visit 8/Week 16 for Cohorts 1 & 2 or Visit 8/Week 14 for Cohort 3 /Week 12 for Cohort 4 
(same visit as the last visit of the main treatment period)..............................................................88 
10.1.4.2 Visit 9/Week 20 for Cohorts 1 & 2 /Week 18 for Cohort 3/Week 16 for Cohort 4 (Phone Call 
Option) ...........................................................................................................................................90 
10.1.4.3 Visit 10/Week 24 for Cohorts 1 & 2 /Week 22 for Cohort 3/Week 20 for Cohort 4 (Phone 
Call Option) ....................................................................................................................................90 
10.1.4.4 Visits 11, 13, 15, 17, 19 (every 24 weeks)/ Visit 11 only for Cohort 4 ...........................................90 
10.1.4.5 Visits 12, 14, 16, 18 (every 24 weeks)/ Visit 12 only for Cohort 4 .................................................91 
10.1.4.6 Visit 20, Week 130 for Cohorts 1 to 3/EOS, Week 48 for Cohort 4 [Visit 13 for Study Flow 
Chart, Main Phase or Visit 20 for eCRF (end of open-label extension period)] ............................92 
10.1.4.7 Follow-up Phone contact at least 10 weeks after the last IMP injection for all cohorts.................93 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................93 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................94 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................95 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s)...........................95 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................95 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................96 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................97 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................97 
10.4.1 
Definitions of adverse events.........................................................................................................97 
10.4.1.1 Adverse event ................................................................................................................................97 
10.4.1.2 Serious adverse event ...................................................................................................................98 
10.4.1.3 Adverse event of special interest...................................................................................................99 
10.4.1.4 Local injection site reactions........................................................................................................100 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.....................................................................................................................................100 
10.4.3 
General guidelines for reporting adverse events.........................................................................100 
10.4.4 
Instructions for reporting serious adverse events........................................................................101 
10.4.5 
Guidelines for reporting adverse events of special interest.........................................................102 
10.4.6 
Guidelines for management of specific laboratory abnormalities................................................102 
10.5 
OBLIGATIONS OF THE SPONSOR ...........................................................................................102 
10.6 
SAFETY INSTRUCTIONS...........................................................................................................103 
10.6.1 
Local tolerability (local injection site reactions)............................................................................103 
10.6.2 
Allergic adverse events................................................................................................................103 
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10.6.2.1 Allergic adverse event with cutaneous involvement ....................................................................103 
10.6.2.2 Acute allergic injection reactions..................................................................................................104 
10.6.3 
Recommendations for managing and monitoring patients with very low LDL-C levels (ie, 
LDL-C<50 mg/dL [1.30 mmol/L]) during the OLE period.............................................................104 
10.7 
ADVERSE EVENTS MONITORING............................................................................................105 
11 
STATISTICAL CONSIDERATIONS............................................................................................106 
11.1 
DETERMINATION OF SAMPLE SIZE.........................................................................................106 
11.2 
DISPOSITION OF PATIENTS .....................................................................................................106 
11.3 
ANALYSIS POPULATIONS.........................................................................................................106 
11.3.1 
Efficacy populations .....................................................................................................................106 
11.3.1.1 Modified intent-to-treat population ...............................................................................................106 
11.3.2 
Safety population .........................................................................................................................107 
11.3.3 
Other analysis population ............................................................................................................107 
11.4 
STATISTICAL METHODS ...........................................................................................................107 
11.4.1 
Extent of study treatment exposure and compliance...................................................................107 
11.4.1.1 Extent of investigational medicinal product exposure..................................................................107 
11.4.1.2 Compliance ..................................................................................................................................108 
11.4.2 
Analyses of efficacy endpoints.....................................................................................................108 
11.4.2.1 Analysis of primary efficacy endpoint(s) ......................................................................................108 
11.4.2.2 Analyses of secondary efficacy endpoints...................................................................................109 
11.4.2.3 Multiplicity considerations ............................................................................................................109 
11.4.3 
Analyses of safety data................................................................................................................109 
11.4.3.1 Adverse events ............................................................................................................................110 
11.4.3.2 Laboratory data and vital signs....................................................................................................110 
11.4.4 
Analyses of other endpoints.........................................................................................................111 
11.4.5 
Analyses of Patient Reported Outcomes (Health-related Quality of Life/health economics 
variables.......................................................................................................................................111 
11.5 
INTERIM ANALYSIS....................................................................................................................111 
12 
ETHICAL AND REGULATORY CONSIDERATIONS.................................................................112 
12.1 
ETHICAL AND REGULATORY STANDARDS............................................................................112 
12.2 
INFORMED CONSENT ...............................................................................................................112 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ............113 
13 
STUDY MONITORING ................................................................................................................114 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).....................................................................114 
13.2 
RESPONSIBILITIES OF THE SPONSOR...................................................................................114 
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13.3 
SOURCE DOCUMENT REQUIREMENTS..................................................................................114 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST....................................................................................................................................115 
13.5 
USE OF COMPUTERIZED SYSTEMS........................................................................................115 
14 
ADDITIONAL REQUIREMENTS.................................................................................................116 
14.1 
CURRICULUM VITAE .................................................................................................................116 
14.2 
RECORD RETENTION IN STUDY SITES ..................................................................................116 
14.3 
CONFIDENTIALITY .....................................................................................................................116 
14.4 
PROPERTY RIGHTS...................................................................................................................117 
14.5 
DATA PROTECTION...................................................................................................................117 
14.6 
INSURANCE COMPENSATION..................................................................................................117 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ...............................118 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE..........................................................................................................................................118 
14.8.1 
By the Sponsor.............................................................................................................................118 
14.8.2 
By the Investigator .......................................................................................................................119 
14.9 
CLINICAL TRIAL RESULTS........................................................................................................119 
14.10 
PUBLICATIONS AND COMMUNICATIONS ...............................................................................119 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................120 
16 
BIBLIOGRAPHIC REFERENCES...............................................................................................121 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
AAP: 
American Academy of Pediatrics, American Academy of Pediatrics 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase, alkaline phosphatase 
ALT: 
alanine aminotransferase 
Apo: 
apolipoprotein 
AST: 
aspartate aminotransferase 
BW: 
body weight 
CHD: 
coronary heart disease 
cIMT: 
intima media thickness of the carotid artery 
CPK: 
creatinine phosphokinase 
CSR: 
clinical study report 
CV/CVD: 
cardiovascular/cardiovascular disease 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid 
DRF: 
discrepancy resolution form 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
ELISA: 
enzyme linked immuno-sorbent assay 
FH: 
familial hypercholesterolemia 
GCP: 
good clinical practice 
HDL-C: 
high density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HLGT: 
high level group term 
ICF: 
informed consent form 
ICH: 
International Conference on Harmonisation 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDH: 
lactate dehydrogenase 
LDL-C: 
low density lipoprotrein cholesterol 
LDL-R: 
low density lipoprotein receptor 
LLN: 
lower limit of normal range 
LMT: 
lipid modifying therapy 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mITT: 
modified intent-to-treat  
MMRM: 
mixed-effect model with repeated measures 
PCSA: 
potentially clinically significant abnormality 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PD: 
pharmacodynamics 
PFS: 
prefilled syringe 
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PK: 
pharmacokinetics 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SOC: 
system organ class  
TG: 
triglycerides 
ULN: 
upper limit of normal range 
γGT: 
gamma-glutamyl transferase 
 
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4 
INTRODUCTION AND RATIONALE 
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by 
severely elevated levels of low-density lipoprotein cholesterol (LDL-C) that lead to premature 
atherosclerosis and cardiovascular disease (CVD) (2). This disorder 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 low 
density lipoprotein receptor (LDL-R) that removes LDL-C from the circulation, and less 
commonly, in the gene for apolipoprotein (Apo) B, which is the major protein of the LDL-C 
particle. In rare cases, the gene coding for PCSK9, an enzyme involved in degrading the LDL-R 
(gain of function mutation), is mutated. Additionally, rare mutations in LDL receptor adaptor 
protein 1 (LDLRAP1), a protein which interacts with the LDL receptor or signal transducing 
adaptor family member 1 (STAP1) gene have been noted.  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 CVD. 
FH is the most clearly documented to have important cardiovascular consequences beginning in 
childhood (3). Even though cardiovascular events are rare in childhood, children with heFH 
already have functional and morphological changes of the vessel wall as illustrated by an impaired 
flow-mediated dilatation of the brachial artery (4) and an increased intima media thickness of the 
carotid artery (cIMT), with a progression rate for cIMT of approximately double to that observed 
in unaffected siblings (3, 5).  Both are surrogate markers for atherosclerotic vascular disease (6) 
and, thus, indicate that the atherosclerotic process has already been initiated early in childhood. 
Indeed, there is now strong evidence that lesions of atherosclerosis found in adults begin in 
childhood and are progressive throughout the life span (7, 8). These findings strongly suggest that 
to be effective at preventing Coronary Heart Disease (CHD), prevention must begin decades prior 
to the onset of symptoms (9). 
Because of the high risk of progression to premature clinical CVD associated with these findings, 
pediatric guidelines recommend LDL-C lowering intervention and specific lipid targets for 
children and adolescents with heFH. An LDL-C level of <130 mg/dL (3.4 mmol/L) is considered 
acceptable and <110 mg/dL (2.85 mmol/L) ideal for children with heFH (10, 11, 12, 1), or the 
achievement of ≥50% reduction in LDL cholesterol (10). 
Recently, the American Heart Association (AHA) has modified the guidelines, suggesting statins 
supplant bile acid sequestrants not only as first-line treatment but also at a younger age (8 versus 
10 years of age) (10). These revised recommendations were supported by the American Academy 
of Pediatrics (AAP) (1), as well as and in the recommendations from the National Lipid 
Association Expert Panel on Familial Hypercholesterolemia, in which it is mentioned that statins 
are the preferred initial pharmacologic treatment in children with FH (13). The highest doses of 
statins tested in pediatric studies resulted in LDL-C reductions of 24% for pravastatin (14), 
27% for lovastatin (15), 40% for atorvastatin (16), and 41% for simvastatin (17). However, use of 
these statins generally does not result in the attainment of the stringent LDL-C target as illustrated 
by the study conducted with atorvastatin in children (16) where the highest dose tested (20 mg) 
resulted in only 60% of the patients who still did not achieve the optimal LDL-C goal of 
110 mg/dL (2.85 mmol/L), reflecting the difficulty in meeting this target in many FH patients. 
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Another 1-year study with rosuvastatin conducted in children with FH aged 10 to 17 years showed 
a 50% reduction in LDL-C with the highest dose of 20 mg, and less than half (40%) of subjects 
reached the more stringent LDL-C goal of 110 mg/dL (2.85 mmol/L) (18). Therefore, novel 
compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. 
Limited data are available for the combination of ezetimibe and simvastatin (19) and are 
consistent with studies conducted in adults, showing an incremental decrease of approximately 
15% in LDL-C levels compared with administration of simvastatin alone. With the highest dose 
of simvastatin (40 mg), significantly more subjects, achieved an LDL-C target of 130 mg/dL 
(3.4 mmol/L) and the optimal LDL-C goal of 110 mg/dL (2.85 mmol/L) in the coadministration 
of ezetimibe with 40 mg simvastatin group than in the simvastatin 40 mg monotherapy group, 
77% vs 53% and 63% vs 27%, respectively (p <0.01 for both comparisons). However the 
therapeutic management of this population requires a careful balance between increased dosing 
(administration of this high simvastatin dose) and potential side effects vs. achieving treatment 
goals. 
Very little information is available on statin intolerance in the pediatric population.  This is likely 
related to the small size or the limited duration of the studies conducted with statins, adverse 
events such as muscle symptoms, Creatine Phosphokinase (CPK) increase, or elevations in 
Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) were reported in some 
patients (20). Therefore statin intolerance in pediatric population cannot be ruled out. This is 
acknowledged by the NICE guidance that recommends to healthcare professionals to consider 
offering non-statin Lipid modifying therapy (LMT) for lowering LDL-C levels in children and 
young people with FH who are intolerant of statins (11). Presently available non statin LMTs 
commonly prescribed in the pediatric population, more particularly ezetimibe and colesevalam, 
appear less effective than statins on LDL-C lowering, and therefore similar issues are met with 
regard to achieving treatment goals. 
Introduction to proprotein convertase subtilisin kexin type 9 (PCSK9): 
Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the subtilisin family of serine 
proteases and is highly expressed in the liver.  PCSK9 is involved in regulating the levels of the 
low-density lipoprotein receptor (LDL-R) protein (21, 22). Once PCSK9 is secreted into plasma it 
directly binds to the LDL-R and promotes its degradation.  The increased degradation of LDLRs 
leads to a reduced LDL-C removal and, therefore higher LDL-C circulating levels.  Experiments 
with mice have shown that increasing PCSK9 protein levels decreases levels of LDL-R protein in 
the liver while PCSK9 knockout mice have increased levels of LDL-R in the liver (23, 24).  
In humans, PCSK9 mutations have been identified: the gain-of-function mutations are rare and 
cause an autosomal dominant form of severe hypercholesterolemia and premature CHD, whereas 
loss of-function mutations are more common and are associated with reduced plasma levels of 
LDL-C and protection from CHD (25, 26).  
Therefore blocking PCSK9 binding to the LDL-R can potentially benefit patients with 
hypercholesterolemia by decreasing their plasma LDL-C levels.  In addition, PCSK9 messenger 
ribonucleic acid (mRNA) and protein levels are increased in response to statins, potentially 
attenuating their cholesterol-lowering effect (21). 
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Summary of adult clinical studies with alirocumab selected for relevant information: 
All relevant information concerning the compound is available in the Clinical Investigator’s 
Brochure (CIB).   
In the Phase 3 program, 2 dosing regimens have been evaluated, every 2 weeks (Q2W) and every 
4 weeks (Q4W).  The doses of alirocumab include 75 mg Q2W, 150 mg Q2W, 150 mg Q4W, and 
300 mg Q4W. Dose adjustment schemes (initiation of alirocumab with 75mg Q2W, 150 mg Q4W 
or 300 mg Q4W, with a potential subsequent adjustment to 150mg Q2W) have been evaluated in 
Phase 3 studies. These studies evaluated heFH patients, non-FH patients, mostly at high/very high 
CV risk, including patients with mixed dyslipidemia and patients with diabetes, and patients not 
taking statins including patients who are intolerant to statins due to skeletal muscle-related 
adverse effects. 
Phase 3 studies that evaluated the Q2W regimen: 
These studies demonstrated reductions in LDL-C from baseline to Week 24 ranging from -42.7% 
to -50.6% in patients administered alirocumab 75 mg with possible up titration to150 mg Q2W, 
and from -45.7% to -61.0% in patients administered alirocumab 150 mg Q2W.  Superiority in 
LDL-C reduction was demonstrated in all placebo-controlled studies with alirocumab 
administered as add-on to a maximally tolerated dose of statin. Superiority in LDL-C reduction 
was also demonstrated in all ezetimibe-controlled studies, with alirocumab being administered as 
add-on to statin, or to LMTs other than statin, or in monotherapy, including patients with a history 
of statin intolerance. 
In all studies, the LDL-C reduction was observed at the first LDL-C measurement following the 
first alirocumab dose (Week 4), and the LDL-C reduction observed at Week 24 was maintained 
through the treatment period (24, 52, 78 or 104 weeks, depending on the study). 
While reductions in LDL-C represent the primary goal of treatment in guidelines and the primary 
efficacy parameter in these studies, other lipid parameters are also associated with CV risk, for 
which alirocumab demonstrated a beneficial or at least neutral effect. Changes in Non-HDL-C, 
Apo B, and Total-C at Week 24 tend to correlate to some degree with LDL-C since LDL-C is the 
major component of non-HDL-C and Total-C. A consistent decrease in Lp(a) (ranging from 
-16.7% to -30.3%) was observed with alirocumab.  Treatment with alirocumab was associated 
with modest but consistent changes in fasting TGs (decrease from baseline ranging from -6.0% to 
-15.6% overall, and from -14.4% to -32.0% in patients with mixed dyslipidemia) and HDL-C 
(increase from baseline from +3.5% to +8.8%). In statin-treated patients, the effect of alirocumab 
on TGs was significantly greater than placebo in most studies, but not significantly different from 
ezetimibe.  
Phase 3 studies that evaluated Q4W regimen:   
Two studies EFC13786-DBTP and R727-CL-1308, have evaluated 150 mg Q4W and 300 mg 
Q4W, respectively, as initiation dose regimen with a possible dose adjustment to 150 mg Q2W. 
For both studies, LDL-C reduction was observed at Week 4, and was maintained over the whole 
duration of the study up to Week 24 for EFC13786-DBTP, and up to Week 48 for R727-CL-1308. 
As with Q2W dosing, changes in Non-HDL-C, Apo B, and Total-C tended to correlate with 
LDL-C. 
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The R727-CL-1308 study included patients with and without concomitant statin in two separate 
strata.  In both of these populations, there were statistically significant effects in favor of 
alirocumab 300 mg Q4W with possible dose adjustment to 150 mg Q2W versus placebo for both 
co-primary efficacy endpoints (percent change in LDL-C from baseline to Week 24 and to 
averaged Weeks 21 – 24) and for all key secondary efficacy endpoints (except Apo A-1 for the 
concomitant statin population). For LDL-C reduction, the LS mean treatment difference for 
alirocumab versus placebo at Week 24 was -52.4% and -58.7% for the no concomitant statin 
population and concomitant statin population, respectively.  The results obtained at Week 12 were 
consistent with those at Week 24 for both populations, whereby the Week 12 effect assessed the 
sole contribution of the 300 mg Q4W dose regimen. 
The EFC13786-DBTP study included only patients not receiving statin therapy (many on 
background ezetimibe), with a vast majority of statin intolerant patients.  At Week 24, the LS 
mean treatment difference for alirocumab (150 mg Q4W with possible up-titration to 150 mg 
Q2W) versus placebo of -56.4% was statistically significant for LDL-C reduction.  The results 
obtained at Week 12 showed a statistically significant LS mean treatment difference of  
-44.9%, whereby the Week 12 effect assessed the sole contribution of the 150 mg Q4W dose 
regimen.  The key secondary endpoint was statistically significant up to Lp(a) reduction at 
Week 24. Favorable trends were reported in HDL-C, TG and Apo A-1. 
Safety from Phase 2 and Phase 3 studies: 
Alirocumab administration to date in clinical trials, has been associated with a favorable safety 
and tolerability profile in the completed clinical trials. The pooled safety analysis was performed 
in 5234 patients with hypercholesterolemia from the double-blind phase 2/3 studies receiving 
75 mg Q2W or 150 mg Q2W dosing. Of these, 3340 patients were treated with alirocumab at a 
dose of 75 or 150 mg Q2W. Two pools were analyzed based on the comparator arm in the study 
(placebo-controlled or ezetimibe-controlled).  
In the placebo-controlled and ezetimibe-controlled pooled studies, no dose relationship was noted 
for any adverse events (AEs) and there was no evidence of a pattern in the type of AEs observed. 
The percentages of patients who experienced at least 1 TEAE, at least 1 treatment-emergent SAE 
and any TEAEs leading to permanent treatment discontinuation were similar between the 
alirocumab and control groups.  
Local injection site reactions, allergic reactions, neurologic events and neurocognitive disorders, 
alanine aminotransferase (ALT) increase, hepatic disorders, adjudicated CV events, and 
ophthalmologic disorders were evaluated as adverse events of special interest (AESI); diabetes 
mellitus, and skeletal-muscle related disorders were evaluated as other events of interest. There 
was no clinical concern with neurologic events and neurocognitive disorders, ALT increase and 
hepatic disorders, adjudicated CV events, diabetes mellitus, skeletal-muscle related disorders, and 
ophthalmologic disorders. However, neurocognitive events are considered a potential risk for 
alirocumab and continue to be monitored. 
No particular safety concerns were observed in the group of patients with 2 consecutive LDL-C 
values <25 mg/dL (<0.65 mmol/L). However, in a post-randomization comparison analysis 
(global pool of phase 3 studies) cataract was reported at a higher frequency (2.6%) in alirocumab-
treated patients who achieved 2 consecutive LDL-C values <25 mg/dL (<0.65 mmol/L) compared 
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to alirocumab-treated patients who did not achieve 2 consecutive LDL-C values <25 mg/dL 
(<0.65 mmol/L) (0.8%).  In the pool of placebo-controlled studies, the PT cataract was reported 
with a similar frequency in both the alirocumab and the placebo groups.   There is no mechanistic 
explanation to this finding. This analysis was exploratory in nature, and because of baseline 
differences in the post-randomization subgroups, it should be interpreted with caution. The 
sponsor will continue to monitor the events of cataracts associated to low LDL-C to further 
evaluate this potential risk.  
Injection site reactions (including erythema/redness, itching, swelling, pain, tenderness), upper 
respiratory tract signs and symptoms (including mainly oropharyngeal pain, rhinorrhea, sneezing), 
pruritus, hypersensitivity, eczema nummular, urticaria, and hypersensitivity vasculitis were 
identified as adverse drug reactions (ADRs) for alirocumab. ADRs include AEs for which there is 
some basis to believe that there is a causal relationship between the drug and the occurrence of the 
AE. The most common adverse reaction in patients treated with alirocumab was local injection 
site reactions (6.3% patients in the alirocumab group versus 4.3% in control groups in the global 
pool). 
The analysis of pooled data from Q2W dosing as well as data from individual Phase 2 and Phase 3 
studies demonstrated a favorable safety profile for alirocumab. Overall, the safety profile of the 
alirocumab Q4W dosing regimen was similar to alirocumab Q2W regimen, except for the 
frequency and onset of injection site reactions. Compared to those observed in the 75 Q2W with 
possible up titration to 150 Q2W regimen, local injection site reactions were more frequent, 
started earlier, and lasted longer with the Q4W dosing regimen, but were also transient, non-
serious and not severe. 
Rationale for protocol design: 
This study is designed to evaluate the efficacy, safety and pharmacokinetics (PK) of alirocumab in 
the pediatric population in order to support appropriate dose selection of alirocumab for the 
Phase 3 pediatric study. The study population will consist of children and adolescents aged of 8 to 
17 years with heFH on stable LMT and LDL-C ≥130 mg/dL (3.37 mmol/L).  The stable LMT will 
consist of an optimal stable daily dose of statin therapy ± other LMT(s) for at least 4 weeks prior 
to screening period.  Optimal doses of statin are based on pediatric guidelines followed by the site 
(27 or equivalent reference). 
Based on the final adult population PK model including Phase 3 data, simulations were performed 
to define the pediatric doses. The model included body weight (BW) as a covariate (on clearance) 
and allowed to perform simulations with different BW. The targeted lower dose to be tested in 
pediatric patients was simulated to achieve drug exposure that corresponds to the lowest dose 
evaluated in adult patients, ie, 50 mg Q2W. This 50 mg Q2W dose in adult Phase 2 resulted in 
approximately 40% LDL-C reduction.  The higher dose was simulated to correspond to the lower 
adult therapeutic dose of 75 mg Q2W. Simulations were also conducted to achieve an 
approximately 45-50% LDL-C reduction when alirocumab is administered monthly. Following 
these simulations, a fixed dosage was defined according to BW categories, with staggered doses 
of 30 mg Q2W and 40 mg Q2W or 75mg Q4W for children with a BW below 50 kg, and doses of 
50 mg Q2W and 75 mg Q2W or 150 mg Q4W for children with a BW ≥50 kg.    
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This study will consist of an 8-week open-label dose-finding treatment period with a 
post-treatment follow-up period of 6 weeks (Cohort 3) or 8 weeks (Cohorts 1 & 2) identified as 
main phase; followed by an open-label extension period identified as extension phase. 
In Cohort 1, Cohort 2, and Cohort 3, where each cohort will enroll 10 patients, a minimum 
number of at least 4 patients will be required in one of the two BW categories. This will allow the 
evaluation of the pharmacokinetics/pharmacodynamics (PK/PD) profile in each BW category and 
to compare with PK/PD profile observed in adult patients. 
 
  At the end of the 8-week study treatment period followed by the 6 or 8-week 
post-treatment follow-up period, patients enrolled in Cohort 1 will be offered entry into an open-
label extension study where the dose received during the study treatment period will be continued 
(ie, 30 mg for BW <50 kg and 50 mg for BW ≥50 kg, Q2W). Similar approach will be 
implemented for Cohort 2 (40 mg for BW <50 kg and 75 mg for BW ≥50 kg, Q2W) and Cohort 3 
(75 mg for BW <50 kg and 150 mg for BW ≥50 kg, Q4W).  However, once the final doses for the 
Phase 3 study are selected, then these final doses from the Q2W or Q4W regimens will be 
administered to the patients, based on their body weight (BW) at the time of the dose change, if 
needed and if the device is available.  This alirocumab administration during the open-label 
extension will continue until approximately 10 weeks before the initiation of the pediatric Phase 3 
study or December 2018 at the latest. The patients, after a wash-out period of at least 10 weeks 
after the last injection of alirocumab, will have the opportunity to participate in the Phase 3 study. 
Cohort 4:  
The DFI14223 study has completed the 8-week dose finding treatment period in 31 pediatric 
patients enrolled in the 3 cohorts.  This study started with a fixed dosage according to body weight 
(BW) categories, with sequential  doses of 30 mg Q2W (Cohort 1), 40 mg Q2W (Cohort 2) or 
75 mg (Q4W) (Cohort 3) for patients with a BW <50 kg (ie, lower BW category, LBWC), and 
doses of 50 mg Q2W (Cohort 1), 75 mg Q2W (Cohort 2) or 150 mg Q4W (Cohort 3) for patients 
with a BW ≥50 kg (ie, higher BW category, HBWC). Sequential approach was employed as a 
conservative safety approach in the first evaluation of alirocumab administration in the pediatric 
population, starting with Cohort 1 using lower doses considered suboptimal with regard to the 
efficacy before escalating to the doses that should provide expected efficacy. Regarding the Q2W 
dosing regimen, as expected, the effect on LDL-C and safety were analyzed. The primary efficacy 
endpoint as measured by the percent change in LDL-C from baseline to Week 8 demonstrated a 
greatest reduction, overall, in Cohort 2 (LS mean change from baseline in LDL-C of -46.1%). 
Patients in Cohort 1, overall, had a LS mean change from baseline in LDL-C of -21.2%.  
However, for the Cohort 3 using the Q4W dosing regimen, overall, the LS mean change from 
baseline in LDL-C was -7.7%, with inconsistency between the 2 doses as per BW category (mean 
reduction of LDL-C of -17.5 % with 75 mg Q4W in the LBWC and an mean increase in LDL-C 
of + 4.0% with 150 mg Q4W in the HBWC). For all 6 dose groups, there were no patients with 
treatment emergent serious adverse event, treatment emergent adverse events (TEAE) leading to 
death, or TEAEs leading to permanent treatment discontinuation. There were also no adverse 
events of special interest (AESI) including, neurological events, neurocognitive events, increase in 
ALT, allergic drug reactions, or local injection site reactions or new and clinically significant 
adverse events for all of the 6 dose groups to date. Alirocumab was well tolerated in this pediatric 
population with no observed, particular safety concern. 
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Cohort 3 that evaluated Q4W regimen had overall minimal reductions in LDL-C that were not as 
expected.  Using the Q4W dosing regimen, the primary endpoint measurement of LDL-C at 
Week 8 was obtained 4 weeks after the last injection.  The individual patient results showed that 
there was a varied range of effect on LDL-C for both BW categories, with some patients having 
mild to moderate reductions, while other patients having near neutral changes, and the remaining 
patients having a marked increase. One likely explanation is that the doses for both BW categories 
were not high enough to achieve larger and sustained reductions in the LDL-C over the entire 
dosing interval. This variability over the dosing interval, which was already identified in adults 
with this dosing interval, has also been reported by the other approved PCSK9 inhibitor, 
evolocumab (28), and is thought to be due to the subset of patients with higher rates of PCSK9 
mediated clearance of alirocumab. 
Given these inconclusive results for the Q4W dosing regimen evaluated in Cohort 3, the protocol 
is amended to include an additional cohort (Cohort 4) that will evaluate the Q4W regimen at 
higher doses of 150 mg for BW <50 kg and 300 mg for BW ≥50 kg to evaluate if an effect on 
LDL-C closer to the therapeutic target of 50% can be approached. The dose of 300 mg Q4W is 
currently approved for use in adults in the US and EU. It is anticipated that alirocumab exposures 
in Cohort 4 with the higher doses for both BW categories should be similar to alirocumab 
exposures in adults who have received 300 mg Q4W. The pediatric Steering Committee and the 
pediatric Data Monitoring Committee have specifically endorsed this more extensive effort to 
evaluate these higher doses with a Q4W administration of alirocumab, given the monthly 
convenience for children and adolescents and the favorable safety data to date. Cohort 4 will 
include a total of approximately 10 patients with 4 to 6 patients per body weight category and has 
an overall similar design to Cohort 3 except for a longer main phase (12 weeks) including 2 
additional visits (visit 7 at Week 10 and Visit 8 at Week 12), but without a post – treatment follow 
up period prior to entry into OLE.  
The addition to the higher doses in the Q4W cohort with extended 12 week study duration 
(including 2 new visits at Week 10 and Week 12) for the open label dose-finding period will more 
appropriately ensure that steady state has been reached after 3 alirocumab injections (2 interdose 
intervals) in terms of PK and LDL-C and related parameter reduction efficacy.  An intermediate 
visit between the dosing interval (Week 10) is specifically introduced to better document the PK 
and LDL-C data from the Q4W dosing regimen that is known to show some peak-trough 
variability over the 4-week dosing interval, ie, a peak in the decrease at the mid dosing interval 
time point and trough reduction in LDL-C at the end of dosing interval time period. Thus, 
extending the duration of a higher Q4W dosing regimen to 12 weeks (an additional 4 weeks) will 
secure more comprehensively data on the LDL-C related profile reduction potential of a Q4W 
dosing regimen for alirocumab. 
Given the 12 week duration, only LDL-C and key related parameters (TC, non-HDL-C, and TG) 
will be measured at Week 10 and Week 12 to minimize blood collection. The post-treatment 
follow-up period is no longer needed based on the data collected from the previous 3 cohorts.  
All patients in Cohort 4 will receive alirocumab at 150 mg Q4W for BW <50 mg/300 mg Q4W 
for BW ≥50 kg using prefilled syringes. 
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Cohort 4, similar to the other cohorts, will include alirocumab administration during the open-
label extension that will continue until approximately 10 weeks before the initiation of the 
pediatric phase 3 study or December 2018 at the latest. The patients, after a wash-out period of at 
least 10 weeks after the last injection of alirocumab, will have the opportunity to participate in the 
phase 3 study. Though Cohorts 1 to 3 will be switched to the optimal regimen selected for the 
phase 3 study, Cohort 4 will remain on their initial regimen given the planned study end date of 
December 2018. 
Conclusion on the benefit risk assessment with alirocumab: 
Based on the clinical data available to date in the adult population, treatment with alirocumab has 
demonstrated a significant LDL-C lowering effect in a population of patients with non-FH or with 
heFH. The LDL-C lowering efficacy was associated with consistent decreases in Total-C, Apo B, 
non-HDL-C, a decrease in Lp(a), and a favorable trend for HDL-C and triglycerides.  Maximum 
efficacy was observed as early as 4 weeks after the initial dose, and efficacy was well maintained 
up to 2 years. 
Alirocumab administration to date in clinical trials has been associated with a favorable safety and 
tolerability profile. 
Immunogenicity and systemic hypersensitivity are considered as identified risks. 
Injection site reactions (including erythema/redness, itching, swelling, pain, tenderness), upper 
respiratory tract signs and symptoms (including mainly oropharyngeal pain, rhinorrhea, sneezing), 
pruritus, hypersensitivity, eczema nummular, urticaria, and hypersensitivity vasculitis are 
identified as adverse drug reactions (ADRs) for alirocumab. ADRs include AEs for which there is 
some basis to believe that there is a causal relationship between the drug and the occurrence of the 
AE. 
Monitoring of these AEs will be continued in all studies conducted in adult and pediatric patients. 
There was no safety signal observed with neurologic events, alanine aminotransferase (ALT) 
increase and hepatic disorders, adjudicated CV events, diabetes mellitus, skeletal-muscle related 
disorders and ophthalmologic disorders in the alirocumab-treated group overall, but more 
cataracts (2.6%) were noted in patients treated with alirocumab who achieved 2 consecutive 
LDL-C values <25 mg/dL compared to 0.8% of alirocumab-treated patients who did not achieve 
such low levels. Although limitation has to be consider with regard to this post-randomization 
comparison and there were no statistically significant differences in the incidence of cataracts in 
this subgroup of patients when compared to control groups, cataract in patients with very low 
LDL-C levels is considered as a potential risk and the Sponsor will continue to monitor this 
potential risk. There was no safety signal observed for neurocognitive disorders, however, the 
Sponsor will monitor this potential risk as an adverse event of special interest in this study. 
An independent Data Monitoring Committee (DMC) dedicated to the pediatric clinical program 
conducted with alirocumab will meet periodically to review the safety data collected in this study. 
This specific study is undertaken to demonstrate the safety and the reduction of LDL-C with 
alirocumab in the heFH pediatric population and to support appropriate dose selection for the 
Phase 3 study. Because of the rapid clinical progression of atherosclerotic disease in children and 
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adults with familial hypercholesterolemia pediatric guidelines recommend LDL-C lowering 
intervention starting with statins. However, not all patients can achieve target LDL-C reductions 
with currently available LMTs, and these pediatric patients represent a group with an identified 
unmet medical need that can be addressed by adding alirocumab to their LDL-C lowering 
therapies. Different doses according to BW categories (<50 kg and ≥50 kg) will be evaluated 
through, in the first step, through 3 sequential independent cohorts with treatment duration of 
8 weeks, followed by 6 or 8-week post-treatment follow-up period. An additional cohort, Cohort 
4, will evaluate further the Q4W dosing regimen over a treatment of 12 weeks. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of the study is to evaluate the effect of alirocumab administered Q2W or 
Q4W on low-density lipoprotein cholesterol (LDL-C) levels after 8 weeks of treatment in 
heterozygous familial hypercholesterolemia (heFH) patients aged of 8 to 17 years, with LDL-C 
≥130 mg/dL (3.37 mmol/L) on optimal stable daily dose of statin therapy ± other lipid modifying 
therapies (LMTs) or a stable dose of non-statin LMTs in case of intolerance to statins, for at least 
4 weeks prior to the screening period.  
5.2 
SECONDARY 
• 
To evaluate the safety and tolerability of alirocumab.  
• 
To evaluate the pharmacokinetics profile of alirocumab.  
• 
To evaluate the effects of alirocumab on other lipid parameters  (eg, Apolipoprotein B 
(Apo B), non-high density lipoprotein cholesterol (non-HDL-C), Total-Cholesterol 
(Total-C), high-density lipoprotein cholesterol (HDL-C), Lipoprotein (a) (Lp[a]), 
Triglycerides (TGs), Apolipoprotein A-1 (Apo A-1) levels after 8 weeks of treatment.  
• 
To evaluate the development of anti- alirocumab antibodies. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This study is an open-label, dose-finding, sequential group, multi-national, multi-center study 
with repeated dose of subcutaneous (SC) alirocumab injections administered every 2 weeks 
(Q2W) or every 4 weeks (Q4W) in children and adolescents aged of 8 to 17 years with heFH 
having LDL-C ≥130 mg/dL (3.37 mmol/L). A sequential enrollment into the 4 separate and 
independent Cohorts 1 to 4, is applied. Patients should be treated with an optimal dose of statin 
with or without other LMT(s), or non-statin LMT(s) if statin intolerant, at stable daily dose(s) for 
at least 4 weeks.  The optimal dose of statin is defined as the stable daily dose prescribed based on 
regional practice or local guidelines or is the stable daily dose that is maximally tolerated due to 
adverse effects on higher doses. For patients not receiving maximally tolerated dose of statin, 
statin intensification should be carefully considered prior to inclusion in this study in order to 
ensure that the addition of a non-statin LDL-C lowering therapy (ie, alirocumab) would be the 
next appropriate step in the management of the patient’s hypercholesterolemia.  The highest dose 
of statin should not exceed the maximum labeled dose of statin for pediatric patients as per the 
local prescribing information. Each independent cohort below will include 10 patients with no less 
than 4 patients in each BW category: 
• 
Cohort 1 will receive 30 mg Q2W for body weight (BW) <50 kg and 50 mg Q2W for BW 
≥50 kg. 
• 
Cohort 2 will receive 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW ≥50 kg. 
• 
Cohort 3 will receive 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg.  
• 
Cohort 4 will receive 150 mg Q4W for BW <50 kg and 300 mg Q4W for BW ≥50 kg. 
For each cohort, the study consists of a main phase and an optional extension phase.  The main 
phase is comprised of 3 periods; screening (including run-in, if applicable), open-label dose 
finding treatment, and follow-up only for Cohorts 1, 2, and 3, and 2 periods: screening (including 
run-in, if applicable) and open-label dose finding treatment for Cohort 4.These periods of the 
main phase are described as below. 
MAIN PHASE: 
Screening Period: 
• 
The screening period will last up to 6 (+1) weeks, with patients to be enrolled as soon as 
all inclusion and no exclusion criteria are met.   
- 
Patients who consent to participate in the study, but who have not been on stable 
LMTs for at least 4 weeks or require statin intensification when initially seen, can 
participate in a run-in period until LMT dose(s) have been stable for 4 weeks, and be 
enrolled when eligibility is confirmed, including eligible LDL-C value obtained after 
stable LMT dosing has been maintained for at least 4 weeks. Stable LMT refers to 
patients receiving either stable optimal daily dose of statin ±other LMT(s) or stable 
dose of non-statin LMT(s) if statin intolerance for at least 4 weeks prior to screening.  
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It is not authorized to select patients treated with statin de novo, to avoid unstable lipid 
modifying treatment (LMT) during the screening period.  
- 
Patients suspected of having heFH but without confirmation (prior genetic testing 
results obtained or diagnosed clinically by Simon Broome criteria) will undergo 
genetic testing, once separate consent for heFH genotyping is signed, and can be 
enrolled when eligibility is confirmed. This genotyping will be mandatory for patients 
without either clinical diagnosis or without previous documented genotyping who 
consent to participate in the study.   
This genotyping testing is offered optionally to others whose heFH diagnosis has 
already been confirmed (prior genetic testing results obtained or diagnosed clinically 
by Simon Broome criteria).  If patients agree to perform this centralized genotyping 
and/or they agree to use a previous documented genotyping, they will be required to 
sign a separate genetic testing informed consent form (ICF) prior to collection of the 
DNA sample and/or request for previous genotyping results.   
If the diagnosis of heFH to establish eligibility is based on clinical criteria or a   
documented previous genotyping, the results of this elective centralized genotyping 
will not impact their eligibility inclusion. 
- 
The report of the heFH genotyping done as part of this study will provide an 
interpretation of the results.  However, all patients should have their results reviewed 
with a genetics counselor or equivalent.  Genetic testing performed will be limited to 
testing for heFH-associated genes only.  All samples will be destroyed once testing is 
completed.  No additional genetic testing and no long-term storage will be done for 
these samples. 
- 
Special procedures, including procedures for collection, handling, storage and 
shipment of DNA specimens for genetic testing for heFH, are summarized in the 
genetic testing manual provided by the central lab performing heFH testing. 
All patients who successfully screen for Cohort 1 and are not included in Cohort 1, due to 
the appropriate Cohort 1 weight group being fully enrolled, may participate to Cohort 2 
but only after eligibility, including safety assessments, is reconfirmed.  Patients who are 
successfully screened for Cohort 2 but are not enrolled, due to the appropriate Cohort 2 
weight group being fully enrolled, may participate in Cohort 3 without the need to repeat 
the run-in/screening period if there is no more than 3 months between eligibility 
confirmation and inclusion.  In such a circumstance, the run-in/screening period from 
Cohort 2 will substitute for the run-in/screening period for Cohort 3. If there is more than 
3 months between initial screening and planned enrollment in Cohort 3, patient eligibility, 
including safety assessments, must be reconfirmed.   
Safety and eligibility assessments noted above include all lab tests listed as exclusionary, 
based on specified results. 
Patients should be instructed to follow a diet in accordance with the American Academy of 
Pediatrics (AAP) guidelines (1) or equivalent throughout the entire study (ie, both phases). 
The dietician or site staff with appropriate training will review the patient’s diet at the 
screening visit and periodically throughout the study. 
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Main Open-Label Dose Finding Treatment Period: 
• 
An open-label dose finding treatment period of 8 weeks with alirocumab for Cohorts 1 to 
3, and 12 weeks for Cohort 4. Four independent cohorts (Cohorts 1 to 4) will be 
administered SC alirocumab injections Q2W or Q4W in a sequential enrollment.   
• 
The DMC will review data on a regular basis during the dose finding treatment period. 
• 
After Cohort 1 completes the open-label dose finding treatment period, the DMC will 
continue to review the safety data and make a recommendation on dose escalation to 
Cohorts 2 and 3.  Cohort 2 will initially begin enrollment.  Once enrollment is completed 
for Cohort 2, then this will immediately be followed by enrollment into Cohort 3 (ie, 
sequential enrollment).  Cohort 4 is an independent cohort with a separate enrollment. 
• 
Cohorts 1 and 2 (Q2W): Alirocumab injections will be prepared from vials by the 
pharmacist (or equivalent). Detailed instructions on preparation of injections from vials 
will be provided in a separate document.  Alirocumab injections will be administered at 
Weeks 0, 2, 4, and 6.  The Weeks 0 and 4 alirocumab injections will be administered at the 
clinical site by the site staff.  The Weeks 2 and 6 alirocumab injections will be 
administered at the clinical site by the site staff or at the patient’s home by a health care 
professional, depending upon local arrangements and preferences of the 
investigator/patient.   
• 
Cohort 3 (Q4W): Alirocumab injections will be prepared from vials by the pharmacist (or 
equivalent). Detailed instructions on preparation of injections from vials will be provided 
in a separate document.  Alirocumab injections will be administered at Weeks 0 and 4 at 
the clinical site by the site staff.   
• 
Cohort 4 (Q4W): Alirocumab injections will be administered with prefilled syringes. 
Alirocumab injections will be administered Week 0, Week 4, and Week 8 at the clinical 
site by site staff. 
• 
The lipid results from specimens obtained during the open-label dose finding treatment 
period will be masked for the clinical site/Investigator and patients. No attempts should be 
made by the investigator or patient to routinely have the patient’s lipid values 
independently evaluated after entry into the open-label dose finding treatment period and 
until the final follow-up visit for Cohort 1, Cohort 2, and Cohort 3, and entry into the OLE 
period for Cohort 4.  The sponsor and the DMC will closely monitor the lipid results 
during the 8-week open-label dose finding treatment period.  If any safety concerns are 
noted during this period, including very low LDL-C levels (ie, LDL-C <50 mg/dL 
[1.30 mmol/L] on one or more occasion), then appropriate action will be taken by the 
Sponsor in consultation with the DMC. 
Follow-Up Period, only for Cohorts 1 to 3: 
• 
A follow-up period (off treatment) of 6 (Cohort 3) or 8 weeks (Cohorts 1 and 2) after the 
end of open-label dose finding treatment period visit. For these 3 cohorts, the final follow-
up visit corresponds to 10 weeks after the last alirocumab injection administered during 
the open-label dose finding treatment period, since the last injection for Cohorts 1 & 2 is 
Week 6 and for Cohort 3 it is Week 4. 
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The daily optimal dose of statin or of other LMT (if applicable) should be stable from screening 
through the end of the follow-up visit unless there is a safety concern, as per the Investigator’s 
judgment.  
Cohorts 1 to 3 will have a follow-up period before entry in the extension period.  
Open-label extension treatment period: 
At the end of the follow-up period of the main phase for Cohorts 1 to 3 and end of the 12 week 
open label dose-finding for Cohort 4, patients enrolled in all cohorts who successfully complete 
(provided they have not experienced AEs leading to permanent discontinuation during the main 
treatment period, or had significant protocol deviations, in the investigator’s judgment) the main 
phase will be offered entry into an optional extension phase. The extension phase includes an 
open-label extension (OLE) period as follows: 
• 
All doses/dose regimen administered during the open-label dose finding treatment period 
of the main phase are expected to be efficacious.  Thus, the initial dose of alirocumab that 
will be administered Q2W or Q4W during the OLE period, will be a continuation of the 
same doses/dose regimen administered during the open-label dose finding treatment period 
of the main phase.  However, once the final optimal doses for the phase 3 study are 
selected, then these final optimal doses from the Q2W or Q4W regimen will be 
administered to all patients during the OLE period, based on the patient’s body weight at 
the time of the dose change. For Cohort 4, patients will remain on their initial regimen 
given the planned study end date of December 2018. 
• 
For Cohorts 1 to 3, alirocumab injections may be prepared from vials by the pharmacist 
(or equivalent) or supplied as prefilled syringes (PFS) depending on availability and 
additional considerations:   
- 
If the PFS is available in the extension phase, then patients may either switch from 
alirocumab injections prepared from vials to PFS or directly initiate PFS (depending 
on patient’s date of entry into the extension phase).  After appropriate training, the 
parent/guardian or patient (if appropriate) will administer the PFS at home or another 
preferred location. In certain cases, alternative arrangements may be made for the 
administration of the PFS,  
- 
If the PFS is not available in the extension phase, then alirocumab injections prepared 
from vials will be administered at the clinical site (by the site staff) or at the patient’s 
home or another preferred location contingent upon alternative arrangements being 
made for such an administration.   
• 
All patients from all cohorts that participate in the DFI14223 study will have the 
opportunity to enroll in the pediatric phase 3 study provided that they meet the eligibility 
criteria.  The alirocumab administrations during the OLE period will continue until at least 
10 weeks (corresponding to the wash out period) before the initiation of the pediatric 
phase 3 study in the site where the patient is potentially participating or December 2018 at 
the latest.  
• 
The lipid levels will be communicated to the investigator during the OLE period. The 
Investigator will be responsible, based on his/her own judgment related to the patients’ 
LDL-C levels and the safety profile, to continue or discontinue alirocumab throughout the 
study.  The daily dose of statin should be maintained; in particular any decreases in statin 
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dose are strongly discouraged, except in case of medical reason. The statin dose should not 
be decreased to adjust to the degree of LDL-C lowering; the Investigator has the option to 
discontinue alirocumab. Other LMT (if applicable) can be modified based on the 
Investigator’s judgment throughout the study. Further recommendations for the 
management and monitoring of patients who achieve very low LDL-C levels (ie, 
LDL-C <50 mg/dL [1.30 mmol/L] on one or more occasion) are provided in Section 
10.6.3. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
Main open-label treatment phase: 
For Cohorts 1 to 3, a study duration of approximately 16-23 weeks (screening/run in period: up to 
6 [+1] weeks, main open-label treatment period: 8 weeks, follow-up period: 6-8 weeks)   
For Cohort 4, a study duration of approximately 14-19 weeks (screening period: up to 6 [+1] 
weeks, open-label dose-finding treatment period: 12 weeks). 
Open-label extension phase: 
Patients who enroll in the open-label extension treatment period will continue alirocumab 
administration until at least 10 weeks before the initiation of the pediatric Phase 3 study in the site 
where the patient is potentially participating. Therefore, patients who consent to participate in the 
pediatric phase 3 study could have their last alirocumab injection in the OLE period up to 
December 2018, depending on timing of site initiation for the phase 3 study planned to be done no 
later than December 2018. All other patients, enrolled in the OLE period, who decline the 
participation in the phase 3 study, will have their last alirocumab injection on December 2018. 
This corresponds to a maximum of approximately 24 months for the first patients enrolled in 
Cohorts 1 to 3. For Cohort 4, this corresponds to a maximum of approximately 7 months for the 
first patients enrolled. 
For both phases, patients who experience an ongoing Serious Adverse Event (SAE) or an Adverse 
Event of Special Interest (AESI), at the pre-specified study end-date, should be followed until 
resolution, stabilization, or death and related data will be collected.     
End of study per patient: 
If patient does not participate to the open label extension period, then the end of the study is the 
last on site visit as scheduled by protocol (ie, visit Week 14 or Week 12 (Cohorts 3 & 4, 
respectively) or Week 16 (Cohorts 1 & 2) or the resolution/stabilization of all SAEs, and AESI, 
whatever comes last. 
If patient participates in the open label extension period, then the end of the study is the last on 
site visit as scheduled by protocol (ie, visits will continue until visit end of OLE at least 2 or 
4 weeks after last alirocumab injection (with a follow-up phone call at least 10 weeks after the last 
alirocumab administration) before the initiation of the pediatric Phase 3 study in the site where the 
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patient is potentially participating or December 2018, at the latest, or the resolution/stabilization 
of all SAEs, and AESI, whatever comes last.   
A follow-up phone contact will take place at least 10 weeks after the last IMP of each cohort, 
including Cohort 4. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is defined as being the last visit/contact of the patients at the study 
level. 
6.3 
INTERIM ANALYSIS 
No formal interim analysis is planned.  However, analyses will be conducted at the end of the 
main phase to select the dose that will be used in the Phase 3 study. 
6.4 
STUDY COMMITTEES 
Steering Committee: 
The Steering Committee is composed of university-based physicians (experts in pediatric lipids 
field, and/or pediatric cardiology) with clinical and methodological expertise, working in 
collaboration with the Sponsor. 
The Steering Committee will provide scientific and strategic direction for the trial and will have 
overall responsibility for its execution. The Steering Committee will provide guidance on 
producing and conducting a scientifically sound design and ensuring accurate reporting of the 
study. The Steering Committee will address and resolve scientific issues encountered during the 
study. The Steering Committee will also review the recommendations from the DMC throughout 
the study.  
Among its responsibilities, the Steering Committee will review data during the conduct of the 
study. The Steering Committee will also review the recommendations from the Data Monitoring 
Committee throughout the study. The Steering Committee members and Sponsor will participate 
in regular meetings. Detailed activities and responsibilities of the Steering Committee are 
described in the Steering Committee charter.   
Data Monitoring Committee (DMC): 
The DMC is composed of external, independent expert physicians with experience in pediatric 
lipids field and/or pediatric cardiology.  The independent DMC will monitor periodically patient 
safety by conducting reviews of accumulated safety data, including Cohort 4.  The DMC will 
provide the Sponsor and the Steering Committee with appropriate recommendations on the 
conduct of the clinical trial to ensure the protection and safety of the patients enrolled in the study. 
In addition, the DMC will also institute any measures that may be required for ensuring the 
integrity of the study results during the study execution.  The DMC will review data on a regular 
basis during the dose finding treatment period.  The DMC is tasked to provide recommendations 
periodically and on dose escalation decision from Cohort 1 to Cohorts 2, 3.   
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All activities and responsibilities of the DMC are described in the DMC charter.   
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
Patients meeting all of the following inclusion criteria will be considered for enrollment into the 
study: 
I 01. Children and adolescent male and female patients aged 8**** to l7 years at the time of 
signed informed consent. 
For Russia only:  
Male and female patients aged ≥12 and ≤17 years at the time of signed informed consent 
I 02. Patients with diagnosis of heterozygous familial hypercholesterolemia (heFH) through 
genotyping or clinical critiera.* 
I 03. Patients treated with optimal dose of statin** ± other LMT(s) or non-statin LMT(s) if 
statin intolerant*** at stable dose for at least 4 weeks. 
I 04. Patients with calculated LDL-C greater than or equal to 130 mg/dL (≥3.37 mmol/L) 
obtained during the screening period after the patient has been on stable LMT (ie, stable 
optimal dose of statin ± other stable LMTs or stable non-statin LMTs in statin intolerant 
patients) treatment for at least 4 weeks. 
I 05. Patients with body weight greater than or equal to 25 kg. 
I 06. Patients aged of 8 to 9 years to be at Tanner stage 1 and patients aged of 10 to 17 years to 
be at least at Tanner stage 2 in their development. 
I 07. A signed informed consent indicating parental permission with or without patient assent, 
depending on capacity for understanding based on developmental maturity. In cases 
involving emancipated or mature minors with adequate decision-making capacity, or when 
otherwise permitted by law, a signed informed consent directly from patients. 
*  
Diagnosis of heFH must be made either by previous genotyping, current genotyping, or by 
clinical criteria according to Simon Broome criteria.  Previous genotyping refers to 
documented results that are available from prior genotyping testing supporting a diagnosis 
of heFH. Current centralized genotyping refers to patients consenting to undergo 
mandatory genotyping during the screening period with results supporting a diagnosis of 
heFH.  The clinical diagnosis should be based on the Simon Broome criteria for possible or 
definite FH.  (see Appendix F).  Once eligibility is confirmed based on prior genetic 
testing or Simon Broome criteria, results of elective genetic testing will not impact 
patient’s eligibility. 
**  
The optimal dose of statin is defined as the stable daily dose prescribed based on regional 
practice or local guidelines or is the stable daily dose that is maximally tolerated due to 
adverse effects on higher doses. For patients not receiving the maximally tolerated dose of 
statin, statin intensification should be carefully considered prior to inclusion in this study 
in order to ensure that the addition of a non-statin LDL-C lowering therapy (ie, 
alirocumab) would be the next appropriate step in the management of the patient’s 
hypercholesterolemia. The highest dose of statin should not exceed the maximum labeled 
dose of statin for pediatric patients as per the local prescribing information. 
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*** 
Statin intolerant patient is defined as the inability to tolerate at least 2 statins: one statin at 
the lowest daily starting dose, AND another statin at any dose, due to skeletal muscle-
related symptoms, other than those due to strain or trauma, such as pain, aches, weakness, 
or cramping, that began or increased during statin therapy and stopped when statin therapy 
was discontinued. Patients not receiving a daily regimen of a statin (eg, 1 to 3 times 
weekly) are also considered as not able to tolerate a daily dose. 
****  Patients age of 8 to less than 10 years have had other available interventions to lower 
calculated LDL-C but these have been insufficient. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following subsection. 
7.2.1 Exclusion criteria related to study methodology 
E 01. Age of less than 8 or greater than 17 years at the time of signed informed consent. 
E 02. Calculated LDL-C <130 mg/dL (3.37 mmol/L) during the screening period, after patient 
has been on stable LMT for at least 4 weeks. 
E 03. Patient without a diagnosis of heFH by genotyping or clinical criteria.  
E 04. Patients aged of 8 to <10 years in whom other available interventions to lower LDL-C 
have been sufficient. 
E 05. Patients not on a stable dose of LMT (including statin, as applicable) for at least 4 weeks 
prior to the screening visit and from screening visit to Day 1. 
E 06. Daily dose of statin that is above the maximum recommended dose for pediatric patients as 
per the local prescribing label. 
E 07. Use of nutraceutical products or over the counter therapies that may affect lipids which 
have not been at a stable dose for at least 4 weeks prior to the screening visit. 
E 08. Patients not previously instructed on a cholesterol-lowering diet prior to the screening 
visit.   
E 09. Body weight <25 kg. 
E 10. Patients aged of 8 to 9 years not being at Tanner Stage 1 and patients aged of 10 to 
17 years not being at least at Tanner Stage 2 in their development. 
E 11. Patients with secondary hyperlipidemia. 
E 12. Patients with diagnosis of homozygous familial hypercholesterolemia. 
E 13. Patient who has received lipid apheresis treatment within 2 months prior to the screening 
period, or has plans to receive it during the study. 
E 14. Known history of type 1 or type 2 diabetes mellitus. 
E 15. Known history of thyroid disease.  
E 16. Known history of hypertension. 
E 17. Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening visit. 
E 18. Severe renal impairment (ie, eGFR <30 mL/min/1.73 m2 at the screening visit). 
E 19. ALT or AST >2 xULN (1 repeat lab is allowed). 
E 20. CPK >3 xULN (1 repeat lab is allowed). 
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E 21. Patient/parents who withdraws consent during the screening period (patient who is not 
willing to continue or fails to return).    
E 22. Conditions/situations or laboratory findings such as: 
• 
Any clinically significant abnormality identified at the time of screening that in the 
judgment of the Investigator or any sub-Investigator would preclude safe completion of 
the study or constrain endpoints assessment such as major systemic diseases.   
• 
Patients considered by the Investigator or any sub-Investigator as inappropriate for this 
study for any reason, eg,: 
- 
Those deemed unable to meet specific protocol requirements, such as scheduled visits,   
- 
Those deemed unable to administer or tolerate long-term injections as per the patient 
or the investigator,   
- 
Presence of any other conditions (eg, geographic, social….) actual or anticipated, that 
the Investigator feels would restrict or limit the patient’s participation for the duration 
of the study,   
- 
Uncooperative or any condition that could make the patient potentially non-compliant 
to the study procedures. 
E 23. Treatment with any investigational medicinal product (IMP) within 8 weeks or 5 half-lives 
prior to the screening period, whichever is longer.  
Note: If half-life is not known, then 8 weeks should be applied for non-biological IMP and 
6 months for biological IMP. 
7.2.2 Exclusion criteria related to mandatory background therapies  
E 24. All contraindications to the background statins or other LMTs (as applicable) 
warning/precaution of use (when appropriate) as displayed in the respective National 
Product Labeling. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab  
E 25. Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections. 
E 26. Females who have experienced menarche or females of childbearing potential who are 
sexually active who are unwilling or unable to be tested for pregnancy. 
E 27. Positive pregnancy test in females who have experienced menarche or females of 
childbearing potential who are sexually active.  
E 28. Females who are breast-feeding. 
E 29. Females of childbearing potential who are sexually active and not protected by highly 
effective contraceptive 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: Females of childbearing potential who are sexually active or females who have experienced 
menarche must have a confirmed negative pregnancy test at screening and other study visits. 
Females of childbearing potential who are sexually active must use an effective contraceptive 
method throughout the entire duration of the study treatment and for at least 10 weeks after the 
last injection.  The applied methods of contraception have to meet the criteria for a highly 
effective method of birth control according to the "International Conference on Harmonisation of 
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Technical Requirements for Registration of Pharmaceuticals for Human Use. M3(R2): Guidance 
on nonclinical safety studies for the conduct of human clinical trials and marketing authorization 
for pharmaceuticals. ICH. 2009 Jun: 1-25." (24). See Appendix G. 
7.2.4 Additional exclusion criteria during or at the end of screening or run-in phase 
before inclusion  
E 30. Patient who has withdrawn consent before inclusion (starting from signed informed 
consent). 
E 31. Despite screening of the patient, inclusion is stopped at the study level. 
7.3 
EXCLUSION CRITERIA FOR THE OPEN-LABEL EXTENSION TREATMENT PERIOD  
7.3.1 Exclusion criteria related to study methodology 
E 32. Significant protocol deviation in the main phase based on the Investigator judgment, such 
as non-compliance by the patient.   
E 33. Patient who experienced an adverse event leading to permanent discontinuation from the 
main open label dose finding treatment period.   
E 34. Patients having any new condition or worsening of existing condition which in the opinion 
of the Investigator would make the patient unsuitable for entry into the extension phase, or 
could interfere with the patient participating in or completing the study.   
7.3.2 Exclusion criteria related to the current knowledge of alirocumab 
E 35. Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections. 
E 36. Positive pregnancy test at last visit of the main treatment period (Week 14 [Cohort 3]/ 
Week16 [Cohorts 1 & 2], Visit 8).   
E 37. Females who have experienced menarche or females 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.   
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
For Cohorts 1 to 3, sterile alirocumab drug product will be supplied at a concentration of 
150 mg/mL as 1.2 mL minimum extractable volume in a 3 mL vial filled with 1.9 mL solution for 
the main treatment period and in 3 mL vials (or in prefilled syringes if available) for patient 
included in the extension period.  
A detailed manual for alirocumab solution preparation will be provided to the pharmacist 
(or equivalent) for individual dose preparation.  
For Cohort 4, sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL as 
1 mL volume in a prefilled syringe (PFS). 
Main treatment period (Open-Label, Repeated Dose-Finding, Sequential Group): 
The different doses prepared according to the cohort and the body weight will be: 
• 
For Cohort 1: 30 mg Q2W for BW <50 kg and 50 mg Q2W for BW ≥50 kg. 
• 
For Cohort 2: 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW ≥50 kg. 
• 
For Cohort 3: 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg. 
• 
For Cohort 4: 150 mg Q4W for BW <50 kg and 300 mg Q4W for BW ≥50 kg. 
The body weight assessed at inclusion visit will be the reference for alirocumab solution 
preparation. 
For Cohorts 1 & 2: The study treatment is a single SC injection of 0.5 mL for 30, 40, 50 or 75 mg 
dose of alirocumab (according to the cohort and the body weight) extracted from vials, 
administered every 2 weeks in the abdomen, thigh, or outer area of the upper arm.   
For Cohort 3: The study treatment is a single SC injection of 1 mL for 75 or 150 mg dose of 
alirocumab (according to the body weight) extracted from vials, administered every 4 weeks in 
the abdomen, thigh, or outer area of the upper arm.   
For Cohort 4, sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL as 
1 mL volume in a prefilled syringe (PFS). 
For Cohort 4: The study treatment is a single SC injection of 1 mL for 150 mg dose of alirocumab 
and 2 injections of 1 mL containing 150 mg each to provide a total 300 mg (2 mL) of alirocumab 
through PFS administered every 4 weeks in the abdomen, thigh, or outer area of the arm.  
Dosing for the main dose finding treatment period should ideally be administered Q2W SC or 
Q4W SC at approximately the same time of the day; however, it is acceptable to have a treatment 
window of ±3 days.  The time of day is based on the patient’s preference. 
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Open-label extension (OLE) treatment period: 
For Cohorts 1 to 3, alirocumab injections may be prepared from vials by the pharmacist (or 
equivalent) or supplied as prefilled syringes (PFS) depending on availability and additional 
considerations.   
If the PFS is available in the extension phase, then patients may either switch from alirocumab 
injections prepared from vials to PFS or directly initiate PFS (depending on patient’s date of entry 
into the extension phase).  After appropriate training, the parent/guardian or patient (if 
appropriate) will administer the PFS at home or another preferred location.  In certain cases, 
alternative arrangements may be made for the administration of alirocumab with PFS. 
If the PFS is not available in the extension phase for Cohorts 1 to 3, then alirocumab injections 
prepared from vials will be administered at the clinical site (by the site staff) or at the patient’s 
home or another preferred location contingent upon alternative arrangements being made for such 
an administration. 
The alirocumab dose/dose regimen received during the open-label dose finding treatment period 
of the main phase will be continued every 2 weeks or every 4 weeks during the OLE period, since 
 
.    
However, once the final optimal doses for the Phase 3 study are selected, and if device is 
available, then these final optimal doses from the Q2W or Q4W regimen will be administered to 
all patients in Cohorts 1 to 3 during the OLE period, based on their body weight at the time of the 
dose change.  
For Cohorts 1 & 2: The study treatment is a single SC injection of 0.5 mL for 30, 40, 50 or 75 mg 
dose of alirocumab (according to the last dose in each cohort and DMC recommendations) 
provided in a prefilled syringe or in a syringe (extracted from vial), administered every 2 weeks in 
the abdomen, thigh, or outer area of the upper arm.  Study drug will be administered by SC 
injection Q2W, starting at Week 16 and continuing up to the last injection, 2 weeks before the end 
of the open-label extension period.  
For Cohort 3: The study treatment is a single SC injection of 1 mL for 75 or 150 mg dose of 
alirocumab (according to the body weight, the last dose  and DMC recommendations) provided in 
a prefilled syringe or in a syringe (extracted from vial), administered every 4 weeks in the 
abdomen, thigh, or outer area of the upper arm.  Study drug will be administered by SC injection 
Q4W, starting at Week 14 and continuing up to the last injection, 4 weeks before the end of the 
open-label extension period.  
For Cohort 4, sterile alirocumab drug product will be supplied at a concentration of 150 mg/mL as 
1 mL volume in a prefilled syringe (PFS). 
For Cohort 4: The study treatment is a single SC injection of 1 mL for 150 mg dose of alirocumab 
and 2 injections of 1 mL containing 150 mg each to provide a  total 300 mg dose (2 mL) of 
alirocumab through PFS, administered every 4 weeks in the abdomen, thigh, or outer area of the 
upper arm. Study drug will be administered by SC injection Q4W, starting at Week 12 and 
continuing up to the last injection, 4 weeks before the end of the open-label extension period. 
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Dosing for the open-label extension treatment period should ideally be administered Q2W SC or 
Q4W SC at approximately the same time of the day; however, it is acceptable to have a treatment 
window of ±3 days.  The time of day is based on the patient’s preference. 
Alirocumab administration will continue until at least 10 weeks before the initiation of the 
pediatric Phase 3 study in the site where the patient is potentially participating or December 2018, 
whichever comes first.  
In the event an injection is delayed by more than 7 days or is completely missed, the patient 
should return to the original schedule of study drug dosing without administering additional 
injections.  If the delay is less than or equal to 7 days from the missed date, the patient should 
administer the delayed injection and then resume the original dosing schedule.   
Detailed instructions for transport, storage, preparation, and administration of IMP will be 
provided by the site to the patient/caregiver.   
8.1.1 Route and method of administration 
A manual for alirocumab administration (injection instruction manual) will be provided to 
investigators (or parents/patients according to the phase of the study) containing detailed 
instructions on use. 
During the main treatment dose finding study period for Cohorts 1 and 2, the injections will be 
administered by the staff at the clinical site or by a trained health care professional at home for 
visits Week 2 and Week 6, the injections at Week 0 and 4 will be administered at the clinical site 
by the study staff. For Cohort 3 the injections at Week 0, and at Week 4 will be administered at 
the clinical site by the study staff.  For Cohort 4, the injections at Week 0, Week 4, and Week 8 
will be administered at the clinical site by the study staff. During the open-label extension, 
alirocumab could be administered at clinical site or by study nurse at home or by self-injection or 
by another designated person (such as a parent, etc…) depending on availability or not of the 
prefilled syringes. The used syringe will be discarded in a sharps container which will be provided 
to staff site/nurse/patients. It is recommended that alirocumab injections be rotated within an 
anatomical area (eg, right thigh then left thigh or right abdomen then left abdomen).  Staff 
site/Nurse/Patients also have the option to inject in a different anatomical area (eg, thigh then 
abdomen) during the study.  If another concomitant drug or vaccine is being injected at the same 
site planned for alirocumab injection, then the staff site/nurse/patient should be advised to use an 
alternate location for administration of alirocumab.   
IMP must be stored between +2°C and +8°C, and administered at room temperature. Specific 
information regarding dose preparation and administration is given in the relevant manuals.   
Instructions as outlined in the relevant manuals should be provided to the investigator/nurse (or 
another designated person who will administer the injections) at training and as needed during the 
course of the study.  Close supervision and feedback should be given at the training visit if 
applicable and other visits as needed.  Anyone that plans to administer IMP must be trained by the 
study staff.   
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8.1.2 Timing of administration 
During the main dose finding treatment period the first alirocumab injection for each cohort 
will start at Week 0 (after each respective screening period and DMC agreement for Cohorts 2 
and 3) as soon as possible after the call for inclusion using the treatment kit number provided by 
the IRT according to cohort number and body weight.  The first injection after call for inclusion 
will be done at the site by the investigator staff. Patients will be monitored at the investigational 
site for at least 30 minutes after this first injection.   
The investigator staff will administer subsequent injections on site at the clinic, according to the 
dosing schedule at approximately the same time of the day. On days where the clinic study visit 
coincides with dosing, the dose of study drug will be administered after all study assessments 
have been performed and all laboratory samples (including PK) collected.  For visits where home 
injection is allowed, the health care professional will administer the injection at the patient’s 
home, as described in the relevant manuals. 
During the main dose finding treatment period, alirocumab will be administered subcutaneously 
every 2 weeks or every 4 weeks at approximately the same time of the day; however it is 
acceptable to have a window period of ±3 days.   
Follow-up period during the main phase without treatment 
No alirocumab administration between W8 and W16 for Cohort 1. 
No alirocumab administration between W8 and W16 for Cohort 2. 
No alirocumab administration between W8 and W14 for Cohort 3. 
There is no follow up period for Cohort 4. 
During the open-label extension period for Cohorts 1 & 2 the first injection administration will 
start at Week 16 after the last injection administration at Week 6 (ie, 10 weeks after the last 
administration of alirocumab. The treatment kit(s) number(s) will be provided by IRT according 
to the last dose administered in Cohort1/Cohort 2. The first injection of the extension period will 
be done at the site by the investigator staff.  If the self-injections by patient or another designated 
person (such as parent, nurse, etc.) are decided during the extension period a training injection 
should be planned 2 weeks before the first self-injection, under direct site staff supervision.   
During the open-label extension period for Cohort 3, the first injection administration will start 
at Week14 after the last injection administration at Week 4 (ie, 10 weeks after the last 
administration of alirocumab). The treatment kit number will be provided by IRT according to the 
last dose administered in Cohort 3. The first injection of the extension period will be done at the 
site by the investigator staff.  If the self-injections by patient or another designated person (such as 
parent, nurse, etc.) are decided during the extension period a training injection should be planned 
4 weeks before the first self-injection, under direct site staff supervision.   
During the open-label extension period for Cohort 4, the first injection administration will start 
at Week 12 at the end of the 12-week open-label dose finding. The treatment kit number will be 
provided by IRT according to the last dose administered in Cohort 4. The first injection of the 
extension period will be done at the site by the investigator staff.  If the self-injections by patient 
or another designated person (such as parent, nurse, etc.) are decided during the extension period a 
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training injection should be planned 4 weeks before the first self-injection, under direct site staff 
supervision.    
During the extension treatment period, IMP should ideally be administered every 2 weeks SC or 
every 4 weeks at approximately the same time of the day; however it is acceptable to have a 
window period of ±3 days. The time of the day is based on visit’s time or patient’s preference in 
case of self-injections.   
If by mistake or due to other circumstances an injection is delayed by more than 7 days or 
completely missed (for Cohorts 1 and 2) or by more than 14 days or completely missed (for 
Cohort 3 and Cohort 4), then the patient should return to the original schedule of study treatment 
administration without administering delayed injections.  On the other hand, if the delay is less 
than or equal to 7 days (for Cohorts 1 and 2) from the missed date or if the delay is less than or 
equal to 14 days for (Cohort 3 and Cohort 4) from the missed date, then the patient should 
administer the delayed injection and then resume the original schedule of study treatment 
administration. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The following classes of drugs are identified as non-IMP because the medication is a potential 
background therapy: 
• 
Statins. 
• 
Cholesterol absorption inhibitors (ezetimibe). 
• 
Bile acid-binding sequestrants (such as cholestyramine, colestipol, colesevelam). 
• 
Nicotinic acid. 
• 
Fenofibrate. 
• 
Omega-3 fatty acids (≥1000 mg daily). 
8.3 
BLINDING PROCEDURES 
8.3.1 IMP  
Not applicable, this study is an open-label design. 
8.3.2 Lipid parameters 
Lipid parameter values from blood samples obtained after the inclusion visit and during the main 
phase, run by the central lab, will not be communicated to the sites so that the patient’s LDL-C 
values do not influence the Investigator’s safety evaluation during the main treatment period for 
all cohorts and up to the end of the follow-up period for Cohorts 1-3.    
During the open-label extension period, the lipid levels will be communicated to the investigator. 
The Investigator will be responsible, based on his/her own judgment related to the patients’ 
LDL-C levels and the safety profile, to continue or discontinue alirocumab throughout the study.  
The reasons of any adjustment should be documented and recorded in the e-CRF. 
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8.3.3 Anti-alirocumab antibodies 
Patients’ anti-alirocumab antibody results will not be communicated to the sites, during the main 
phase, so that the patient’s ADA levels do not influence the Investigator’s safety evaluation 
during the main dose finding treatment period for all cohorts and up to the end of the follow-up 
period for Cohorts 1-3.   
Patients who do not enter the extension phase or who prematurely discontinue the main phase and 
have a titer at or above 240 for anti-alirocumab antibody at the follow-up visit (for Cohorts 1-3) or 
at the end of the dose finding treatment period (for Cohort 4) will have additional antibody 
sample(s), at 6 to 12 months after the last dose and thereafter about every 3 to 6 months until titer 
returns below 240. Patients who enter the extension phase will be monitored for anti-alirocumab 
antibodies as per the study flowchart (Section 1.4).   
8.3.4 Committee 
The DMC will receive unblinded lipid parameter results and confidential reports (Section 6.4).   
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The list of treatment kit number will be generated centrally by Sanofi.  The IMP (Cohorts 1 & 2 
(Q2W) or Cohort 3 (Q4W), body weight less than 50 kg or greater or equal to 50 kg) will be 
packaged in accordance with this list.  The below table represents the allocation according to the 
doses/ dose regimen: 
Table 1 - Allocation according to the doses/dose regimen for dose-finding treatment period and 
extension period until PFS will be available 
 
30 mg Q2W 
40 mg Q2W 
50 mg Q2W 
75 mg Q2W 
75 mg Q4W 
150 mg Q4W
Solvent for 
alirocumab vial 
1 
2 
1 
0 
1 
0 
150 mg vial 
1 
1 
1 
1 
1 
1 
 
The Trial Supply Operations Manager (TSOM) will provide the list of treatment kit numbers. 
Then, this centralized treatment allocation system provider will generate the patient list according 
to which it will allocate the treatment kits to the patients.   
Patients will be allocated to receive repeated dose of SC alirocumab injections administered every 
2 weeks (Q2W) or every 4 weeks (Q4W) in 4 independent cohorts of children and adolescents 
aged 8 to 17 years. Each independent cohort below will include up to 10 patients with no less than 
4 patients in each BW category: 
• 
Cohort 1 will receive 30 mg Q2W for body weight (BW) <50 kg and 50 mg Q2W for 
BW ≥50 kg. 
• 
Cohort 2 will receive 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW ≥50 kg. 
• 
Cohort 3 will receive 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg. 
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• 
Cohort 4 will receive 150 mg Q4W for BW <50 kg and 300 mg Q4W for BW >50 kg. 
For Cohorts 1 & 2: The treatment kit numbers will be allocated using the centralized treatment 
allocation system on visit 2 (Day 1, Week 0 to Week 6 according to the cohort and the body 
weight: main treatment period), and then at Week 16 according to the cohort (open label dose 
finding treatment period) and every 3 months (open label extension treatment period) when PFS 
are available or every 2 weeks if PFS are not available as resupply visits, and at unscheduled 
visits, if needed.  
For Cohort 3: The treatment kit numbers will be allocated using the centralized treatment 
allocation system on visit 2 (Day 1, Week 0 and second injection, Week 4 according to the body 
weight: main treatment period), and then at Week 14 (open label dose finding treatment period) 
and every 3 months (open label extension treatment period) when PFS are available or every 
4 weeks if PFS are not available as resupply visits, and at unscheduled visits, if needed.  
For Cohort 4: The treatment kit numbers will be allocated using the centralized treatment 
allocation system on visit 2 (Day 1, Week 0 and second injection, Week 4 according to the body 
weight: main treatment period, with third injection, Week 8), and then at Week 12 (open label 
dose finding treatment period) and every 3 months (open label extension treatment period).  
Before allocating a treatment kit to the patient, the investigator or designee will have to contact 
the centralized treatment allocation system.   
An included patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file 
regardless of whether the treatment kit will be used or not. A patient cannot be included more than 
once in the study.  If a treatment is used without contacting the centralized treatment allocation 
system, then the patient will be considered as not included and withdrawn from the study.   
Two types of centralized treatment allocation system will be used, the Interactive Voice Response 
System (IVRS) and the Interactive Web Response System (IWRS) depending on the choice of the 
site. Interactive response technology (IRT) covers both centralized treatment allocation.  
8.5 
PACKAGING AND LABELING  
Open Label dose finding treatment period:  
For Cohorts 1, 2 and 3: Each kit will contain one vial: either a vial of alirocumab 150 mg/mL or a 
vial solvent for alirocumab. The number of kits and types of kits (active or solvent) to be 
dispensed depend on the treatment doses / dose regimen (see Table 1).   
For Cohort 4, patients will receive 1 or 2 kit(s) for the 12 week alirocumab treatment period 
depending on the dose group (1 kit for 150mg Q4W & 2 kits for 300mg Q4W). Each kit will 
contain 4 PFS of alirocumab 150 mg/mL 
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Open Label Extension period:  
If PFS are available: 
Cohorts 1 & 2: patients will receive 2 kits for 12-weeks alirocumab treatment period. Each kit will 
contain 4 PFS. 
Cohort 3: patients will receive 1 kit for 12-weeks alirocumab treatment period. Each kit will 
contain 4 PFS. 
Cohort 4: patients will receive 1 or 2 kit(s) of PFS for up to a 12 week alirocumab treatment 
period, depending on dose group.  
If PFS are not available for Cohorts 1 to 3: 
The packaging will be the same as for Open Label Dose finding:  
Each kit will contain one vial: either a vial of alirocumab 150 mg/mL or a vial solvent for 
alirocumab. The number of kits and types of kits (active or solvent) to be dispensed depend on the 
treatment doses / dose regimen (see Table 1).   
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP will be stored in a refrigerator between +2°C and +8°C (36°-46° F) by the site. The 
temperature of the site refrigerator should be checked 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 local regulations, labeling specifications, policies and procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the alirocumab should be managed 
according to the rules provided by the Sponsor. 
During the extension period 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 in case of self-injections or injections administered by parent or designated 
person.   
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, the nurse or other personnel allowed to store, prepare 
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. 
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All IMPs will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allows the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
IMP administration data will be recorded by the investigator on eCRF for the main treatment 
period and when alirocumab is prepared from vials during the extension phase and by 
patients/parents on a patient’s diary in case of self-injection with prefilled syringes during the 
extension period.   
Measures taken to ensure and document IMP compliance and accountability (vials and PFS if 
available) are described below: 
• 
The investigator or designee will obtain via IVRS/IWRS the treatment kit number(s) and 
he/she will dispense the treatment kit(s) to the patient.   
• 
The accountability at site is to be performed at IMP kit re-supply visits only (see 
Section 10.1).  During the extension period in case of self-injections, the used and unused 
kit(s) should be brought back to such visits for accountability purposes.   
• 
The investigator or designee will complete the corresponding treatment log form from 
patient’s diary.   
• 
The investigator/study coordinator will enter data in the appropriate e-CRF pages, 
according to data recorded in the treatment log form.   
• 
The monitor will check the data consistency between e-CRF pages, treatment log forms 
using patient’s diary, and returned unused syringes 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 not allowed in the country, all treatments kits will 
be retrieved by the Sponsor.   
For background LMT (statin or other LMT) not provided by the Sponsor, tracking and 
reconciliation has to be achieved by the Investigator according to the system proposed by the 
Sponsor.  
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8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s) 
(until follow-up visit).   
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 
(other than those that are prohibited during the study) may be given at the discretion of the 
investigator, with a stable dose (statin ± other LMT).  Besides the specific information related to 
concomitant medications provided in this section, any other concomitant medication(s) will be 
allowed and will have to be recorded in the e-CRF and source data.   
Nutraceutical products or over-the-counter therapies (with the exception of prohibited 
medications, see Section 8.8.3) that may affect lipids are allowed only if they have been used at a 
stable dose for at least 4 weeks prior to screening visit, during the screening period and 
maintained during the first 8 weeks of the main treatment period and follow-up period if 
applicable.  During the extension period, modification to these nutraceutical products or 
over-the-counter therapies is allowed but in general should be avoided.  Examples of such 
nutraceutical products or over-the-counter therapies include omega-3 fatty acids, plant stanols 
such as found in Benecol, flax seed oil, and psyllium.   
Any adjustment will be documented in the e-CRF.   
8.8.1 Management of background lipid modifying therapy 
Patients must have been on stable optimal dose of statin with or without other LMT(s) for at least 
4 weeks prior to the screening LDL-C sample being obtained, and from the screening visit to 
Day 1. 
For background LMT (statin ± other LMT), sites must follow the national product label for the 
safety monitoring and management of patients.   
Main treatment phase: 
From the inclusion visit (Day 1) until Week 14 or 16 end of the follow-up period for Cohorts 1-3 
or until Week 12 end of the open label dose finding treatment period for Cohort 4, the background 
LMT should not be changed. No dose adjustment, discontinuation or initiation of other statins or 
other LMT should take place during this time, barring exceptional circumstances whereby 
overriding concerns warrant such changes, as per investigator’s judgment. 
During the main treatment phase, lipid profile values from samples obtained after inclusion will 
be blinded. 
Extension treatment phase: 
During the optional extension phase the lipid levels will be communicated to the investigators. 
The Investigator will be responsible, based on his/her own judgment related to the patients’ 
LDL-C levels and the safety profile, to continue or discontinue alirocumab throughout the study.  
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The daily dose of statin should be maintained; in particular any decreases in statin dose are 
strongly discouraged, except in case of medical reason. The statin dose should not be decreased to 
adjust to the degree of LDL-C lowering; the Investigator has the option to discontinue alirocumab. 
Other LMT (if applicable) can be modified based on the Investigator’s judgment throughout the 
study. 
Any adjustment will be documented in the e-CRF.   
8.8.2 Contraception: 
Females of childbearing potential who are sexually active must use an effective contraceptive 
method throughout the entire duration of the study treatment (including main treatment period and 
extension phase, as applicable) and for at least 10 weeks after the last IMP injection (see 
Appendix G).   
8.8.3 Prohibited concomitant medications 
• 
Prohibited concomitant medications from the initial screening visit until the follow-up 
visit for Cohorts 1-4 / end of open label dose finding treatment period visit include the 
following: 
- 
Oral and injectable corticosteroids, 
- 
Fibrates (except fenofibrates), 
- 
Immunosuppressants. 
• 
Prohibited concomitant medications from the start of the open-label extension period until 
the end of study will include the same prohibited concomitant medication as in the main 
treatment period.   
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
9.1.1 Primary efficacy endpoint 
The primary efficacy endpoint will be the percent change in calculated LDL-C from baseline to 
Week 8, which is defined as: 100x (calculated LDL-C value at Week 8 minus calculated LDL-C 
value at baseline)/calculated LDL-C value at baseline.   
The baseline calculated LDL-C value will be the last LDL-C level obtained before the first 
injection IMP. For patients included and not treated, the baseline value is defined as the last 
available value obtained up to inclusion.   
The calculated LDL-C at Week 8 will be the LDL-C level obtained within the Week 8 analysis 
window.  
All calculated LDL-C values (scheduled or unscheduled, fasting or not fasting) may be used in the 
analyses if appropriate according to above definition and analysis windows used to allocate a time 
point to a measurement. Analysis windows will be defined in the Statistical Analysis Plan (SAP).   
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoint(s) 
• 
The absolute change in calculated LDL-C from baseline to Week 8. 
• 
The proportion of patients achieving a calculated LDL-C <130 mg/dL (3.37 mmol/L) at 
Week 8. 
• 
The proportion of patients achieving a calculated LDL-C level <110 mg/dL (2.84 mmol/L) 
at Week 8. 
• 
The percent change in LDL-C from baseline to Week 12 only for Cohort 4. 
• 
The percent change in Apo B from baseline to Week 8. Same definition and rules as for 
the primary endpoint.   
• 
The percent change in non-HDL-C from baseline to Week 8. Same definition and rules as 
for the primary endpoint.   
• 
The percent change in Total-C from baseline to Week 8. Same definition and rules as for 
the primary endpoint.   
• 
The percent change in Lp(a) from baseline to Week 8. Same definition and rules as for the 
primary endpoint. 
• 
The percent change in TG from baseline to Week 8. Same definition and rules as for the 
primary endpoint. 
• 
The percent change in HDL-C from baseline to Week 8. Same definition and rules as for 
the primary endpoint.   
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• 
The percent change in Apo A-1 from baseline to Week 8. Same definition and rules as for 
the primary endpoint.   
• 
The absolute change in Apo B from baseline to Week 8. 
• 
The absolute change in non HDL-C from baseline to Week 8. 
• 
The absolute change in Total-C from baseline to Week 8. 
• 
The absolute change in Lp(a) from baseline to Week 8. 
• 
The absolute change in HDL-C from baseline to Week 8. 
• 
The absolute change in TG from baseline to Week 8. 
• 
The absolute change in Apo A-1 from baseline to Week 8. 
• 
The absolute change in ratio Apo B/Apo A-1 from baseline to Week 8. 
9.2.2 Efficacy assessment method 
9.2.2.1 Lipid parameters 
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 1.3 and Section 1.4. LDL-C will be calculated using the 
Friedewald formula by the Central Laboratory as per the schedule in Section 1.3 and Section 1.4. 
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 Reference Laboratory 
Manual.   
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4.   
9.2.3 Safety endpoints  
The safety endpoints will be adverse events, serious adverse events, adverse events of special 
interest, laboratory data, vital signs, Tanner stage assessment, body weight, and height assessed 
throughout the study.   
9.2.3.1 Observation period 
The observation of safety data will be as follows: 
• 
Pretreatment period: The Pretreatment observation period is defined from the signed 
informed consent up to the first dose of IMP.   
• 
Treatment emergent adverse event (TEAE) period: The TEAE observation period is 
defined as the time from the first dose of IMP to the last dose of IMP injection +70 days 
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(10 weeks) as residual effect of alirocumab is possible until 10 weeks after the stop of 
treatment IMP injection.   
• 
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 6.2.2).   
9.2.3.2 Adverse event 
All AEs reported by the Investigator, will be described.   
All AEs will be coded to a “Lowest Level Term”, “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.   
Groupings of AEs may include the following: 
• 
General allergic events (AESIs or not, see Section 10.4.1.3).   
• 
Local injection site reactions deemed to be allergic (AESIs or not, see Section 10.4.1.3).   
• 
Neurologic adverse events (AESIs or not, see Section 10.4.1.3). 
• 
Neurocognitive events. 
• 
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 
for patients in the Q2 week regimen and <14 calendar days for patients in the Q4 week 
regimen, or twice the planned dose at one injection due to IMP preparation error), to 
be reported using the corresponding screens in the eCRF using the term “symptomatic 
overdose (accidental or intentional)”. The patient should be monitored and appropriate 
symptomatic treatment instituted,   
• 
Pregnancy of female patient (including male patient’s partner). 
• 
ALT increase. 
Adverse event observation period: 
• 
The AE observations are per the observation periods defined above.   
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 6.2.2).   
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9.2.3.3 Safety laboratory 
• 
The clinical laboratory data consist of blood analysis, hematology (RBC count, 
hemoglobin, hematocrit, platelets, WBC count with differential blood count), standard 
chemistry (glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, urea 
nitrogen, creatinine, uric acid, total protein, lactate dehydrogenase (LDH), albumin, 
γ Glutamyl Transferase [γGT]), liver panel (ALT, AST, ALP, and total bilirubin), CPK, 
cortisol (with reflexive ACTH levels if cortisol <lower limit of normal range [LLN]) and 
dehydroepiandrosterone sulfate (DHEAS), luteinizing hormone (LH) and follicle-
stimulating hormone (FSH), testosterone (male) and estradiol (females),vitamins A 
(retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone).   
Some additional safety laboratory parameters may be reflexively measured, based on actual data 
(please refer to Section 10.4.6). 
Clinical laboratory values will be analyzed after conversion into standard international units.   
Standard international units will be used in all listings and tables.   
9.2.4 Vital signs measurement 
Vital signs include: heart rate, systolic and diastolic BP in sitting position.   
9.2.5 Tanner stages measurement 
The Tanner stages will be measured (see Appendix E) throughout the study according to the 
schedule in Section 1.3 and Section 1.4.  The Tanner stages assessment for each patient at each 
site should be performed, if possible by the same investigator/designee trained to assess pubertal 
development. 
9.3 
OTHER ENDPOINTS 
9.3.1 ANTI-ALIROCUMAB ANTIBODY ASSESSMENTS 
Anti-alirocumab antibodies include the antibody status (positive/negative) and antibody titers.   
9.3.1.1 Sampling time 
Serum samples for anti- alirocumab antibody determination will be drawn periodically throughout 
the study as per schedule noted in the study flowchart of Section 1.3 and Section 1.4.  All 
scheduled samples will be obtained before IMP injection (predose).  Patients who prematurely 
discontinue the main phase or do not enter the optional extension phase, prematurely discontinue 
the extension phase or decide not to proceed to the Phase 3 study and who have a titer at or above 
240 for anti- alirocumab antibody at follow-up visit (for Cohorts 1-3) / end of dose finding 
treatment period (Cohort 4) / end of extension phase will have additional antibody sample(s), at 
6 to 12 months after the last dose and thereafter about every 3 to 6 months until titer returns below 
240.  The sponsor will notify the sites.   
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9.3.1.2 Sampling procedure 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites.  Five (5) mL blood volume is to be collected 
for each anti- alirocumab antibody sample.   
9.3.1.3 Bioanalytical method 
All anti- alirocumab antibody (ADA; anti-drug antibody) samples will be analyzed by the 
Regeneron Clinical Bioanalysis Group.   
Anti- alirocumab antibody samples will be analyzed using a validated non-quantitative, titer-based 
bridging immunoassay.  It involves an initial screen, a confirmation assay based on drug 
specificity, and a measurement of the titer of anti-alirocumab antibodies in the sample. 
 
 
 
Samples that are positive in the ADA assay will be assessed for neutralizing antibodies using a 
validated, non-quantitative, competitive ligand binding assay (Bioanalytical Validation Report 
 
9.4 
OTHER ENDPOINTS 
9.4.1 Pharmacokinetics 
Total serum alirocumab concentrations, as well as total and free PCSK9 concentrations will be 
measured from the same PK sample. 
9.4.1.1 Sampling time 
Serum samples for total alirocumab concentration will be collected before IMP (pre-dose) at 
Week 0 (inclusion visit) and then at several visits until the end of the follow-up period (for 
Cohorts 1-3) / end of dose finding treatment period (Cohort 4), as per the study flowchart (see 
Section 1.3). 
Exact date and time of last IMP administration and PK sampling are to be recorded. 
9.4.1.2 Pharmacokinetics handling procedure 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual which will be provided to sites. Five (5) mL blood volume is to be collected for 
each PK sample.   
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Table 2 - Pharmacokinetics handling for alirocumab  
Sample type 
alirocumab 
Matrix 
serum 
Blood sample volume 
5 mL 
Anticoagulant 
none 
Blood handling procedures 
See laboratory manual 
Storage conditions 
 -20°C (-80°C preferred) 
 
9.4.1.3 Bioanalytical method 
All PK samples will be analyzed by the Regeneron Clinical Bioanalysis Group. PK samples will 
be analyzed for the determination of total alirocumab concentrations (ie, free alirocumab and 
alirocumab present in PCSK9: alirocumab complexes) using a validated enzyme-linked 
immunosorbent assay (ELISA).
 
 
PK samples will be also analyzed for the determination of the total and free PCSK9 levels using 
validated ELISA. 
9.4.2 Pharmacogenetic assessment 
No pharmacogenetic testing will be done in this study. 
9.4.3 Pharmacodynamic variables 
The PD effect of alirocumab corresponding to the effect on LDL-C is described in the efficacy 
section (see Section 9.2.2). 
9.4.4 Efficacy and safety during the extension phase 
The long-term efficacy and safety of alirocumab will be evaluated during the extension phase.   
9.5 
FUTURE USE OF SAMPLES 
Not applicable. 
9.6 
APPROPRIATENESS OF MEASUREMENTS  
See Section 4. 
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10 
STUDY PROCEDURES 
For all visits after Day 1/Week 0 (inclusion visit), a timeframe of a certain number of days will be 
allowed.  The window period for all visits until Week 8 is ±3 days and for the follow-up period 
and Visits 9 and 10 it is ±7 days.  During the open label extension period, the visit window is 
±14 days for Visits 11 onward, and ±7 days for the end of treatment visit and the end of OLE 
visit. 
For all visits after Day 1/inclusion visit, if one visit date is changed, then the next visit should take 
place according to the original schedule as outlined in Section 1.3 and Section 1.4.   
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 8 hours fast and refrain from smoking) for all site visits 
throughout the study. Blood sampling for adrenal gland, pituitary and gonadal hormones should 
be obtained in the morning and at the same time if possible. Alcohol consumption within 48 hours 
and intense physical exercise within 24 hours preceding the blood sampling are discouraged.   
Note: if the patient is not in fasting conditions, the blood sample will not be collected and a new 
appointment will be given the day after (or as close as possible to this date) to the patient with 
instruction to be fasted (see above conditions).   
Laboratory tests: 
The laboratory data are collected in accordance with the study schedule in Section 1.3 and 
Section 1.4, and forwarded to the central laboratory: 
• 
Hematology - complete blood cell count including hematocrit, hemoglobin, red blood cell 
count, white blood cell count with differential count and platelets. 
• 
Chemistry - glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorus, urea 
nitrogen, creatinine, uric acid, lactate dehydrogenase, total protein, albumin and gamma 
GT. Note: eGFR and creatinine clearance will be calculated at screening; creatinine 
clearance will be calculated for all subsequent visits where chemistry lab testing is 
performed. 
• 
Lipid panel 1: TC, calculated LDL-C, HDL-C, TG, non-HDL-C. 
• 
Lipid panel 2: Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a). 
• 
Liver panel: ALT, AST, ALP (alkaline phosphatase) and total bilirubin (in case of total 
bilirubin values above the normal range, differentiation into conjugated and 
non-conjugated bilirubin will occur automatically). 
• 
Creatine Phosphokinase (CPK). 
• 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN) and 
dehydroepiandrosterone sulfate (DHEAS). 
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• 
Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). 
• 
Gonadal hormones: testosterone (male) and estradiol (females). 
• 
Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K 
(phylloquinone). 
• 
Serum pregnancy test.  Pregnancy test should be done on females of childbearing potential 
who are sexually active or females who have experienced menarche.  The Screening 
(Week -2) pregnancy test should be a blood test.  All other pregnancy tests will be with a 
local urine pregnancy test.  
Notes: Any clinically relevant abnormal laboratory value should be immediately rechecked 
(whenever possible using the central laboratory) for confirmation before making any decision 
for the concerned patient.  It should be documented as an AE/SAE as applicable.  Please also 
refer to Section 10.4. 
Instructions for the central laboratory will be given in a specific manual provided to each 
investigator. 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D.   
CPK-MB and Troponin I should be performed by local laboratory and data collected in case of 
serious cardiac event. 
Pharmacokinetic samples: 
Serum samples for assessment of alirocumab concentration will be obtained periodically 
throughout the study as per schedule note in study flowchart of Section 1.3.   
For all cohorts, blood samples will be collected before IMP injection for visits 2 (Week 0), 
4 (Week 4), 6 (Week 8), then for Cohorts 1 to 3 at visit 8 (Week 14/16 [for patients entering the 
extension phase]) and, for Cohort 4, at visit 4 (Week 4), visit 6 (Week 8), visit 7 (Week 10), and 
visit 8 (Week 12).   
Blood samples should be collected before IMP injection.   
Physical examination: 
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart Section 1.3 and Section 1.4.  If a new clinically significant abnormality or 
worsening from baseline is detected after inclusion, then an AE should be reported and the patient 
should be considered for further clinical investigations and/or specialist consultation as per the 
Investigator’s medical judgment.   
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 5 minutes).  The use of calibrated apparatus with age 
related cuff size is mandatory. Values are to be recorded in the e-CRF; both systolic BP and 
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diastolic BP should be recorded.  At the first screening visit, BP should be measured in both arms.  
The arm with the highest diastolic pressure will be determined at this visit, and BP should be 
measured on this arm throughout the study. This highest value will be recorded in the e-CRF.   
Heart rate will be measured at the time of the measurement of BP.   
Tanner stages: 
The Tanner stages (29, 30) should be measured by the Investigator at the time points indicated in 
the study schedule flowchart Section 1.3.  Tanner stages are provided in Appendix E. The Tanner 
stages assessment for each patient at each site should be performed, if possible by the same 
investigator/designee trained to assess pubertal development. 
Body weight and height: 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder.  The same scale should be used throughout the study.   
The use of calibrated balance scales is mandatory. Self-reported weights are not acceptable; 
patients must not read the scales themselves. Height needs to be measured as self-reported heights 
are not acceptable.   
10.1 
VISITS SCHEDULE 
10.1.1 Screening period 
Only patients who meet/are likely to meet the inclusion criteria as noted in Section 7.1 should be 
screened.  The screening period (including run in) will take place up to 6 (+1) weeks or 42 (+7) 
days (and as short as possible, upon receipt of laboratory eligibility criteria) prior to 
inclusion/Day 1 visit, and may include more than one site visit for patients for whom not all 
screening procedures can be done at the first visit.  The screening visit can take place from 
42 (+7) days before the inclusion visit (for patients without a stable background LMT [optimal 
statin dose ± other LMTs or non-statin LMTs if statin intolerant] for at least 4 weeks prior to the 
screening visit and/or patients suspected of being heFH but without a confirmed diagnosis and 
consenting to undergo the centralized genotyping) up to 14 (-7) days before the inclusion visit (for 
patients with a stable LMT background therapy [optimal statin dosing±other LMT] for at least 
4 weeks prior to the screening visit and confirmed diagnosis of heFH.  Not all screening 
assessments and procedures need to be done at the same visit.  The sample for lipid testing must 
be obtained only after the patient has been on a stable LMT therapy (optimal statin dose ± other 
LMT) for at least 4 weeks. 
During the screening period the following procedures should be followed: 
Visit 1 (Week -6 (+1) to Week -2 (-1)) at clinical site: 
• 
Complete informed consent - the patient and their parents 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. 
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• 
Complete informed consent for genetic testing for patient electing to undergo genotyping 
for heFH and/or for use of previous documented genotyping. Written informed consent for 
the study must be obtained prior to genotyping consent and sampling. 
• 
Contact IVRS/IWRS for notification of screening. Patient number will be allocated by the 
IVRS/IWRS.  This patient number is composed of a 12-digit number containing the 3-digit 
country code, the 4-digit center code and the 5-digit patient chronological number (the 
5-digit patient chronological number is 00001 for the first patient screened in a center, 
00002 for the second patient screened in the same center).   
• 
Assess inclusion/exclusion criteria. 
• 
Obtain patient demography – age, gender, race, and ethnicity. 
• 
Obtain medical history, surgical history, alcohol habits and smoking habits for 
adolescents. 
• 
Obtain family medical history (including risk factors relating to premature CHD, see 
Appendix F: Simon Broome Register Diagnostic Criteria for heFH), allergy. 
• 
Document prior medication history within the previous 12 weeks, especially for lipid 
modifying therapy (including statin) and nutraceutical products that may affect lipids (eg, 
omega-3 fatty acids, plant stanols such as found in Benecol, flax seed oil, psyllium). 
• 
Record concomitant medications. 
• 
Check stability of background LMT. 
• 
Get body weight and height measurements. 
• 
Get Tanner stage measurement by the same investigator/designee at each visit if possible. 
• 
Perform physical examination.  Take vital signs including HR and BP. 
• 
Genotyping if patient consents to undergo centralized genotyping for heFH (Note: Buccal 
swab, saliva, or blood sample needed; if blood sample is drawn for genotyping only, the 
patient does not need to be fasting).  
• 
Collect AEs from this point onward: 
- 
All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study until the post study treatment follow-up visit.   
• 
Obtain fasting blood sample for: 
- 
Lipid panel 1: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C,   
- 
Lipid panel 2: Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a), 
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, and γGT,   
- 
Liver panel (ALT, AST, ALP, and total bilirubin),   
- 
CPK,  
- 
Pregnancy test (blood test) for females who have experienced menarche. 
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• 
An appointment will be given for the next visit.   
• 
Give instruction on diet: Patients will be instructed to follow a diet in accordance with the 
American Academy of Pediatrics guidelines (1) or equivalent throughout the entire study 
(ie, both phases).  
• 
Give instruction on stable background LMT: Patients will be instructed to be treated with 
stable optimal dose of statin ± other LMT for at least 4 weeks, if not already on stable 
optimal dosing for at least 4 weeks, or to continue the LMTs at the same dose.  
Note:  All patients will be qualified for inclusion based on the confirmation of heFH 
diagnosis by genotyping or clinical criteria, stable dose of LMT (including statin at 
optimal dose, unless intolerant) for at least 4 weeks prior to the screening visit, and by the 
LDL-C value obtained during the screening period, on stable dose of statins ± other LMTs 
after at least 4 weeks. 
All patients who successfully screen for Cohort 1 and are not included in Cohort 1, due to 
the appropriate Cohort 1 weight group being fully enrolled, may participate to Cohort 2 
but only after eligibility, including safety assessments, is reconfirmed.  Patients who are 
successfully screened for Cohort 2 but are not enrolled, due to the appropriate Cohort 2 
weight group being fully enrolled, may participate in Cohort 3 without the need to repeat 
the run-in/screening period if there is no more than 3 months between eligibility 
confirmation  and inclusion.  In such a circumstance, the run-in/screening period from 
Cohort 2 will substitute for the run-in/screening period for Cohort 3. If there is more than 
3 months between initial screening and planned enrollment in Cohort 3, patient eligibility, 
including safety assessments, must be reconfirmed.   
Safety and eligibility assessments noted above include all lab tests listed as exclusionary, 
based on specified results. 
Patients should be instructed to follow a diet in accordance with the American Academy of 
Pediatrics (AAP) guidelines (1) or equivalent throughout the entire study (ie, both phases). 
The dietician or site staff with appropriate training will review the patient’s diet at the 
screening visit and periodically throughout the study. 
10.1.2 Dose finding Treatment Period  
The timelines of the visits should be the same for each Cohort, but patients from Cohort 2 will be 
included after patients from Cohort 1 complete the open label dose finding treatment period and 
after DMC recommendation on dose escalation. Patients from Cohort 3 will be included after 
patients from Cohort 2 complete enrollment. 
• 
Cohorts 1 & 2: screening visits from W-6 to W-2 (±1), inclusion visit W0, study visits 
W2, W4, W6, end of main treatment period visit W8, first follow-up visit W12, second 
follow-up visit W16. 
• 
Cohort 3: screening visits from W-6 to W-2 (±1), inclusion visit W0, study visits W2, 
W4,  W6, end of main treatment period visit W8, first follow-up visit W10, second follow-
up visit W14. 
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• 
Cohort 4: screening visits from W-6 to W-2 (±1), inclusion visit W0, study visits W2, 
W4, W6, W8, W10 and end of main treatment period visit W12. 
10.1.2.1 Inclusion visit (Visit 2/Week 0/Day 1) at clinical site  
• 
Assess Inclusion/Exclusion Criteria in particular confirmation of heFH diagnosis by 
genotyping or clinical criteria.   
• 
Collect AEs.   
• 
Record concomitant medication.   
• 
Check stability of background LMT. 
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.   
• 
Perform physical examination.   
• 
Get body weight measurement.   
• 
Take vital signs including HR and BP.   
• 
Urine pregnancy test (females who have experienced menarche only).   
• 
Obtain fasting blood sample for: 
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio 
Apo B/Apo A-1, and Lp(a),   
- 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN), 
dehydroepiandrosterone sulfate (DHEAS), 
- 
Gonadal and pituitary hormones: testosterone (male) and estradiol (female), luteinizing 
hormone (LH), follicle-stimulating hormone (FSH), 
- 
Fat soluble vitamins: retinol (vitamin A), 25hydroxy-vitamin D (vitamin D), 
alpha-tocopherol (vitamin E), phylloquinone (vitamin K). 
• 
Anti-alirocumab antibodies.   
• 
Serum alirocumab concentration (PK).  
• 
PCSK9 levels (free and total). 
• 
If the patient is confirmed eligible (and in fasting conditions), the Investigator will start the 
next study procedures: 
- 
Contact IVRS/IWRS for notification of inclusion. Investigators should never allocate a 
treatment kit number to a patient without contacting IVRS/IWRS.  IVRS/IWRS 
contact for allocation of a batch number for inclusion kit,   
- 
Record batch number allocated in e-CRF,   
- 
Main treatment period IMP kits dispensation as per treatment kit numbers provided by 
IVRS along with schedule reminder for visits.  The investigator/patient injection 
instruction manual and treatment administration package should be provided to the 
investigator staff.     
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- 
The first alirocumab injection will take place at the study site, but only after the 
collection of the fasting blood samples and after the assessment of all evaluations 
planned at that visit.  The patient should be observed for at least 30 minutes after the 
first injection.   
• 
Reminder: 
- 
An appointment will be given for the next study site visit or visit at patient’s home.     
10.1.2.2 Visit 3/Week 2, (Day 14 ±3) at clinical site or nurse visit at patient’s home.  For 
Cohort 3 and Cohort 4, a phone call may be done instead.  
• 
Collect AEs. 
• 
Record concomitant medication. 
• 
IVRS/IWRS contact. 
• 
Check of stability of background LMT. 
• 
For Cohorts 1 & 2: The second alirocumab injection will take place at the study site or 
patient’s home, but only after the assessment of all evaluations planned at that visit (no 
injection for Cohort 3 or Cohort 4 at this visit).   
• 
Reminders: 
- 
An appointment will be given for the next study site visit,   
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8-hour fast and refrain 
from smoking) for next study site visit. Also, alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the next study site visit are 
discouraged.   
10.1.2.3 Visit 4/Week 4 (Day 28 ±3) at clinical site 
• 
Collect AEs.   
• 
Record concomitant medication. 
• 
Get body weight measurement.   
• 
IVRS/IWRS contact. 
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.   
• 
Take vital signs including HR and BP.   
• 
Check of stability of background LMT. 
• 
Obtain fasting blood sample for: 
- 
Liver panel (ALT, AST, ALP, and total bilirubin),   
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, and γGT,   
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- 
Lipids:  total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, 
- 
CPK, 
- 
Serum alirocumab concentration (PK),   
- 
PCSK9 levels (free and total). 
• 
For Cohorts 1 & 2: The third alirocumab injection will take place at the study site, but only 
after the assessment of all evaluations planned at that visit.  For Cohort 3: the second and 
last alirocumab injection of this period will take place at the study site, but only after the 
assessment of all evaluations planned at that visit. 
• 
For Cohort 4, the second injection out of 3 of this period will take place at the study site. 
• 
Reminder: 
- 
An appointment will be given for the next study site visit or visit at patient’s home.   
10.1.2.4 Visit 5/Week 6 (Day 42 ±3) at clinical site or nurse visit at patient’s home. For 
Cohorts 3 and 4, a phone call may be done instead.  
• 
Collect AEs. 
• 
Record concomitant medication. 
• 
IVRS/IWRS contact. 
• 
Check of stability of background LMT. 
• 
For Cohorts 1 & 2: The fourth and the last alirocumab injection for this period will take 
place at the study site or the patient’s home, but only after the assessment of all 
evaluations planned at that visit (no injection for Cohort 3 or 4 at this visit).   
• 
Reminders: 
- 
An appointment will be given for the next study site visit,   
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8-hour fast and refrain 
from smoking) for next study site visit. Also, alcohol consumption within 48 hours and 
intense physical exercise within 24 hours preceding the next study site visit are 
discouraged.   
10.1.2.5 Visit 6/Week 8 (Day 56 ±3)/ at clinical site (end of the OL dose finding treatment 
period)  
• 
Collect AEs.   
• 
Record concomitant medication.   
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.   
• 
Perform physical examination.   
• 
Get body weight measurement.   
• 
Take vital signs including HR and BP.   
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• 
Urine pregnancy test (female who have experienced menarche only).   
• 
Obtain fasting blood sample for:  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio 
Apo B/Apo A-1, and Lp(a),   
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, and γGT,   
- 
Liver panel (ALT, AST, ALP, and total bilirubin),   
- 
CPK,   
- 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN), 
dehydroepiandrosterone sulfate (DHEAS), 
- 
Gonadal and pituitary hormones: testosterone (male) and estradiol (female), luteinizing 
hormone (LH), follicle-stimulating hormone (FSH), 
- 
Fat soluble vitamins: retinol (vitamin A), 25hydroxy-vitamin D (vitamin D), 
alpha-tocopherol (vitamin E), phylloquinone (vitamin K). 
• 
Anti-alirocumab antibodies.   
• 
Serum alirocumab concentration (PK).  
• 
PCSK9 levels (free and total). 
• 
Check of stability of background LMT.  
• 
Reminder:  
- 
An appointment will be given for the next study site visit or phone call visit 
(first follow-up study visit).   
• 
For Cohort 4, the final third injection of this period will take place at the study site  
10.1.2.6 Visit 7/Week 10 (Day 70 ±7) at clinical site (Cohort 4 Only): 
• 
Collect AEs.   
• 
Record concomitant medication. 
• 
Obtain fasting blood sample for: 
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C. 
- 
PCSK9 levels (free and total) / Serum alirocumab concentration (PK). 
10.1.2.7 Visit 8/Week 12 (end of the OL dose finding treatment period) (Cohort 4 only) 
• 
Collect AEs.   
• 
Record concomitant medication. 
• 
Get body weight and height measurements. 
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• 
Assess Tanner stage.  
• 
Take vital signs including HR and BP. 
• 
IVRS/IWRS contact. 
• 
Check of stability of background LMT. 
• 
Urine pregnancy test (female who have experienced menarche only).   
• 
Obtain fasting blood samples for: 
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C. 
- 
PCSK9 levels (free and total) / Serum alirocumab concentration (PK). 
10.1.3 Follow-Up Period 
The follow-up period is mandatory for cohorts 1-3 but not for Cohort 4. 
10.1.3.1 First Follow-Up Visit (Visit 7 / Week 10/Day 70 ±7 [Cohort 3] / Week 12/Day 84 ±7 
[Cohorts 1 & 2]) at clinical site or phone call if no safety concerns by the 
investigator at the previous visit or between the 2 visits “visit 6” and “visit 7” 
• 
Collect AEs.   
• 
Record concomitant medication.  
• 
Perform physical examination (only in case of clinically relevant abnormality at the end of 
treatment visit) if visit at clinical site.   
10.1.3.2 Second Follow-Up Visit (Visit 8 / Week 14 for Cohort 3/Day 98 ±7/ Week 16 for 
Cohorts 1 & 2 / Day 112 ±7) at clinical site (end of the main study period). 
• 
Collect AEs.   
• 
Record concomitant medication.   
• 
Get body weight and height measurements.   
• 
Take vital signs including HR and BP.   
• 
Perform physical examination (only in case of clinically relevant abnormality at the 
Week 8/end of treatment visit).   
• 
Get Tanner stages measurement by the same investigator/designee at each visit if possible.  
• 
IVRS/IWRS contact to document the end of the main phase period and the start of the 
optional open-label extension period if patient agrees for participation in this extension.   
• 
Urine pregnancy test (females who have experienced menarche only).   
• 
Obtain fasting blood sample for:  
• 
Anti-alirocumab antibodies,   
• 
Serum alirocumab concentration (PK),  
• 
PCSK9 levels (free and total). 
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• 
Only in case of clinically relevant abnormal values for these parameters at the end of 
treatment visit will the following be obtained at this visit: 
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, and γGT,   
- 
Liver panel (ALT, AST, ALP and total bilirubin),   
- 
CPK.   
10.1.4 Open label extension treatment period (OLETP, optional) 
Patients who successfully complete the main treatment period and follow-up period will be 
eligible (provided they have not experienced AEs leading to permanent discontinuation during the 
main treatment period, or had significant protocol deviations, in the Investigator’s judgment) to 
enter an optional open-label treatment period.  Treatment for these patients will start after the 
follow-up period and the last dose/dose regimen of the main treatment period should be 
administered again during this extension period (start Week 16 for Cohorts 1 and 2, and Week 14 
for Cohort 3). Cohort 4 will start the extension phase on Week 12 or have the option of direct 
entry into the phase 3 study. 
This dose/dose regimen may be modified after the final doses for the Phase 3 study have been 
selected and based on the body weight at the time of possible dose change for Cohorts 1-3 and 
will not be modified for Cohort 4 as these patients will remain on their initial regimen given the 
planned study end date of December 2018. Alirocumab administration will be continued until at 
least 10 weeks before the initiation of the pediatric phase 3 study in the site where the patient is 
potentially participating or December 2018, whichever comes first.   
• 
During the OLETP:  
• 
A window of ±7 days or ±14 days according the visit is authorized for each visit planned 
every 12 weeks from Week 16 or Week 14 to Week 130 for all cohorts (see Section 1.4),   
- 
An IVRS/IWRS contact for open-label extension treatment allocation should be done 
every 2 weeks by the investigator to prepare for using vials in Cohorts 1 & 2 until 
availability of PFS. 
10.1.4.1 Visit 8/Week 16 for Cohorts 1 & 2 or Visit 8/Week 14 for Cohort 3 /Week 12 for 
Cohort 4 (same visit as the last visit of the main treatment period) 
At this visit, patients will undergo end of follow-up period assessments and baseline open-label 
extension treatment period assessments, as appropriate, concurrently.  Study site personnel should 
review treatment requirements of the open-label extension treatment period with patients and 
remind patients that dosing in the open-label extension treatment period begins at this visit.  The 
following information will be collected: 
• 
Assess Exclusion Criteria for open-label extension treatment period (see Section 7.3).   
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• 
All evaluations performed for the end of the follow-up period are the same for the first 
visit of the open-label extension treatment period (see previous Section) except blood 
sample for lipids evaluation.   
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent. 
• 
Check of stability of LMT dosing. 
• 
Urine pregnancy test (females who have experienced menarche only).  
• 
If the patient is confirmed eligible (and in fasting conditions), the Investigator will start the 
next study procedures:  
- 
IVRS/IWRS contact for open-label extension treatment allocation of one 7-digit 
treatment kit number according to the treatment number list for the alirocumab 
injections. Investigators should never allocate a treatment kit number to a patient 
without contacting IVRS/IWRS.   
• 
If the prefilled syringe becomes available: open-label extension treatment IMP kits 
dispensation as per treatment kit numbers provided by IVRS along with schedule 
reminder. Injection training to be provided.  The patient injection instruction manual and 
treatment administration package should be provided. The patient’s diary should be given 
and instructions on its completion should be reviewed for Cohorts 1 to 3.   
• 
The first open-label extension alirocumab 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 this visit.  Close supervision, feedback and training (if prefilled 
syringes) to be provided for IMP administration in case of self-injection or injection 
administered by parent/legal custodian.    
• 
Obtain fasting blood sample for:  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio 
Apo B/Apo A-1, and Lp(a) for Cohorts 1 to 3, 
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C for Cohort 4.   
• 
Reminders:  
- 
An appointment will be given for the next study site visit,   
- 
Patient to bring the diary, and used and unused kits, at the next study site visit 
(if applicable ie, prefilled syringes).   
• 
The alirocumab injections should be done every 2 weeks for Cohorts 1 and 2 or every 
4 weeks for Cohort 3 and Cohort 4 at clinical site, by a health care professional at patients’ 
home, or by patient or representative (parent…) at home according to the type of supplied 
syringe (prefilled or not) during all the extension period.  This alirocumab administration 
during the open-label extension will continue until approximately 10 weeks before the 
initiation of the pediatric Phase 3 study or December 2018, at the latest. 
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10.1.4.2 Visit 9/Week 20 for Cohorts 1 & 2 /Week 18 for Cohort 3/Week 16 for Cohort 4 
(Phone Call Option) 
• 
Collect AEs.  
• 
Record concomitant medication.  
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent. 
• 
Review patient’s diary and compliance check of IMP if applicable.  
• 
Check of stability of LMT dosing.   
• 
Reminders:  
• 
An appointment will be given for the next study site visit,   
• 
Patient to bring the diary, and used and unused kits, at the next study site visit 
(if applicable ie, prefilled syringes).   
10.1.4.3 Visit 10/Week 24 for Cohorts 1 & 2 /Week 22 for Cohort 3/Week 20 for Cohort 4 
(Phone Call Option) 
• 
Collect AEs.   
• 
Record concomitant medication.  
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.  
• 
Check of stability of LMT dosing.   
• 
Reminders:  
- 
An appointment will be given for the next study site visit,   
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged,   
- 
Patient to bring the diary, and used and unused kits, at the next study site visit 
(if applicable ie, prefilled syringes).   
10.1.4.4 Visits 11, 13, 15, 17, 19 (every 24 weeks)/ Visit 11 only for Cohort 4 
• 
Collect AEs.   
• 
Record concomitant medication.     
• 
Urine pregnancy test (females who have experienced menarche only).   
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.  
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• 
If the prefilled syringe becomes available: Data collection on alirocumab administration 
and alirocumab compliance check by review of diary and treatment kit accountability for 
Cohorts 1 to 3.   
• 
Cohort 4 will receive second alirocumab allocation and administration for OLE phase. 
• 
Check of stability of background LMT.  
• 
IVRS/IWRS contact to get treatment kit number for 1 kit resupply.   
• 
Obtain fasting blood sample for:  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, 
ratio Apo B/Apo A-1, and Lp(a) for Cohorts 1 to 3.  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C for Cohort 4. 
- 
Liver panel (ALT, AST, ALP, and total bilirubin),  
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, LDH, albumin, and γGT, 
- 
CPK, 
- 
Anti-alirocumab antibodies, 
- 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN), 
dehydroepiandrosterone sulfate (DHEAS), 
- 
Gonadal and pituitary hormones: testosterone (male) and estradiol (female), luteinizing 
hormone (LH), follicle-stimulating hormone (FSH), 
- 
Fat soluble vitamins: retinol (vitamin A), 25hydroxy-vitamin D (vitamin D), 
alpha-tocopherol (vitamin E), phylloquinone (vitamin K). 
• 
Reminders: 
- 
An appointment will be given for the next study site visit,   
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged,   
- 
Patient to bring the diary, and used and unused kits at the next study site visit.   
10.1.4.5 Visits 12, 14, 16, 18 (every 24 weeks)/ Visit 12 only for Cohort 4 
• 
Collect AEs.   
• 
Record concomitant medication.   
• 
Perform physical examination.  
• 
Get body weight and height measurements. 
• 
Get Tanner stage measurement by the same investigator/designee at each visit if possible.  
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Amended Clinical Trial Protocol NO. 02  
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Page 92 
• 
Take vital signs including HR and BP.   
• 
Urine pregnancy test (females who have experienced menarche only).   
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.    
• 
If the prefilled syringe becomes available: Data collection on alirocumab administration 
and alirocumab compliance check by review of diary and treatment kit accountability.   
• 
Check of stability of background LMT.   
• 
IVRS/IWRS contact to get treatment kit number for 1 kit resupply.   
• 
Obtain fasting blood sample for:  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio 
Apo B/Apo A-1, and Lp(a), for Cohorts 1 to 3.  
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C for Cohort 4.   
• 
Reminders: 
- 
An appointment will be given for the next study site visit,   
- 
Remind patient to be in fasting conditions (ie, overnight, at least 8 hours fast and 
refrain from smoking) for next study site visit. Also, alcohol consumption within 
48 hours and intense physical exercise within 24 hours preceding the next study site 
visit are discouraged,   
- 
Patient to bring the diary, and used and unused kits at the next study site visit.   
• 
Cohort 4 will receive third and final alirocumab allocation and administration for OLE 
phase. 
10.1.4.6 Visit 20, Week 130 for Cohorts 1 to 3/EOS, Week 48 for Cohort 4 [Visit 13 for Study 
Flow Chart, Main Phase or Visit 20 for eCRF (end of open-label extension period)] 
• 
Collect AEs.   
• 
Record concomitant medication.   
• 
Perform physical examination.   
• 
Get body weight and height measurement.  
• 
Take vital signs including HR and BP.   
• 
Get Tanner stage measurement by the same investigator/designee at each visit if possible.   
• 
Review patient’s diet. Patient should be on a diet in accordance with the American 
Academy of Pediatrics guidelines (1) or equivalent.    
• 
IVRS/IWRS contact to document the end of OLETP treatment, no injection will be done 
at this visit.   
• 
If prefilled syringe becomes available: Data collection on IMP administration and IMP 
compliance check by review of diary and treatment kit accountability.   
• 
Check of stability of background LMT.   
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• 
Urine pregnancy test (females who have experienced menarches only).   
• 
Obtain fasting blood sample for: 
- 
Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio 
Apo B/Apo A-1, and Lp(a), for Cohorts 1 to 3, 
- 
 Lipids: total-C, calculated LDL-C, HDL-C, TG, non-HDL-C for Cohort 4, 
- 
Hematology: red blood cell count including hematocrit, hemoglobin, WBC count with 
differential count and platelets,   
- 
Chemistry: glucose, sodium, potassium, chloride, bicarbonate, calcium, phosphorous, 
urea nitrogen, creatinine, uric acid, total protein, albumin, and γGT,   
- 
Liver panel (ALT, AST, ALP, and total bilirubin), 
- 
Adrenal gland hormones: cortisol (with reflexive ACTH levels if cortisol <LLN), 
dehydroepiandrosterone sulfate (DHEAS), 
- 
Gonadal and pituitary hormones: testosterone (male) and estradiol (female), luteinizing 
hormone (LH), follicle-stimulating hormone (FSH), 
- 
Fat soluble vitamins: retinol (vitamin A), 25hydroxy-vitamin D (vitamin D), 
alpha-tocopherol (vitamin E), phylloquinone (vitamin K),  
- 
CPK,   
- 
Anti-alirocumab antibodies.   
10.1.4.7 Follow-up Phone contact at least 10 weeks after the last IMP injection for all 
cohorts  
• 
Collect AEs if any.   
• 
Record concomitant medication.  
• 
In case of clinically relevant abnormality not recovered at the end of OLE visit, plan an 
unscheduled visit & perform physical examination/ laboratory examinations if needed.   
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: 
• 
Agreement, date, and signature of informed consent mentioning the study identification.   
• 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology.   
• 
Contraception methods for females of child-bearing potential who are sexually active.   
• 
Previous and concomitant medication (including the lipid modifying therapy).   
• 
Study identification.   
• 
Treatment number, dates of administration.   
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• 
Dates of visits and assessments including the examination report.   
• 
Vital signs, height, body weight, Tanner stage.   
• 
Faxed central lab reports (dated and signed by the Principal Investigator or 
subinvestigator).   
• 
IVRS/IWRS confirmation fax (screening, screen failure, inclusion, treatment reallocation, 
discontinuation, end of open-label dose finding treatment period, end of follow-up period, 
start of extension period, end of study).   
• 
Adverse events and follow-up: 
- 
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the follow-
up of the SAE.   
• 
Date of premature study discontinuation (if any) and reason.   
Source documentation may be found in the following: 
• 
Patient’s identity.   
• 
Medical history.   
• 
Hospital records.   
• 
Nursing notes.   
• 
Physician’s notes.   
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. If 
possible, the patients should be assessed using the procedures defined above. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the CRF. In any case, the 
patient should remain in the study as long as possible during the main treatment period. 
Pregnancy will lead to definitive treatment discontinuation in all cases.   
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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 eCRF screens when 
considered as confirmed.   
Treatment interruption is defined as one or more scheduled injections that are not administered to 
the patient as decided by the Investigator.   
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 if they decide to do so, at any time and irrespective of 
the reason, or this may be the Investigator’s decision. All efforts should be made to document the 
reasons for treatment discontinuation and this should be documented in the e-CRF.   
Patients should discontinue the IMP for the following reasons: 
• 
Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females of child-bearing potential who are sexually active only).   
• 
Acute injection reaction of clinical concern.   
• 
Serious adverse event (or non-serious but severe in intensity) of hypersensitivity reaction 
considered related to alirocumab.   
• 
At patient/parents request (ie, withdrawal of the consent for treatment).   
• 
If, in the Investigator's opinion, continuation with the administration of the IMP would be 
detrimental to the patient's well-being.   
• 
Intercurrent condition that requires discontinuation of the IMP. 
• 
At the specific request of the Sponsor.  
• 
Patient receives treatment prior to inclusion.   
Any abnormal laboratory value will be immediately rechecked for confirmation (within 24 hours 
if possible), before making a decision of discontinuation of the IMP for the concerned patient 
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10.3.4 Handling of patients after permanent treatment discontinuation 
Patients who prematurely discontinue study treatment (regardless of the reason) during the dose 
finding treatment period should undergo the following visits:   
• 
At the time of treatment discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at end of open-label dose finding 
treatment period visit except lipids, PK and ADA (this should take place within 5 days of 
treatment discontinuation, if possible), except if the timing of this visit corresponds to 
Week 8 visit. Lipids, PK and ADA should be assessed in an additional unscheduled visit: 
- 
Cohorts 1 and 2 (Q2W): This visit should take place 14 to 21 days after last 
alirocumab injection. 
- 
Cohort 3 & Cohort 4 (Q4W): this visit should take place 28 to 35 days after last 
alirocumab injection. 
• 
Week 8 visit, as described in Section 1.3, regardless of its timing in relation to the last 
alirocumab injection. 
All efforts should be done to perform these assessments.   
Patients who prematurely discontinue study treatment (regardless of the reason) during the open-
label extension period should undergo an unscheduled visit with assessments normally planned at 
end of open-label extension period visit except lipids and ADA (this should take place within 5 
days of treatment discontinuation, if possible). Lipids and ADA should be assessed in an 
additional unscheduled visit: 
• 
Cohorts 1 & 2 (Q2W): This visit should take place 14 to 21 days after last alirocumab 
injection. 
• 
Cohort 3 & Cohort 4 (Q4W): this visit should take place 28 to 35 days after last 
alirocumab injection. 
Whatever the period of premature treatment discontinuation, 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.  A final end of study visit can take place with assessments as specified in the end of 
study visit 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.   
For patients included and not treated, all efforts should be made to perform the Week 8 visit in 
order to collect the laboratory data and at the least, the lipid parameters.   
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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. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records checks. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. If 
possible, the patients should be assessed using the procedure defined above.   
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit including a pharmacokinetics sample, if appropriate. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.   
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented   
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient (eg, contacting patient’s family or private physician, review available registries or 
health care database), and to determine his/her health status, including at least his/her vital status.  
Attempts to contact such patients must be documented in the patient’s records (eg, times and dates 
of attempted telephone contact, receipt for sending a registered letter).   
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-included (treated) in the study. Their 
inclusion and treatment number must not be reused.   
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
Please refer to Appendix B for 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. 
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10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Is life-threatening, or 
 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
 
the patient was at risk of death at the time of the event; it does not refer to an event which 
 
hypothetically might have caused death if it were more severe. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important event. 
 
Medical and scientific judgment should be exercised in deciding whether expedited 
 
reporting is appropriate in other situations, such as important medical events that may not 
 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered as a medically important event. The 
list is not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
 
Allergic bronchospasm,  
 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
 
Convulsions (seizures, epilepsy, epileptic fit, absence seizures, etc).  
• 
Development of drug dependence or drug abuse, 
• 
ALT >3 xULN + total bilirubin >2 xULN or asymptomatic ALT increase >10 xULN, 
• 
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,   
• 
Suspected transmission of an infectious agent. 
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10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
Adverse Events of Special Interest (AESI) are AEs (serious or non-serious) that need to be 
monitored, documented, and managed in a prespecified manner described in the protocol. Please 
see Appendix B for additional information.   
For these AEs, the Sponsor will be informed immediately (ie within 24 hours), as per SAEs 
notification described in Section 10.4.1.2 even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF: 
The following AEs are considered as AESIs in the study: 
• 
ALT >3 ULN (Please refer to related flowchart in Appendix B). 
• 
Allergic events: 
- 
Any general allergic events regardless of the cause’ 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.   
- 
All general allergic events, and/or 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).   
• 
Pregnancy: 
- 
Pregnancy occurring in a female patient or the partner of a male patient included in the 
clinical trial. Pregnancy will be recorded as a prespecified AESI with immediate 
notification in all cases. It will be qualified as an SAE only if it fulfills the SAE 
criteria,   
- 
In the event of pregnancy of a female patient included in the trial, IMP should be 
discontinued,   
- 
The follow-up of the pregnancy in a female participant or in a female partner of a male 
participant will be mandatory until the outcome has been determined.   
• 
Symptomatic Overdose with IMP alirocumab: 
- 
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 
for Q2W regimen or 2 or more injections from the treatment kit are administered in 
<14 calendar days for Q4W regimen) to be reported using the corresponding screens in 
the eCRF using the term “symptomatic overdose (accidental [or intentional])”. The 
patient should be monitored and appropriate symptomatic treatment instituted if 
needed,   
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- 
The circumstances of the overdose should be clearly specified in the verbatim,   
• 
Neurologic Events: 
- 
Neurologic Events that require additional examinations/procedures and/or referral to a 
specialist should be reported as an AESI. If the event does not require additional 
examinations/ procedures and/or referral to a specialist, it should be reported as a 
standard AE.   
• 
Neurocognitive events: 
- 
All neurocognitive events will be considered as AESI. 
10.4.1.4 Local injection site reactions 
Local injection site reactions that are considered by the Investigator as non-allergic events and 
that are related to the alirocumab injection, as opposed to another injectable agent, should be 
further characterized by evaluating the related symptoms that comprise an injection site reaction 
such as but not limited to redness, pain, etc. If the patient experiences a local injection site 
reaction with no signs or symptoms except for erythema/redness, and/or swelling, and the 
diameter of the erythema/ redness, or swelling measure <2.5 cm, no AE for local injection site 
reaction needs to be reported as this is not typically considered a clinically important finding. 
However, if the patient has a reaction of swelling with a diameter <2.5 cm that interferes with 
activity, then it should be considered as a clinically relevant finding and should be reported as an 
AE with a corresponding grade of moderate or severe, in accordance with Appendix C. Special 
eCRF 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”, the 
individual components being described in the specific eCRF screen.  
If a local topical anesthetic is used before alirocumab injection, the time of local anesthetic 
administration, the time of alirocumab administration and the time of AE will be recorded in the 
eCRF. 
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
Not applicable. 
10.4.3 General guidelines for reporting adverse events 
All AEs regardless of seriousness or relationship to IMP, spanning from the signature of the 
informed consent form, until the end of the study (post study treatment follow-up visit), are to be 
recorded on the corresponding screen(s) included in the eCRF.   
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.   
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Laboratory, vital signs are to be recorded as AEs only if: 
• 
Symptomatic and/or 
• 
Requiring either corrective treatment or consultation, and/or 
• 
Leading to IMP discontinuation or modification of dosing, and/or 
• 
Fulfilling a seriousness criterion, and/or 
• 
Defined as an AE of special interest with immediate notification.   
See Appendix B for a summary of AE reporting guidelines.   
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. 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. 
10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of a SAE, the Investigator or any designees must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send the notification to the Monitoring Team and 
Pharmacovigilance after approval of the Investigator within the e-CRF or after a standard 
delay.  
• 
SEND (within 24 hours) (preferably by fax or e-mail) the 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 source document provided to the Sponsor.  For laboratory results, include the 
laboratory normal ranges.   
• 
All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
patient status) should be sent (by fax or e-mail) to the Monitoring Team within 24 hours of 
knowledge.  In addition, any effort should be made to further document each Serious AE 
that is fatal or life threatening within the week (7 days) following initial notification.   
• 
A backup plan will be used (using paper flow) when the e-CRF system does not work.   
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
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10.4.5 Guidelines for reporting adverse events of special interest   
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Appendix B, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. Instructions for 
AE reporting are summarized in Section 10.4. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix D.  
The following laboratory abnormalities with prespecified monitoring should be monitored, 
documented, and managed by the investigators according to the related flowchart in protocol in 
Appendix B and Appendix D: 
• 
Neutropenia.   
• 
Thrombocytopenia.   
• 
Increase in ALT.   
• 
Acute renal insufficiency.  
• 
Increase in CPK and suspicion of rhabdomyolysis.   
Use of local labs for follow-up testing should be considered.  In case the amount of blood needed 
to perform all follow-up testing noted in the algorithms exceeds what can be safely drawn or 
exceeds local requirements, clinical judgment should be used to prioritize tests obtained. In the 
algorithms, except when specified to be permanent, treatment discontinuation should be 
temporary, at least until a cause for the abnormality is found.  Clinical judgment should be used to 
determine if and when study treatment should be resumed.  
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs, that are both unexpected and at least reasonably related to the IMP (Suspected 
Unexpected Serious Adverse Reaction [SUSAR]), to the regulatory authorities, IECs/IRBs 
as appropriate and to the Investigators.    
• 
All SAEs, that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• 
The following AESIs to those regulatory authorities who require such reporting: 
- 
ALT >3 ULN, 
- 
Allergic events, 
- 
Pregnancy, 
- 
Symptomatic Overdose with IMP alirocumab, 
- 
Neurologic Events, 
- 
Neurocognitive events, 
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- 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this 
protocol will be considered as unexpected.   
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR).   
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Local tolerability (local injection site reactions) 
In case the Investigator or the patient/parent recognizes any signs of local intolerability, then this 
should be treated and followed up as per the Investigator’s medical judgment.  See Section 
10.4.1.4 and Appendix C for further information.   
10.6.2 Allergic adverse events  
Specific eCRF screens are to be filled in to assess allergic adverse events or allergic-like AE that 
may occur during the clinical studies conducted with alirocumab.   
Sometimes transient injection site reactions, irritant in nature, may occur, requiring no 
intervention and being of dubious significance.  These reactions would not be considered to be 
allergic reactions.   
Adverse events that may constitute an allergic reaction (eg, generalized itch, nasal itch, swelling 
at injection site, flushing, hives, swelling at lips, eyes, face, tongue, hands, feet, lump in throat, 
difficulty to swallow, hoarseness, change in pitch of voice, incapacity to speak, wheezing, chest 
tightness, stridor, etc.) should be considered to be reported on the General Allergic adverse event 
and/or Local Injection Site Reaction Complementary Form.   
Local injection site reactions deemed to be allergic should 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 Section 10.6.2.1 and General 
Allergic adverse event Complementary form should be completed.   
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP.  See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.2 for criteria for permanent treatment discontinuation.   
10.6.2.1 Allergic adverse event with cutaneous involvement 
Adverse events with cutaneous involvement which are obviously of allergic origin or injection 
site reactions which progress/expand/worsen/etc. should be evaluated by a dermatologist as soon 
as possible, and preferably within one week of the site first becoming aware of the event.   
The Investigator should evaluate the patient for possible etiologies (new medications, etc.) and 
extracutaneous symptoms and signs.  An unscheduled Central Laboratory assessment for 
hematology, chemistry, liver panel, PK, 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 
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which may later be collected by the sponsor.  The Investigator will provide a summary of the 
patient's case, reason for consultation, and information being requested to the consulting 
dermatologist.   
A full consultation report should be sent by the dermatologist to the Investigator.  The full report 
should contain, at a minimum, the following information; a detailed description of the rash (such 
as the morphology [lesion type], shape of individual lesions, arrangement of multiple lesions [eg, 
scattered, grouped, linear], distribution, color, consistency, presence of pruritus or pain, and other 
clinical signs) and in case a skin biopsy (including histopathology and immunofluorescence) was 
done (if it was deemed necessary as per the dermatologist’s or Investigator’s medical judgment), 
the results of this investigation with, if applicable, a specific diagnosis of the AE.  The 
Investigator will fax the full report and the corrected AE form if necessary, to the Monitoring 
Team Representative within 24 hours.   
10.6.2.2 Acute allergic injection reactions 
Acute allergic injection reaction (which are considered under the category of general allergic drug 
reactions) is defined as any adverse event 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 site 
visits.   
Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the inclusion visit.  Patients should be treated symptomatically if any AEs are 
observed.  Patients are to remain at the site until any acute injection reaction is assessed as stable, 
per the Investigator’s discretion.  General Allergic Reaction and/or Local Injection Site Reaction 
Complementary Form will have to be completed.   
10.6.3 Recommendations for managing and monitoring patients with very low LDL-C 
levels (ie, LDL-C<50 mg/dL [1.30 mmol/L]) during the OLE period 
If a patient achieves a very low LDL-C level (ie, LDL-C<50mg/dL [1.30 mmol/L] on one or more 
occasion) during the OLE period, then the Investigator will: 
• 
Call the patient / parent as soon as possible to inquire about interval occurrence of AEs, 
particularly any AEs related to visual problems. 
• 
Decide whether the patient should be requested to rapidly have an unscheduled site visit, 
or assessment could be done at the next scheduled visit. 
• 
At the site visit, plan for the following, based on Investigator’s medical judgment: 
- 
Assess the need to have blood drawn from the patient for a repeat lipid assessment in 
order to confirm the observation of very low LDL-C, 
- 
Assess the need for conducting clinical investigations, arranging specialist 
consultation(s) as needed, including with an eye specialist in case of visual problems, 
as needed, and any relevant additional work-up, 
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- 
Assess the need for alirocumab treatment temporary or permanent discontinuation, or 
continuation. Regardless of the action taken regarding alirocumab treatment, the 
patient should continue the study, 
- 
Assess the need to have blood drawn from the patient for adrenal gland hormones, 
gonadal hormones, pituitary hormones, and fat soluble vitamins if not planned per 
protocol at this visit. 
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 (CSR). 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
No power sample size calculations were performed for the main phase. A sample size of 
10 patients per cohort is empirical and based on the sample size of the Phase 1 studies (R727-CL-
904 and R727-CL-1001) conducted in adults. No less than 4 patients with BW <50 kg and no less 
than 4 patients with BW ≥50 kg will be enrolled in 4 independent cohorts (Cohort 1, Cohort 2, 
Cohort 3, and Cohort 4), which will allow the evaluation of the 
pharmacokinetics/pharmacodynamics (PK/PD) profile and safety of different alirocumab 
doses/dose regimen in each BW category and to compare with PK/PD profile and safety observed 
in adult patients. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent. 
Included patients consist of all screened patients, with open-label treatment kit numbers allocated 
and recorded in the IVRS/IWRS database, regardless of whether the treatment kits were used or 
not. Patients treated without being included or treated with an open-label treatment kit before the 
inclusion will not be considered as included and will not be included in any analysis population. 
The safety experience of patients treated and not included will be reported separately. 
For any patient included more than once, only the data associated with the first inclusion will be 
used in any analysis population. The safety experience associated with any later inclusion will be 
assessed separately. 
The safety experience of patients treated and not included will be reported separately, and these 
patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
The primary efficacy analysis population will be the modified intent-to-treat (mITT) population as 
defined below. 
11.3.1.1 Modified intent-to-treat population 
Modified ITT (mITT) population is defined as all included patients who took at least one dose or 
part of a dose of IMP during the open-label dose-finding period and had an evaluable primary 
endpoint. The primary endpoint is considered as evaluable when both of the following conditions 
are met: 
• 
Availability of at least 1 calculated LDL-C value before first open-label IMP (see Section 
9.1.1).  
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• 
Availability of at least 1 calculated LDL-C value during the main efficacy period and in 
one analysis window up to Week 8 analysis window. 
Patients in the mITT population will be analyzed according to the alirocumab dose allocated by 
IVRS. 
11.3.2 Safety population 
The Safety population considered for safety analyses will be the included population who did 
actually receive at least one dose or part of a dose of the open-label IMP. Patients will be analyzed 
according to the dose of alirocumab actually received.  
In addition:  
• 
Included patients for whom it is unclear whether they took the study medication will be 
included in the safety population as assigned by the IVRS. 
• 
For patients receiving IMP from more than 1 alirocumab dose during the open-label dose-
finding treatment period, the alirocumab dose for as-treated analysis will be the one to 
which the patient was treated with the longest duration. 
11.3.3 Other analysis population  
The PK analysis will be performed on all treated patients (safety population) with at least one 
evaluable blood sample for PK post first open-label IMP injection. 
The anti-alirocumab antibody analysis will be performed on all treated patients (safety population) 
with a blood sample on Week 0 (baseline) and at least one evaluable blood sample for antibodies 
post first open-label IMP injection. 
11.4 
STATISTICAL METHODS 
The following sections detail the analyses of the open-label dose finding treatment period. 
Analyses of open-label extension period will be done separately and will be detailed in the SAP. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual alirocumab dose received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The duration of IMP injection exposure in weeks will be defined as: (last dose of open-label IMP 
injection date - first dose of open-label IMP injection date +14)/7 (for Cohorts 1 & 2) or (last dose 
of open-label IMP injection date - first dose of open-label IMP injection date +28)/7 (for 
Cohorts 3 & 4), regardless of unplanned intermittent discontinuations. 
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11.4.1.2 Compliance 
Compliance will be assessed using the injection frequency defined for each patient as the average 
number of days between 2 injections, that is: (last injection date – first injection date)/(number of 
injections -1) and will be summarized descriptively (N, Mean, SD, Median, Min and Max). 
11.4.2 Analyses of efficacy endpoints 
There will be no formal statistical test for the efficacy endpoints. All efficacy analyses will be 
descriptive. 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
The primary analysis will be based on an on-treatment approach, and will use LDL-C values 
collected during the efficacy treatment period. The efficacy treatment period is defined as the 
period from first alirocumab injection to last alirocumab injection +21 days (for Cohorts 1 & 2) or 
+ 35 days (for Cohort 3 & Cohort 4) during the open-label dose finding treatment period. 
The percent change from baseline in calculated LDL-C at Week 8 as defined in Section 9.1.1 will 
be analyzed in the mITT population using a mixed-effect model with repeated measures 
(MMRM) approach to handle missing data. All post-baseline data available during the open-label 
dose-finding treatment period and within analysis windows will be used and the missing data will 
not be imputed. The model will include the fixed categorical effects of alirocumab doses/dose 
regimen (30 mg Q2W [<50 kg], 40 mg Q2W [<50 kg], 50 mg Q2W [≥50 kg], and 75 mg Q2W 
[≥50 kg]) and Q4W (75 mg Q4W [<50 kg] , 150 mg Q4W [≥50 kg], 150 mg Q4W [<50 kg] and 
300 mg Q4W ([≥50 kg]), time point (Week 4, Week 8), dose-by-time point interaction, as well as, 
the continuous fixed covariates of baseline LDL-C value and baseline value-by-time point 
interaction. 
This model will be run using SAS Mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation. This model will provide baseline adjusted least-squares 
means estimates at Week 8 for each alirocumab dose, with their corresponding SEs and 95% CIs. 
In addition, LS mean with 95% confidence intervals will be provided for each cohort using 
appropriate contrasts. 
Additionally, for Cohort 4 only, the percent change from baseline in calculated LDL-C at Week 
12 will be analyzed using the same model as for the primary endpoint: All post-baseline data 
available during the open-label dose-finding treatment period and within analysis windows for 
Cohort 4 will be used and the missing data will not be imputed. The model will include the fixed 
categorical effects of alirocumab doses/dose regimen (150 mg Q4W [<50 kg] and 300 mg Q4W 
([≥50 kg]), time point (Week 4, Week 8, Week10, Week 12), dose-by-time point interaction, as 
well as, the continuous fixed covariates of baseline LDL-C value and baseline value-by-time 
point. This model will provide baseline adjusted least-squares means estimates at Week 12 for 
each alirocumab dose of Cohort 4, with their corresponding SEs and 95% CIs. In addition, LS 
mean with 95% confidence intervals will be provided for cohort 4 overall using appropriate 
contrasts. 
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11.4.2.2 Analyses of secondary efficacy endpoints 
Continuous secondary variables defined in Section 9.2 will be analyzed in the mITT population 
using the same MMRM model as for the primary endpoint with the corresponding baseline value 
as covariate. For TG and Lp(a) known to have non Gaussian distribution, the methodology that 
will be used will be described in the SAP. 
For binary secondary efficacy variables defined in Section 9.2, the methodology that will be used 
will be described in the SAP. 
Percent change, and when appropriate absolute change from baseline in calculated LDL-C, 
total C, HDL-C, TG, and non-HDL-C will be summarized at each time point in the mITT 
population (including Week 10 and W12 time points for Cohort 4). All measurements, scheduled 
or unscheduled, collected from screening up to 21 days (for Cohorts 1 & 2) or + 35 days (for 
Cohorts 3 & 4) after the last open-label 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) and plots will be provided for other 
efficacy parameters: Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp(a). 
11.4.2.3 Multiplicity considerations 
Since there will be no formal statistical test for the efficacy endpoints, no adjustment for 
multiplicity will be made. 
11.4.3 Analyses of safety data  
The summary of safety results will be presented by alirocumab dose. No formal inferential testing 
will be performed. Summaries will be descriptive in nature. 
All safety analyses will be performed on the Safety population using the following common rule: 
• 
The baseline value is defined as the last available value before first open-label IMP. 
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 open-label IMP to the last dose of open-label IMP injection +21 days 
(for Cohorts 1 & 2) or + 35 days (for Cohorts 3 & 4). 
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AE definition: 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
Pre-treatment period. 
• 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became 
serious during the TEAE period. 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
Post-treatment period. 
Drug-induced liver injury: 
Liver function tests, namely ALT, AST, ALP and total bilirubin, are used to assess possible drug 
induced liver toxicity. The proportion of patients with PCSA values at any post-baseline visit by 
baseline status will be displayed by treatment group for each parameter. A graph of distribution of 
peak values of ALT versus peak values of total bilirubin will also be presented. Note that the ALT 
and total bilirubin values will be presented on a logarithmic scale. The graph will be divided into 
4 quadrants with a vertical line corresponding to 3 xULN for ALT and a horizontal line 
corresponding to 2 xULN for total bilirubin. 
The incidence of liver-related AEs will be summarized by treatment group. The selection of 
preferred terms will be based on standardized MedDRA query (SMQ) Hepatic disorder. 
11.4.3.1 Adverse events 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order for each treatment group, the number (n) and percentage 
(%) of patients experiencing an AE. Multiple occurrences of the same event in the same patient 
will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent AESI (defined with a PT or a prespecified grouping), all treatment 
emergent SAEs and all TEAEs leading to permanent treatment discontinuation. If any clinically 
significant signal is detected and need further characterization or for AE of clinical interest, 
exploration of time to onset will be performed for these selected TEAEs. 
11.4.3.2 Laboratory data and vital signs 
The summary statistics (including mean, median, Q1, Q3, standard error, minimum and 
maximum) of all laboratory variables and all vital signs parameters (raw data and changes from 
baseline) will be calculated for each visit, last and worst value assessed during the treatment 
period and presented by treatment group. For selected parameters, mean changes from baseline 
with the corresponding standard error will be plotted over time (at same time points) in each 
treatment group. 
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The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized by treatment group whatever the baseline level and/or according to the following 
baseline categories: 
• 
Normal/missing. 
• 
Abnormal according to PCSA criterion or criteria. 
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided. 
11.4.4 Analyses of other endpoints 
Serum total alirocumab concentrations, total and free PCSK9 concentrations will be summarized 
by alirocumab dose and visit using descriptive statistics.  Serum concentration time profiles will 
be provided by alirocumab dose. Additional plots will be prepared, as deemed necessary.  
Serum total alirocumab concentrations will be used for population PK modeling and the results of 
population PK modeling will be reported separately from the study report. 
Further details will be provided in SAP. 
The ADA status (positive/negative) and ADA titers will be summarized by visit using descriptive 
statistics. If appropriate, correlations between ADA titers, safety, and/or efficacy endpoints will be 
provided by graphical methods. Further details will be provided in SAP. 
11.4.5 Analyses of Patient Reported Outcomes (Health-related Quality of Life/health 
economics variables 
Not applicable. 
11.5 
INTERIM ANALYSIS 
There will be no interim analysis.  However, analyses will be conducted at the end of the main 
phase to select the dose that will be used in the Phase 3 study.   
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the International Conference on Harmonisation (ICH) guidelines for good 
clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, should fully inform the patient (and the parent[s] or guardian[s]) of all pertinent 
aspects of the clinical trial including the written information given 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 informed consent form should be signed, 
name filled in and personally dated by the patient’s parent(s) or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion.  Local law 
must be observed in deciding whether 1 or both parents/guardians consent is required.  If only 
1 parent or guardian signs the consent form, the Investigator must document the reason for only 
1 parent or guardian’s signature. 
In addition, participants will assent as detailed below or will follow the Ethics Committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center (age of 
assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements): 
Participants who can read the assent form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the assent form to confirm that 
assent was given. 
The informed consent form and the assent 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. 
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In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
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 or legal representative.  
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. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
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 regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The 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 
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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 may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• 
The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
• 
Patient race or ethnicity "Caucasian/white, Black, Asian/Oriental, others" will be collected 
in this study because these data are required by several regulatory authorities (eg, on afro 
American population for FDA, on Japanese population for the PMDA in Japan, or on 
Chinese population for the CFDA in China). 
• 
The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). 
They may be further processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice 
(GCP) and applicable regulatory requirements, the Investigator should permit auditing by or on 
the behalf of the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor 
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio. 
• 
Patient enrollment is unsatisfactory. 
• 
The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• 
Non-compliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• 
The total number of patients is included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study and is free to publish, and 
to communicate the recommendations made by the DMC, using all existing or future means of 
communication with an agreement between both parties. 
The Steering Committee involved in the clinical trial will be responsible for the first international 
publication on the study.  
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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 and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. In case of 
substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
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