Clinical trial NCT03510884
Conditions: Hypercholesterolaemia
Sponsor: Sanofi
Start date: 2018-05-31; Completion date: 2022-08-05
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) and every 4 weeks (Q4W) versus placebo after 24 weeks of double-blind (DB) treatment on low-density lipoprotein cholesterol (LDL-C) levels in participants with heterozygous familial hypercholesterolemia (heFH) 8 to 17 years of age 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.

Secondary Objectives:

* To evaluate the efficacy of alirocumab versus placebo on LDL-C levels.
* To evaluate the effects of alirocumab versus placebo on other lipid parameters.
* To evaluate the safety and tolerability of alirocumab in comparison with placebo.
* To evaluate the efficacy, safety, and tolerability of alirocumab after open label treatment.
* To evaluate the development of anti-alirocumab antibodies.

Detailed description:
The study duration was approximately up to 110 weeks (run-in period \[if needed\]: up to 4 weeks \[+2 days\], screening period: up to 2 weeks \[+5 days\], double-blind treatment period: 24 weeks, open label (OL) treatment period: 80 weeks).

Arms: arm 1: Participants received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their body weight (BW) (less than \[\<\] 50 kilograms \[kg\] or greater than or equal to \[\>=\] 50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 40 milligrams (mg) (for BW \<50 kg) or 75 mg (for BW \>=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW \<50 kg) or 75 mg to 150 mg (for BW \>=50 kg) or down titrated as 75 mg to 40 mg (for BW \<50 kg) or 150 mg to 75 mg (for BW \>=50 kg). arm 2: Participants received SC injection of alirocumab 40 mg (for BW \<50 kg) or 75 mg (for BW \>=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level was \>=110 milligrams per deciliter (mg/dL) (2.85 millimoles per liter \[mmol/L\]) at Week 8. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 40 mg (for BW \<50 kg) or 75 mg (for BW \>=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW \<50 kg) or 75 mg to 150 mg (for BW \>=50 kg) or down titrated as 75 mg to 40 mg (for BW \<50 kg) or 150 mg to 75 mg (for BW \>=50 kg). arm 3: Participants received SC injection of placebo (matched to alirocumab) based on their BW (\<50 kg or \>=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) Q4W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW \<50 kg) or 300 mg Q4W to 150 mg Q2W (for BW \>=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW \<50 kg) or 150 mg Q2W to 75 mg Q2W (for BW \>=50 kg). arm 4: Participants received SC injection of alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level \>=110 mg/dL (2.85 mmol/L) at Week 8. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW \<50 kg) or 300 mg Q4W to 150 mg Q2W (for BW \>=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW \<50 kg) or 150 mg Q2W to 75 mg Q2W (for BW \>=50 kg).
Interventions: intervention 1: Alirocumab SAR236553 (REGN727) intervention 2: Rosuvastatin intervention 3: Atorvastatin intervention 4: Simvastatin intervention 5: Pravastatin intervention 6: Lovastatin intervention 7: Fluvastatin intervention 8: Ezetimibe intervention 9: Cholestyramine intervention 10: Nicotinic acid intervention 11: Fenofibrate intervention 12: Omega-3 fatty acids intervention 13: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form:solution Route of administration: subcutaneous injection intervention 2: Pharmaceutical form:tablet Route of administration: oral intervention 3: Pharmaceutical form:Tablet Route of administration: Oral intervention 4: Pharmaceutical form:Tablet Route of administration: Oral intervention 5: Pharmaceutical form:Tablet Route of administration: Oral intervention 6: Pharmaceutical form:Tablet Route of administration: Oral intervention 7: Pharmaceutical form:Capsule Route of administration: Oral intervention 8: Pharmaceutical form:Tablet Route of administration: Oral intervention 9: Pharmaceutical form:oral suspension Route of administration: oral intervention 10: Pharmaceutical form:Tablet Route of administration: Oral intervention 11: Pharmaceutical form:Tablet Route of administration: Oral intervention 12: Pharmaceutical form:capsule Route of administration: oral intervention 13: Pharmaceutical form:solution Route of administration: subcutaneous injection

Protocol documents:
Prot_000.pdf: 


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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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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/Countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
All 
06-Jan-2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
02-Jan-2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
13-Sep-2018, version 1 (electronic 1.0) 
Original Protocol 
 
21-Dec-2017, version 1 (electronic 3.0) 
AMENDED PROTOCOL 03 (06-JAN-2021) 
This amended protocol 03 is considered to be substantial based on the criteria set forth in 
Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The main reasons for this protocol amendment are the following:  
• To enable changes in statistical analyses to reflect the sequential enrolment in the 
2 cohorts of patients defined by the dosing regimen (see further details below), since 
enrolment in the every 4 weeks (Q4W) cohort started when enrolment in the every 
2 weeks (Q2W) cohort was completed, 
• To include the possibility to perform remote monitoring in the context of regional or 
national emergency such as the current COVID-19 pandemic, and  
• To clarify the flexibility that the Interactive Response Technology (IRT) system allows 
during the open-label extension period with regard to the dose adjustment of alirocumab. 
This protocol amendment replaces the 2 primary efficacy hypotheses comparing each 
alirocumab treatment regimen (Q2W, Q4W) versus a pooled placebo group combining Q2W and 
Q4W regimens by a comparison of each alirocumab group versus its contemporaneously 
randomized placebo group (ie, of the same dosing regimen cohort).  
This change is driven by a potential temporal bias introduced from sequentially randomizing 
patients into the first dosing regimen cohort (Q2W), followed by the second dosing regimen 
cohort (Q4W). Two randomization schemes were produced for this study, with a distinct 
randomization scheme for each dosing regimen cohort. Therefore, patient background 
characteristics are expected to be equally distributed between treatment groups within a dosing 
regimen cohort by randomization process, but not necessarily between the 2 cohorts. Pooling 
placebo patients’ data from both dosing regimen cohorts could introduce a potential temporal bias 
that would not be balanced by a similar bias in each of the alirocumab cohort groups.  


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Specifically, this protocol amendment plans that each alirocumab regimen group will be 
compared to the contemporaneously randomized placebo regimen group within each distinct 
cohort. This will align the primary efficacy hypothesis treatment comparisons with the 
randomization scheme for each distinct cohort.  
As already defined in the amended protocol 2, the Bonferroni adjustment for multiplicity control 
will be applied to the primary efficacy endpoint to control the Type-I error, specifically, using a 
two-sided alpha level of 0.025 within each cohort treatment group comparison. Multiplicity 
testing of the key secondary endpoints will follow the amended protocol 2, specifically, the 
overall Type-I error will be controlled by the use of a sequential inferential approach applied 
independently within each dosing regimen cohort (Q2W and Q4W). Statistical significance of the 
primary parameter at the 0.025 alpha level is required before drawing inferential conclusions for 
that dosing regimen cohort about first key secondary parameter, and so on for the remaining key 
secondary parameters within the cohort (defined in Section 9.2.1). 
The Bonferroni adjustment and this fixed hierarchical approach will ensure a strong control of the 
overall Type-I error rate for the study at the 0.05 level. The current study sample size is sufficient 
to provide power >90% for testing treatment effect of the primary efficacy endpoint within each 
cohort at a 2-sided 0.025 alpha level, taking into consideration the reduced sample size of the 
placebo group. 
With respect to safety, in an effort to reduce the temporal bias impact, the present protocol 
amendment will align the safety result summaries with the already executed randomization 
scheme within each regimen cohort, showing each alirocumab regimen group with the 
corresponding placebo regimen group. Additionally, a standard data pooling strategy follows, 
combining study treatment groups (alirocumab, placebo) regardless of regimen cohort. Pooling 
safety assessments across the cohorts aims at increasing the chance to identify a safety signal. 
Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
Clinical Trial Summary - Study 
Design,  
And 
Section 8.1 Investigational 
Medicinal Product(s) 
Update to clarify that the IRT system offers flexibility 
for dose adjustment of alirocumab in the open-label 
treatment period based on body weight (BW) change 
(from Week 24 onwards), low density lipoprotein 
cholesterol (LDL-C) levels (from Week 32).  
The Investigator is able to adjust 
the dose of alirocumab, for 
increasing the efficacy or the 
purpose of patient safety. 
Clinical Trial Summary - 
Statistical Considerations,  
And 
Section 11.1 Determination of 
Sample Size 
Revision of the 2 main comparisons: in each dosing 
regimen cohort, the alirocumab dosing regimen 
group will be compared to its contemporaneously 
randomized placebo group (ie, of the same dosing 
regimen cohort). Study power has been updated 
accordingly. 
Revisions in order to specify 
analyzing each of the 
two randomized dosing regimen 
cohorts separately (use of the 
contemporaneously randomized 
placebo group for each dosing 
regimen cohort (Q2W, Q4W) 
instead of a combined placebo 
group) (refer to the rationale 
above). 


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Section # and name 
Description of change 
Brief rationale 
Clinical Trial Summary - 
Statistical Consideration,  
And 
Section 11.4.2 Analyses of 
efficacy endpoints 
Revision of the comparisons and of the statistical 
models (a separate model will be run for each 
dosing regimen cohort) 
Revisions in order to specify 
analyzing each of the 
two randomized dosing regimen 
cohorts separately (use of the 
contemporaneously randomized 
placebo group for each dosing 
regimen cohort (Q2W, Q4W) 
instead of a combined placebo 
group) (refer to the rationale 
above). 
To be consistent with the significance level that will 
be used for tests (2.5% two-sided), 97.5% CI will be 
computed instead of 95% CI. 
Since two-sided test with a 
significance level of 2.5% will be 
performed, 97.5% CI will be 
computed instead of 95% CI for 
primary and secondary efficacy 
endpoints. 
Clinical Trial Summary - 
Statistical Consideration,  
And 
Section 11.4.3 Analyses of 
safety data 
Revision of the treatment groups to be displayed in 
safety result summaries: by treatment groups within 
each dosing regimen cohort; and by treatment 
group regardless of the dosing regimen cohorts 
(pooled across cohorts). 
Comparing alirocumab and placebo 
within dosing regimen cohort might 
reduce the impact of temporal bias. 
Pooling safety assessments across 
the cohorts aims at increasing the 
chance to identify a safety signal. 
Section 6.3 Two-Step analysis 
Details added to clarify the two-step analysis 
process at the completion of the double-blind 
treatment period and the whole study, respectively.  
To define and clarity the two-step 
analysis 
Section 10.2 Definition of 
Source Data 
Updated IRT listings 
Clarity 
Section 10.4.4 Instructions for 
reporting serious adverse events 
Change the description of process for the 
management of complementary source documents 
As per new process, PI or any 
designees should no longer 
proactively send source 
documentations 
Section 11.4.2.3 Multiplicity 
consider 
Update added for clarity  
Clarity 
Section 11.4.3 Analyses of 
safety data 
Addition of the definition of the treatment period for 
the Q4W dosing regimen cohort 
Information omitted by error in the 
previous version 
Section 11.4.4 Other endpoints 
Revision of the treatment groups to be displayed in 
accordance with safety summaries 
Comparing alirocumab and placebo 
within dosing regimen cohort might 
reduce the impact of temporal bias. 
Pooling safety assessments across 
the cohorts aims at increasing the 
chance to identify a safety signal. 
Section 11.5 Two-Step analysis 
Update and reference to Section 6.3 added for 
clarity  
Clarity 


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Section # and name 
Description of change 
Brief rationale 
Section 13.2 Responsibilities of 
the Sponsor  
Addition of the following text: "Monitoring details 
describing strategy (eg, risk-based initiatives in 
operations and quality such as Risk Management 
and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and 
requirements, including handling of noncompliance 
issues and monitoring techniques (central, remote, 
or on-site monitoring) are provided in separate study 
documents". 
To include the possibility to perform 
remote monitoring in the context of 
regional or national emergency 
such as the current COVID-19 
pandemic 
Appendix E Flow mediated 
dilatation exploratory sub-study 
of EFC14643 protocol 
Addition of the dosing regimen cohort and the 
treatment-by-dosing regimen cohort effects in the 
statistical model 
 
The use of the multiple imputations process is 
removed.  
Information omitted by error in the 
previous version 
 
 
Due to the very exploratory nature 
of the flow mediated dilatation 
(FMD) sub-study, the multiple 
imputations process will not be 
applied 
Appendix K Contingency 
Measures for regional or 
national emergency that is 
declared by a governmental 
agency 
Addition of contingency measures for a regional or 
national emergency that can be declared by a 
governmental agency such as the current 
COVID-19 pandemic. 
To ensure the safety of the 
participants, to consider continuity 
of the clinical study conduct, protect 
trial integrity, and assist in 
maintaining compliance with Good 
Clinical Practice in Conduct of 
Clinical Trials Guidance during an 
emergency that prevents access to 
the study site.  
Other Changes 
Minor grammatical and editorial revisions 
throughout protocol. Addition of word “cohort” at 
relevant places throughout protocol. 
Appendix numbers updated 
Editorial and for clarity 


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CLINICAL TRIAL SUMMARY 
 
COMPOUND: 
alirocumab/SAR236553/REGN727 STUDY No.: EFC14643 
TITLE 
A randomized, double-blind, placebo-controlled study followed by an open 
label treatment period to evaluate the efficacy and safety of alirocumab in 
children and adolescents with heterozygous familial hypercholesterolemia  
INVESTIGATOR/TRIAL LOCATION 
Worldwide 
PHASE OF DEVELOPMENT 
Phase 3 
STUDY OBJECTIVE(S)  
 
Primary objective: 
• 
To evaluate the efficacy of alirocumab administered every 
2 weeks (Q2W) and every 4 weeks (Q4W) versus placebo after 
24 weeks of double-blind (DB) treatment on low-density 
lipoprotein cholesterol (LDL-C) levels in patients with 
heterozygous familial hypercholesterolemia (heFH) 8 to 
17 years of age 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. 
Secondary objectives: 
• 
To evaluate the efficacy of alirocumab versus placebo on 
LDL-C levels after 12 weeks of DB treatment.  
• 
To evaluate the effects of alirocumab versus placebo 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 12 and 24 weeks of treatment.  
• 
To evaluate the safety and tolerability of alirocumab after 
24 weeks of treatment in comparison with placebo. 
• 
To evaluate the efficacy, safety and tolerability of alirocumab 
after 80 weeks of open label treatment. 
• 
To evaluate the development of anti-alirocumab antibodies after 
24 weeks of treatment during the double-blind (DB) treatment 
period. 
Other objectives: 
• 
To evaluate the development of anti-alirocumab antibodies after 
80 weeks of open label treatment. 
• 
To evaluate the pharmacokinetics (PK) of alirocumab. 


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STUDY DESIGN 
This study is a randomized, 24-week DB, placebo-controlled, 
parallel-group, multi-national, multi-center study followed by an open label 
treatment period of 80 weeks. Approximately 150 children and 
adolescents aged of 8 to 17 years with heFH and LDL-C ≥130 mg/dL 
(3.37 mmol/L) at screening visit despite stable LMTs will be randomized 
2:1 (alirocumab:placebo). Two dosing regimen, Q2W and Q4W, will be 
evaluated with approximately 75 patients in each dosing regimen cohort. 
The start of the recruitment in the Q4W dosing regimen cohort will depend 
on the status of the recruitment in the Q2W dosing regimen cohort and 
the status of the amendment approval. Stable LMTs are defined as 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. 
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 of higher doses. For patients not 
receiving maximally tolerated statin, statin intensification should be 
carefully considered prior to randomization 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 one with 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. 
Randomization will be stratified according to previous participation (yes or 
no) in the Phase 2 DFI14223 study and baseline body weight (<50 or 
≥50 kg). 
The study consists of a run-in period (as needed), screening period, 
double-blind treatment period, and an open label treatment period. 
Run-in period (as needed): 
The run-in period is up to 4 weeks (+2 days) in duration.  
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 at least 4 weeks. Patients eligible for the run-in period are 
expected to fulfill the LDL-C eligibility criterion at the end of the run-in 
period. Patients who require treatment with statin de novo are not allowed 
to enter the run-in period in order to avoid the potential for multiple 
titration steps.  
Another possible situation requiring the run-in period include patients with 
suspected heFH but without confirmation by previous genetic testing and 
not meeting Simon Broome criteria. Such patients will be asked to 
undergo centralized genetic testing during the run-in period.  
Screening period: 
The screening period is up to 2 weeks (+5 days) in duration.  
Patients who have previously participated in the DFI14223 study and 
have received alirocumab administration during the open label extension 
of the DFI14223 study will require a wash-out period of at least 10 weeks 
between the last injection of alirocumab and the screening lipid 


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assessment at the entry of the screening period. However, as these 
patients have already met this LDL-C requirement when they screened for 
the DFI14223 study they will not be excluded based on the LDL-C value 
obtained during the screening for the EFC14643 study. 
An intermediate visit for injection training may occur during which the 
patient if aged 12 years and above (or another designated person such as 
parent, etc) will be trained to self-inject/inject with placebo for alirocumab 
after the eligibility criteria have been checked and it is confirmed that the 
patient will likely be randomized. Prior to the injection(s), a local topical 
anesthetic may be utilized as per the Investigator recommendation. 
Investigators will have the option of providing a second placebo kit for 
alirocumab for patients/parents who require additional injection training 
prior to randomization.  
Patients can be randomized after injection training and as soon as all 
inclusion and no exclusion criteria are met. 
 
Double-blind treatment period: 
The double-blind treatment period is 24 weeks in duration.  
Two dosing regimens will be evaluated - either Q2W or Q4W; the start of 
the recruitment in the Q4W dosing regimen cohort will depend on the 
status of the recruitment in the Q2W dosing regimen cohort and the status 
of the amendment approval. Patients will be blinded to study treatment 
and randomized to either alirocumab or placebo using a 2:1 ratio for each 
dosing regimen cohort. 
Q2W dosing regimen cohort: 
Approximately 75 patients will participate in the Q2W dosing regimen 
cohort. Patients with BW <50 kg will receive 1 subcutaneous (SC) 
injection of 0.5 mL Q2W of alirocumab or placebo. Patients with BW 
≥50 kg will receive 1 SC injection of 1 mL Q2W of alirocumab or placebo. 
For patients randomized to receive alirocumab the following dose based 
on body weight (BW) will be initially administered: 
• 
40 mg for BW <50 kg or,  
• 
75 mg for BW ≥50 kg. 
At Week 12 patients randomized to alirocumab will either: 
• 
Continue alirocumab 40 mg or 75 mg Q2W, if the Week 8 LDL-
C* is <110 mg/dL (2.85 mmol/L) OR 
• 
Dose up-titrate to alirocumab 75 mg (for patients on 40 mg) or 
150 mg (for patients on 75 mg) if the Week 8 LDL-C* is 
≥110 mg/dL (2.85 mmol/L). 
Q4W dosing regimen cohort: 
Approximately 75 patients will participate in the Q4W dosing regimen 
cohort. During the first 12 weeks of the double-blind period and before 
any possible dose-adjustment to Q2W dosing regimen, all patients will 
receive SC injection(s) Q4W to get a proper evaluation of this dosing 
regimen. After Week 12, with regard to the possible dose-adjustment and 
the maintenance of the blind until the end of the double-blind period, all 
patients will receive SC injection(s) Q2W. Patients receiving alirocumab 
will be under a “sham Q2W*” regimen from Week 12 to Week 24, with 
alirocumab Q4W alternating with placebo Q4W.  
For patients randomized to alirocumab the following dose based on body 
weight (BW) will be initially administered: 


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• 
150 mg Q4W for BW <50 kg or,  
• 
300 mg Q4W for BW ≥50 kg. 
At Week 12 patients randomized to alirocumab will either: 
• 
Continue alirocumab 150 mg or 300 mg Q4W, if the Week 8 
LDL-C is <110 mg/dL (2.85 mmol/L) OR 
• 
Have a dose-adjustment to 75 mg Q2W (for patients on 150 mg 
Q4W) or 150 mg Q2W (for patients on 300mg Q4W) if the 
Week 8 LDL-C is ≥110 mg/dL (2.85 mmol/L). 
*Lipid values obtained at Week 8 for the purpose of up-titration 
will not be communicated to Investigators to maintain the blind. 
The continuation or dose up-titration/dose-adjustment of 
alirocumab will occur in an automated process without site or 
patient awareness.  
The first IMP injection (from the double-blind study treatment kit allocated 
by interactive response technology [IRT]) will be done at the site on the 
day of randomization or as close as possible after randomization into the 
study. Patients will be monitored at the investigational site for at least 
30 minutes after this first double-blind injection. The subsequent injections 
will be done at a patient-preferred location (eg, at home). All the IMP 
injections can be performed by trained patient (self-injection if aged ≥12) 
or parent, or another designated person or alternative arrangements for 
injection administration will be allowed as needed (eg, return to the clinic). 
It is suggested that patients ≥12 years old, who are trained to self-inject, 
do so with parental (or another designated person) supervision; however, 
this is not mandatory. The Investigator may evaluate the sustained 
reliability of this practice on a case by case basis given the variable 
adolescent ages, maturity levels, availability of the caregiver, or other 
relevant considerations, with the patient. The final decision as to whether 
supervision is appropriate for self-injection of alirocumab for patients 
≥12 years old is per Investigator discretion. Prior to any injection, a local 
topical anesthetic may be utilized as per the Investigator.  
Injection training: 
• 
Further injection training can be provided at the randomization 
visit Week 0/Day 1 when the patient/parent or a trained 
designated person injects the first IMP from the double-blind 
study treatment kit allocated by IRT. 
• 
Additional training can be offered at scheduled or unscheduled 
visits with the scheduled double-blind treatment, as per 
patient/parent or Investigator’s judgment. 
The laboratory measurement of lipid parameters will be performed by a 
central lab. The specific results of the central lab testing for lipid 
parameters from samples obtained after randomization and during the 
double-blind treatment period will not be communicated to the sites or to 
the Sponsor’s EFC14643 study team. Instead, the central lab will inform 
sites if patients exceed the triglyceride threshold of 500 mg/dL 
(5.65 mmol/L). Additionally, the site may receive alert related to LDL-C 
<50 mg/dL (1.30 mmol/L) and associated safety concerns identified by 
the independent physician who will carefully monitor, under the auspices 
of the Data Monitoring Committee (DMC), the patient’s LDL-C values 
during the double-blind treatment period. No local lab testing for lipid 
parameters should be performed after randomization and throughout the 


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study. Of note, the independent physician is external to the EFC14643 
study team and not part of any alirocumab activities. 
Statin and other LMT (if applicable) should be stable during double-blind 
treatment period barring exceptional circumstances whereby overriding 
concerns (including but not limited to triglyceride alert posted by the 
central lab) warrant such changes, as per the Investigator’s judgment.  
Patients will be instructed to follow a diet to treat their 
hypercholesterolemia in accordance with local guidelines or local practice 
and they should be on this diet throughout the entire study duration from 
screening.  
Patients, who successfully complete the 24-week double-blind treatment 
period can enter the open label treatment period.  
A flow mediated dilatation (FMD) exploratory sub-study that will assess 
endothelial function in the brachial artery will be conducted in a sub-set of 
the study population during the double-blind treatment period. The details 
are provided in Appendix E. 
Open label treatment period: 
The open label treatment period consists of 80 weeks of open label 
alirocumab SC Q2W or Q4W depending on the dosing regimen initiated 
at randomization.  
The first open label alirocumab injection(s) will be done at the site 
followed by monitoring of the patient for at least 30 minutes. 
At the first open label treatment period visit (ie, Week 24), after 
completion of the double-blind treatment period, depending on the dosing 
regimen cohort participation, both alirocumab and placebo treated 
patients will receive alirocumab either 40 mg Q2W or 150 mg Q4W if BW 
is <50 kg, and 75 mg Q2W or 300 mg Q4W if body weight is ≥50 kg, from 
the weight obtained at the Week 24 visit. 
After Week 24, the Investigator will manage, based on his/her own 
judgment, adjustment of alirocumab dose based on changes in BW. 
However, related to this up-titration/adjustment of the dose, if the 
Investigator considers that the up-titration/adjustment would potentially 
negatively impact patient safety, he/she can exercise his/her judgement in 
a manner that safeguards the safety and wellbeing of the patient. The 
following will be applied based on changes in BW: 
• 
If currently on 40 mg Q2W then adjust dose to 75 mg Q2W if 
BW changes from <50 kg to ≥50 kg. 
• 
If currently on 150 mg Q4W then adjust dose to 300 mg Q4W if 
BW changes from <50 kg to ≥50 kg.  
For patients whose weight oscillates around 50 kg the dose will be 
adjusted only once during the open-label treatment period. 
The lipid levels will be communicated to the Investigator during the open 
label treatment period from the second visit (ie, Week 32) onwards. The 
IRT system is set up to allow the Investigator based on his/her own 
judgment related to the patient’s LDL-C levels and the safety profile, to 
up-titrate, down-titrate, maintain the dose of alirocumab or discontinue 
alirocumab throughout the study. 
From Week 32 onwards: 
Q2W dosing regimen cohort: The following up-titration or down-titration of 
alirocumab doses will be possible: 


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Up-titration: 
• 
40 mg to 75 mg Q2W if BW <50 kg.  
• 
75 mg to 150 mg Q2W if BW ≥50 kg. 
Down-titration: 
• 
75 mg to 40 mg Q2W if BW <50 kg. 
• 
150 mg to 75 mg Q2W if BW ≥50 kg. 
Q4W dosing regimen cohort: 
Dose-adjustment will be possible, as follows: 
• 
150 mg Q4W to 75 mg Q2W if BW <50 kg. 
• 
300 mg Q4W to 150 mg Q2W if BW ≥50 kg. 
The statin dose should not be decreased to adjust to the degree of LDL-C 
lowering and should not be increased unless otherwise indicated. 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 LDL-C levels <50 mg/dL 
(1.30 mmol/L) on one or more occasion are provided in Section 10.6.2.3.  
STUDY POPULATION  
Main selection criteria: 
Inclusion criteria: 
1. 
Male and female children and adolescents aged 8 to  
17 years diagnosed with heterozygous familial 
hypercholesterolemia * inadequately controlled (see threshold 
mentioned in the exclusion criterion 2)** despite treatment with 
optimal dose of statin *** with or without other LMTs, or 
non-statin LMTs if statin intolerant ****, at stable dose(s) for at 
least 4 weeks *****. 
2. 
A signed informed consent indicating parental permission with 
or without patient assent, depending on capacity for 
understanding based on developmental maturity and local 
requirements. 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 centralized 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 run-in period with results 
supporting a diagnosis of heFH. The clinical diagnosis should be 
based on the Simon Broome criteria for possible or definite heFH 
 (see Appendix A). Once eligibility is confirmed based on prior 
genetic testing or Simon Broome criteria, results of elective genetic 
testing will not impact patient’s eligibility.  
**  
Patients who have previously participated in the DFI14223 study 
have already met this LDL-C requirement when they screened for 
the DFI14223 study and thus will not be excluded based on LDL-C 
<130 mg/dL (3.37 mmol/L). 
*** 
The optimal dose of statin is defined as the stable daily dose 
prescribed based on regional practice or local guidelines or is the 


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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 randomization 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. 
***** Before enrolling more than 2 siblings, the Investigator should 
discuss with the Sponsor study team. 
Key Exclusion criteria (additional details are in 
Section 7.2): 
1. 
Children and adolescents aged less than 8 years or more than 
17 years at the time of informed consent signature unless 
different local regulation applies (eg, for Russia only: patients 
aged less than 12 years or more than 17 years at the time of 
informed consent signature). 
Note: Patients aged of 8 to less than 10 years who have not had previous 
attempts to lower LDL-C by other means will be excluded. 
2. 
Patients with LDL-C <130 mg/dL (3.37 mmol/L) (ie, adequately 
controlled) 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. 
Note: Patients who have previously participated in the DFI14223 study 
have already met this LDL-C requirement when they screened for the 
DFI14223 study and thus will not be excluded based on 
LDL-C <130 mg/dL (3.37 mmol/L).  
3. 
Patients with BW less than 25 kg.  
4. 
Patients aged of 8 to 9 years not at Tanner Stage 1 and 
patients aged of 10 to 17 years not at least at Tanner Stage 2 in 
their development. 
5. 
Patients with secondary hyperlipidemia (such as 
decompensated hypothyroidism, nephrotic syndrome, 
obstructive liver disease, anorexia nervosa, obesity, and drug 
treatment [eg, isotretinoids]). 
6. 
Patients diagnosed with homozygous familial 
hypercholesterolemia. 
7. 
Patients who have received lipid apheresis treatment within 
2 months prior to the screening period, or have plans to receive 
it during the study. 
8. 
Patients with uncontrolled (ie, HbA1c levels above local 
guidelines or equivalent) Type 1 or 2 diabetes mellitus. 


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9. 
Patients with known uncontrolled thyroid disease (ie, thyroid 
stimulating hormone levels above or below the laboratory’s 
reference range within the past 6 months that were obtained 
due to clinical indication).  
10. Patients with uncontrolled (ie, systolic blood pressure [SBP] or 
diastolic blood pressure [DBP] above local guidelines or 
equivalent) hypertension. 
11. Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening 
visit. 
12. Severe renal impairment (ie, estimated glomerular filtration rate 
[eGFR] <30 mL/min/1.73 m2) at the screening visit. 
13. Alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST] >2 x upper limit of normal [ULN] (1 repeat lab is allowed). 
14. Creatine phosphokinase (CPK) >3 x ULN (1 repeat lab is 
allowed). 
Total expected number of patients: 
Approximately 150 patients (approximately 75 patients in each dosing 
regimen cohort) 
Expected number of sites: 
Approximately 70 sites 
STUDY TREATMENT(s) 
 
Investigational medicinal product(s)  
Formulation: 
alirocumab and placebo for alirocumab 
Prefilled syringes (PFS) with finger grip, to be replaced by PFS with safety 
system (PFS-S) as soon as available: alirocumab 75 mg/mL or  
150 mg/mL solution will be used as described below. 
Q2W dosing regimen cohort: 
• 
BW <50 kg:  
- 
0.5 mL of alirocumab 75 mg/mL solution for 40 mg dose. 
- 
0.5 mL of alirocumab 150 mg/mL solution for 75 mg dose. 
• 
BW ≥50 kg: 
- 
1 mL of alirocumab 75 mg/mL solution for 75 mg dose. 
- 
1 mL of alirocumab 150 mg/mL solution for 150 mg dose.   
 
Matching placebo  
- 
Placebo of 0.5 mL volume for BW <50 kg. 
- 
Placebo of 1 mL volume for BW ≥50 kg. 
Route(s) of administration: 
Q4W dosing regimen cohort: 
- 
1 mL of alirocumab 150 mg/mL solution for 150 mg dose. 
Matching placebo 
- 
Placebo of 1 mL volume regardless of BW category. 
 
Subcutaneous (SC) injections in the abdomen, thigh or outer area of 
upper arm. 


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Dose regimen: 
Q2W dosing regimen cohort: 
• 
Alirocumab 40 mg for BW <50 kg: 
- 
During the entire double-blind period if no up-titration 
needed: 1 SC injection of 0.5 mL Q2W for 40 mg. 
- 
In case of up-titration to 75 mg at Week 12 (LDL-C 
≥110 mg/dL [2.85 mmol/L] at Week 8): 1 SC injection of 
0.5 mL Q2W for 75 mg. 
• 
Alirocumab 75 mg for BW ≥50 kg: 
- 
During the entire double-blind period if no up-titration 
needed: 1 SC injection of 1 mL Q2W for 75 mg. 
• 
In case of up-titration to 150 mg at Week 12 (LDL-C 
≥110 mg/dL [2.85 mmol/L] at Week 8): 1 SC injection of 1 mL 
Q2W for 150 mg. 
Noninvestigational medicinal product(s)  
Q4W dosing regimen cohort: 
• 
Alirocumab 150 mg for BW <50 kg: 
- 
During the first 12 weeks of double-blind period: 
1 SC injection of 1 mL Q4W for 150 mg. 
- 
After Week 12: 1 SC injection of 1 mL Q2W, consisting of 
1 injection of 150 mg Q4W alternating with 1 injection of 
placebo Q4W. 
• 
Alirocumab 300 mg for BW ≥50 kg:  
- 
During the first 12 weeks of double-blind period: 2 SC 
injections of 1 mL each Q4W, consisting of 2 injections of 
150 mg. 
- 
After Week 12: 2 SC injections of 1 mL each Q2W, 
consisting of 2 injections of 150 mg Q4W alternating with 
2 injections of placebo Q4W. 
In case of dose-adjustment at Week 12 (LDL-C ≥110 mg/dL 
[2.85 mmol/L] at Week 8): 
- 
Alirocumab 75 mg Q2W: 1 SC injection of 1 mL Q2W, 
consisting of 1 injection of 75 mg for BW <50 kg. 
- 
Alirocumab 150 mg Q2W: 2 SC injections of 1 mL 
each Q2W, consisting of 1 injection of 150 mg and 
1 injection of placebo for BW ≥50 kg. 
The following classes of drugs (not all of which are indicated for pediatric 
use in all countries; for further information, Investigators should refer to 
their local prescribing information) are identified as noninvestigational 
medicinal product 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). 


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ENDPOINT(S)  
Primary endpoint: 
• 
Percent change in LDL-C from baseline to Week 24 in the 
intent-to-treat (ITT) population, using all LDL-C values 
regardless of adherence to treatment (ITT estimand). 
Key secondary efficacy endpoints: 
• 
Percent change in LDL-C from baseline to Week 12 
(ITT estimand). 
• 
Percent change in Apo B from baseline to Week 24 
(ITT estimand). 
• 
Percent change in non-HDL-C from baseline to Week 24 
(ITT estimand). 
• 
Percent change in Total-C from baseline to Week 24 
(ITT estimand). 
• 
Percent change in Apo B from baseline to Week 12 
(ITT estimand). 
• 
Percent change in non-HDL-C from baseline to Week 12 
(ITT estimand). 
• 
Percent change in Total-C from baseline to Week 12 
(ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 
130 mg/dL (3.37 mmol/L) at Week 24 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 
130 mg/dL (3.37 mmol/L) at Week 12 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 
110 mg/dL (2.84 mmol/L) at Week 24 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 
110 mg/dL (2.84 mmol/L) at Week 12 (ITT estimand). 
• 
Percent change in Lp (a) from baseline to Week 24 
(ITT estimand). 
• 
Percent change in Lp (a) from baseline to Week 12 
(ITT estimand). 
• 
Percent change in HDL-C from baseline to Week 24 
(ITT estimand). 
• 
Percent change in fasting TG from baseline to Week 24 
(ITT estimand). 
• 
Percent change in Apo A-1 from baseline to Week 24 
(ITT estimand). 
• 
Percent change in HDL-C from baseline to Week 12 
(ITT estimand). 
• 
Percent change in fasting TG from baseline to Week 12 
(ITT estimand). 
• 
Percent change in Apo A-1 from baseline to Week 12 
(ITT estimand). 
Safety endpoints: 
• 
Safety parameters: adverse events (AE), serious AE (SAE), AE 
of special interest ([AESI], see list in Section 10.4.1.3), 


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laboratory data, vital signs, body weight, height, Cogstate 
battery test, and Tanner stage assessed throughout the study.  
 
Other secondary efficacy endpoints: 
• 
All primary and key secondary endpoints in the modified ITT 
(mITT) population, using all LDL-C values during the treatment 
period (on-treatment estimand). 
• 
Absolute change in Apo B/Apo A-1 ratio to Week 12 and 
Week 24 (ITT and on-treatment estimands).  
• 
Proportion of patients achieving at least 30% reduction, 
50% reduction in LDL-C at Week 24 (ITT and on-treatment 
estimands). 
• 
Proportion of patients achieving at least 30% reduction, 
50% reduction in LDL-C at Week 12 (ITT and on-treatment 
estimands). 
• 
Percent change in LDL-C from baseline to Week 104 (ITT and 
on-treatment estimands). 
Other endpoints 
• 
Serum alirocumab concentrations assessed throughout the 
study. 
• 
Anti-alirocumab antibodies assessed throughout the study. 
ASSESSMENT SCHEDULE 
Run-in period (as needed): 
The run-in period is up to 4 weeks (+2 days), with 1 visit. Patients can 
enter the screening period as soon as the criteria for stable LMT are met 
and/or centralized genotyping data (if no clinical criteria or previous 
genotyping) is available.  
Screening period: 
The screening period is up to 2 weeks (+5 days) in duration. An 
intermediate/Day 1 visit for injection training may occur during which the 
patient, if aged ≥12 (or another designated person such as parent, etc) 
will be trained to self-inject/inject with placebo. Patients can be 
randomized after injection training and as soon as eligibility is confirmed.  
Double-blind treatment period: 
The double-blind treatment period is 24 weeks in duration. Visits will be 
scheduled as follows: randomization visit (Day 1, Week 0), Week 8, 
Week 12 and Week 24 (end of the double-blind treatment period visit).  
 
Open label treatment period: 
The first open label treatment period visit will overlap with the end of 
double-blind treatment period visit. The second visit will take place at 
Week 32. Subsequent visits will be every 12 weeks until the end of the 
open label treatment period (ie, Week 44, Week 56, Week 68, Week 80, 
Week 92 and Week 104 [end of open label treatment period visit]).  
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
With a randomization ratio of 2:1 (alirocumab: placebo) for each dosing 
regimen cohort, a total sample size of 90 patients (30 in each alirocumab 
dosing regimen group and 15 in each placebo dosing regimen group) will 
have 92% power to detect a difference in mean percent change in LDL-C 
of 30% between each alirocumab dosing regimen group and its 
contemporaneously randomized placebo dosing regimen group, with a 


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0.025 two-sided significance level per comparison and assuming a 
common standard deviation (SD) of 25%. 
Nevertheless, in order to have a sufficient number of pediatric patients for 
properly assessing the safety and tolerability of alirocumab, sample size 
was increased to 150 patients in total (50 in each alirocumab dosing 
regimen group and 25 in each placebo dosing regimen group). The 
enrollment of 150 patients will allow having a safety assessment over 
2 years in approximately 128 patients, assuming a discontinuation rate of 
15%. 
Analysis population: 
The primary efficacy analysis population will be the ITT population, 
defined as all randomized patients.  
Patients in the ITT population will be analyzed according to the treatment 
group allocated by randomization. Analyses will compare each 
alirocumab dosing regimen group to its contemporaneously randomized 
placebo group.  
The safety analysis will be performed on the safety population. The safety 
population consists of the randomized population who did actually receive 
at least one dose or partial dose of investigational product analyzed 
according to the treatment actually received. Safety analyses will present 
each alirocumab dosing regimen group with its contemporaneously 
randomized placebo dosing regimen group and again each treatment 
group (placebo, alirocumab) regardless of the dosing regimen cohorts 
(pooled across the cohorts). 
Primary analysis: 
The percent change in LDL-C from baseline to Week 24 will be analyzed 
in the ITT population using a mixed-effect model with repeated measures 
(MMRM) approach. All post-baseline data available within Week 8 to 
Week 24 analysis windows will be used and missing data will be 
accounted for by the MMRM model. 
A separate model will be run for each dosing regimen cohort, including 
the fixed categorical effects of treatment group (alirocumab, placebo), 
randomization strata, time point (Week 8, Week 12, Week 24), treatment-
by-time point interaction and strata-by-time point interaction, as well as 
the continuous fixed covariates of baseline LDL-C value and baseline 
value-by-time point interaction. Throughout the MMRM models, each 
alirocumab dosing regimen group will be compared to its 
contemporaneously randomized placebo dosing regimen group using 
appropriate contrasts, and the 97.5% confidence interval (CI) of the 
difference will be provided.  
Analysis of secondary endpoints: 
Continuous secondary endpoints with normal distribution will be analyzed 
within each dosing regimen cohort using the same MMRM models as for 
the primary endpoint with the corresponding baseline and post-baseline 
values.  
Analyses of the efficacy parameters during the extension period will be 
only descriptive (description of change [% or absolute] over time).  
Safety analysis: 
Safety analyses will be descriptive based on the safety population. 


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DURATION OF STUDY PERIOD 
(per patient) 
A study duration of up to 110 weeks (run-in period [if needed]: up to 
4 weeks [+2 days], screening period: up to 2 weeks [+5 days], 
double-blind treatment period: 24 weeks, open label treatment period: 
80 weeks). 
STUDY COMMITTEES 
Steering committee:  
 Yes    
 No 
The independent 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. 
Data monitoring committee: 
 Yes    
 No 
An independent DMC for pediatric studies will monitor patient safety by 
conducting reviews of accumulated safety data. 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.  
Adjudication committee:  
 Yes    
 No 
 


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1 
FLOW CHARTS  
1.1 
GRAPHICAL STUDY DESIGN - Q2W DOSING REGIMEN COHORT  
 


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1.2 
GRAPHICAL STUDY DESIGN - Q4W DOSING REGIMEN COHORT  
 


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1.3 
STUDY FLOW CHART  
 
Run-in  
(if 
needed)a 
Screening 
Double- Blind Treatment Period 
Open label Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
7 
8 
9 
10
gg 
11 
12
gg 
13 
14 
Week 
Up to W-6  Up to W-2  Up to W-1b W0/D1 
W8 
W12 
W24c 
W24 
W32 
W44 
W56 
W68 
W80 
W92 
W104d 
Visit Window (+/- days) 
+2 
+5 
+/-7 
 
+/-7 
+/-7 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Informed consent 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
heFH genotyping informed consent 
(if needed)e, f 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient demography 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/family medical history 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol/smoking habits 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
Xg ,h 
 
 
 
 
 
 
 
 
 
 
 
 
 
General physical examination 
Xg 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Measured body weight 
Xg 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Measured height 
Xg 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
Tanner stagei 
Xg 
 
 
 
 
X 
 
 
X 
 
X 
 
 
X 
IRT contact 
X 
X 
X 
X 
 
X 
Xff 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Injection training 
 
 
Xj, l 
Xk, l 
 
 
 
 
 
 
 
 
 
 
 
IMP administration Q2W or Q4W 
regimen (depending on treatment 
allocation) l ,m  
 
 
 
X 
----------------------------------------------------------------------------------------------------------------------→ 


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Run-in  
(if 
needed)a 
Screening 
Double- Blind Treatment Period 
Open label Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
7 
8 
9 
10
gg 
11 
12
gg 
13 
14 
Week 
Up to W-6  Up to W-2  Up to W-1b W0/D1 
W8 
W12 
W24c 
W24 
W32 
W44 
W56 
W68 
W80 
W92 
W104d 
Visit Window (+/- days) 
+2 
+5 
+/-7 
 
+/-7 
+/-7 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Double-blind IMP kit dispensationn 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Compliance check of IMP and data 
collection on IMP administration 
 
 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Open label IMP kit dispensationn 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Check of stability of background LMT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of dieto 
Xg 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total-C, calculated LDL-C, HDL-C, 
TG, non-HDL-Cp, q 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
Apo B, Apo A-1, ratio Apo B/Apo A-1, 
and Lp(a)p, q 
 
 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE recording (if any) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsr 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
Cogstate battery practice tests 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cogstate battery testt 
 
 
 
X 
 
 
X 
 
 
 
 
X 
 
 
X 
Laboratory testingp: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
heFH genotypingf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and chemistryu 
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
HbA1c 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
Creatine phosphokinase (CPK)  
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
 
 
X 
Liver panelv 
 
X 
 
 
 
X 
X 
 
X 
X 
 
X 
 
 
X 


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Run-in  
(if 
needed)a 
Screening 
Double- Blind Treatment Period 
Open label Treatment Period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
7 
8 
9 
10
gg 
11 
12
gg 
13 
14 
Week 
Up to W-6  Up to W-2  Up to W-1b W0/D1 
W8 
W12 
W24c 
W24 
W32 
W44 
W56 
W68 
W80 
W92 
W104d 
Visit Window (+/- days) 
+2 
+5 
+/-7 
 
+/-7 
+/-7 
+/-3 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
+/-7 
Urinalysisw 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
hs-CRP 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
CPK-MB and troponinx 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Adrenal gland hormonesy 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
Gonadal and pituitary hormonesz 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
Fat soluble vitaminsaa 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
X 
Pregnancy testbb 
 
X 
 
X 
 
 
X 
 
X 
X 
 
X 
 
X 
X 
Anti-alirocumab (drug) antibodies 
(ADA)cc 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
 
 
X 
Serum alirocumab concentration 
(Pharmacokinetics)dd  
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Flow mediated dilatation 
assessmentee 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
a Patients, who have not been on stable lipid modifying therapy (LMT)s 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 
at least 4 weeks. Patients with suspected heFH but without confirmation by previous genetic testing and not meeting Simon Broome criteria can undergo centralized genetic testing during the run-in period.  
b The W-1 visit (injection training visit) can take place at the same visit as D1 as per the site or patient preference. 
c End-of-double-blind treatment period visit. This visit will overlap with the first visit of the open label treatment period. 
d End-of-open label treatment period visit. 
e Informed consent should be obtained only once. If patient enters the run-in period then informed consent will be obtained prior to entry into the run-in period. If patient does not require a run-in period, then 
informed consent will be obtained prior to entry into the screening period. 
f 
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 double-blind treatment period.  
g The corresponding assessment should be obtained only once. If patient enters the run-in period then the corresponding assessment will be obtained during the run-in period. If patient does not require a run-in 
period, then the corresponding assessment will be obtained during the screening period. 
h Document prior medication history within the previous 12 weeks, especially for LMT (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). 


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i 
See Appendix B for Tanner stage evaluation. 
j 
Injection training at screening period visit Week -1 is performed with placebo for alirocumab. Investigators will have the option of providing a second placebo kit for alirocumab for patients/parents who require 
additional injection training prior to randomization.  
k Further injection training can be provided at the randomization visit Week 0/Day 1 when the patient/parent or a trained designated person injects the first IMP from the double-blind study treatment kit allocated by 
IRT. Additional training can be offered at scheduled or unscheduled visits with the scheduled double-blind treatment, as per patient/parent or Investigator’s judgment.   
l 
Prior to the injection, a local topical anesthetic may be utilized as per the Investigator. 
m The first IMP injection during the double-blind treatment period will be done at the site on the day of randomization and as close as possible after randomization into the study. The subsequent injections will be 
done at a patient-preferred location (home…). These injections can be performed by trained patient ≥12 years (self-injection) or parent, or another designated person or alternative arrangements for injection 
administration will be allowed as needed. It is suggested that patients ≥12 years old, who are trained to self-inject, do so with parental (or another designated person) supervision; however, this is not mandatory. 
The Investigator may evaluate the sustained reliability of this practice on a case by case basis given the variable adolescent ages, maturity levels, availability of the caregiver, or other relevant considerations, with 
the patient. The final decision as to whether supervision is appropriate for self-injection of alirocumab for patients ≥12 years old is per Investigator discretion. For the Q4W dosing regimen cohort study treatment 
will be administered every 4 weeks (Q4W) for the first 12 weeks of the double-blind period. 
n Along with kit dispensation, the treatment administration package (see Section 8.5) should be given as well as the patient diary and injection instruction manual, as needed. Open label IMP kit delivery direct to 
patient (DTP) on Visit 10 and 12. 
o Patients will be instructed to follow a diet to treat their hypercholesterolemia in accordance with local guidelines or local practice. 
p 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 (estimated total blood volume of 194.8 mL for the entire study); see Section 10. 
q The lipid levels will be blinded throughout the double-blind treatment period. The lipid levels will be communicated to the Investigator during the open label treatment period from Week 32 onwards.  
r 
Vital signs include: heart rate, systolic and diastolic BP in sitting position. 
s Cogstate battery practice test will be administered at randomization visit with recommended 15 minutes break before recorded Cogstate battery test. Morning administration is also recommended for all Cogstate 
tests. 
t 
Cogstate battery test consists of identification test, detection test, one card learning test, and the Groton maze learning test. Morning administration is also recommended for all Cogstate tests. For further details 
see Section 9.2.4.5. 
u 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. (eGFR and creatinine clearance will be calculated at 
screening; creatinine clearance will be calculated for all subsequent visits where chemistry lab testing is performed) 
v Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin (in case of total bilirubin values above the normal range, differentiation into conjugated and non-conjugated bilirubin will occur automatically). 
w Urinalysis: macroscopy will be performed at the central lab. If abnormal, then a standard microscope assessment will be conducted. 
x CPK-MB and troponin levels will be assayed at baseline and at Week 24 and in case of any clinically relevant cardiovascular effect observed in patients. 
y Adrenal gland hormones: cortisol (with reflexive adrenocorticotrophic hormone (ACTH) levels if cortisol < lower limit of normal [LLN]) and dehydroepiandrosterone sulfate (DHEAS). 
z Gonadal hormones: testosterone (males) and estradiol (females). Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). 
aa Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K (phylloquinone). 
bb Pregnancy test with a local urine pregnancy test should be done on females of childbearing potential or females who have experienced menarche (they must have a confirmed negative pregnancy test at 
screening). Pregnancy tests may be performed more frequently in some countries due to local legislations related to women of childbearing potential randomized in clinical trials see Appendix J. The Screening 
(Week -2) pregnancy test should be a blood test. All other pregnancy tests will be with a local urine pregnancy test.   
cc Patient who prematurely discontinue the alirocumab injections or who complete the study but have a titer at or above 240 for ADA at their last 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. 
dd Blood samples should be collected before IMP injection. PK samples will also be used for free and total proprotein convertase subtilisin/kexin type 9 (PCSK9) analysis.  
ee Flow mediated dilatation assessment will be part of a substudy performed at selected sites (see Appendix E). 
ff IRT contact for patient who do not continue in the open label treatment period. 
gg Telephone contact. 


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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 3 
DOCUMENT HISTORY ................................................................................................................................... 3 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 3 
1 
FLOW CHARTS ............................................................................................................................. 20 
1.1 
GRAPHICAL STUDY DESIGN - Q2W DOSING REGIMEN COHORT ......................................... 20 
1.2 
GRAPHICAL STUDY DESIGN - Q4W DOSING REGIMEN COHORT ......................................... 21 
1.3 
STUDY FLOW CHART .................................................................................................................. 22 
2 
TABLE OF CONTENTS ................................................................................................................ 26 
2.1 
LIST OF TABLES ........................................................................................................................... 33 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 34 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 36 
5 
STUDY OBJECTIVES ................................................................................................................... 42 
5.1 
PRIMARY ....................................................................................................................................... 42 
5.2 
SECONDARY ................................................................................................................................ 42 
5.3 
OTHER ........................................................................................................................................... 42 
6 
STUDY DESIGN ............................................................................................................................ 43 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 43 
6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 44 
6.2.1 
Duration of study participation for each patient ............................................................................. 44 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 44 
6.3 
TWO-STEP ANALYSIS ................................................................................................................. 44 
6.4 
STUDY COMMITTEES .................................................................................................................. 44 
6.4.1 
Steering Committee ....................................................................................................................... 44 
6.4.2 
Data Monitoring Committee ........................................................................................................... 45 
7 
SELECTION OF PATIENTS .......................................................................................................... 46 


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7.1 
INCLUSION CRITERIA .................................................................................................................. 46 
7.2 
EXCLUSION CRITERIA ................................................................................................................ 46 
7.2.1 
Exclusion criteria related to study methodology ............................................................................ 47 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies ....... 49 
7.2.3 
Exclusion criteria related to the current knowledge of alirocumab ................................................ 49 
8 
STUDY TREATMENTS ................................................................................................................. 50 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .......................................................................... 50 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................. 54 
8.3 
BLINDING PROCEDURES ............................................................................................................ 54 
8.3.1 
Methods of blinding ........................................................................................................................ 54 
8.3.1.1 
PK and anti-alirocumab antibodies ................................................................................................ 54 
8.3.1.2 
Lipid parameters ............................................................................................................................ 55 
8.3.2 
Randomization code breaking during the double-blind treatment period of the study .................. 55 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 56 
8.5 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING ............................. 56 
8.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 57 
8.7 
RESPONSIBILITIES ...................................................................................................................... 57 
8.7.1 
Treatment accountability and compliance...................................................................................... 58 
8.7.2 
Return and/or destruction of treatments ........................................................................................ 58 
8.8 
CONCOMITANT MEDICATION ..................................................................................................... 59 
8.8.1 
Management of background lipid modifying therapy ..................................................................... 59 
8.8.2 
Contraception ................................................................................................................................. 60 
8.8.3 
Prohibited concomitant medications .............................................................................................. 60 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 61 
9.1 
PRIMARY ENDPOINT ................................................................................................................... 61 
9.1.1 
Primary efficacy endpoint ............................................................................................................... 61 
9.2 
SECONDARY ENDPOINTS .......................................................................................................... 61 
9.2.1 
Key secondary efficacy endpoints ................................................................................................. 61 
9.2.2 
Other secondary efficacy endpoints ............................................................................................... 62 
9.2.3 
Efficacy assessment method ......................................................................................................... 62 
9.2.3.1 
Lipid parameters ............................................................................................................................ 62 
9.2.4 
Safety endpoints ............................................................................................................................ 62 
9.2.4.1 
Observation period ......................................................................................................................... 63 


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9.2.4.2 
Adverse events .............................................................................................................................. 63 
9.2.4.3 
Laboratory safety variables ............................................................................................................ 64 
9.2.4.4 
Vital signs ....................................................................................................................................... 64 
9.2.4.5 
Cogstate battery test ...................................................................................................................... 64 
9.2.4.6 
Tanner stages measurement ......................................................................................................... 64 
9.3 
OTHER ENDPOINTS..................................................................................................................... 65 
9.3.1 
Pharmacokinetics ........................................................................................................................... 65 
9.3.1.1 
Sampling time ................................................................................................................................ 65 
9.3.1.2 
Pharmacokinetics handling procedure ........................................................................................... 65 
9.3.1.3 
Bioanalytical method ...................................................................................................................... 65 
9.3.2 
Anti-alirocumab antibody assessments ......................................................................................... 65 
9.3.2.1 
Sampling time ................................................................................................................................ 66 
9.3.2.2 
Sampling procedure ....................................................................................................................... 66 
9.3.2.3 
Bioanalytical method ...................................................................................................................... 66 
9.3.3 
Pharmacogenetic assessment ....................................................................................................... 66 
9.3.4 
Pharmacodynamic variables .......................................................................................................... 66 
9.3.5 
Low-density lipoprotein-C (LDL-C) <50 mg/dL (<1.30 mmol/L) ..................................................... 66 
9.3.6 
Urinalysis ........................................................................................................................................ 67 
9.3.7 
CPK-MB and cardiac troponin ....................................................................................................... 67 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................ 67 
9.5 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 67 
10 
STUDY PROCEDURES ................................................................................................................ 68 
10.1 
VISIT SCHEDULE .......................................................................................................................... 71 
10.1.1 
Run-in period (Up to Week -6) ....................................................................................................... 71 
10.1.1.1 Visit 1 (Week -6, run-in) ................................................................................................................. 72 
10.1.2 
Screening period (Up to Week -2) ................................................................................................. 72 
10.1.2.1 Visit 2 (Week -2, screening visit) .................................................................................................... 73 
10.1.2.2 Visit 3 (Week -1, injection training) ................................................................................................ 74 
10.1.3 
Twenty-four-week double-blind treatment period .......................................................................... 74 
10.1.3.1 Visit 4 (Week 0, randomization) ..................................................................................................... 75 
10.1.3.2 Visit 5 (Week 8, Day 56 ±7) ........................................................................................................... 76 
10.1.3.3 Visit 6 (Week 12, Day 84 ±7) ......................................................................................................... 76 
10.1.3.4 Visit 7 (Week 24, Day 168 ±3, end of double-blind treatment period) ........................................... 77 
10.1.4 
Eighty-week open label treatment period ...................................................................................... 78 
10.1.4.1 Visit 8 (Week 32, Day 224 ±7) ....................................................................................................... 78 
10.1.4.2 Visit 9 (Week 44, Day 308 ±7) ....................................................................................................... 79 
10.1.4.3 Visit 10 (Week 56, Day 392 ±7, telephone contact) ....................................................................... 80 
10.1.4.4 Visit 11 (Week 68, Day 476 ±7) ..................................................................................................... 80 
10.1.4.5 Visit 12 (Week 80, Day 560 ±7, telephone contact) ....................................................................... 81 
10.1.4.6 Visit 13 (Week 92, Day 644 ±7) ..................................................................................................... 81 


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10.1.4.7 Visit 14, End of Treatment (Week 104, Day 728 ±7) ..................................................................... 82 
10.2 
DEFINITION OF SOURCE DATA .................................................................................................. 83 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION ....................................... 83 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ........................... 84 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ........................... 84 
10.3.3 
List of criteria for permanent treatment discontinuation ................................................................. 84 
10.3.4 
Handling of patients after permanent treatment discontinuation ................................................... 85 
10.3.5 
Procedure and consequence for patient withdrawal from study .................................................... 85 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 86 
10.4.1 
Definitions of adverse events ......................................................................................................... 86 
10.4.1.1 Adverse event ................................................................................................................................ 86 
10.4.1.2 Serious adverse event ................................................................................................................... 86 
10.4.1.3 Adverse event of special interest ................................................................................................... 87 
10.4.1.4 Local injection site reactions .......................................................................................................... 89 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities ....................................................................................................................................... 89 
10.4.3 
General guidelines for reporting adverse events ........................................................................... 89 
10.4.4 
Instructions for reporting serious adverse events .......................................................................... 90 
10.4.5 
Guidelines for reporting adverse events of special interest ........................................................... 91 
10.4.6 
Guidelines for management of specific laboratory abnormalities .................................................. 91 
10.4.7 
Guidelines for reporting product complaints (IMP/NIMP) .............................................................. 92 
10.5 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 92 
10.6 
SAFETY INSTRUCTIONS ............................................................................................................. 93 
10.6.1 
Local tolerability (local injection site reactions) .............................................................................. 93 
10.6.2 
Allergic adverse events .................................................................................................................. 93 
10.6.2.1 Allergic adverse event with cutaneous involvement ...................................................................... 93 
10.6.2.2 Acute allergic injection reactions .................................................................................................... 94 
10.6.2.3 Independent physician monitoring for patients reaching LDL-C levels <50 mg/dL 
(1.30 mmol/L) during the double-blind treatment period and recommendations for the 
Investigator in case of an alert ....................................................................................................... 94 
10.6.2.4 Recommendations for managing and monitoring patients with very low LDL-C levels (ie, 
LDL-C<50 mg/dL [1.30 mmol/L]) during the open label treatment period ..................................... 95 
10.7 
ADVERSE EVENTS MONITORING .............................................................................................. 95 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 96 
11.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 96 
11.2 
DISPOSITION OF PATIENTS ....................................................................................................... 96 


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11.3 
ANALYSIS POPULATIONS ........................................................................................................... 97 
11.3.1 
Efficacy populations ....................................................................................................................... 97 
11.3.1.1 Intent-to-treat population ................................................................................................................ 97 
11.3.1.2 Modified intent-to-treat population ................................................................................................. 97 
11.3.2 
Safety population ........................................................................................................................... 97 
11.3.3 
Other analysis population .............................................................................................................. 97 
11.4 
STATISTICAL METHODS ............................................................................................................. 98 
11.4.1 
Extent of study treatment exposure and compliance ..................................................................... 98 
11.4.1.1 Extent of investigational medicinal product exposure .................................................................... 98 
11.4.1.2 Compliance .................................................................................................................................... 98 
11.4.2 
Analyses of efficacy endpoints ....................................................................................................... 99 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................ 99 
11.4.2.2 Analyses of secondary efficacy endpoints ................................................................................... 100 
11.4.2.3 Multiplicity considerations ............................................................................................................ 101 
11.4.3 
Analyses of safety data ................................................................................................................ 102 
11.4.3.1 Adverse events ............................................................................................................................ 103 
11.4.3.2 Laboratory data and vital signs .................................................................................................... 104 
11.4.3.3 Cogstate battery test .................................................................................................................... 104 
11.4.4 
Other endpoints ............................................................................................................................ 104 
11.4.4.1 Pharmacokinetics ......................................................................................................................... 104 
11.4.4.2 Anti-alirocumab antibody assessments ....................................................................................... 105 
11.4.4.3 LDL-C less than 50 mg/dL (1.30 mmol/L) .................................................................................... 105 
11.4.4.4 Urinalysis ...................................................................................................................................... 105 
11.4.4.5 CPK-MB and troponin .................................................................................................................. 105 
11.5 
TWO-STEP ANALYSIS ............................................................................................................... 105 
12 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 106 
12.1 
ETHICAL AND REGULATORY STANDARDS ............................................................................ 106 
12.2 
INFORMED CONSENT ............................................................................................................... 106 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................. 107 
13 
STUDY MONITORING................................................................................................................. 109 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ..................................................................... 109 
13.2 
RESPONSIBILITIES OF THE SPONSOR ................................................................................... 109 
13.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................. 110 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST .................................................................................................................................... 110 
13.5 
USE OF COMPUTERIZED SYSTEMS ........................................................................................ 110 


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14 
ADDITIONAL REQUIREMENTS ................................................................................................. 111 
14.1 
CURRICULUM VITAE.................................................................................................................. 111 
14.2 
RECORD RETENTION IN STUDY SITES .................................................................................. 111 
14.3 
CONFIDENTIALITY ..................................................................................................................... 111 
14.4 
PROPERTY RIGHTS ................................................................................................................... 112 
14.5 
DATA PROTECTION ................................................................................................................... 112 
14.6 
INSURANCE COMPENSATION .................................................................................................. 112 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ............................... 113 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE .......................................................................................................................................... 113 
14.8.1 
By the Sponsor ............................................................................................................................. 113 
14.8.2 
By the Investigator ....................................................................................................................... 114 
14.9 
CLINICAL TRIAL RESULTS ........................................................................................................ 114 
14.10 
PUBLICATIONS AND COMMUNICATIONS ............................................................................... 114 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 115 
16 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 116 
17 
APPENDICES .............................................................................................................................. 124 
APPENDIX A 
SIMON BROOME REGISTER DIAGNOSTIC CRITERIA FOR HETEROZYGOUS 
FAMILIAL HYPERCHOLESTEROLEMIA .................................................................................... 124 
APPENDIX B 
TANNER STAGES ............................................................................................................. 125 
APPENDIX C 
COGSTATE BATTERY TEST ........................................................................................... 127 
APPENDIX D 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION .................................................................................................... 129 
APPENDIX E 
FLOW MEDIATED DILATATION EXPLORATORY SUB-STUDY OF EFC14643 
PROTOCOL ................................................................................................................................. 131 
APPENDIX F 
SUMMARY OF ADVERSE EVENT REPORTING INSTRUCTIONS ................................. 137 
APPENDIX G 
ASSESSMENT OF LOCAL INJECTION SITE REACTIONS ............................................ 139 
APPENDIX H 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI .................................................................................................... 140 
APPENDIX I 
PEDIATRIC FORMULAS FOR EGFR AND CREATININE CLEARANCE .......................... 145 


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APPENDIX J 
COUNTRY SPECIFIC REQUIREMENTS .......................................................................... 146 
APPENDIX K 
CONTINGENCY MEASURES FOR REGIONAL OR NATIONAL EMERGENCY 
THAT IS DECLARED BY A GOVERNMENTAL AGENCY .......................................................... 147 
APPENDIX L 
PROTOCOL AMENDMENT HISTORY .............................................................................. 148 
 


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2.1 
LIST OF TABLES  
Table 1 - Pharmacokinetics handling for alirocumab .................................................................................... 65 
Table 2 - Summary of adverse event reporting instructions .......................................................................... 91 
 


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LIST OF ABBREVIATIONS  
 
ACTH: 
adenocorticotrophic hormone 
ADA: 
anti-alirocumab (drug) antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
Apo: 
apolipoprotein 
Apo A-1: 
apolipoprotein A-1 
Apo B: 
apolipoprotein B 
AST: 
aspartate aminotransferase 
BP: 
blood pressure 
BW: 
body weight 
CHD: 
coronary heart disease 
CPK: 
creatine phosphokinase 
CVD: 
cardiovascular disease 
DB: 
double-blind 
DBP: 
diastolic blood pressure 
DHEAS: 
dehydroepiandrosterone sulfate 
DMC: 
Data Monitoring Committee 
DTP: 
direct-to-patient 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
ELISA: 
enzyme-linked immunosorbent assay 
FMD: 
flow mediated dilatation 
GCP: 
good clinical practice 
HDL-C: 
high density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HLGT: 
high-level group term 
ICH: 
international conference for harmonization 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
interactive response technolgy 
ITT: 
intent-to-treat 
LDL-C: 
low density lipoprotein cholesterol 
LDL-R: 
low density lipoprotein receptor 
LLN: 
lower limit of normal 
LLQ: 
lower limit of qualification 
LMT: 
lipid modifying therapy 
Lp: 
lipoprotein 
MedDRA: 
Medical Dictionary for Regulatory Activities 


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NIMP: 
non-investigational medicinal product 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PFS: 
pre-filled syringes 
PK: 
pharmacokinetics 
PT: 
preferred term 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SM: 
Site Monitor 
SOC: 
system organ class  
TG: 
triglyceride 
ULN: 
upper limit of normal 


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4 
INTRODUCTION AND RATIONALE  
Alirocumab is a fully human monoclonal antibody that targets proprotein convertase subtilisin 
kexin type 9 (PCSK9). PCSK9 belongs to the subtilisin family of serine proteases and is highly 
expressed in the liver. PCSK9 is involved in regulating the levels of the low-density lipoprotein 
receptor (LDL-R) protein (1, 2). 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 
low-density lipoprotein cholesterol (LDL-C) removal and, therefore higher LDL-C circulating 
levels. In humans, PCSK9 mutations have been identified; the gain-of-function mutations are rare 
and cause an autosomal dominant form of severe hypercholesterolemia and premature Coronary 
Heart Disease (CHD), whereas loss of-function mutations are more common and are associated 
with reduced plasma levels of LDL-C and protection from CHD (3, 4). 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 (1). 
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by 
severely elevated levels of LDL-C that lead to premature atherosclerosis and cardiovascular 
disease (CVD) (5). 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 LDL-C can cause FH. These include mutations in the 
gene coding for the 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. Although genetic testing is useful in the 
diagnosis of heFH, it has limitations such as it may fail to diagnose some patients with heFH. 
There are patients who have clinical heFH but no known genetic basis for their heFH. Five to 
30% of cases of phenotypic FH may arise from mutations in unidentified genes or have a 
polygenic cause (6). Accordingly, the protocol allows for patients to be included with either a 
clinical diagnosis or a genetic diagnosis of heFH. 
FH is the most clearly documented to have important cardiovascular consequences beginning in 
childhood (7). 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 (FMD) of the brachial artery (8) 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 (9). Both are surrogate markers for atherosclerotic vascular 
disease (10) 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 (11, 12). These findings strongly 


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suggest that to be effective at preventing CHD, prevention must begin decades prior to the onset 
of symptoms (13) and support the target population being evaluated in this study. 
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 (3.37 mmol/L) is considered 
acceptable and <110 mg/dL (2.85 mmol/L) ideal for children with heFH (14, 15, 16, 17), or the 
achievement of ≥50% reduction in LDL-C (14). Thus, the protocol will include patients with a 
screening LDL-C ≥130 mg/dL (3.37 mmol/L) despite being treated with stable LMTs.  
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) (14). These revised recommendations were supported by the American Academy of 
Pediatrics (AAP) (17), 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 (18). The highest doses of 
statins tested in pediatric studies resulted in LDL-C reductions of 24% for pravastatin (19), 
27% for lovastatin (20), 40% for atorvastatin (21), and 41% for simvastatin (22). 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 (21) 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. 
Another 1-year study with rosuvastatin conducted in children with FH aged 10 to 17 years showed 
that less than half (40%) of subjects reached the more stringent LDL-C goal of 110 mg/dL 
(2.85 mmol/L) (23). Therefore, novel compounds that further reduce LDL-C levels when added to 
statin therapy are of interest. Limited data are available for the combination of ezetimibe and 
simvastatin (24) 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 (3.37 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% versus 53% and 63% versus 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 versus achieving treatment goals. Taken together, this 
information supports the age of patients included in this study as well as the definition of stable 
LMTs as provided for in the inclusion criteria of the protocol and its mandatory use as 
background therapy. Stable LMTs include stable optimal doses of statin which are based on 
pediatric guidelines which will be followed by the site (25). 
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 (AE) such as muscle symptoms, creatine phosphokinase (CPK) increase, or elevations in 
aspartate aminotransferase (AST)/alanine aminotransferase (ALT) were reported in some patients 
(26). 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 


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young people with FH who are intolerant of statins (15). 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. It is recognized that there is no consensus definition for statin 
intolerance. The protocol provides for a definition of statin intolerance that was utilized in the 
adult alirocumab program. This strict definition has been discussed and agreed upon by the 
Pediatric Steering Committee. 
This study is designed to evaluate the efficacy and safety of alirocumab in the pediatric 
population. It is a randomized, 24-week double-blind (DB), placebo-controlled, parallel group 
study with an open label treatment period. The assessment of the primary endpoint of LDL-C at 
Week 24 represents the time point at which stable efficacy is already achieved and maintained 
based on the data from the large adult alirocumab program. The double-blind treatment duration 
of 24 weeks as compared with placebo as well as the 80-week open label treatment period should 
provide a reasonable duration of safety experience in this patient population who are expected to 
ultimately derive potential benefit from the drug. The choice of control of an injectable placebo 
containing the same formulation as alirocumab is appropriate for the objectives of this study since 
it will provide the most robust assessment of efficacy and safety of alirocumab. It should be noted 
that all patients will be on an optimal dose of statin with or without other LMT (or non-statin 
LMT only if statin intolerant according to a strict definition) and that this should continue 
throughout the study. Additionally, the patients who are randomized to the placebo group will also 
have the opportunity to enter into an 80-week open label treatment period.  
Preliminary clinical data from the DFI14223 study, were based on 31 pediatric patients in 
3 different cohorts. This Phase 2 study evaluated a fixed dosage according to body weight (BW) 
categories, with staggered doses of 30 mg every two weeks (Q2W) (Cohort 1) and 40 mg Q2W 
(Cohort 2) or 75 mg every four weeks (Q4W) (Cohort 3) for children with a BW below 50 kg 
(ie, lower BW category), and doses of 50 mg Q2W (Cohort 1) and 75 mg Q2W (Cohort 2) or 
150 mg Q4W (Cohort 3) for children with a BW ≥50 kg (ie, higher BW category). Staggered 
doses were employed as a cautious approach in the first introduction of alirocumab in the 
pediatric population where it was expected that the 40 mg Q2W for BW<50 kg and 75 mg Q2W 
for BW ≥50 kg would be the efficacious dose. The effect on LDL-C and the safety were analyzed. 
The primary efficacy endpoint as measured by the percent change from baseline in LDL-C at 
Week 8 demonstrated a greater reduction in LDL-C, overall, in Cohort 2 using the Q2W dosing 
regimen (LS mean change from baseline in LDL-C -46.1% ) with a mean reduction observed in 
both BW categories (-40.4% with 40 mg Q2W in the lower BW category, and -49.8% with 75 mg 
Q2W in the higher BW category), as compared with the Cohort 1 using as well the Q2W dosing 
regimen (LS mean change from baseline in LDL-C -21.2% with a mean reduction not consistent 
across the 2 doses, -41.2%with the 30 mg Q2W dose in the lower BW category) versus -7.9% 
with the 50 mg Q2W dose in the higher BW category. Regarding the Cohort 3, overall the LS 
mean change from baseline in LDL-C was -7.7%, with a mean reduction of -17.5% with the 
75 mg Q4W dose in the lower BW category and a mean increase of +4.0% with the 150 mg Q4W 
in the higher BW category. Similarly at Week 8, the largest proportion of patients in the 2 BW 
categories reaching both the target of LDL-C<130 mg/dL (3.37 mmol/L) and LDL-C <110 mg/dL 
(2.85 mmol/L) was observed with the 2 doses (40 mg Q2W/75 mg Q2W) as per BW category 
(<50 kg/≥50 kg) of Cohort 2. Overall for combined doses, the proportion of patients who achieved 


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a LDL-C value <110 mg/dL (2.85 mmol/L) was 76.4%. 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 no adverse events of 
special interest (AESI) including, neurological events, neurocognitive events, increase in ALT, 
allergic drug reactions, or local injection site reactions for all of the 6 dose groups. Alirocumab 
was well tolerated with a favorable safety profile in all cohorts and dose groups. 
Given the unexpected results observed for the Q4W dosing regimen as described above for 
Cohort 3 with 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg), no formal 
conclusion could be drawn. The doses evaluated were likely not high enough to achieve larger and 
sustained reductions in the LDL-C over the entire dosing interval in children receiving statin as 
background therapy. Therefore, before investigating this Q4W dosing regimen in the 
Phase 3 EFC14643 study, further evaluation with higher doses 150 mg/300 mg Q4W depending 
on the BW category was conducted through an additional Cohort 4 in the Phase 2 DFI14223study. 
The primary efficacy endpoint, as measured by the percent change from baseline in LDL-C at 
Week 8, for Cohort 4 (mean LS change from baseline -44.5%) showed a clinically meaningful 
reduction comparable to results observed for Cohort 2 using the 40 mg and 75 mg Q2W dosing 
regimen (mean LS change from baseline -46.1%). Substantial reductions were seen across both 
Cohort 4 doses ranging from -31.9% to -59.8 % for 150 mg and 300 mg Q4W, respectively. 
Overall for combined doses, the proportion of patients who achieved a LDL-C value <110 mg/dL 
(2.85 mmol/L) was 86.4%. Alirocumab was well tolerated with a similar favorable safety profile 
in Cohort 4 as compared with the other cohorts. No new clinically significant safety findings were 
noted in pediatric patients treated with alirocumab in this additional cohort.  
Based on these results, the doses selected to be evaluated for the EFC14643 study are 40 mg Q2W 
for BW<50 kg and 75 mg Q2W for BW ≥50 kg in the Q2W dose regimen, and 150 mg Q4W for 
BW<50 kg and 300 mg Q4W for BW ≥50 kg in the Q4W dose regimen. However as described 
above although a majority of patients achieved a LDL-C value <110 mg/dL (2.85 mmol/L) 
(76.4% of patients in Cohort 2, and 86.4% in Cohort 4), about 20% of patients still had elevated 
LDL-C in the context of the lifelong exposure to high levels of plasma LDL-C and the increased 
risk of developing atherosclerosis. It is therefore the expectation that using an up-
titration/dose-adjustment scheme as already done for adults will result in additional decrease of 
LDL-C and will optimize the proportion of patients achieving the LDL-C ideal goal. Regarding 
the up-titration scheme and based on the data from Phase 3 adults studies, doubling the dose of 
alirocumab should result in an additional decrease in LDL-C of about 10%.  
Given the baseline levels expected in this heFH pediatric population, the chance to have patients 
experiencing LDL-C levels <50 mg/dL is expected to be very low. Nevertheless, as done in the 
adult development program, a specific monitoring plan for patients reaching LDL-C values below 
50 mg/dL will be implemented with the collaboration of the DMC and an independent physician. 
Therefore, the following scheme will be applied according to the BW category: 
• Q2W dosing regimen: A starting dose of 40 mg Q2W with possible up-titration to 
75 mg Q2W for BW <50 kg, and a starting dose of 75 mg Q2W with possible up-titration 
to 150 mg Q2W for BW ≥50 kg.  


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• Q4W dosing regimen: A starting dose of 150 mg Q4W with possible dose-adjustment to 
75 mg Q2W for BW <50 kg and a starting dose of 300 mg Q4W with possible 
dose-adjustment to 150 mg Q2W for BW ≥50 kg. 
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- high-density lipoprotein-C (non-HDL-C), a decrease in lipoprotein Lp(a), and a favorable 
trend for high-density lipoprotein-C (HDL-C) and triglycerides (TG). Maximum efficacy was 
observed as early as 4 weeks after the initial dose, and efficacy was well maintained up to 2 years. 
In the DFI14223 pediatric study, treatment with alirocumab over 8 weeks demonstrated 
significant LDL-C lowering effect with both the Q2W and Q4W dosing regimen. The percent 
change from baseline in LDL-C at Week 8 demonstrated a greater and consistent reduction, 
overall, in Cohort 2 using the Q2W dosing regimen and in Cohort 4 using the Q4W dosing 
regimen as compared with Cohorts 1 and 3. 
Alirocumab administration to date in clinical trials conducted in adults has been associated with a 
favorable safety and tolerability profile. 
Immunogenicity and systemic hypersensitivity are considered as identified risks for alirocumab. 
The following safety information is based on the adult clinical trials. 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. 
In addition in adults there was no safety signal observed with neurologic events, alanine 
aminotransferase (ALT) increase and hepatic disorders, adjudicated cardiovascular 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 (0.65 mmol/L) compared to 
0.8% of alirocumab-treated patients who did not achieve such low levels. Although limitation has 
to be considered 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 (AESI). 


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In the DFI14223 pediatric study, treatment with alirocumab over 8 weeks and during open label 
extension showed that alirocumab was well tolerated with a favorable safety profile in all cohorts 
and dose groups. No new clinically significant safety findings were noted in patients treated with 
alirocumab.  
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. 
With regard to the neurocognitive function, a specific assessment will be performed through 
formal neurocognitive testing with Cogstate battery test in this study. 
This specific study is undertaken to demonstrate the efficacy and safety of alirocumab in the heFH 
pediatric population. Because of the rapid clinical progression of atherosclerotic disease in 
children and adults with familial hypercholesterolemia pediatric guidelines (14, 15, 16, 17, 18) 
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. 


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5 
STUDY OBJECTIVES  
5.1 
PRIMARY  
To evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) and every 4 weeks 
(Q4W) versus placebo after 24 weeks of double-blind treatment on low-density lipoprotein 
cholesterol (LDL-C) levels in patients with heterozygous familial hypercholesterolemia (heFH) 
8 to 17 years of age 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. 
5.2 
SECONDARY  
• To evaluate the efficacy of alirocumab versus placebo on LDL-C levels after 12 weeks of 
double-blind treatment.  
• To evaluate the effects of alirocumab versus placebo 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 12 and 24 weeks of 
treatment.  
• To evaluate the safety and tolerability of alirocumab after 24 weeks of treatment in 
comparison with placebo. 
• To evaluate the efficacy, safety and tolerability of alirocumab after 80 weeks of open label 
treatment. 
• To evaluate the development of anti-alirocumab antibodies after 24 weeks of treatment 
during the double-blind treatment period. 
5.3 
OTHER  
• To evaluate the development of anti-alirocumab antibodies after 80 weeks of open label 
treatment. 
• To evaluate the pharmacokinetics (PK) of alirocumab. 


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6 
STUDY DESIGN  
6.1 
DESCRIPTION OF THE STUDY  
This study is a Phase 3, randomized, 24-week double-blind treatment, placebo-controlled, 
parallel- group, multi-national, multi-center study followed by an open label treatment period of 
80 weeks.  
Approximately 150 children and adolescents aged of 8 to 17 years with heFH and LDL-C 
≥130 mg/dL (3.37 mmol/L) at screening visit despite stable LMTs will be randomized with a 
2:1 ratio (alirocumab: placebo). Two dosing regimens, Q2W and Q4W, will be evaluated with 
approximately 75 patients in each dosing regimen cohort. The start of the recruitment in the Q4W 
dosing regimen cohort will depend on the status of the recruitment in the Q2W dosing regimen 
cohort and the status of the amendment approval. This process will be managed by the Interactive 
Response Technology (IRT) system, depending on the overall recruitment status and amendment 
approval status. All efforts will be made to achieve adequate representation across age groups.  
Stable LMTs are defined as 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. 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 of higher doses. For patients not 
receiving maximally tolerated statin, statin intensification should be carefully considered prior to 
randomization 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 one with 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. 
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 double-blind 
treatment period. 
Randomization will be stratified according to previous participation (yes or no) in the Phase 2 
DFI14223 study and baseline BW (<50 or ≥50 kg). 
The study consists of a run-in period (as needed), screening period, double-blind treatment period, 
and an open label treatment period. 


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6.2 
DURATION OF STUDY PARTICIPATION  
6.2.1 Duration of study participation for each patient  
The study comprises 4 periods as described below (please see the graphical study design and 
study flowchart in Section 1.1 and Section 1.3, respectively): 
• A run-in period (if needed) up to 4 weeks (+2 days) in duration. 
• A screening period up to 2 weeks (+5 days) in duration. 
• A double-blind treatment Period 24 weeks in duration. 
• A 80-week open label treatment period. 
The total duration of the study will be up to 110 weeks for each patient. 
A detailed description of the assessments performed in each study period is provided in  
Section 10.1. 
6.2.2 Determination of end of clinical trial (all patients)  
The end of the study is defined as the last patient last visit planned per protocol. 
6.3 
TWO-STEP ANALYSIS  
The analyses will be conducted in 2 steps. The first analysis will be conducted when all patients 
have been randomized and all data up to Week 24 (double-blind period) have been collected and 
validated; this will consist of the final analysis of the double-blind primary and secondary 
endpoints and safety up to Week 24. The safety analysis of the open-label treatment period will be 
performed on all safety data collected and validated at the time of the first analysis. The first 
analysis may be used for regulatory consultation purpose. 
The second analysis will be conducted at the end of the study with the data from the open-label 
treatment period and will consist of the final analysis of the open-label treatment period for the 
safety and other efficacy measures. 
6.4 
STUDY COMMITTEES  
6.4.1 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 


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scientific issues encountered during the study. The Steering Committee will also review the 
recommendations from the DMC throughout the study. 
Detailed activities and responsibilities of the Steering Committee are described in the Steering 
Committee charter. 
6.4.2 Data Monitoring Committee  
An independent DMC for pediatric studies will monitor patient safety by conducting reviews of 
accumulated safety data. 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 be charged with reviewing the safety of patients with LDL-C <50 mg/dL 
(1.30 mmol/L) and more particularly, will review AE potentially associated with LDL-C 
<50 mg/dL (1.30 mmol/L) (see Section 10.6.2.3) in conjunction with the independent physician 
that is external to the EFC14643 study team and not part of any alirocumab activities. Only the 
independent physician will have access to the patient information during the double-blind 
treatment period. Details will be given in the DMC charter. 


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7 
SELECTION OF PATIENTS  
7.1 
INCLUSION CRITERIA  
I 01. Male and female children and adolescents aged 8 to 17 years diagnosed with heterozygous 
familial hypercholesterolemia1 inadequately controlled (see threshold mentioned in the 
exclusion criterion 2)2 despite treatment with optimal dose of statin3 with or without other 
LMTs, or non-statin LMTs if statin intolerant4, at stable dose(s) for at least 4 weeks5. 
I 02. A signed informed consent indicating parental permission with or without patient assent, 
depending on capacity for understanding based on developmental maturity and local 
requirements. 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. 
7.2 
EXCLUSION CRITERIA  
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections:  
                                                 
1 Diagnosis of heFH must be made either by previous genotyping, current centralized 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 run-in period with results 
supporting a diagnosis of heFH. The clinical diagnosis should be based on the Simon Broome criteria for 
possible or definite heFH (see Appendix A). Once eligibility is confirmed based on prior genetic testing 
or Simon Broome criteria, results of elective genetic testing will not impact patient’s eligibility.  
2 Patients who have previously participated in the DFI14223 study have already met this LDL-C 
requirement when they screened for the DFI14223 study and thus will not be excluded based on LDL-C 
<130 mg/dL (3.37 mmol/L). 
3 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 randomization 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.  
4 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. 
5 Before enrolling more than 2 siblings, the Investigator should discuss with the Sponsor study team. 


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7.2.1 Exclusion criteria related to study methodology  
E 01. Children and adolescents aged less than 8 years or more than 17 years at the time of 
informed consent signature unless different local regulation applies (eg, for Russia only: 
patients aged less than 12 years or more than 17 years at the time of informed consent 
signature). 
Note: Patients aged of 8 to less than 10 years who have not had previous attempts to lower 
LDL-C by other means will be excluded. 
E 02. Patients with LDL-C less than 130 mg/dL (3.37 mmol/L) (ie, adequately controlled) 
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. 
Note: Patients who have previously participated in the DFI14223 study have already met 
this LDL-C requirement when they screened for the DFI14223 study and thus will not be 
excluded based on LDL-C <130 mg/dL (3.37 mmol/L). 
E 03. Patients with body weight less than 25 kg.  
E 04. Patients aged of 8 to 9 years not at Tanner Stage 1 and patients aged of 10 to 17 years not 
at least at Tanner Stage 2 in their development (See Appendix B). 
E 05. Daily dose of statin that is above the maximum recommended dose for pediatric patients as 
per the local prescribing label. 
E 06. Patients who will receive statin de novo during the run-in period. 
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. Patients with secondary hyperlipidemia (such as decompensated hypothyroidism, 
nephrotic syndrome, obstructive liver disease, anorexia nervosa, obesity, and drug 
treatment [eg, isotretinoids]). 
E 10. Patients diagnosed with homozygous familial hypercholesterolemia. 
E 11. Patients who have received lipid apheresis treatment within 2 months prior to the screening 
period, or have plans to receive it during the study. 
E 12. Patients with uncontrolled (ie, HbA1c levels above local guidelines or equivalent) 
Type 1 or 2 diabetes mellitus. 


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E 13. Patients with known uncontrolled thyroid disease (ie, thyroid stimulating hormone levels 
above or below the laboratory’s reference range within the past 6 months that were 
obtained due to clinical indication).  
E 14. Use of systemic corticosteroids.  
Note: Topical, intra-articular, nasal, inhaled and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed. 
E 15. Patients with uncontrolled (ie, systolic blood pressure [SBP] or diastolic blood pressure 
[DBP] above local guidelines or equivalent) hypertension. 
E 16. Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening visit. 
E 17. Severe renal impairment (ie, estimated glomerular filtration rate [eGFR] 
<30 mL/min/1.73 m2 at the screening visit). 
E 18. ALT or AST >2 x upper limit of normal (ULN) (1 repeat lab is allowed). 
E 19. CPK >3 x ULN (1 repeat lab is allowed). 
Note: If any of the above liver function tests or CPK are out of range a test can be 
repeated once, using the central laboratory services. 
E 20. Patient/parents who withdraws consent during the screening period (patient who is not 
willing to continue or fails to return).  
E 21. 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 22. Known or suspected alcohol and/or drug abuse. 


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E 23. Patients who have previously received evolocumab.  
E 24. Treatment with any investigational medicinal product (IMP) within 8 weeks or 5 half-lives 
prior to the screening period, whichever is longer (except for patients who participated in 
the DFI14223 study, where within 10 weeks will be applied for alirocumab 
administration).  
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 the active comparator and/or mandatory background 
therapies  
E 25.  All contraindications to the background statins or other LMTs (as applicable) or 
warning/precaution of use (when appropriate) as displayed in the respective National 
Product Labeling. 
7.2.3 Exclusion criteria related to the current knowledge of alirocumab  
E 26.  Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections. 
E 27.  Females who have experienced menarche who are unwilling or unable to be tested for 
pregnancy.  
Note: Females who have experienced menarche must have a confirmed negative 
pregnancy test at screening and other study visits. Pregnancy tests may be performed more 
frequently in some countries due to local legislations related to women of childbearing 
potential randomized in clinical trials. 
E 28.  Positive pregnancy test in females who have experienced menarche.  
E 29.  Females who are breast-feeding. 
E 30.  Females of childbearing potential not protected by highly-effective method(s) of birth 
control (see contraceptive guidance in Appendix D). 
Note: Females of childbearing potential must use an effective contraceptive method 
throughout the entire duration of the study treatment and for at least 10 weeks after the 
last injection. 


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8 
STUDY TREATMENTS  
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S)  
IMP: alirocumab and placebo for alirocumab 
Formulation: Prefilled syringes (PFS) for subcutaneous injections with finger grip, to be replaced 
by PFS with safety system (PFS-S) as soon as available: alirocumab 75 mg/mL or 150 mg/mL 
solution will be used as described below: 
Q2W dosing regimen cohort: 
• BW <50 kg: 
- 
0.5 mL of alirocumab 75 mg/mL solution for 40 mg dose, 
- 
0.5 mL of alirocumab 150 mg/mL solution for 75 mg dose. 
• BW ≥50 kg: 
- 
1 mL of alirocumab 75 mg/mL solution for 75 mg dose, 
- 
1 mL of alirocumab 150 mg/mL solution for 150 mg dose. 
Placebo formulation: Sterile solution consisting of 10 mM histidine, pH 6.0, polysorbate 20, and 
sucrose as described below: 
• Placebo of 0.5 mL volume for BW <50 kg. 
• Placebo of 1 mL volume for BW ≥50 kg. 
Q4W dosing regimen cohort: 
• 1 mL of alirocumab 150 mg/mL solution for 150 mg dose. 
Placebo formulation: Sterile solution consisting of 10 mM histidine, pH 6.0, polysorbate 20, and 
sucrose as described below: 
- 
Placebo of 1 mL volume regardless of BW category. 
Route of administration: Subcutaneous (SC) injections in the abdomen, thigh or outer area of 
upper arm. 
Dose regimen double-blind period: 
Q2W dosing regimen cohort: 
During the double-blind (DB) treatment period, for up to half of the total patient population 
(approximately 75 patients) alirocumab or placebo will be administered Q2W SC, starting at the 
randomization Visit (Week 0) continuing up to the end of the DB period. 
• During the first 12 weeks 
- 
Alirocumab 40 mg: 1 SC injection of 0.5 mL Q2W for BW <50 kg.  


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- 
Alirocumab 75 mg: 1 SC injection of 1 mL Q2W for BW ≥50 kg. 
• At Week 12, based on their LDL-C at Week 8, patients randomized to alirocumab will, in 
a blinded manner, either: 
- 
Continue alirocumab 40 mg or 75 mg Q2W, if the Week 8 LDL-C is <110 mg/dL 
(2.85 mmol/L) OR 
- 
Receive a dose that is up-titrated to alirocumab 75 mg (for patients on 40 mg) or 
150 mg (for patients on 75 mg) Q2W, if the Week 8 LDL-C* is ≥110 mg/dL 
(2.85 mmol/L). 
Q4W dosing regimen cohort: 
The remaining half of the patient population (ie, approximately 75 patients) will be enrolled to a 
Q4W dosing regimen cohort. The start of this Q4W dosing regimen cohort will depend on the 
status of the recruitment in the Q2W dosing regimen cohort and the status of the amendment 
approval. During the first 12 weeks of the double-blind period and before any possible dose-
adjustment to Q2W dosing regimen, all patients will receive SC injection(s) Q4W to get a proper 
evaluation of this dosing regimen. After Week 12 with regard to the possible dose-adjustment and 
the maintenance of the blind until the end of the double-blind period, all patients will receive SC 
injection(s) Q2W. Patients receiving alirocumab will be under a “sham Q2W*” regimen from 
Week 12 to Week 24 with alirocumab Q4W alternating with placebo Q4W. 
• During the first 12 weeks: 
- 
Alirocumab 150 mg for BW <50 kg: 1 SC injection of 1 mL Q4W, consisting of 
1 injection of 150 mg. 
- 
Alirocumab 300 mg for BW ≥50 kg: 2 SC injections of 1 mL each Q4W, consisting of 
2 injections of 150 mg. 
• At Week 12, based on their LDL-C at Week 8, patients randomized to alirocumab will, in 
a blinded manner: 
- 
For BW <50 kg, either continue alirocumab 150 mg with 1 SC injection of 1 Ml Q4W 
alternating with 1 injection of placebo Q4W OR if LDL-C ≥110 mg/dL (2.85 mmol/L) 
receive a dose that is dose -adjusted to 75 mg Q2W with 1 SC injection of 1 mL of 
75 mg.  
- 
For BW ≥50 kg, either continue alirocumab 300 mg with 2 SC injections of 1 mL each 
Q4W (consisting of 2 injections of 150 mg Q4W alternating with 2 injections of 
placebo Q4W) OR if LDL-C ≥110 mg/dL [2.85 mmol/L] receive a dose that is dose -
adjusted to 150 mg Q2W with 2 SC injections of 1 mL each (consisting of 1 injection 
of 150 mg and 1 injection of placebo). 
*Lipid values obtained at Week 8 for the purpose of up-titration/dose-adjustment will not be 
communicated to Investigators to maintain the blind. The continuation or dose up-
titration/dose-adjustment of alirocumab will occur in an automated process without site or patient 
awareness.  


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 Open label period 
The open label treatment period consists of 80 weeks of open label alirocumab SC Q2W or Q4W 
depending on the dosing regimen initiated at randomization. 
At the first open label treatment period visit (ie, Week 24), after completion of the double-blind 
treatment period, depending on the dosing regimen cohort participation, both alirocumab and 
placebo treated patients will receive alirocumab either 40 mg Q2W or 150 mg Q4W if BW is 
<50 kg, and 75 mg Q2W or 300 mg Q4W if BW is ≥50 kg, from the weight obtained at the 
Week 24 visit. 
After Week 24, the Investigator will manage, based on his/her own judgment, adjustment of 
alirocumab dose based on changes in BW. However, related to this up-titration/ adjustment of the 
dose, if the Investigator considers that the up-titration/adjustment would potentially negatively 
impact patient safety, he/she can exercise his/her judgement in a manner that safeguards the safety 
and wellbeing of the patient. The following will be applied based on changes in BW: 
• If currently on 40 mg Q2W then adjust dose to 75 mg Q2W if BW changes from <50 kg to 
≥50 kg. 
• If currently on 150 mg Q4W then adjust dose to 300 mg Q4W if BW changes from <50 kg 
to ≥50 kg.  
For patients whose weight oscillates around 50 kg the dose will be adjusted only once during the 
open-label treatment period. 
The lipid levels will be communicated to the Investigator during the open label treatment period 
from the second visit (ie, Week 32) onwards. The IRT system is set up to allow the Investigator 
based on his/her own judgment related to the patient’s LDL-C levels and the safety profile, to up-
titrate, down-titrate, maintain the dose of alirocumab or discontinue alirocumab throughout the 
study.  
From Week 32 onwards, based on the patient LDL-C value, the following change of alirocumab 
doses will be possible: 
Q2W dosing regimen cohort: 
Up-titration: 
• 40 mg to 75 mg Q2W if BW <50 kg.  
• 75 mg to 150 mg Q2W if BW ≥50 kg.  
Down-titration: 
• 75 mg to 40 mg Q2W if BW <50 kg. 
• 150 mg to 75 mg Q2W if BW ≥50 kg. 


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Q4W dosing regimen cohort: 
• 150 mg Q4W to 75 mg Q2W if BW <50 kg. 
• 300 mg Q4W to 150 mg Q2W if BW ≥50 kg. 
A manual for IMP administration (injection instruction manual) will be provided to patients 
containing detailed instructions on use. The IMP could be administered by self-injection (only 
patients with age ≥12 can self-inject) or by another designated person (such as a parent, nurse etc). 
The used PFS will be discarded in a sharps container which will be provided to patients. Patients 
will be asked to store the IMP in a refrigerator. Prior to administration, the IMP should be set in a 
safe location at room temperature for about 30 to 40 minutes. Thereafter, the IMP should be 
administered as soon as possible. 
Double-blind IMP will start as soon as possible after the call for randomization using the 
treatment kit numbers provided by the Interactive Response Technology (IRT). If possible, the 
first injection after randomization will be done at the investigational site by the patient or another 
designated person (such as parent, nurse, etc) under direct site staff supervision. Patients will be 
monitored at the investigational site for at least 30 minutes after this first double-blind injection. 
IMP should ideally be administered SC at approximately the same time of the day; however, it is 
acceptable to have a window period of ±3 days. The time of the day is based on patient's 
preference. If by mistake or due to other circumstances an injection is delayed by more than 
7 days or completely missed, then the patient should return to the original schedule of study 
treatment administration without administering delayed injections. On the other hand, if the delay 
is less than or equal to 7 days from the missed date, then the patient should administer the delayed 
injection and then resume the original schedule of study treatment administration.  
All of the IMP injections can be performed by trained patient ≥12 years (self-injection) or parent, 
or another designated person or alternative arrangements for injection administration will be 
allowed as needed [eg, if the patient, or caregiver(s) do not develop the comfort to inject the 
investigational drug at home, or the Investigator determines that patient (or caregiver) injection at 
home is not appropriate, injections can be performed at the site by way of unscheduled visits]. It is 
suggested that patients ≥12 years old, who are trained to self-inject, do so with parental (or 
another designated person) supervision; however, this is not mandatory. The Investigator may 
evaluate the sustained reliability of this practice on a case by case basis given the variable 
adolescent ages, maturity levels, availability of the caregiver, or other relevant considerations, 
with the patient. The final decision as to whether supervision is appropriate for self-injection of 
alirocumab for patients ≥12 years old is per Investigator discretion. Prior to any injection, a local 
topical anesthetic may be utilized as per the Investigator. 
Provision of investigational medicinal product: 
Patients will have the option, where available to receive the IMP at home using a Direct-To-
Patient (DTP) service provider on appropriate visits. Patient identification remains confidential 
and will not be disclosed to study Sponsor. For this reason, the IMP delivery will be managed by 
the service provider. The clinical site will instruct the patient, as appropriate, as to how the DTP 
process operates before the DTP process starts. 


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8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S)  
The following classes of drugs (not all of which are indicated for pediatric use in all countries; for 
further information, Investigators should refer to their local prescribing information) are identified 
as noninvestigational medicinal products (NIMP) 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). 
An additional open label treatment period with alirocumab will be offered for this patient 
population. Treatment will continue until one of the following occurs: 
• Risk/benefit of alirocumab in this patient population is deemed not favorable. 
• The study will end in July 2023 or until the drug is approved for the patient in the 
respective country, whatever comes first. 
8.3 
BLINDING PROCEDURES  
8.3.1 Methods of blinding  
During the double-blind treatment period, alirocumab and placebo for alirocumab will be 
provided in identically matched PFS (with or without safety system, depending on the time in the 
study) and packaged identically which includes labeling to protect the blind. Each double-blind 
treatment kit will be labeled with a number, which will be generated by a computer program from 
Sanofi. The treatment kit numbers will be obtained by the Investigator at the time of patient 
randomization and subsequent patient visits scheduled via a centralized treatment allocation 
system that will be available 24 hours-a-day, 7 days-a-week. In accordance with the double-blind 
design, study patients, Investigators and study site personnel will remain blinded to study 
treatment and will not have access to the randomization (treatment codes) except under 
circumstances described in Section 8.3.2.  
8.3.1.1 PK and anti-alirocumab antibodies  
At the assay institutions charged for PK/anti-alirocumab (drug) antibodies (ADA) measurements, 
some of the samples will be analyzed prior to database lock leading to unblinding of responsible 
bioanalysts. Bioanalysts are excluded from the operation’s team and a process will be set up to 
prevent any potential unblinding. Patients’ anti-alirocumab antibody results will not be 
communicated to the sites, during the double-blind phase, so that the patient’s ADA levels do not 
influence the Investigator’s safety evaluation. 


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Patients who do not enter the open label treatment period or who prematurely discontinue the 
double-blind phase and have a titer at or above 240 for anti-alirocumab antibody at the end of 
treatment visit 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 open 
label treatment period will be monitored for anti-alirocumab antibodies as per the study flowchart 
(Section 1.3).  
8.3.1.2 Lipid parameters  
Lipid parameter values from blood samples obtained after the randomization visit and during the 
double-blind 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 or potentially break 
the blind. The Sponsor’s EFC14643 study team will not have access to these values either.  
During the open label treatment period, from Week 32 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 up-titrate, down-titrate, maintain the dose of 
alirocumab or discontinue alirocumab throughout the study. The reasons of any adjustment should 
be documented and recorded in the electronic case report form (e-CRF).  
8.3.2 Randomization code breaking during the double-blind treatment period of the study  
In case of an Adverse Event (AE), the code must be broken by the site only in exceptional 
circumstances when knowledge of the IMP is essential for treating the patient. If possible, a 
contact should be initiated with the Monitoring Team/Medical Monitor before breaking the code. 
All calls will be documented by the Monitoring Team as appropriate to include date and time of 
the call, name of the person contacted within the Monitoring Team, patient ID, documentation of 
the request, and decision for unblinding or not.  
Code breaking can be performed at any time by using the proper module of the centralized 
treatment allocation system and/or by calling any other phone number provided by the Sponsor 
for that purpose. However, it is preferable to contact the Medical Monitor to discuss the case 
before unblinding the case.  
If the blind is broken, the Investigator must document the date, time of day, and reason for code 
breaking, and report this information (or “relevant information as required by”) on the appropriate 
page of the e-CRF. Note that when documenting the reason for unblinding, the Investigator must 
not provide any detail regarding the nature of the IMP. The Investigator should not divulge IMP 
detail to the Sponsor’s representative from the EFC14643 study or to any staff members until 
database closure. Furthermore, when completing forms (eg, AE, serious AE [SAE]), the study 
treatment should not be disclosed on the forms.  
The code-breaking can also be performed by contacting the "24 hour alert system"; but this 
system should be used in very exceptional cases only (ie, unavailability of a centralized treatment 
allocation system or inability to contact Investigator and/or site staff). However, the preferred 
option is to unblind using a centralized treatment allocation system. The Investigators will be 


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informed by the clinical monitoring team about the availability of the local code-breaking details 
(through an emergency centralized 24 hour telephone system for use with e-SMS). A patient card, 
including the relevant “24 hour alert system” telephone number will be provided to every patient 
who will participate in the study.  
Unblinding may also be performed by the Sponsor for some Serious Adverse Events that are both 
related and unexpected in order to conform to regulatory reporting requirements. Refer to  
Section 10.5 for suspected unexpected serious adverse drug reaction unblinding by the Sponsor. 
If the code is broken by the Investigator, the patient must withdraw from IMP administration. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP  
The lists of treatment kit numbers will be generated centrally by Sanofi; separate lists will be 
prepared for Q2W and Q4W dosing regimen cohort. The IMPs will be packaged in accordance 
with those lists. 
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.  
Two dosing regimens will be evaluated - either Q2W or Q4W. For each dosing regimen cohort 
patients will be allocated to receive repeated doses of SC alirocumab injections or matching 
placebo. 
Before allocating a treatment kit to the patient, the Investigator or designee will have to contact 
the centralized treatment allocation system.  
A randomized patient is defined as a patient who is registered and assigned with a treatment kit 
number from the centralized treatment allocation system, as documented from its log file 
regardless of whether the treatment kit will be used or not. A patient cannot be randomized more 
than once in the study. If a treatment is used without contacting the centralized treatment 
allocation system, then the patient will be considered as not randomized and withdrawn from the 
study.  
Two types of centralized treatment allocation 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 
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING  
For the double-blind treatment period, each kit will contain pre-filled syringes with finger grip 
(PFS) to be replaced by pre-filled syringes with safety system (PFS-S) when they become 
available of alirocumab 75 mg/mL or alirocumab 150 mg/mL or placebo for alirocumab as 
described in Section 8.1.  


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For the open label treatment period, each kit will contain pre-filled syringes (PFS-S) of 
alirocumab as described in Section 8.1.  
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. Any 
temperature excursion during transportation to the site or during storage at site should be promptly 
reported to the Sponsor who will assess the suitability for use of the IMPs. 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the alirocumab must be managed 
according to the rules provided by the Sponsor. 
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. 
NOTE: Exceptionally, after discussion between Site and Sponsor (eg, patient unable to attend a 
clinic visit due to special circumstances) some IMP kits could be supplied, when feasible, directly 
from site to patient via a Sponsor-approved courier company. This process (which requires 
maintenance of the cold chain) would be implemented only at selected sites/countries (where 
certain conditions would be fulfilled, and where permitted locally) and for selected patients (who 
could handle and would consent to such a process). This direct-to-patient (DTP) process will be 
described in detail in a separate document and would be implemented after appropriate training 
of Monitoring Teams and Investigational Sites. 
8.7 
RESPONSIBILITIES  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP/NIMP (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) should be promptly notified 


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to the Sponsor. Some deficiencies may be recorded through a complaint procedure  
(see Section 10.4.7). 
A potential defect in the quality of IMP/NIMP 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 the IMP/NIMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party, allow the 
IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
8.7.1 Treatment accountability and compliance  
IMP administration data will be recorded by the Investigator on e-CRF and by patients/parents on 
a patient's diary. Measures taken to ensure and document IMP compliance and accountability are 
described below: 
• The Investigator or designee will obtain via IRT 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). 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). 
Concomitant medications will not be provided by Sanofi. 
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 double-blind treatment period. During the open label treatment 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.  
Double-blind treatment phase: 
From the randomization visit (Day 1) until Week 24 of the double-blind treatment period, 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 double-blind treatment phase, lipid profile values from samples obtained after 
randomization will be blinded. 
Open label treatment period: 
During the open label treatment period, starting after the Visit 7 (Week 24), the lipid levels will be 
communicated to the Investigators from Visit 8 (Week 32). 
The Investigator will be responsible, based on his/her own judgment related to the patients’ 
LDL-C levels and the safety profile, to up-titrate, down titrate, maintain the dose of alirocumab or 


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discontinue alirocumab throughout the study. 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 
(including addition of another LMT) 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 must use an effective contraceptive method throughout the 
entire duration of the study treatment (including the double-blind treatment period and the open 
label treatment period) and for at least 10 weeks after the last IMP injection  
(see Appendix D).  
8.8.3 Prohibited concomitant medications  
Prohibited concomitant medications from the initial screening visit until the follow-up visit 
include the following: 
• Oral and injectable corticosteroids. 
• Fibrates (except fenofibrates). 
• Immunosuppressants. 
Prohibited concomitant medications from the start of the open label treatment 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  
Percent change in LDL-C from baseline to Week 24 in the intent-to-treat (ITT) population, using 
all LDL-C values regardless of adherence to treatment (ITT estimand). 
The LDL-C at Week 24 will be the LDL-C level obtained within the Week 24 analysis window. 
All calculated and measured LDL-C values (scheduled or unscheduled, fasting or not fasting) may 
be used to provide a value for the primary efficacy endpoint if appropriate according to above 
definition. In case both calculated and measured LDL-C are provided for the same sampling, the 
measured LDL-C will be considered. The analysis window used to allocate a time point to a 
measurement will be defined in the SAP.  
9.2 
SECONDARY ENDPOINTS  
9.2.1 Key secondary efficacy endpoints  
• Percent change in LDL-C from baseline to Week 12 (ITT estimand). 
• Percent change in Apo B from baseline to Week 24 (ITT estimand). 
• Percent change in non-HDL-C from baseline to Week 24 (ITT estimand). 
• Percent change in Total-C from baseline to Week 24 (ITT estimand). 
• Percent change in Apo B from baseline to Week 12 (ITT estimand). 
• Percent change in non-HDL-C from baseline to Week 12 (ITT estimand). 
• Percent change in Total-C from baseline to Week 12 (ITT estimand). 
• Proportion of patients achieving a LDL-C level lower than 130 mg/dL (3.37 mmol/L) at 
Week 24 (ITT estimand). 
• Proportion of patients achieving a LDL-C level lower than 130 mg/dL (3.37 mmol/L) at 
Week 12 (ITT estimand). 
• Proportion of patients achieving a LDL-C level lower than 110 mg/dL (2.84 mmol/L) at 
Week 24 (ITT estimand). 
• Proportion of patients achieving a LDL-C level lower than 110 mg/dL (2.84 mmol/L) at 
Week 12 (ITT estimand). 
• Percent change in Lp (a) from baseline to Week 24 (ITT estimand). 
• Percent change in Lp (a) from baseline to Week 12 (ITT estimand). 
• Percent change in HDL-C from baseline to Week 24 (ITT estimand). 


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• Percent change in fasting TG from baseline to Week 24 (ITT estimand). 
• Percent change in Apo A-1 from baseline to Week 24 (ITT estimand). 
• Percent change in HDL-C from baseline to Week 12 (ITT estimand). 
• Percent change in fasting TG from baseline to Week 12 (ITT estimand). 
• Percent change in Apo A-1 from baseline to Week 12 (ITT estimand). 
9.2.2 Other secondary efficacy endpoints  
• All primary and key secondary endpoints in the modified ITT (mITT) population, using all 
LDL-C values during the treatment period (on-treatment estimand). 
• Absolute change in Apo B/Apo A-1 ratio to Week 12 and Week 24 (ITT and on-treatment 
estimands)  
• Proportion of patients achieving at least 30% reduction, 50% reduction in LDL-C at 
Week 24 (ITT and on-treatment estimands) 
• Proportion of patients achieving at least 30% reduction, 50% reduction in LDL-C at 
Week 12 (ITT and on-treatment estimands) 
• Percent change in LDL-C from baseline to Week 104 (ITT and on-treatment estimands). 
9.2.3 Efficacy assessment method  
9.2.3.1 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. LDL-C will be calculated using the Friedewald 
formula by the Central Laboratory as per the schedule in Section 1.3. 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.  
9.2.4 Safety endpoints  
Safety parameters: adverse events (AE), serious AE (SAE), AE of special interest ([AESI] 
laboratory data, vital signs, body weight, height, Cogstate battery test, and Tanner stage will be 
assessed throughout the study.  


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An AESI is an AE (serious or non-serious) of scientific and medical interest 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. 
The AESIs are defined in Section 10.4.1.3. 
9.2.4.1 Observation period  
The observation of safety data will be as follows: 
• Pre-treatment period: The Pre-treatment observation period is defined from the signed 
informed consent up to the first dose of double-blind IMP.  
• Double-blind treatment-emergent adverse event (TEAE) period: The double-blind TEAE 
observation period is defined as the time from the first dose of double-blind IMP to the last 
dose of double-blind IMP injection +70 days (10 weeks) for those patients not proceeding 
into the open label treatment period as residual effect of alirocumab is possible until  
10 weeks after the stop of treatment IMP injection, or up to the day before first dose of 
open label IMP for those patients proceeding into the open label treatment period.  
• Open label TEAE period: The open label TEAE observation period is defined as the time 
from the first dose of open label IMP to the last dose of open label IMP injection +70 days 
(10 weeks).  
• Post-treatment period: The post-treatment observation period is defined as the time 
starting the day after the end of the double-blind and open label TEAE periods up to the 
end of the study for each patient. 
9.2.4.2 Adverse events  
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 (AESIs or not, see Section 10.4.1.3).  
• Neurologic adverse events (AESIs or not, see Section 10.4.1.3). 
• Neurocognitive events. 


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• Symptomatic overdose with IMP:  
- 
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic injection counts) and 
defined as at least twice of the intended dose within the intended therapeutic interval 
(ie, 2 or more injections from the treatment kit are administered in <7 calendar days to 
be reported using the corresponding screens in the e-CRF using the term “symptomatic 
overdose (accidental or intentional)”. The patient should be monitored and appropriate 
symptomatic treatment instituted if needed.  
• 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). 
9.2.4.3 Laboratory safety variables  
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry). 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables.  
High-sensitivity C reactive protein (hs-CRP) will be monitored at baseline and at Week 24. 
9.2.4.4 Vital signs  
Vital signs include: heart rate, systolic and diastolic blood pressure (BP) in sitting position.  
9.2.4.5 Cogstate battery test  
Cogstate battery test consists of identification test, detection test, one card learning test, and 
Groton maze learning test. The results will be automatically calculated. Details are provided in 
Section 10.  
9.2.4.6 Tanner stages measurement  
The Tanner stages will be measured (see Appendix B) throughout the study according to the 
schedule in Section 1.3. 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. 


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9.3 
OTHER ENDPOINTS  
9.3.1 Pharmacokinetics  
Total serum alirocumab concentrations, as well as total and free PCSK9 concentrations will be 
measured from the same PK sample. 
9.3.1.1 Sampling time  
Serum samples for total alirocumab concentration will be collected before IMP (pre-dose) at 
Week 0 (randomization visit) and then at several visits as per the study flowchart  
(see Section 1.3). 
Exact date and time of last IMP administration and PK sampling are to be recorded. 
9.3.1.2 Pharmacokinetics handling procedure  
Table 1 - 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 [-4 F°] (-80°C [-112 F°] preferred) 
9.3.1.3 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). The lower limit of quantification (LLQ) for this assay is  
0.078 μg/mL 
. 
PK samples will be also analyzed for the determination of the total and free PCSK9 levels using 
validated ELISA. The LLQ is 0.156 μg/mL for the total PCSK9 assay 
 and 0.0312 μg/mL for the free PCSK9 assay 
. 
9.3.2 Anti-alirocumab antibody assessments  
Anti-alirocumab antibodies (ADA) include the antibody status (positive/negative), antibody titers 
and neutralizing activity for positive ADA. 


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9.3.2.1 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. All scheduled samples will 
be obtained before IMP injection (predose). 
9.3.2.2 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. 
9.3.2.3 Bioanalytical method  
All anti-alirocumab antibody (ADA) 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 
 
  
 
 
9.3.3 Pharmacogenetic assessment  
No pharmacogenetic testing will be done in this study. 
9.3.4 Pharmacodynamic variables  
The PD effect of alirocumab corresponding to the effect on LDL-C is described in the efficacy 
section (see Section 9.1.1 and Section 9.2.1). 
9.3.5 Low-density lipoprotein-C (LDL-C) <50 mg/dL (<1.30 mmol/L)  
Other endpoints related to LDL-C <50 mg/dL (1.30 mmol/L) will be the proportion of patients 
with 2 consecutives results, spaced out by at least 21 days, of LDL-C <50 mg/dL (1.30 mmol/L), 
LDL-C <25 mg/dL (0.65 mmol/L), LDL-C <15 mg/dL (0.39 mmol/L) during the treatment period 
and the time to the first LDL-C <50 mg/dL (1.30 mmol/L) for these patients. 


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9.3.6 Urinalysis  
Urine test will be monitored at baseline and at Week 24. Macroscopy will be performed at the 
central lab. If abnormal, then a standard microscope assessment will be conducted. 
9.3.7 CPK-MB and cardiac troponin  
CPK-MB and cardiac troponin levels will be assessed at baseline and at Week 24 and in case of 
any clinically relevant cardiovascular effect observed in patients. 
9.4 
FUTURE USE OF SAMPLES  
Not applicable. 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
See Section 4. 


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10 
STUDY PROCEDURES  
For all visits after Day 1/Week 0 (randomization visit), a timeframe of a certain number of days 
will be allowed. The window period for all visits including during the open label treatment period 
is ±7 days except for Week 24 (±3 days). 
For all visits after Day 1/randomization visit, if one visit date is changed, then the next visit 
should take place according to the original schedule as outlined in Section 1.3. 
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. 
Of note, appropriate visits at patient’s home may occur, if nursing services are available.  
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).  
In case only a limited amount of blood can be drawn, specific tests performed for each sample 
obtained will be prioritized (the total max blood volume of 38.0 mL/day or 50.9 mL/month 
[27, 28, 29]). 
Laboratory tests: 
The laboratory data are collected in accordance with the study schedule in Section 1.3 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. The formula for calculating eGFR and creatinine clearance is provided in 
Appendix I. 
• 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). 


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• Liver panel: ALT, AST, alkaline phosphatase (ALP) 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). 
• HbA1c. 
• Hs-CRP. 
• CPK-MB, troponin. 
• Adrenal gland hormones: cortisol (with reflexive adrenocorticotrophic hormone [ACTH] 
levels if cortisol <LLN) and dehydroepiandrosterone sulfate (DHEAS). 
• 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). 
• Pregnancy test: pregnancy test should be done on females of childbearing potential 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.  
• Urinalysis: macroscopy will be performed at the central lab. If abnormal, then a standard 
microscope assessment will be conducted. 
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 H. 
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. Blood samples should 
be collected before IMP injection. PK samples will also be used for free and total PCSK9 
analysis. 
Physical examination: 
A general physical examination should be performed at the time points indicated in the study 
schedule flowchart Section 1.3. If a new clinically significant abnormality or worsening from 
baseline is detected after randomization, then an AE should be reported and the patient should be 
considered for further clinical investigations and/or specialist consultation as per the 
Investigator’s medical judgment.  


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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 if possible (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 
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 in sitting position at the time of the measurement of BP.  
Cogstate battery test: 
The Cogstate battery test (30) will include a detection test, identification test, one card learning 
test, and Groton maze learning test. These individual tests assess maturing cognition across a 
broad number of key developmental functions such as processing speed, attention, visual learning 
and executive functioning, respectively. Details of the Cogstate battery test are provided in 
Appendix C. Briefly, the battery of tests is administered by trained clinical site personnel and will 
take the patient approximately 16 to 19 minutes to complete. It will be administered electronically 
and is standardized. The results will be automatically calculated. The results will not be used for 
detection of adverse events and will not trigger further consultation or investigation. 
Tanner stages: 
The Tanner stages (31, 32) 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 B. 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, if 
possible.  
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.  
Training for new device: 
If a new device is introduced during the course of the study, training will be scheduled 
accordingly at the next planned visit prior to the first administration. 
Flow mediated dilatation assessment: 
Will be conducted in a subset of population as part of a sub-study (see Appendix E). 


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10.1 
VISIT SCHEDULE  
The visit schedule and procedures/assessments are listed in the study flow chart in Section 1.3. 
The aim of this section is to provide details on how some of the procedures/assessments have to 
be performed. The study consists of 12 on-site visits and 2 telephonic visits. 
Only patients who meet/are likely to meet the inclusion criteria as noted in Section 7.1 should be 
screened.  
The run-in and screening periods will take place up to 6 weeks (+2 days) or 42 (+2) days (and as 
short as possible, upon receipt of laboratory eligibility criteria) prior to randomization/ 
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.  
For patients who consent to participate in the study, but who do not have a stable background 
LMT [optimal statin dose ± other LMTs or non-statin LMTs if statin intolerant] for at least  
4 weeks and/or patients suspected of being heFH but without a confirmed diagnosis and 
consenting to undergo the centralized genotyping, a run-in period up to 4 weeks (+2 days) in 
duration will be allowed. 
The screening visit can take place up to 14 (+5) days before the randomization 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. 
10.1.1 Run-in period (Up to Week -6)  
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 at least 4 weeks. 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 who will be treated with statin de novo to avoid the potential for 
multiple titration steps during the run-in period. The run-in period is up to 4 weeks (+2 days) in 
duration.  
Another possible situation requiring the run-in period include patients with suspected heFH but 
without confirmation by previous genetic testing and not meeting Simon Broome criteria. Such 
patients will be asked to undergo centralized genetic testing during the run-in period.  
Patients who have previously participated in the DFI14223 study and have received alirocumab 
administration during the open label extension of the DFI14223 study will require a wash-out 
period of at least 10 weeks between the last injection of alirocumab and the screening lipid 
assessment at the entry of the screening period. 


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10.1.1.1 Visit 1 (Week -6, run-in)  
• Obtaining the informed consent: 
- 
The patient will receive verbal information concerning the aims and methods of the 
study, its constraints and risks and the study duration. Written information will be 
provided to the patient. Written informed consent must be signed by the patient and 
Investigator prior to any investigations 
• Obtaining the heFH Genotyping Informed Consent from the dedicated section in the main 
ICF (if needed) 
• Assessment of inclusion/exclusion criteria 
• Collection of demographic data (age, gender, race and ethnic origin) 
• Medical/surgical/family medical history  
• Record habits: alcohol habits (during the last 12 months), smoking status 
• Prior medication history (within the previous 12 weeks) 
• Physical examination including vital signs (SBP and DBP in sitting position, heart rate in 
sitting position) in both arms 
• Body weight measurement 
• Height without shoes 
• Tanner stage 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs from this point onward: 
- 
All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study 
• heFH genotyping (if needed) 
• IRT will be contacted for notification of screening and for patient number allocation 
10.1.2 Screening period (Up to Week -2)  
The duration of the screening period is up to 2 weeks from Visit 2 (Week -2) to Visit 4 (Week 0) 
which has a window of 14 + 5 days. 
Patients will be screened at Visit 2. All laboratory tests measured at central laboratory needed for 
checking the exclusion criteria of the patients will be performed during the screening period. 
Patients who meet the inclusion criteria and who have no exclusion criteria, as noted in  
Section 7.1 and Section 7.2, will be randomized at Visit 4 (Week 0) after the injection training 
visit (unless deemed not needed). The IRT will be contacted at Visit 1 for notification of 
screening and for patient number allocation. 


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10.1.2.1 Visit 2 (Week -2, screening visit)  
For the complete list and contents of procedures/assessments scheduled for the screening period, 
please refer to the “Study Flow Chart” in Section 1.3 and for detailed description of assessments 
Section 9 and Section 10.6. 
The following procedures/assessments will be performed at Visit 2 (Week -2): 
• Obtaining the informed consent (if the patient did not have a run-in period): 
- 
The patient will receive verbal information concerning the aims and methods of the 
study, its constraints and risks and the study duration. Written information will be 
provided to the patient. Written informed consent must be signed by the patient and 
Investigator prior to any investigations 
• IRT will be notified (allocation of patient number, registration of screening, collection of 
demographic information). The 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 (which is 00001 for the first patient screened in a center, 00002 for 
the second patient screened in the same center, etc) 
• Assessment of inclusion/exclusion criteria 
• If not collected before: 
- 
Collection of demographic data (age, gender, race and ethnic origin) 
- 
Medical/surgical/family medical history  
- 
Record habits: alcohol habits (during the last 12 months), smoking status 
- 
Prior medication history (within the previous 12 weeks) 
- 
Physical examination including vital signs (systolic blood pressure [SBP] and diastolic 
blood pressure [DBP] in sitting position, heart rate in sitting position). 
- 
Body weight measurement 
- 
Height without shoes 
- 
Tanner stage 
- 
Review of diet 
• Check of stability of background LMT 
• Collect AEs 
• Vital signs 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C  
- 
Hematology and chemistry 
- 
HbA1c 
- 
Creatine phosphokinase  
- 
Liver panel 
- 
Pregnancy test 


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10.1.2.2 Visit 3 (Week -1, injection training)  
An intermediate visit for injection training may occur during which the patient (if aged 12 years 
and above or another designated person such as parent, etc) will be trained to self-inject/inject 
with placebo for alirocumab after the eligibility criteria have been checked and it is confirmed that 
the patient will likely be randomized. Prior to the injection, a local topical anesthetic may be 
utilized as per the Investigator recommendation. Investigators will have the option of providing a 
second placebo kit for alirocumab for patients/parents who require additional injection training 
prior to randomization. Please note that this visit (injection training visit) can take place at the 
same visit as D1 as per the site or patient preference. 
The following additional procedures/assessments will be performed at the injection training visit 
(Week -1): 
• IRT contact 
• Check of stability of background LMT 
• Collect AEs 
10.1.3 Twenty-four-week double-blind treatment period  
The double-blind treatment period is 24 weeks in duration. Patients will be blinded to study 
treatment (alirocumab or placebo).  
For dosing and timing of injection details, see Section 8.1. 
The laboratory measurement of lipid parameters will be performed by a central lab. Local lab 
testing for lipid parameters is generally prohibited after randomization of the patient. The specific 
results of the central lab testing for lipid parameters from samples obtained after randomization 
and during the double-blind treatment period will not be communicated to the sites or the 
Sponsor’s EFC14643 study team. Instead, the central lab will inform sites of triglyceride alert (if 
patients exceed the triglyceride threshold of 500 mg/dL [5.65 mmol/L]). Additionally, the site 
may receive alert related to LDL-C <50 mg/dL (1.30 mmol/L) based on safety concerns by the 
independent physician who will carefully monitor the patient’s LDL-C values during the 
double-blind treatment period under the auspices of the DMC. The independent physician is 
external to the EFC14643 study team and not part of any alirocumab activities. 
Statin and other LMT (if applicable) should be stable during double-blind treatment period 
barring exceptional circumstances whereby overriding concerns (including but not limited to 
triglyceride alert posted by the central lab) warrant such changes, as per the Investigator’s 
judgment. Patients will be instructed to follow a diet to treat their hypercholesterolemia in 
accordance with local guidelines or local practice and they should be on this diet throughout the 
entire study duration from screening.  
A flow mediated dilatation exploratory sub-study will be conducted in a sub-set of the study 
population. The details are provided in Appendix E. 


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10.1.3.1 Visit 4 (Week 0, randomization)  
The following procedures/assessments will be performed at the randomization visit: 
• Assessment of inclusion/exclusion criteria 
• Body weight 
• IRT contact 
• Randomization 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Vital signs 
• Cogstate battery practice test 
• Cogstate battery test 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a) 
- 
Hs-CRP 
- 
CPK-MB, troponin 
- 
Adrenal gland hormones 
- 
Gonadal and pituitary hormones 
- 
Fat soluble vitamins 
- 
Anti-alirocumab antibodies (ADA) 
- 
Serum alirocumab concentration (Pharmacokinetics)  
• Injection training (optional) 
• Urinalysis 
• Pregnancy test 
• Double-blind IMP kit dispensation 
• IMP administration patients will remain under observation at the site for 30 minutes post-
injection 
• Flow mediated dilatation assessment only for patient included in the sub-study. 
Injection training: Further injection training can be provided at the randomization visit  
Week 0/Day 1 when the patient/parent or a trained designated person injects the first IMP from 


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the double-blind study treatment kit allocated by IRT. Additional training can be offered at 
scheduled or unscheduled visits with the scheduled double-blind treatment, as per patient/parent 
or Investigator’s judgment. 
10.1.3.2 Visit 5 (Week 8, Day 56 ±7)  
The following procedures/assessments will be performed at Visit 5. 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Collect AEs 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Serum alirocumab concentration (Pharmacokinetics)  
• IMP administration. 
10.1.3.3 Visit 6 (Week 12, Day 84 ±7)  
The following procedures/assessments will be performed at Visit 6. 
• Body weight 
• IRT contact 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Vital signs 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a) 
- 
Hematology and chemistry 
- 
Creatine phosphokinase  
- 
Liver panel 
- 
Anti-alirocumab antibodies (ADA) 
- 
Serum alirocumab concentration (Pharmacokinetics) 


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• Double-blind IMP kit dispensation 
• IMP administration. 
10.1.3.4 Visit 7 (Week 24, Day 168 ±3, end of double-blind treatment period)  
The following procedures/assessments will be performed at Visit 7. 
• Physical examination including vital signs (systolic blood pressure [SBP] and diastolic 
blood pressure [DBP] in sitting position, heart rate in sitting position) 
• Body weight 
• Height without shoes 
• Tanner stage 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Cogstate battery test 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a) 
- 
Hematology and chemistry 
- 
HbA1c 
- 
Creatine phosphokinase  
- 
Liver panel 
- 
Hs-CRP 
- 
CPK-MB, troponin 
- 
Adrenal gland hormones 
- 
Gonadal and pituitary hormones 
- 
Fat soluble vitamins 
- 
Anti-alirocumab antibodies (ADA) 
- 
Serum alirocumab concentration (Pharmacokinetics)  
• Urinalysis 
• Pregnancy test 


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• IRT contact to document end of double-blind treatment for patient not continuing in the 
open label part 
• Flow mediated dilatation assessment only for patient included in the sub-study. 
In addition, for patients continuing into the open label part, the following procedures/assessments 
will be performed: 
• IRT contact 
• Open label IMP kit dispensation 
• IMP administration 
10.1.4 Eighty-week open label treatment period  
After patients successfully complete the 24-week double-blind treatment period, they can enter the 
open label treatment period which consists of 80 weeks of open label alirocumab.  
The first open label alirocumab injection will be done at the site followed by monitoring of the 
patient for at least 30 minutes. The patient’s regimen will be a continuation of their regimen from 
the double-blind treatment period. The dose of alirocumab may be adjusted based on patients 
body weight (ie, patients who previously were with BW <50 kg can be dose adjusted if their 
weight is ≥50 kg) at each study visit starting from the first visit (ie, Week 24) of the open label 
treatment period. For patients whose weight varies close to 50 kg the dose will be adjusted only 
once at the onset of the open label treatment period. 
The lipid levels will be communicated to the Investigator during the open label treatment period 
from the second visit (ie, Week 32) onwards. The Investigator will be responsible, based on 
his/her own judgment related to the patients’ LDL-C levels and the safety profile, to up-titrate, 
down-titrate, maintain the dose of alirocumab or discontinue throughout the study. The statin dose 
should not be decreased to adjust to the degree of LDL-C lowering and should not be increased; 
unless otherwise indicated. 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 LDL-C levels <50 mg/dL (1.30 mmol/L) on one or more occasion are 
provided in the protocol. 
10.1.4.1 Visit 8 (Week 32, Day 224 ±7)  
The following procedures/assessments will be performed at Visit 8: 
• Body weight 
• IRT contact 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 


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• Review of diet 
• Collect AEs 
• Vital signs 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology and chemistry 
- 
Creatine phosphokinase 
- 
Liver panel 
• Pregnancy test  
• Open label IMP kit dispensation 
• IMP administration 
10.1.4.2 Visit 9 (Week 44, Day 308 ±7)  
The following procedures/assessments will be performed at Visit 9: 
• Physical examination including vital signs (systolic blood pressure [SBP] and diastolic 
blood pressure [DBP] in sitting position, heart rate in sitting position). 
• Body weight 
• Height without shoes 
• Tanner stage 
• IRT contact 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Vital signs 
• Fasting blood sampling for: 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology and chemistry 
- 
Creatine phosphokinase (CPK) 
- 
Liver panel 
- 
Adrenal gland hormones 


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- 
Gonadal and pituitary hormones 
- 
Fat soluble vitamins 
• Pregnancy test  
• Open label IMP kit dispensation 
• IMP administration 
10.1.4.3 Visit 10 (Week 56, Day 392 ±7, telephone contact)  
The following procedures/assessments will be performed remotely at Visit 10: 
• IRT contact 
• Open label IMP kit delivery DTP (if applicable) 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs  
• IMP administration 
10.1.4.4 Visit 11 (Week 68, Day 476 ±7)  
The following procedures/assessments will be performed at Visit 11: 
• Physical examination including vital signs (systolic blood pressure [SBP] and diastolic 
blood pressure [DBP] in sitting position, heart rate in sitting position). 
• Body weight  
• Height without shoes 
• Tanner stage 
• IRT contact 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Vital signs 
• Cogstate battery test 
• Fasting blood sampling for: 


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- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology and chemistry 
- 
HbA1c 
- 
Creatine phosphokinase  
- 
Liver panel 
- 
Adrenal gland hormones 
- 
Gonadal and pituitary hormones 
- 
Fat soluble vitamins  
- 
Anti-alirocumab antibodies (ADA) 
• Pregnancy test 
• Open label IMP kit dispensation 
• IMP administration 
10.1.4.5 Visit 12 (Week 80, Day 560 ±7, telephone contact)  
The following procedures/assessments will be performed remotely at Visit 12: 
• IRT contact 
• Open label IMP kit delivery (DTP) (if applicable) 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• IMP administration 
10.1.4.6 Visit 13 (Week 92, Day 644 ±7)  
The following procedures/assessments will be performed at Visit 13: 
• Body weight measurement 
• IRT contact 
• Compliance check of IMP and data collection on IMP administration 
• Open label IMP kit dispensation 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 


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• Collect AEs 
• Pregnancy test  
• IMP administration 
10.1.4.7 Visit 14, End of Treatment (Week 104, Day 728 ±7)  
The following procedures/assessments will be performed at Visit 14: 
• Physical examination including vital signs (systolic blood pressure [SBP] and diastolic 
blood pressure [DBP] in sitting position, heart rate in sitting position) 
• Body weight 
• Height without shoes 
• Tanner stage 
• Compliance check of IMP and data collection on IMP administration 
• Concomitant medication recording 
• Check of stability of background LMT 
• Review of diet 
• Collect AEs 
• Vital signs 
• Cogstate battery test 
• Fasting blood sampling for: 
- 
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp(a) 
- 
Total-C, LDL-C, HDL-C, TG, non-HDL-C 
- 
Hematology and chemistry 
- 
HbA1c 
- 
Creatine phosphokinase (CPK) 
- 
Liver panel 
- 
Adrenal gland hormones 
- 
Gonadal and pituitary hormones 
- 
Fat soluble vitamins 
- 
Anti-alirocumab antibodies (ADA) 
• Pregnancy test 
• IRT contact to document end of open label treatment 


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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 childbearing potential who are sexually active. 
• Previous and concomitant medication (including the lipid modifying therapy). 
• Study identification. 
• Treatment number, dates of administration. 
• Dates of visits and assessments including the examination report. 
• Vital signs, height, body weight, Tanner stage. 
• Faxed central lab reports (dated and signed by the Principal Investigator or 
Sub-Investigator). 
• IRT confirmation fax (run-in, screening, screen failure, randomization, treatment 
(re)allocation, discontinuation, end of double-blind treatment period, end of open label 
treatment period, dose change alert). 
• 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 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 


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a last resort. Any IMP discontinuation must be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
 Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s)  
Temporary treatment discontinuation (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 must be recorded by the Investigator in the appropriate e-CRF 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 is any treatment discontinuation associated with the 
definitive decision from the Investigator not to re-expose the patient to the IMP at any time during 
the study, or from the patient not to be re-exposed to the IMP whatever the reason. 
10.3.3 List of criteria for permanent treatment discontinuation  
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
Patients should discontinue the IMP for the following reasons: 
• Pregnancy, intention for pregnancy, or no longer with effective contraceptive method of 
birth control (females of childbearing 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 randomization. 


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Any abnormal laboratory value will be immediately rechecked for confirmation (within 24 hours 
if possible), before making a decision of discontinuation of the IMP for the concerned patient 
Any code-breaking requested by the Investigator will lead to permanent treatment discontinuation. 
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
10.3.4 Handling of patients after permanent treatment discontinuation  
In case of permanent treatment discontinuation, the recommendation is to limit the collection to 
critical data, ie, primary endpoint/main secondary endpoint and safety endpoints. 
Patients who prematurely discontinue study treatment (regardless of the reason) should undergo 
the following visits: 
Premature treatment discontinuation during the double-blind treatment period:  
• At the time of treatment discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at end of treatment period visit 
including lipids, PK and ADA.  
• Week 24 visit, as described in Section 1.3, should be performed regardless of timing of the 
last alirocumab injection, including for patients included and not treated. 
All efforts should be done to perform these assessments. 
Premature treatment discontinuation during the open label treatment period:  
• 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 treatment period 
visit including lipids and ADA.  
• Week 104 visit, as described in Section 1.3, should be performed regardless of timing of 
the last alirocumab injection. 
Whatever the period of premature treatment discontinuation, the patient, at a minimum, should be 
followed up for recovery or stabilization of any AE as specified in this protocol. 
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”. IRT should be notified when a patient prematurely discontinues study treatment. 
10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason without any effect on their care. However, if patients no longer 
wish to take the IMP, they will be encouraged to remain in the study. 


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The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Patients who withdraw from the study treatment should be explicitly asked about the contribution 
of possible AEs to their decision, and any AE information elicited must be documented.  
All study withdrawals must be recorded by the Investigator in the appropriate screens of the  
e-CRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a patient may withdraw his/her consent to stop participating in the study. 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 record checks. The 
site should document any case of withdrawal of consent. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator must make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter).  
Patients who have withdrawn from the study cannot be re-included (treated) in the study. Their 
randomization and treatment number must not be reused. 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING  
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event  
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
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 


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• 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 a medically important event. The list is not 
intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc) 
• Development of drug dependence or drug abuse 
• ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN 
• Suicide attempt or any event suggestive of suicidality 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
• Bullous cutaneous eruptions 
• Cancers diagnosed during the study 
• Chronic neurodegenerative diseases (newly diagnosed) 
• Suspected transmission of an infectious agent 
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, modified 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 pre-specified manner described in the protocol. Please 
see Appendix F for additional information. 


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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 (if baseline ALT < ULN), or ALT ≥2 times the baseline value (if baseline 
ALT ≥ ULN) (see the “Increase in ALT” flow diagram in Appendix H of the protocol). 
• Allergic events: 
- 
Any general allergic events regardless of the cause 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 require completion of the specific e-CRF screen 
(see Section 10.6.2). 
• Local injection site reactions: 
- 
Local injection site reactions 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 local injection site reactions 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 pre-specified 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) to 
be reported using the corresponding screens in the e-CRF using the term “symptomatic 
overdose (accidental [or intentional])”. The patient should be monitored and 
appropriate symptomatic treatment instituted if needed, 
- 
The circumstances of the overdose should be clearly specified in the verbatim, 


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• Neurologic Events: 
- 
Neurologic Events that require additional examinations/procedures and/or referral to a 
specialist should be reported as an AESI. If the event does not require additional 
examinations/procedures and/or referral to a specialist, it should be reported as a 
standard 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 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 G. 
Special e-CRF screens will need to be completed. If such an AE was to occur, then do not report 
the individual components of the reaction but rather the term “local injection site reaction”, the 
individual components being described in the specific e-CRF 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 
e-CRF. 
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 as defined by the protocol for that patient, are to 
be recorded on the corresponding page(s) or screen(s) of the e-CRF. 
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. 
Laboratory, vital signs are to be recorded as AEs only if:  


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• 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. 
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. At the prespecified study end-
date, patients who experience an ongoing SAE or an AESI should be followed until resolution, 
stabilization, or death and related data will be collected.  
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. 
Instructions for AE reporting are summarized in Table 2 and in Appendix F. 
10.4.4 Instructions for reporting serious adverse events  
In the case of occurrence of an 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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In such case, 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. 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 Section 10.4.4, 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 Table 2 and in Appendix F. 
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 H.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol Appendix H.  
• Neutropenia 
• Thrombocytopenia 
• Acute renal insufficiency 
• Increase in ALT 
• Suspicion of rhabdomyolysis 
Table 2 - Summary of adverse event reporting instructions  
Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case Report Form completion 
AE 
form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse Event  
(non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event  
(non-AESI or AESI) 
Expedited  
(within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited  
(within 
24 hours) 
Allergic events meeting AESI 
criteria 
Yes 
Yes 
No 
 
 
LISR meeting AESI criteria 
Yes  
Yes 
Yes 
 
 
Pregnancy 
Yes 
Yes 
Yes 
 
 
Symptomatic overdose 
Yes 
Yes 
No 
 
 
ALT>3 ULN 
(if baseline ALT < ULN), or 
ALT ≥2 times the baseline value 
(if baseline ALT ≥ ULN) 
Yes 
Yes 
Yes 
 
 
Neurologic events meeting AESI 
criteria 
Yes 
Yes 
Yes 
 
 
Neurocognitive events 
Yes 
Yes 
Yes 


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10.4.7 Guidelines for reporting product complaints (IMP/NIMP)  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Non investigational medicinal product include rescue medication, challenge agents, products use 
to assess endpoints in the clinical trial, concomitant products systematically prescribed to the 
study patients, and background treatment. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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 (SUSAR), to 
the regulatory authorities, independent ethics committee (IECs)/institutional review boards 
(IRBs) as appropriate and to the Investigators.  
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• The following AESIs to those regulatory authorities who require such reporting: 
- 
ALT >3 ULN (if baseline ALT < ULN), or ALT ≥2 times the baseline value (if 
baseline ALT ≥ ULN), 
- 
Allergic events that require consultation with another physician, 
- 
Local injection site reactions that require consultation with another physician, 
- 
Pregnancy, 
- 
Symptomatic overdose with IMP alirocumab, 
- 
Neurologic events that require additional examinations/procedures and/or referral to a 
specialist, 
- 
Neurocognitive events, 
- 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this 
protocol will be considered as unexpected. 
Adverse events that are considered expected will be specified by the reference safety information.  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 


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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.  
10.6.2 Allergic adverse events  
Specific e-CRF 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 documented on the General Allergic adverse event and/or Local 
Injection Site Reaction Complementary Form. 
All local injection site reactions 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 the specific General Allergic 
adverse event and/or Local Injection Site Reaction Complementary form should be completed. 
The IMP should be immediately interrupted (temporarily discontinued) if there is a suspicion of 
an allergic event related to IMP. See Section 10.3.1 for further information on treatment 
interruption and Section 10.3.2 for criteria for permanent treatment discontinuation. 
10.6.2.1 Allergic adverse event with cutaneous involvement  
Adverse events with cutaneous involvement which are obviously of allergic origin or injection 
site reactions which progress/expand/worsen/etc should be evaluated by a dermatologist as soon 
as possible, and preferably within one week of the site first becoming aware of the event. 
The Investigator should evaluate the patient for possible etiologies (new medications, etc) and 
extracutaneous symptoms and signs. An unscheduled 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 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 


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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 randomization visit. Patients should be treated symptomatically if any AEs 
are observed. Patients are to remain at the site until any acute injection reaction is assessed as 
stable, per the Investigator’s discretion. General Allergic Reaction and/or Local Injection Site 
Reaction Complementary Form will have to be completed. 
10.6.2.3  Independent physician monitoring for patients reaching LDL-C levels <50 mg/dL 
(1.30 mmol/L) during the double-blind treatment period and recommendations for 
the Investigator in case of an alert  
An independent physician, that is external to the EFC14643 clinical trial team, will be notified by 
the central laboratory of LDL-C values reaching <50 mg/dL (1.30 mmol/L). The independent 
physician will have access to patient information during the double-blind treatment period that the 
Sponsor’s EFC14643 study team will not have any access to. The independent physician will get 
central laboratory results. The independent physician will review the case in detail including 
unmasked LDL-C values and patient safety data. Based upon the clinical judgment of the 
independent physician, and after consulting with the DMC, the central laboratory may be 
instructed to send a site alert for corresponding patient. If no site alert is deemed needed, then the 
independent physician will continue to closely monitor the patient's data throughout the 
double-blind treatment period and may consider instructing the central lab to issue an alert at any 
time after discussions with the DMC. Further details of this monitoring and responsibilities will 
be thoroughly described in the independent physician related documents and the DMC charter. 
If the site receives an alert, the Investigator should follow the recommend steps as outlined below: 
• Call the patient as soon as possible to inquire about interval occurrence of AEs, 
particularly any AEs related to visual problems. 


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• 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 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, 
- 
 Assess the need for study treatment temporary or permanent discontinuation, or 
continuation. Regardless of the action taken regarding study 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. 
10.6.2.4 Recommendations for managing and monitoring patients with very low LDL-C 
levels (ie, LDL-C<50 mg/dL [1.30 mmol/L]) during the open label treatment period  
If a patient achieves a very low LDL-C level (ie, LDL-C<50 mg/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,  
- 
Assess the need for alirocumab treatment temporary or permanent discontinuation, or 
maintenance of the dose or down-titration (if possible) of the dose.  
- 
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. 


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11 
STATISTICAL CONSIDERATIONS  
11.1 
DETERMINATION OF SAMPLE SIZE  
Each alirocumab dosing regimen group will be compared to its contemporaneously randomized 
placebo group (ie, of the same dosing regimen cohort) as follows: 
• alirocumab Q2W versus placebo Q2W 
• alirocumab Q4W versus placebo Q4W. 
Of note, Q2W and Q4W refer to the dosing regimens initiated at randomization. 
Multiplicity will be controlled using Bonferroni adjustment, hence using a two-sided alpha level 
of 0.025 for each comparison. 
With a randomization ratio of 2:1 (alirocumab: placebo) for each dosing regimen cohort, a total 
sample size of 90 patients (30 in each alirocumab dosing regimen group and 15 in each placebo 
dosing regimen group) will have 92% power to detect a difference in mean percent change in 
LDL-C of 30% between each alirocumab dosing regimen group and its contemporaneously 
randomized placebo dosing regimen group, with a 0.025 two-sided significance level per 
comparison and assuming a common standard deviation (SD) of 25%. 
Nevertheless, to have a sufficient number of pediatric patients for properly assessing the safety 
and tolerability of alirocumab, sample size was increased to 150 patients in total (50 in each 
alirocumab dosing regimen group and 25 in each placebo dosing regimen group). The enrollment 
of 150 patients will allow having a safety assessment over 2 years in approximately 128 patients, 
assuming a discontinuation rate of 15%. 
Calculations were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS  
Screened patients are defined as any patient who signed the informed consent. 
Randomized patients consist of all screened patients, with a double-blind treatment kit number 
allocated and recorded in the IRT database, regardless of whether the treatment kit was used or 
not. Patients treated without being randomized or treated with a double-blind treatment kit before 
the randomization will not be considered as randomized and will not be included in any analysis 
population. The safety experience of patients treated and not randomized will be reported 
separately. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 


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11.3 
ANALYSIS POPULATIONS  
11.3.1 Efficacy populations  
The primary efficacy analysis population will be the ITT population as defined below.  
11.3.1.1 Intent-to-treat population  
The ITT population is defined as all randomized patients.  
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment).  
11.3.1.2 Modified intent-to-treat population  
The mITT population is defined as all randomized patients who actually received at least one dose 
or partial dose of double-blind Investigational Medicinal Product (IMP). 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization.  
11.3.2 Safety population  
The safety analysis will be performed on the safety population. The safety population consists of 
the randomized population who did actually receive at least one dose or partial dose of 
investigational product.  
Patients in the safety population will be analyzed according to the treatment actually received.  
In addition:  
• Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• For patients receiving more than 1 study treatment during the trial, the treatment group 
allocation for as-treated analysis will be the one to which the patient was treated with the 
longest duration.  
11.3.3 Other analysis population  
The anti-alirocumab antibody analysis will be performed on all treated patients (safety population) 
with a blood sample on Week 0 (baseline) and at least one evaluable blood sample for antibodies 
post first double-blind IMP injection. 


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The PK analysis will be performed on all randomized and treated patients (safety population) with 
at least one available PK sample post first double-blind IMP injection. 
The analysis of the open label extension (OLE) data will be performed on the OLE population 
defined as patients who did actually receive at least one dose or partial dose of investigational 
product during the open label treatment period. 
11.4 
STATISTICAL METHODS  
This section describes the statistical methods for the analysis of the double-blind treatment period. 
The statistical methods for the analysis of the open label treatment period will be described in the 
statistical analysis plan (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 treatment received within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure  
The total exposure will be assessed by:  
• Duration of IMP exposure in weeks defined as: 
- 
For the Q2W dosing regimen cohort: (last dose of double-blind IMP injection date - 
first dose of double-blind IMP injection date + 14 days)/7, regardless of unplanned 
intermittent discontinuations. 
- 
For the Q4W dosing regimen cohort: (last dose of double-blind IMP injection date - 
first dose of double-blind IMP injection date + 28 days for patients who stopped 
definitively the IMP before the switch to Q2W regimen at Week 12 (actual or sham), 
+14 days otherwise)/7, regardless of unplanned intermittent discontinuations. 
• The total number of injections by patient. 
The number (n) and percentage (%) of patients with an up-titration in the alirocumab groups will 
be described. 
11.4.1.2 Compliance  
Compliance will be assessed using the following parameters: 
• The injection frequency will be defined for each patient as the average number of days 
between 2 double-blind injections, that is: (last double-blind dose date - first double-blind 
dose date)/(number of double-blind injections -1). 
This parameter will be summarized descriptively (N, Mean, SD, Median, Min and Max). 


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11.4.2 Analyses of efficacy endpoints  
In the double-blind period, statistical analyses for the primary and secondary efficacy endpoints 
will compare each alirocumab dosing regimen group versus its contemporaneously randomized 
placebo group (ie, of the same dosing regimen cohort) as follows: 
• alirocumab Q2W versus placebo Q2W 
• alirocumab Q4W versus placebo Q4W 
Of note, Q2W and Q4W refer to the dosing regimens initiated at randomization. 
Efficacy endpoints analyzed with the ITT estimand will be analyzed in the ITT population. 
Efficacy endpoints analyzed with the on-treatment estimand will be analyzed in the mITT 
population. 
Analyses of the efficacy parameters during the extension period will be only descriptive.  
11.4.2.1 Analysis of primary efficacy endpoint(s)  
The percent change from baseline in LDL-C (see Section 9.1) to Week 24 will be analyzed using 
a MMRM model within each dosing regimen cohort. All post-baseline data available within 
Week 8 to Week 24 analysis windows will be used and missing data will be accounted for by the 
MMRM model. 
For the Q2W dosing regimen cohort, the model will include the fixed categorical effects of 
treatment group (alirocumab, placebo), randomization strata (previous participation [yes or no] to 
DFI14223 study, baseline body weight [<50 or ≥50 kg]), time point (Week 8, Week 12, 
Week 24), treatment-by-time point interaction, and strata-by-time point interaction, as well as the 
continuous fixed covariates of baseline LDL-C value and baseline value-by-time point interaction. 
The same model will be run for the Q4W dosing regimen cohort except that strata related to the 
previous participation in the DFI14223 Phase 2 study will not be included in the model, as too few 
patients from this Phase 2 study are enrolled in the Q4W dosing regimen cohort due to the late 
start of enrollment in this cohort. 
 Model assumptions for normality will be explored prior to the analysis testing.  
These two models 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. 
Throughout the MMRM models, least-square (LS) mean and standard error (SE) at Week 24 will 
be provided for each treatment group within each dosing regimen cohort and LS means difference 
will be provided for the comparison of each alirocumab dosing regimen group versus its 
contemporaneously randomized placebo group (ie, of the same dosing regimen cohort), with the 
SE, 97.5% confidence interval (CI) and p-value, using appropriate contrasts.  


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Robustness of this statistical method will be assessed via sensitivity analysis detailed in the SAP, 
applying different imputations for missing LDL-C values during the treatment period and missing 
LDL-C values during the post-treatment period (ie pattern mixture model). 
11.4.2.2 Analyses of secondary efficacy endpoints  
Multiple types of measurements are planned to be analyzed (see Section 9.2) during differing time 
points in the trial, specifically continuous measurements expected to have a normal distribution 
(example: percent change in LDL-C), continuous measurements expected to have a non-normal 
distribution (example: TG), and binary measurements (example: proportion of patients achieving 
a LDL-C <130 mg/dL). 
Continuous endpoints anticipated to have a normal distribution 
Continuous secondary efficacy endpoints analyzed with the ITT estimand and anticipated to have 
a normal distribution (ie, lipids other than TG and Lp(a)) will be analyzed within each dosing 
regimen cohort, using the same MMRM models as for the primary endpoint with the 
corresponding baseline and post-baseline values.  
Continuous secondary efficacy endpoints analyzed with the on-treatment estimand and anticipated 
to have a normal distribution will be analyzed using the same MMRM models within each dosing 
regimen cohort, but only including on-treatment values. The treatment period is defined as: 
• For the Q2W dosing regimen cohort, the time period from the first double-blind IMP 
injection up to the day of last double-blind IMP injection +21 days. 
• For the Q4W dosing regimen cohort, the time period from the first double-blind IMP 
injection up to the day of last double-blind IMP injection +35 days for patients who 
stopped definitively the IMP before the switch to Q2W regimen at Week 12 (actual or 
sham), +21 days otherwise. 
Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints analyzed with the ITT estimand and anticipated to have 
a non-normal distribution (ie, TG and Lp(a)), will be analyzed using a robust regression model 
(ie, ROBUSTREG SAS procedure with M-estimation option). 
For the Q2W dosing regimen cohort, the model will include treatment group (alirocumab, 
placebo) and randomization strata (previous participation [yes or no] to Phase 2 DFI14223 study, 
baseline body weight [<50 or ≥50 kg]) as main effects and corresponding baseline value as 
covariate. 
For the Q4W dosing regimen cohort, the model will include treatment group and randomization 
strata (baseline body weight [<50 or ≥50 kg]) as main effects and corresponding baseline value as 
covariate. 
 Missing values will be addressed using a multiple imputation approach, which will be described 
in the SAP. The imputation model will at least include the variables included in the robust 


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regression model. The treatment group combined means will be provided with respective SE 
estimates. The combined mean difference between the treatment groups will be provided with the 
SE, 97.5% CI and p-value. 
Continuous secondary efficacy endpoints analyzed with the on-treatment estimand and anticipated 
to have a non-normal distribution will be analyzed using the same imputation and analysis models 
within each dosing regimen cohort but only including on-treatment values in these models. 
Binary endpoints 
Binary secondary efficacy endpoints analyzed with the ITT estimand will be analyzed using 
stratified logistic regression. 
For the Q2W dosing regimen cohort, the model will include treatment group (alirocumab, 
placebo) as main effect and corresponding baseline value as covariate, stratified by randomization 
factors (previous participation [yes or no] to DFI14223 study, baseline body weight [<50 or 
≥50 kg]). 
For the Q4W dosing regimen cohort, the model will include treatment group (alirocumab, 
placebo) as main effect and corresponding baseline value as covariate, stratified by randomization 
factor (baseline body weight [<50 or ≥50 kg]).  
Missing values will be addressed using a multiple imputation approach which will be described in 
the SAP. The imputation model will at least include the variables included in the logistic 
regression model. Treatment effects (within each dosing regimen cohort) will be compared and 
the combined odds ratio estimate between the treatment groups, with their corresponding 
97.5% CIs and p-value will be provided. 
In the data dependent case that the logistic regression method is not applicable (eg, the response 
rate is zero in 1 treatment group and thus the maximum likelihood estimate may not exist), the 
Last Observation Carried Forward (LOCF) approach would be used for handling of missing 
values and a stratified exact conditional logistic regression would be performed to compare 
treatment effects. 
Binary secondary efficacy endpoints analyzed with the on-treatment estimand will be analyzed 
using the same imputation and analysis models within each dosing regimen cohort but only 
including on-treatment values in these models. 
In addition, the difference in terms of percent change from baseline in LDL-C between the 
2 alirocumab dosing regimen groups will be explored. 
Analyses of the efficacy parameters during the extension period will be only descriptive.  
11.4.2.3 Multiplicity considerations  
The Bonferroni adjustment will be applied to handle multiplicity for the comparison of each 
alirocumab dosing regimen group versus its contemporaneously randomized placebo group 


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(ie, alirocumab Q4W versus placebo Q4W and alirocumab Q2W versus placebo Q2W) for the 
primary efficacy endpoint (0.025 two-sided alpha level will apply for each comparison). 
In order to handle multiple key secondary endpoints, the overall Type-I error will be controlled by 
the use of a sequential inferential approach applied independently within each dosing regimen 
cohort (Q2W and Q4W). Statistical significance of the primary parameter at the 2-sided 
0.025 alpha level is required before drawing inferential conclusions for that dosing regimen cohort 
about first key secondary parameter (refer to order of list in Section 9.2.1). Inferential conclusions 
about successive key secondary parameters for a given dosing regimen cohort require statistical 
significance of the prior one in that dosing regimen cohort.  
The Bonferroni adjustment and this fixed hierarchical approach will ensure a strong control of the 
overall Type-I error rate for the study at the 0.05 level. 
No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only (no claim).  
11.4.3 Analyses of safety data  
The summary of safety results (see Section 9.2.4) will be presented by treatment group (placebo, 
alirocumab) within each dosing regimen cohort, and by treatment group regardless of the dosing 
regimen cohorts (pooled across the cohorts). 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 double-blind IMP 
injection. 
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: 
- 
For the Q2W dosing regimen cohort, as the time from first dose of double-blind IMP 
injection to the last dose of double-blind IMP injection +21 days. 
- 
For the Q4W dosing regimen cohort, as the time from first dose of double-blind IMP 
injection to the last dose of double-blind IMP injection +35 days for patients who 
stopped definitively the IMP before the switch to Q2W regimen at Week 12 (actual or 
sham), +21 days otherwise 


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Adverse event (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, AP and total bilirubin, are used to assess possible drug-
induced liver toxicity. The proportion of patients with PCSA values at any post-baseline visit by 
baseline status will be displayed by treatment group for each parameter. A graph of distribution of 
peak values of ALT versus peak values of total bilirubin will also be presented. Note that the ALT 
and total bilirubin values are presented on a logarithmic scale. The graph will be divided into 
4 quadrants with a vertical line corresponding to 3 x ULN for ALT and a horizontal line 
corresponding to 2 x ULN for total bilirubin. 
The incidence of liver-related AEs will be summarized by treatment group. The selection of PT 
will be based on standardized MedDRA query (SMQ) Hepatic disorder.  
11.4.3.1 Adverse events  
Adverse event incidence tables will present by 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 and grouping of terms (prespecified grouping eg, Allergic 
events, LISR), all treatment-emergent SAEs and all TEAEs leading to permanent treatment 
discontinuation. 
Deaths: 
The following deaths summaries will be generated: 
• Number (%) of patients who died by study period (TEAE, onstudy, post-study) 
summarized on the safety population by treatment received. 
• Death in non-randomized patients or randomized and not treated patients. 
• TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT. 


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11.4.3.2 Laboratory data and vital signs  
The summary statistics (including mean, median, Q1, Q3, standard error, minimum and 
maximum) of all laboratory variables, all vital signs parameters (raw data and changes from 
baseline) will be calculated for each visit, last and worst value assessed during the treatment 
period and presented by treatment group. For selected parameters, mean changes from baseline 
with the corresponding standard error will be plotted over time (at same time points) in each 
treatment group. 
The incidence of PCSAs at any time during the TEAE period (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. 
High-sensitivity-CRP (value and percent change from baseline) at Week 24 will be summarized 
on the safety population using number of available data, mean, SD, median, Q1, Q3, minimum, 
and maximum for each treatment group. In addition, the incidence of PCSA at any time during the 
TEAE period will be summarized by treatment group using descriptive statistics. 
Further details on the analyses of laboratory parameters will be provided in SAP. 
11.4.3.3 Cogstate battery test  
Cognitive scores (including by domains: Detection Test [DET; Psychomotor Function], 
Identification Test [IDN; Attention]; One Card Learning Test [OCL; Visual Learning]; Groton 
Maze Learning Task [GML; Executive Function]) will be described by treatment group on the 
safety population. 
11.4.4 Other endpoints  
The summary of other endpoints (for definitions see Section 9.3) will be presented by treatment 
group (placebo, alirocumab) within each dosing regimen cohort. A summary by treatment group 
regardless of the dosing regimen cohorts (pooled across the cohorts) will be also displayed, except 
for pharmacokinetics and anti-alirocumab antibody assessments.  
11.4.4.1 Pharmacokinetics  
Serum total alirocumab concentrations, total and free PCSK9 concentrations will be summarized 
by treatment group and visit using descriptive statistics. Serum concentration time profiles will be 
provided by treatment group. Further details will be provided in the SAP. 


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Serum total alirocumab concentrations might be used for population PK modeling if considered 
necessary and the results of population PK modeling will be reported separately from the study 
report. 
11.4.4.2 Anti-alirocumab antibody assessments  
The antibody status (positive/negative) and antibody titers will be summarized by treatment group 
and visit using descriptive statistics. If appropriate, correlations between antibody titers, safety 
and/or efficacy endpoints will be provided. 
11.4.4.3 LDL-C less than 50 mg/dL (1.30 mmol/L)  
The number and percentage of patients with two consecutives results, spaced out by at least  
21 days, of calculated LDL-C <50 mg/dL (1.30 mmol/L), calculated LDL-C <25 mg/dL 
(0.65 mmol/L), calculated LDL-C <15 mg/dL (0.39 mmol/L) and the time to the 
first LDL-C <50 mg/dL (1.30 mmol/L) respectively, will be provided by treatment group. 
Further details will be provided in SAP. 
11.4.4.4 Urinalysis  
The proportion of patients with at least one finding of proteinuria, hematuria or an abnormality on 
urine microscopy during the TEAE period will be summarized by treatment group using 
descriptive statistics. 
11.4.4.5 CPK-MB and troponin  
CPK-MB and troponin (value and percent change from baseline) at Week 24 will be summarized 
on the safety population using number of available data, mean, SD, median, Q1, Q3, minimum, 
and maximum for each treatment group. In addition, the incidence of PCSA at any time during the 
TEAE period will be summarized by treatment group using descriptive statistics. 
11.5 
TWO-STEP ANALYSIS  
The analyses will be conducted in 2 steps (see details in Section 6.3). The first analysis would not 
be conducted before completion of the double-blind treatment period.  
Since the double-blind primary and key secondary efficacy analyses will have been concluded at 
the time of the first analysis, the overall significance level remains at 0.05 for the 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, and delegated Investigator 
staff and Sub-Investigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the 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. 
Prior to collection of blood for genotyping for heFH and/or for use of previous documented 
genotyping, the optional informed consent section within the main informed consent form 
(written) should be signed, name filled in, and personally dated by the patient or by the subject’s 
legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written optional informed consent form will be 
provided to the subject. 
The informed consent form and the optional genotyping informed consent obtained 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 
HEALTH AUTHORITIES AND 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 health authorities (competent regulatory authority) and 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 with any 
addenda or labeling documents summary of product characteristics, package insert, Investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The 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 health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They 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 


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sent to the IRB/IEC and to health authorities (competent regulatory authority), as required by 
local regulation. 
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 e-CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
Investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-Investigators shall be appointed and listed in a timely manner. The Sub-
Investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR  
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the e-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. Source document requirements. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in separate study documents. 


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13.3 
SOURCE DOCUMENT REQUIREMENTS  
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-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 e-CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST  
It is the responsibility of the Investigator to maintain adequate and accurate e-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 trial master file. 


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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 Sub-Investigator 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, 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 Sub-Investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-Investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-Investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 


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14.4 
PROPERTY RIGHTS  
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Sub-Investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-Investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION  
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
• 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, 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 
• Noncompliance of the Investigator or Sub-Investigator, 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 are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 


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14.8.2 By the Investigator  
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS  
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). The 
Sponsor has the right at any time to publish the results of the study. 


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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS  
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to 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 
BIBLIOGRAPHIC REFERENCES  
1. De Jongh S, Lilien MR, op’t Roodt J, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy 
restores endothelial function in children with familial hypercholesterolemia. J Am Coll 
Cardiol. 2002;40:2117-21. 
2. Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, et al. Arterial intima-
media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 
2004;363:369-70. 
3. Sankatsing RR, de Groot E, Jukema JW, de Feyter PJ, Pennell DJ, Schoenhagen P, et al. 
Surrogate markers for atherosclerotic disease. Curr Opin Lipidol. 2005;16:434-41. 
4. Newman WP 3rd, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, et al. 
Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The 
Bogalusa Heart Study. N Engl J Med. 1986;314:138-44. 
5. Stein AE, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a 
monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl J Med. 2012;366:1108-18. 
6. McGill HC Jr, McMahan CA, Zieske AW, Sloop GD, Walcott JV, Troxclair DA, et al. 
Associations of coronary heart disease risk factors with the intermediate lesion of 
atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth 
(PDAY) Research Group. Arterioscler Thromb Vasc Biol. 2000;20:1998-2004. 
7. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and 
efficacy of a monoclonal antibody to proprotein convertase Subtilisin/Kexin Type 9 serine 
protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving 
ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344-53. 
8. McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: 
implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. 
Circulation. 2008;117:1216-27. 
9. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low 
LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72. 
10. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546-7. 
11. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet 
AL, Valle D, Sly WS, editors. The metabolic and molecular bases of inherited disease. 8th ed. 
New York( NY): McGraw-Hill; 2001. p. 2863-913. 
12. Wiegman A, Gidding SS, Watts GF, Chapman NJ, Ginsberg HN, Cuchel M, et al. Familial 
hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing 
detection and treatment. Eur Heart J. 2015;36:2425-37. 


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EFC14643 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 117 
13. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. 
Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the 
American Heart Association Expert Panel on population and prevention science; the Councils 
on cardiovascular disease in the young, epidemiology and prevention, nutrition, physical 
activity and metabolism, high blood pressure research, cardiovascular nursing, and the kidney 
in heart disease; and the Interdisciplinary Working Group on quality of care and outcome 
research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114:2710-38. 
14. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, et al. 
Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific 
statement from the American Heart Association atherosclerosis, Hypertension, and Obesity in 
Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on 
Cardiovascular Nursing. Circulation. 2007;115:1948-67. 
15. NICE clinical guideline. Identification and management of familial hypercholesterolemia. 
London: National Institute for Health and Clinical Excellence. 2008. 
16. National Cholesterol Education Program (NCEP): highlights of the report of the expert panel 
on blood cholesterol levels in children and adolescents. Pediatrics. 1992;89:495-501. 
17. American Academy of Pediatrics. Committee on Nutrition. Cholesterol in childhood. 
Pediatrics. 1998;101:141-7. 
18. Daniels SR, Gidding SS, de Ferranti SD, National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations 
from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin 
Lipidol. 2011;5:S30-7. 
19. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Büller HR, et al. Efficacy and 
safety of statin therapy in children with familial hypercholesterolemia: a randomized 
controlled trial. JAMA. 2004;292:331-7. 
20. Stein EA, Illingworth DR, Kwiterovich PO Jr, Liacouras CA, Siimes MA, Jacobson MS, et al. 
Efficacy and safety of lovastatin in adolescent males with heterozygous familial 
hypercholesterolemia: a randomized controlled trial. JAMA. 1999;281:137-44. 
21. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and 
adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, 
randomized, placebo-controlled trial. J Pediatr. 2003;143:74-80. 
22. De Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, et al. Efficacy and safety of 
statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, 
placebo-controlled trial with simvastatin. Circulation. 2002;106:2231-7. 
23. Avis HJ, Hutten BA, Gagne C, Langslet G, McCrindle BW, Wiegman A, et al. Efficacy and 
safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll 
Cardiol. 2010;55:1121-6. 


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EFC14643 - alirocumab 
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Page 118 
24. Van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, et al. Efficacy 
and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous 
familial hypercholesterolemia. J Am Coll Cardiol. 2008;52:1421-9. 
25. Eiland LS, Luttrell PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr 
Pharmacol Ther. 2010;15:160-72. 
26. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial 
hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: 
clinical guidance from the National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. 
27. HHS.gov. OHRP expedited review categories (1998) [Online]. 2016 [cited 2017 Sep 19]. 
Available from: URL:https://www.hhs.gov/ohrp/regulations-and-policy/guidance/categories-
of-research-expedited-review-procedure-1998/index.html 
28. WHO. Blood sample volumes in child health research: review of safe limits [Online]. [cited 
2017 Sep 19]. Available from: URL:http://www.who.int/bulletin/volumes/89/1/BLT-10-
080010-table-T2.html 
29. European Union. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. Eur J Health Law. 2008;15(2):223-50. 
30. Allen KL, Byrne SM, Hii H, van Eekelen A, Mattes E, Foster JK. Neurocognitive functioning 
in adolescents with eating disorders: a population-based study. Cognitive Neuropsychiatry. 
2012. 
31. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45:13-23. 
32. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44:291-303. 
33. Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, et al. Arterial intima-
media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 
2004;363:369-70. 
34. Sankatsing RR, de Groot E, Jukema JW, de Feyter PJ, Pennell DJ, Schoenhagen P, et al. 
Surrogate markers for atherosclerotic disease. Curr Opin Lipidol. 2005;16:434-41. 
35. Newman WP 3rd, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, et al. 
Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The 
Bogalusa Heart Study. N Engl J Med. 1986;314:138-44. 
36. Stein AE, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a 
monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl J Med. 2012;366:1108-18. 


Amended Clinical Trial Protocol 03  
06-Jan-2021 
EFC14643 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 119 
37. McGill HC Jr, McMahan CA, Zieske AW, Sloop GD, Walcott JV, Troxclair DA, et al. 
Associations of coronary heart disease risk factors with the intermediate lesion of 
atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth 
(PDAY) Research Group. Arterioscler Thromb Vasc Biol. 2000;20:1998-2004. 
38. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and 
efficacy of a monoclonal antibody to proprotein convertase Subtilisin/Kexin Type 9 serine 
protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving 
ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344-53. 
39. McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: 
implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. 
Circulation. 2008;117:1216-27. 
40. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low 
LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72. 
41. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546-7. 
42. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet 
AL, Valle D, Sly WS, editors. The metabolic and molecular bases of inherited disease. 8th ed. 
New York( NY): McGraw-Hill; 2001. p. 2863-913. 
43. Wiegman A, Gidding SS, Watts GF, Chapman NJ, Ginsberg HN, Cuchel M, et al. Familial 
hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing 
detection and treatment. Eur Heart J. 2015;36:2425-37. 
44. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. 
Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the 
American Heart Association Expert Panel on population and prevention science; the Councils 
on cardiovascular disease in the young, epidemiology and prevention, nutrition, physical 
activity and metabolism, high blood pressure research, cardiovascular nursing, and the kidney 
in heart disease; and the Interdisciplinary Working Group on quality of care and outcome 
research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114:2710-38. 
45. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, et al. 
Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific 
statement from the American Heart Association atherosclerosis, Hypertension, and Obesity in 
Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on 
Cardiovascular Nursing. Circulation. 2007;115:1948-67. 
46. NICE clinical guideline. Identification and management of familial hypercholesterolemia. 
London: National Institute for Health and Clinical Excellence. 2008. 
47. National Cholesterol Education Program (NCEP): highlights of the report of the expert panel 
on blood cholesterol levels in children and adolescents. Pediatrics. 1992;89:495-501. 


Amended Clinical Trial Protocol 03  
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EFC14643 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 120 
48. American Academy of Pediatrics. Committee on Nutrition. Cholesterol in childhood. 
Pediatrics. 1998;101:141-7. 
49. Daniels SR, Gidding SS, de Ferranti SD, National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations 
from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin 
Lipidol. 2011;5:S30-7. 
50. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Büller HR, et al. Efficacy and 
safety of statin therapy in children with familial hypercholesterolemia: a randomized 
controlled trial. JAMA. 2004;292:331-7. 
51. Stein EA, Illingworth DR, Kwiterovich PO Jr, Liacouras CA, Siimes MA, Jacobson MS, et al. 
Efficacy and safety of lovastatin in adolescent males with heterozygous familial 
hypercholesterolemia: a randomized controlled trial. JAMA. 1999;281:137-44. 
52. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and 
adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, 
randomized, placebo-controlled trial. J Pediatr. 2003;143:74-80. 
53. De Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, et al. Efficacy and safety of 
statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, 
placebo-controlled trial with simvastatin. Circulation. 2002;106:2231-7. 
54. Avis HJ, Hutten BA, Gagne C, Langslet G, McCrindle BW, Wiegman A, et al. Efficacy and 
safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll 
Cardiol. 2010;55:1121-6. 
55. Van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, et al. Efficacy 
and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous 
familial hypercholesterolemia. J Am Coll Cardiol. 2008;52:1421-9. 
56. Eiland LS, Luttrell PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr 
Pharmacol Ther. 2010;15:160-72. 
57. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial 
hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: 
clinical guidance from the National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. 
58. HHS.gov. OHRP expedited review categories (1998) [Online]. 2016 [cited 2017 Sep 19]. 
Available from: URL:https://www.hhs.gov/ohrp/regulations-and-policy/guidance/categories-
of-research-expedited-review-procedure-1998/index.html 
59. WHO. Blood sample volumes in child health research: review of safe limits [Online]. [cited 
2017 Sep 19]. Available from: URL:http://www.who.int/bulletin/volumes/89/1/BLT-10-
080010-table-T2.html 


Amended Clinical Trial Protocol 03  
06-Jan-2021 
EFC14643 - alirocumab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
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60. European Union. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. Eur J Health Law. 2008;15(2):223-50. 
61. Allen KL, Byrne SM, Hii H, van Eekelen A, Mattes E, Foster JK. Neurocognitive functioning 
in adolescents with eating disorders: a population-based study. Cognitive Neuropsychiatry. 
2012. 
62. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45:13-23. 
63. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44:291-303.  
64. Wiegman A, de Groot E, Hutten BA, Rodenburg J, Gort J, Bakker HD, et al. Arterial intima-
media thickness in children heterozygous for familial hypercholesterolaemia. Lancet. 
2004;363:369-70. 
65. Sankatsing RR, de Groot E, Jukema JW, de Feyter PJ, Pennell DJ, Schoenhagen P, et al. 
Surrogate markers for atherosclerotic disease. Curr Opin Lipidol. 2005;16:434-41. 
66. Newman WP 3rd, Freedman DS, Voors AW, Gard PD, Srinivasan SR, Cresanta JL, et al. 
Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The 
Bogalusa Heart Study. N Engl J Med. 1986;314:138-44. 
67. Stein AE, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a 
monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl J Med. 2012;366:1108-18. 
68. McGill HC Jr, McMahan CA, Zieske AW, Sloop GD, Walcott JV, Troxclair DA, et al. 
Associations of coronary heart disease risk factors with the intermediate lesion of 
atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth 
(PDAY) Research Group. Arterioscler Thromb Vasc Biol. 2000;20:1998-2004. 
69. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and 
efficacy of a monoclonal antibody to proprotein convertase Subtilisin/Kexin Type 9 serine 
protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving 
ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59:2344-53. 
70. McGill HC Jr, McMahan CA, Gidding SS. Preventing heart disease in the 21st century: 
implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. 
Circulation. 2008;117:1216-27. 
71. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low 
LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-72. 
72. Steinberg D, Witztum JL. Inhibition of PCSK9: a powerful weapon for achieving ideal LDL 
cholesterol levels. Proc Natl Acad Sci U S A. 2009;106:9546-7. 


Amended Clinical Trial Protocol 03  
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Version number: 1 
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Page 122 
73. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet 
AL, Valle D, Sly WS, editors. The metabolic and molecular bases of inherited disease. 8th ed. 
New York( NY): McGraw-Hill; 2001. p. 2863-913. 
74. Wiegman A, Gidding SS, Watts GF, Chapman NJ, Ginsberg HN, Cuchel M, et al. Familial 
hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing 
detection and treatment. Eur Heart J. 2015;36:2425-37. 
75. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, et al. 
Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the 
American Heart Association Expert Panel on population and prevention science; the Councils 
on cardiovascular disease in the young, epidemiology and prevention, nutrition, physical 
activity and metabolism, high blood pressure research, cardiovascular nursing, and the kidney 
in heart disease; and the Interdisciplinary Working Group on quality of care and outcome 
research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114:2710-38. 
76. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, et al. 
Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific 
statement from the American Heart Association atherosclerosis, Hypertension, and Obesity in 
Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on 
Cardiovascular Nursing. Circulation. 2007;115:1948-67. 
77. NICE clinical guideline. Identification and management of familial hypercholesterolemia. 
London: National Institute for Health and Clinical Excellence. 2008. 
78. National Cholesterol Education Program (NCEP): highlights of the report of the expert panel 
on blood cholesterol levels in children and adolescents. Pediatrics. 1992;89:495-501. 
79. American Academy of Pediatrics. Committee on Nutrition. Cholesterol in childhood. 
Pediatrics. 1998;101:141-7. 
80. Daniels SR, Gidding SS, de Ferranti SD, National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. Pediatric aspects of familial hypercholesterolemias: recommendations 
from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin 
Lipidol. 2011;5:S30-7. 
81. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Büller HR, et al. Efficacy and 
safety of statin therapy in children with familial hypercholesterolemia: a randomized 
controlled trial. JAMA. 2004;292:331-7. 
82. Stein EA, Illingworth DR, Kwiterovich PO Jr, Liacouras CA, Siimes MA, Jacobson MS, et al. 
Efficacy and safety of lovastatin in adolescent males with heterozygous familial 
hypercholesterolemia: a randomized controlled trial. JAMA. 1999;281:137-44. 
83. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and 
adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, 
randomized, placebo-controlled trial. J Pediatr. 2003;143:74-80. 


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Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 123 
84. De Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, et al. Efficacy and safety of 
statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, 
placebo-controlled trial with simvastatin. Circulation. 2002;106:2231-7. 
85. Avis HJ, Hutten BA, Gagne C, Langslet G, McCrindle BW, Wiegman A, et al. Efficacy and 
safety of rosuvastatin therapy for children with familial hypercholesterolemia. J Am Coll 
Cardiol. 2010;55:1121-6. 
86. Van der Graaf A, Cuffie-Jackson C, Vissers MN, Trip MD, Gagné C, Shi G, et al. Efficacy 
and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous 
familial hypercholesterolemia. J Am Coll Cardiol. 2008;52:1421-9. 
87. Eiland LS, Luttrell PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr 
Pharmacol Ther. 2010;15:160-72. 
88. Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, Robinson JG, et al. Familial 
hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: 
clinical guidance from the National Lipid Association Expert Panel on Familial 
Hypercholesterolemia. J Clin Lipidol. 2011;5:S1-8. 
89. HHS.gov. OHRP expedited review categories (1998) [Online]. 2016 [cited 2017 Sep 19]. 
Available from: URL:https://www.hhs.gov/ohrp/regulations-and-policy/guidance/categories-
of-research-expedited-review-procedure-1998/index.html 
90. WHO. Blood sample volumes in child health research: review of safe limits [Online]. [cited 
2017 Sep 19]. Available from: URL:http://www.who.int/bulletin/volumes/89/1/BLT-10-
080010-table-T2.html 
91. European Union. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. Eur J Health Law. 2008;15(2):223-50. 
92. Allen KL, Byrne SM, Hii H, van Eekelen A, Mattes E, Foster JK. Neurocognitive functioning 
in adolescents with eating disorders: a population-based study. Cognitive Neuropsychiatry. 
2012. 
93. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45:13-23. 
94. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44:291-303. 
 


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17 
APPENDICES  
Appendix A 
Simon Broome register diagnostic criteria for heterozygous familial 
hypercholesterolemia  
Definite familial hypercholesterolemia is defined as: 
• Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult (Levels either pre-treatment or highest on treatment). 
PLUS 
• Tendon xanthomas in patient, or in 1st degree relative (parent, sibling, child), or in 
2nd degree relative (grandparent, uncle, aunt). 
OR 
• DNA-based evidence of an LDL receptor mutation or familial defective Apo B-100. 
Possible familial hypercholesterolemia is defined as: 
• Total-C >6.7 mmol/L (260 mg/dL) or LDL cholesterol above 4.0 mmol/L (155 mg/dL) in 
a child <16 years or Total-C >7.5 mmol/L (290 mg/dL) or LDL cholesterol above 
4.9 mmol/L (190 mg/dL) in an adult (Levels either pre-treatment or highest on treatment). 
And at least one of the following: 
• Family history of MI below 50 years of age in 2nd degree relative or below 60 years of 
age in 1st degree relative. 
• Family history of raised cholesterols >7.5 mmol/L (290 mg/dL) in adult 1st or 2nd degree 
relative or >6.7 mmol/L (260 mg/dL) in child or sibling under 16 years of age. 


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Appendix B 
Tanner stages  
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 (1, 2). 
• Boys - development of external genitalia 
- 
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and 
proportion as in early childhood. 
- 
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of 
the scrotal skin. There is also some reddening of the scrotal skin. 
- 
Stage 3: Growth of the penis has occurred, at first mainly in length but with some 
increase in breadth. There has been further growth of testes and scrotum. 
- 
Stage 4: Penis further enlarged in length and breadth with development of glans. 
Testes and scrotum further enlarged. There is also further darkening of the scrotal skin. 
- 
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after 
Stage 5 is reached. 
• Girls - breast development 
- 
Stage 1: Pre-adolescent; elevation of papilla only. 
- 
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, 
enlargement of areola diameter. 
- 
Stage 3: Further enlargement of breast and areola, with no separation of their contours. 
- 
Stage 4: Projection of areola and papilla to form a secondary mound above the level of 
the breast. 
- 
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the 
general contour of the breast.  
• Boys/Girls - pubic hair 
- 
Stage 1: Pre-adolescent; the vellus over the pubes is not further developed than that 
over the anterior abdominal wall, ie, no pubic hair. 
- 
Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only 
slightly curled, appearing chiefly at the base of the penis (boys) or along the labia 
(girls).  
- 
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over 
the junction of the pubes.  
- 
Stage 4: Hair is now adult in type, but the area covered by it is still considerably 
smaller than in most adults. There is no spread to the medial surface of the thighs. 
- 
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically 
feminine pattern (girls). Spread to the medial surface of the thighs, but not up the linea 
alba or elsewhere above the base of the inverse triangle. 


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BIBLIOGRAPHIC REFERENCES 
1. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45:13-23. 
2. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis 
Child. 1969;44:291-303. 
 


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Appendix C 
Cogstate battery test  
The Cogstate battery test will include a detection test, identification test, one card learning test, 
and Groton maze learning test. These individual tests assess maturing cognition across a broad 
number of key developmental functions such as processing speed, attention, visual learning and 
executive functioning, respectively. Details of the Cogstate battery test are provided in the 
description subsection below. Briefly, the battery of tests is administered by trained clinical site 
personnel and will take the patient approximately 16 to 19 minutes to complete. It will be 
administered electronically and is standardized. The results will be automatically calculated. The 
results will not be used for detection of adverse events and will not trigger further consultation or 
investigation. 
Cogstate battery test description: 
• Detection (DET; Psychomotor Function) 
The Detection test is a measure of psychomotor function and uses a well-validated simple 
reaction time paradigm with playing card stimuli. In this test, the playing cards all depict 
the same joker. The subject is asked to press the Yes key as soon as the card in the center 
of the screen turns face up. The software measures the speed and accuracy of each 
response.  
Duration of Test: 3 minutes 
• Identification (IDN; Attention) 
The Identification test is a measure of visual attention and uses a well-validated choice 
reaction time paradigm with playing card stimuli. In this test, the playing cards are all 
either red or black jokers. The subject is asked whether the card displayed in the center of 
the screen is red. The subject responds by pressing the Yes key when the joker card is red 
and No when it is black. The software measures the speed and accuracy of each response. 
Duration of Test: 3 minutes 
• One Card Learning (OCL; Visual Learning) 
The One Card Learning test is a measure of visual learning and uses a well-validated 
pattern separation paradigm with playing card stimuli. In this test, the playing cards are 
identical to those found in a standard deck of 52 playing cards (without the joker cards). 
The subject is asked whether the card displayed in the center of the screen was seen 
previously in this test. The subject responds by pressing the Yes or No key. The software 
measures the speed and accuracy of each response.  
Duration of Test: 6 minutes 


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• The Groton Maze Learning Test (GML; Executive Function) 
The Groton Maze Learning test is a measure of problem solving and reasoning and uses a 
well-validated maze learning paradigm. In this test, the subject is shown a 10 × 10 grid of 
boxes on a computer screen. A 28-step pathway is hidden among these 100 possible 
locations. Each box represents move locations, and the grid refers to the box array 
(ie, 10 × 10). Subjects are required to find the hidden pathway guided by four search rules. 
These rules are: do not move diagonally, do not move more than one box (ie, do not 
jump), do not move back on the pathway, and return to the last correct location after an 
error. At each step only the most recently selected box is shown. Feedback is given with 
visual and auditory cues (green check marks and red crosses) to indicate whether the 
selected box is correct or incorrect. The head of path, or the last correct location, flashes 
with a green check when two errors are made in succession to indicate to the subject that 
they must return to this location. There are [20] well-matched alternate pathways 
available. The software records each move as an error or as a correct move.  
Duration of Test: 7 minutes 


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Appendix D 
Guidance on contraceptive methods and collection of pregnancy 
information  
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Sexual counseling should be provided to patients when indicated. 
Female subjects: 
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly6 
• Combined (estrogen- and progestogen-containing ) hormonal contraception associated 
with inhibition of ovulation: 
- 
Oral, 
- 
Intravaginal, 
- 
Transdermal. 
• Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral, 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
• Intrauterine device (IUD). 
• Intrauterine hormone-releasing system (IUS). 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the subject. 
                                                 
6 Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for subjects participating in 
clinical studies. 


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COLLECTION OF PREGNANCY INFORMATION 
Female subjects who become pregnant 
• The Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. 
• Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. 
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 
• In this study pregnancy is considered to be an AESI and will be reported as such, any 
pregnancy complication or elective termination of a pregnancy will be reported as an AE 
or SAE. 
• A spontaneous abortion is always considered to be an SAE and will be reported as such. 
• Any SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting. 
Male subjects with partners of reproductive potential who become pregnant 
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. This applies 
only to subjects who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
• Partner will also be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. 
• Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status (presence 
or absence of anomalies) or indication for procedure. 


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Appendix E 
Flow mediated dilatation exploratory sub-study of EFC14643 
protocol  
Protocol Number: Exploratory Sub-study of EFC14643 Protocol: Flow Mediated Dilatation 
(FMD) Sub-study 
SUBSTUDY PROTOCOL ACKNOWLEDGEMENT 
I have read this exploratory sub-study of EFC14643 protocol: FMD sub-study, and understand 
that it and an accompanying additional informed consent must be reviewed by the Institutional 
Review Board/Ethics Committee overseeing the conduct of the study and approved or given 
favorable opinion before implementation. 
Introduction 
The healthy endothelium plays a principal role in keeping arterial homoeostasis. Many of its 
functions are controlled by the bioavailability of nitric oxide, including inflammation, adhesion, 
coagulation, smooth muscle cell proliferation, and vasomotion (1). The vascular endothelial layer 
has anti-atherogenic properties. However, this physiological atheroprotective function of the 
endothelium can be diminished in the presence of atherosclerotic risk factors and toxic substances 
and conditions (2). The diminution of endothelial function may play a role in atherogenesis, which 
may occur before structural and clinical atherosclerosis (3). In addition to being an early event in 
atherogenesis, endothelial dysfunction is influential in the later stages of atherosclerotic diseases, 
predisposing individuals to complications, such as thrombotic events. Endothelial dysfunction is 
characterized by reduced bioavailability of nitric oxide through decreased production and/or 
increased degradation of nitric oxide. Even with adequate production, nitric oxide may not reach 
its biological targets (vascular smooth muscle and circulating cells) to exert its effect because of 
the lack of its bioavailability. In hyperlipidemia, excess LDL synthesis increases the formation of 
oxidized LDL. The resultant increase of oxidative stress enhances nitric oxide destruction, thereby 
reducing its biological effects and attenuating endothelium-dependent vasodilation (4).  
Flow-mediated dilatation (FMD) measures the vasomotor effects of this modification in the 
phenotype of the arterial wall and can therefore be used to study the vascular biology of 
atherosclerosis as it progresses from childhood (5). Over the past several decades, a noninvasive 
technique has matured to evaluate FMD, an endothelium-dependent function, in the brachial 
artery. This stimulus incites the endothelium to release nitric oxide (NO) with resultant 
vasodilation that can be imaged and quantitated as an index of vasomotor function (6). The use of 
ultrasound to assess FMD is noninvasive, and safe and has been applied in prior clinical trial in a 
similar setting (7). The test is based on the measurement of the brachial artery diameter at baseline 
and after an increase in blood flow caused by inflating and then deflating a forearm blood pressure 
cuff. In this test, the proportional increase in luminal diameter induced by hyperemia is calculated 
and used as a marker of systemic endothelial function.  
In the general population, several risk factors that are associated with CVD such as hypertension, 
diabetes, hyperlipidemia, hyperhomocysteinemia, inflammation, advanced age, and cigarette 
smoking have been associated with impairment in FMD prior to vascular disease (8). 


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Improvement in endothelial function has been noted following statin treatment in adults with 
coronary artery disease and in asymptomatic patients with cardiovascular risk factors (9). While 
most factors, which improve endothelial function, have been shown to be of cardiovascular 
benefit, exceptions include antioxidant supplementation and hormone replacement therapies. 
These 2 later agents have shown improvement in endothelial function but without corresponding 
cardiovascular benefit. 
The negative effect of cholesterol on endothelial function was initially observed in pediatric 
patients with heFH from as early as 8 years of age (4). In this study, the degree of endothelial 
impairment as measured by FMD obtained via high resolution ultrasound correlated with both 
LDL-C and Lp(a) levels. Other studies have also shown that children with heFH have reduced 
endothelial function (as measured by FMD) as compared to healthy controls and that the degree of 
endothelial function was worse in the patients who had a family history of premature CVD (8). 
Early simvastatin therapy of 10 to 40 mg daily restores endothelial function in 28 weeks in 9- to 
18-year-old children with heFH (10) as measured by FMD of the brachial artery. However, 
despite this promising result whether an improvement in endothelial function during childhood 
will translate into decreased risk of future cardiovascular disease is unknown (7). 
Primary objective 
To explore the effect of alirocumab versus placebo on endothelial function after 24 weeks of 
treatment in heterozygous familial hypercholesterolemia (heFH) patients aged of 8 to 17 years 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. 
Study design 
Select sites from the EFC14643 trial, will be asked to participate in the sub-study. Study centers 
that have access to the assessment of FMD will be approached. These centers that are willing to 
take part in the sub-study must undergo further qualification. Sites selected to participate in the 
sub-study will have IRB/EC approval for the main EFC14643 study and for the sub-study and an 
additional informed consent.  
Patients who have provided signed informed consent for the main study of the EFC14643 trial at 
these select sites will be asked to participate in the sub-study. The participation in the sub-study is 
voluntary and declining participation in the sub-study does not prevent participation in the main 
study. Once the additional written informed consent is obtained for the sub-study and if patients 
fulfil the additional eligibility criteria for the sub-study, then they will undergo a baseline FMD 
assessment during the screening period. The patients will undergo a second FMD assessment at 
Week 24.  
A standardized setting for testing will be implemented (11). Experienced ultrasonographers who 
will be involved in image acquisition will be trained prior to undertaking FMD assessments. The 
same scanning protocol will be employed at all sites. The same trained ultrasonographer should 
perform the FMD assessment at baseline and Week 24 on the patient, if at all possible. A central 
reading lab will review and analyze the images. Details will be provided in separate study related 


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documents. As the FMD assessment will take place during the double-blind treatment period, the 
personal involved in the FMD assessments will be blinded, including the central reading lab. 
To assess brachial FMD, the brachial artery diameter will be measured both at rest and during the 
reactive hyperemia. Reactive hyperemia will be induced by sphygmomanometer or equivalent 
placed around the forearm, followed by release. The vessel diameter after reactive hyperemia will 
be expressed as the percentage relative to the resting scan (ie, [lumen diameter after reactive 
hyperemia – lumen diameter at rest]/lumen diameter at rest *100). The per cent maximum flow 
meditated dilatation of the brachial artery measured via ultrasound will be determined by a central 
reading laboratory with pre-specified methodology as detailed in the study related documents. 
Primary endpoint 
The absolute change from baseline to Week 24 in flow mediated dilatation of the brachial artery 
(as determined by the central reading laboratory) regardless of adherence to treatment (ITT 
estimand).  
Study procedures 
Each patient will undergo an FMD assessment at baseline and at Week 24. The baseline FMD 
assessment can be done at Week -2, Week -1 or another day of the screening period, or on Day 1, 
but prior to randomization into the main EFC14643 study. The Week 24 FMD assessment can be 
done on the same day as the Week 24 visit or at an alternative day corresponding to the time 
window (+/- 3 days) of the main EFC14643 study. However, the Week 24 FMD assessment must 
be done prior to entry into the open label treatment period.  
Numerous factors affect flow mediated vascular reactivity. Thus, patients will need to comply 
with more details provided in the consent form. Briefly, patients will need to be fasting for at 
least 8 to 12 h before the FMD assessment. All vasoactive medications should be withheld for at 
least four half-lives, if possible. In addition, subjects will be asked to refrain from exercise and 
should not ingest substances that might affect FMD such as caffeine, high-fat foods and vitamin C 
or use tobacco for at least 4 to 6 h before the study.  
The site will have access to an ultrasound system with specific equipment requirements as 
detailed in the study related documents. The same scanning protocol (which will be provided in 
study related documents) will be implemented across sites. During the procedure, the subject will 
be supine with the arm in a comfortable and outstretched position. A sphymomanometric cuff or 
equivalent will be placed on the forearm. After the patient has an adequate period of rest (which 
will be standardized), a baseline rest image and associated data will be acquired by the trained 
operator. Thereafter, arterial occlusion is created by cuff inflation or equivalent. Deflation of the 
cuff or equivalent will induce a brief high flow state through the brachial artery (reactive 
hyperemia) to accommodate the resistance vessels. The resulting increase in shear stress causes 
the brachial artery to dilate. An image and associated data will be acquired during this reactive 
hyperemia period. The total duration of the FMD assessment at either baseline or Week 24 is 
expected to be approximately 30 minutes. 


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Selection of patients 
Additional inclusion criteria: 
• A signed informed consent for FMD sub-study of EFC14643 protocol 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. 
Additional exclusion criteria: 
• Patients who withdraw consent for FMD sub-study of EFC14643 protocol during the 
screening period (patient who is not willing to continue or anticipated not to continue).  
• Patients who are anticipated to have difficulty with complying with the procedure for the 
FMD assessment, based on Investigator judgment. 
• Patients who are anticipated to require prohibited new (ie, treatment initiated after 
Week 0 FMD and until Week 24 FMD) concomitant medications. 
• Patients who have initiated treatment with prohibited new concomitant medications within 
the past 4 weeks from the Week 0 FMD.  
Patients who are not eligible for the sub-study based on the additional eligibility criteria may still 
take part in the main study of the EFC14643 protocol. 
Prohibited new concomitant medications 
Patients should avoid new treatment with the following medications as they may confound the 
results of the FMD (9): 
• Vitamin C 
• Vitamin E 
• Angiotensin Converting Enzyme (ACE) inhibitors 
• Angiotensin Receptor Blockers (ARBs) 
• Estrogen 
Patients, who are already taking the above concomitant medications prior to the Week 0 FMD 
assessment, may continue to take these medications during the study only if they will continue 
them at a stable dose until the Week 24 FMD assessment.  
Handling of patient after permanent treatment discontinuation and of patient study 
discontinuation 
Patients who wish to withdraw their participation in this sub-study may do so at any time. If they 
do so, they may continue participation in the main study. Patients, who discontinue the main 
study, must also discontinue participation in the sub-study. 


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Patients, who prematurely discontinue study treatment (regardless of the reason) and continue the 
main study, should be encouraged to complete the scheduled Week 24 FMD assessment.  
Statistical considerations 
Sample Size Determination and Randomization: 
Assuming that 30 to 39 patients (regardless of the dosing regimen cohort: 20 to 26 in the 
alirocumab group and 10 to 13 in the placebo group) will participate to the sub-study, the 
statistical power to demonstrate superiority of alirocumab versus placebo at 0.05 two sided 
significance level is provided in Table 1 according to several assumptions for the mean difference 
and standard deviation (SD) of the absolute change from baseline to Week 24. 
Table 1 - Statistical power according to mean difference and SD of the FMD absolute change from 
baseline to Week 24 
Expected 
number of 
patients  
(2:1 ratio) 
Standard 
deviation  
(%) 
Delta mean (%) 
2 
2.5 
3 
30 
2.5 
51% 
70% 
84% 
 
4 
23% 
34% 
46% 
39 
2.5 
63% 
81% 
93% 
 
4 
29% 
43% 
57% 
Analysis:  
The absolute change from baseline in FMD at Week 24 will be analyzed using an ANCOVA 
model. The model will include the fixed categorical effects of treatment group (alirocumab, 
placebo), the dosing regimen cohorts (Q2W, Q4W), the treatment by dosing regimen cohort 
interaction and the continuous fixed covariate of baseline FMD value. Model assumptions for 
normality will be explored prior to the analysis testing. Throughout the ANCOVA model, 
least-square (LS) mean and standard error (SE) will be provided for each treatment group and LS 
means difference will be provided for the comparison of the alirocumab group versus the placebo 
group with the 95% CI, using appropriate contrasts. 
All Week 24 FMD values will be included in the analysis regardless of individual patient 
adherence to treatment. 
Administration 
Informed Consent: 
A separate informed consent will be obtained from patients who voluntarily agree to participate in 
the sub-study. The Informed Consent Form reflecting this sub-study will be submitted for review 
and approval to the IRB/EC charged with this responsibility.  


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Confidentiality: 
Data collection and handling by the Sponsor for this sub-study will be will be in accordance with 
that described in the main EFC14643 protocol, and every effort will be made to protect patient 
confidentiality. In case the results are published, they will be done so anonymously. 
Institutional Review Board/Ethics Committee: 
This sub-study, the Informed Consent Form for this sub-study, and any advertisement for patient 
recruitment will be submitted for review and approval to the IRB/EC charged with this 
responsibility. 
Records Retention: 
Investigators must retain records pertaining to this sub-study as described in the main 
EFC14643 study protocol. 
BIBLIOGRAPHIC REFERENCES 
1. Charakida M, Masi S, Loukogeorgakis SP and Deanfield JE. The role of flow-mediated 
dilatation in the evaluation and development of antiatherosclerotic drugs. Curr Opin 
Lipidol. 2009;20(6):460-6. 
2. Sorensen KE, Celermajer DS, Georgakopoulos D, Hatcher G, Betteridge DJ, Deanfield JE. 
Impairment of endothelium-dependent dilation is an early event in children with familial 
hypercholesterolemia and is related to the lipoprotein(a) level. J Clin Invest. 1994;93:50. 
3. Charakida M, Masi S, Luscher TF, Kastelein JJP, and Deanfield JE. Assessment of 
atherosclerosis: the role of flow-mediated dilatation. Eur Heart J. 2010;31:2854-61. 
4. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the Ultrasound Assessment 
of Endothelial-Dependent Flow-Mediated Vasodilation of the Brachial Artery. J Am Coll 
Cardiol. 2002;39(2):257-65. 
5. Vanhoutte PM. 1998. Endothelial dysfunction and inhibition of converting enzyme. Eur 
Heart J. 1998;19(Suppl J):J7-15. 
6. Ross R. The pathogenesis of atherosclerosis - an update. N Engl J Med. 1986;314:488-
500. 
7. Vallance P, Chan N. Endothelial function and nitric oxide:clinical relevance. Heart. 
2001;3:342. 
8. De Jongh S, Lilien MR, op’t Roodt J, et al. 2002. Early statin therapy restores endothelial 
function in children with familial hypercholesterolemia. J Am Coll Cardiol. 40:2117-21. 
9. Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and 
clinical relevance. Circulation. 2007;115:1285-95. 
10. Järvisalo MJ, Raitakari OT. Ultrasound assessment of endothelial function in children. 
Vasc Health Risk Manag. 2005;1(3):227-33. 
11. Jongh S, Lilien MR, Bakker HD, et al. Family history of cardiovascular events and 
endothelial dysfunction in children with familial hypercholesterolemia. Atherosclerosis. 
2002;163:193-7. 


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Appendix F 
Summary of adverse event reporting instructions  
 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case report form completion 
AE 
form 
Safety 
Complementary 
Forma 
Other 
specific 
forms 
Adverse Event  
(non-SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI. 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited  
(within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.4.1.2. 
Yes 
Yes 
No, 
unless 
applicable 
Adverse Event of 
Special Interest (AESI) 
(non-SAE) 
Expedited  
(within 
24 hours) 
Pregnancy of female patient/subject 
(including male subject’s partner) in 
Section 10.4.1.3. 
Yes 
Yes 
Yes 
Symptomatic overdose with IMP. 
Yes 
Yes 
No 
Increase in ALT as follows: 
-ALT >3 x ULN (if baseline ALT 
< ULN), or ALT ≥2 times the 
baseline value (if baseline ALT 
≥ ULN) 
Please refer to related flowchart per 
Appendix H. 
Yes 
Yes 
Yes 
General allergic event regardless of 
the cause and requiring consultation 
with another physician as specified in 
Section 10.4.1.3. 
Yes 
No 
Yesb 
Local Injections site reactions related 
to IMP and requiring consultation 
with another physician as specified in  
Section 10.4.1.3. 
Yes 
Yes 
Yesb 
Neurocognitive events in 
Section 10.4.1.3. 
Yes 
Yes 
Yes 
Neurologic events (requiring 
additional examinations/procedures 
and/or consultation with a specialist, 
as described in Section 10.4.3). 
Yes 
Yes 
Yes 
AE 
Routine 
Neurologic events without requiring 
consultation with another physician 
as per Section 10.4.1.3. 
Yes 
No 
Yesb 
Allergic events without requiring 
consultation with another physician 
as per Section 10.4.1.4. 
Yes 
No 
Yesb 
Local injection site reaction related to 
IMP without requiring consultation 
with another physician as per 
Section 10.4.1.4. 
Yes 
No 
Yesb 
Laboratory, vital sign,  
Routine 
Neutropenia (per Appendix H). 
Yes 
No 
No 
Thrombocytopenia (per Appendix H). 
Yes 
No 
No 


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Event category 
Reporting 
timeframe 
Specific events in this 
category 
Case report form completion 
AE 
form 
Safety 
Complementary 
Forma 
Other 
specific 
forms 
(non-SAE, non-AESI) 
that is:  
- Symptomatic 
- Requiring corrective 
treatment or 
consultation 
- Leading to IMP 
discontinuation or 
dose regimen 
modification  
 
Acute renal insufficiency  
(per Appendix H). 
Yes 
No 
No 
Increase in CPK and suspicion of 
rhabdomyolysis (per Appendix H). 
Yes 
No 
No 
Death from any cause 
Expedited 
 
Yes 
Yes 
Yes 
a Completion of a Safety Complementary Form is required for any AE meeting a seriousness or AESI criterion, even if this is 
not otherwise required according to the table for a particular type of AE. 
b The appropriate Complementary Form should be completed as applicable according to the type of reaction (general or 
local). However, for local injection site reactions that progress/expand/worsen/etc, both Complementary Forms should be 
completed. 


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Appendix G 
Assessment of local injection site reactions  
 
Local, Non-
allergic reaction 
to injectable 
product 
Mild  
(Grade 1) 
Moderate  
(Grade 2) 
Severe  
(Grade 3) 
Very severe 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Interferes with activity or 
repeated use of non-
narcotic pain reliever 
Prevents daily activity or 
repeated use of narcotic 
pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at rest 
ER visit or 
hospitalization 
Erythema/Redness * 
2.5 - 5 cm 
5.1 - 10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Swelling ** 
2.5 - 5 cm and does 
not interfere with 
activity 
5.1 - 10 cm or interferes 
with activity 
>10 cm or prevents daily 
activity 
Necrosis 
Itching 
Does not interfere 
with activity 
Interferes with activity or 
repeated use of topical or 
systemic treatment 
Prevents daily activity or 
leads to other significant 
dermatologic conditions 
(such as infection, 
scarring, etc) 
Emergency Room 
(ER) visit or 
hospitalization 
Other (Please 
specify)*** 
No modification of 
daily activities and/or 
does not require 
symptomatic 
treatment. 
Hinders normal daily 
activities and/or requires 
symptomatic treatment. 
Prevents daily activities 
and requires 
symptomatic treatment. 
Emergency Room 
(ER) visit or 
hospitalization 
* 
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous 
variable 
** Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
*** Please specify the other signs or symptoms (for example, hematoma, discoloration, reactivation, etc) 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials April 2005. 
 


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Appendix H 
General guidance for the follow-up of laboratory abnormalities by 
sanofi  
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.4.3 is met. 


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Appendix I 
Pediatric formulas for eGFR and creatinine clearance  
 
 


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Appendix J 
Country specific requirements  
AMENDMENT FOR NORWAY, ARGENTINA, CZECH REPUBLIC AND ALL 
APPLICABLE COUNTRIES 
For Norway, Argentina, the Czech Republic and all applicable countries, in accordance with the 
guidelines of the clinical trials facilitation group (CTFG) and their specific requirements to do 
monthly pregnancy tests, urine pregnancy tests will be performed as follows: 
• From Visits 4 to 14, during clinic visits; and  
• At home for all other time points’ in-between visits. On a monthly basis, urine pregnancy 
tests should be performed if the patient is at home. A member of site staff will contact the 
patient via telephone to check on home pregnancy tests performed by the patient at the 
following time points: 
Weeks 4, 16, 20, 28, 36, 40, 48, 52, 56, 60, 64, 72, 76, 80, 84, 88, 96, and 100 
Sexual counseling should be provided to patients when indicated. In the event that a pregnancy 
test performed at home is reported to be positive, please invite the patient to the clinic for an 
immediate repeat testing to confirm. For more guidance see Appendix D. 
Of note, in the protocol generic wording was already used to allow pregnancy tests to be 
performed more frequently in some countries due to local legislations related to women of 
childbearing potential randomized in clinical trials.  
 
 


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Appendix K 
Contingency Measures for regional or national emergency that is 
declared by a governmental agency  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, and terrorist attack) may prevent access to the clinical trial 
site. 
Remote monitoring, also referred to as off-site monitoring, enables clinical research associates 
Site Monitor (SM) to remotely conduct monitoring activities without physically traveling to the 
site. 
Deploying remote monitoring, inclusive of remote source data verification, should always be 
driven by risk assessment and analysis at the outset.  
Due to levels of safety information required for the EFC14643 study, attempts should be made to 
perform all assessments in accordance with the approved protocol to the extent possible. In case 
this is not possible due to a temporary disruption caused by an emergency, focus should be given 
to assessments necessary to ensure the safety of participants and those important to preserving the 
main scientific value of the study. 
The decision for each individual participant to remain on treatment and/or in the study should be 
made on a case by case basis based on best Investigator medical judgment. The clinical judgment 
of the treating physician should guide the management plan of each participant based on 
individual benefit/risk assessment and the evolving situation at the site. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and efficacy data as listed below: 
- 
Blood sampling for LDL-C at baseline, Week 8, Week 12, and Week 24 
- 
Blood sampling for lipid parameters (Apo B, non-HDL-C, Total-C, Lp(a), TG, 
HDL-C, and Apo A-1) at baseline, Week 8, Week 12 and Week 24 
- 
AE collection reported, including AE complementary forms 
- 
injection site reactions 
- 
Laboratory parameters - adrenal gland hormones; gonadal and pituitary hormones 
- 
Collection of weight at Day 1, at Week 24 (time of dose evaluation) and after Week 24 
up to the last IMP dispensation 
- 
Collection of Tanner Stage at Screening Visit 1 or Visit 2 and at last patient visit  
- 
Blood sampling for PK and ADA parameters at any visit 
• If onsite visits are not possible, remote visit windows may be extended for assessments of 
any of the data listed above that cannot be obtained remotely within the visit window 
planned per protocol 
• Use of local clinic or laboratory locations may be allowed for the laboratory procedures 
from the list above except for lipid parameters during the double-blind treatment period 
• Contingencies implemented due to emergency will be documented. 


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Appendix L 
Protocol amendment history  
The Protocol Amendment Summary of Changes Table for the current amended protocol 03 is 
located directly before Clinical Trial Summary. 
AMENDED PROTOCOL 02 (02-JAN-2019) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it either significantly impacts the safety or physical integrity of 
participants or the scientific value of the study.  
OVERALL RATIONALE FOR THE AMENDMENT 
The main reason for this protocol amendment is to include the Q4W dosing regimen alongside the 
Q2W dosing regimen currently ongoing. This Q4W dosing regimen should be applicable to 
approximately half of the heFH patients to be randomized in the Phase 3 EFC14643 study 
(ie, approximately 75 patients). 
The selection of the Q2W dosing regimen currently evaluated in this Phase 3 EFC14643 study 
was based on the results of the Phase 2 DFI14223 study, as described in Section 4 - Introduction 
and Rationale. This Phase 2 study was an 8 week open label, sequential, repeated dose-finding 
study to evaluate the efficacy and safety of alirocumab in children and adolescents with heFH 
through 3 cohorts, initially; the repeated dose-finding study was followed by an open label 
extension phase. Two body weight (BW) categories (BW <50 kg and BW ≥50 kg) were used and 
patients were treated with a fixed dosage of alirocumab in each BW category according to the 
evaluated cohort, as described below:  
• Cohort 1: 30 mg Q2W for BW <50 kg and 50 mg Q2W for BW ≥50 kg.  
• Cohort 2: 40 mg Q2W for BW <50 kg and 75 mg Q2W for BW ≥50 kg.  
• Cohort 3: 75 mg Q4W for BW <50 kg and 150 mg Q4W for BW ≥50 kg. 
Following the review of the combined efficacy, safety and pharmacokinetics results of the 
first 3 cohorts, doses of the Cohort 2 were selected for the Q2W regimen since the results 
observed were those expected to provide an overall reduction in LDL-C of -46.1%. Consistent 
reductions were seen across the 2 doses ranging from -40.6% to -49.8% for 40 mg Q2W and 
75 mg Q2W, respectively. 
For the Q4W dosing regimen no formal conclusion could be drawn given the unexpected results 
observed in Cohort 3. The doses evaluated were likely not high enough to achieve larger and 
sustained reductions in the LDL-C over the entire dosing interval in children receiving statin as 
background therapy. Therefore, an additional cohort (Cohort 4) was added in the 
Phase 2 DFI14223 study to evaluate further the Q4W dose regimen using higher doses of 
150 mg/300 mg Q4W depending on the BW category.  


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Regarding this Cohort 4, the primary efficacy endpoint as measured by the percent change from 
baseline in LDL-C at Week 8 showed a comparable reduction to that observed in Cohort 2 with a 
mean LS change from baseline of -46.1% and -44.5% for Cohort 2 and Cohort 4, respectively. 
Substantial reductions were seen in both BW categories ranging from -31.9% for 150 mg Q4W in 
the lower BW category to -59.8 % for 300 mg Q4W in the higher BW category. Overall, 
alirocumab was well tolerated with a favorable safety profile in this additional cohort over the 
open label dose finding and the open label extension (OLDFI/OLE) combined period, as already 
observed in the first 3 cohorts. No new clinically significant safety findings were noted in these 
patients treated with alirocumab. 
Based on the positive results from Cohort 4, the doses of 150 mg and 300 mg Q4W have been 
deemed efficacious and to be adequately safe, and therefore will be also evaluated in the 
Phase 3 EFC14643 study. Similar to what is done in the study for the Q2W dosing regimen, a 
dose-adjustment will be allowed to optimize the response as needed. Rules for the 
dose-adjustment will be similar to those applied for the Q2W dosing regimen as shown below: 
Patients enrolled in the Q4W alirocumab dosing regimen will receive: 
• 150 mg Q4W for BW <50 kg or,  
• 300 mg Q4W for BW ≥50 kg. 
At Week 12: 
• If the Week 8 LDL-C is <110 mg/dL (2.85 mmol/L), patients will continue alirocumab 
150 mg or 300 mg Q4W according to BW category. 
• If the Week 8 LDL-C is ≥110 mg/dL (2.85 mmol/L), patients will have a change in the 
dose from 150 mg Q4W to 75 mg Q2W or from 300mg Q4W to 150 mg Q2W, in a 
blinded manner. 


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Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
Clinical Trial Summary - Primary objective; 
Section 5.1 Primary 
Every 4 week (Q4W) efficacy evaluation has 
been added to the primary objectives. 
Based on positive results from 
Cohort 4 of the 
Phase 2 DFI14223 study, 
efficacy and safety 
assessments of the Q4W 
dosing regimen are also 
planned in this study. 
Revisions presented in this 
section of the table are related 
to the addition of the Q4W 
dosing regimen in the study.  
Clinical Trial Summary - Study design: 
Double-blind treatment period 
Dosing regimen of Q4W (alirocumab 150 mg 
and 300 mg; n~75 patients) is added and 
number of enrolled patients in Q2W dosing 
regimen who will be administered study 
treatment (alirocumab 40 mg and 75 mg is 
changed to approximately half; n~75). 
Clinical Trial Summary - Study design: 
Double- blind treatment period and Open 
label treatment period; Study Flow chart 1.3 
Description of the Q4W dosing regimen and 
information on maintaining the blind is added 
for patients in Q4W dosing regimen to indicate 
administration of alirocumab every 4 weeks 
during the first 12 weeks and then after 
Week 12 administration of alirocumab every 
4 weeks alternating with placebo every 
4 weeks in order to maintain the blind at the 
time of a possible dose-adjustment. 
Clinical Trial Summary - Study design: 
Open label treatment period 
Dose-adjustment information at Week 24 and 
from Week 32 added for patients enrolled 
Q4W dosing regimen. 
Clinical Trial Summary - Investigational 
medicinal products: Formulation, 
Section 8.1: Investigational medicinal 
products 
1 mL of alirocumab 150 mg/mL solution for 
150 mg dose added. 
Clinical Trial Summary - Investigational 
medicinal products: Dose regimen; 
Section 8.1: Investigational medicinal 
products 
Information of the Q4W dose used added: 
alirocumab 150 mg Q4W for BW <50 kg and 
300 mg Q4W for BW ≥50 kg. 
Clinical Trial Summary - Statistical 
consideration 
Revision of statistical analysis - sample size 
determination and addition of alirocumab Q4W 
and placebo Q4W to the treatment groups to 
be analyzed 
Section 11.1 Determination of sample size 
Description of sample size calculations and 
considerations for the Q2W and Q4W dosing 
regimens 
Section 11.4.1.1 Extent of Investigational 
Medicinal Product exposure 
Description of the duration of exposure is 
added for the Q4W dosing regimen 
Section 11.4.2.3 Multiplicity considerations 
A revision and description of how the 
multiplicity will be handled. 
Flow chart 1.2: Graphical study design - 
Q4W dosing regimen 
Graphical study design for Q4W dosing 
regimen added as Flow chart 1.2 
Section 4: Introduction and rationale 
Addition of clinical information of the additional 
cohort (Cohort 4) conducted with Q4W dosing 
regimen in the DFI14223 that support the 
evaluation of the Q4W dosing regimen in the 
EFC 14643 study. 


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Section # and name 
Description of change 
Brief rationale 
Clinical Trial Summary - Study design: 
Open label treatment period 
Correction in the Q2W dose-adjustment 
according to BW as per Investigator’s 
judgment. 
Error in the information of the 
dose adjustment for the Q2W 
according to BW as per 
investigator’s judgement; only 
dose adjustment from 40 mg 
to 75 mg is possible if BW 
becomes ≥50 kg. 
Flow chart 1.1: Graphical study design - 
Q2W dosing regimen 
Information on the fact that from the total 
number of 150 patients, half of those will be 
enrolled in each dosing regimen has been 
added. 
Although the overall number 
of patients (150) is not 
modified, approximately half 
of this number will be enrolled 
in each of the Q2W and Q4W 
dose regimens, respectively. 
Throughout 
Appendix J 
 
Minor editorial revisions to reflect the rationale 
stated above. 
Addition of the Czech Republic and all 
applicable countries to Appendix J (currently 
provisioned as a country specific change in 
the protocol). 
 
Minor, hence not summarized.  
To clarify that all countries are 
allowed to perform the 
monthly urine pregnancy 
tests, in keeping with the 
clinical trials facilitation group 
(CTFG) guidelines. 
 


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Amended protocol 01 (13-Sep-2018) 
This amended protocol (amendment 01) is considered to be nonsubstantial based on the criteria 
set forth in Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union because it neither significantly impacts the safety or physical integrity of 
participants nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The protocol description of the independent physician is being revised to show that he/she is 
external to the EFC14643 study, and not necessarily external to the Sponsor. 
Since the main purpose of using an independent physician involved in the monitoring of patients 
reaching LDL-C levels <50 mg/dL (1.30 mmol/L) during the 24-week double-blind treatment 
period is to have an individual that is not part of the EFC14643 study team, the Sponsor’s initial 
intention was to use a physician part of an academic group, however the attempt to implement 
such a process within the study teams predetermined timelines was not possible. As a result, the 
Sponsor will use physicians within the company who are not part of the EFC14643 study team 
and as well not involved in any alirocumab activities. The protocol is revised accordingly to 
clarify that other physicians can be involved in the process of this monitoring, as long as they are 
external to the EFC14643 study team and any alirocumab activities. This change will allow the 
Sponsor to respect the objectives set forth in the original protocol with regard to the monitoring of 
patients reaching LDL-C levels <50 mg/dL (1.30 mmol/L) during the 24-week double-blind 
treatment period. The blinding process remains unchanged for the EFC14643 study team. 
Requests have been received from the Norwegian and Argentinian regulatory agencies for 
monthly pregnancy tests on all female patients of childbearing potential throughout the entire 
study in accordance to the clinical trials facilitation group (CTFG) guideline on 
“Recommendations related to contraception and pregnancy testing in clinical trials”. As a result, 
in these countries logistic aspects will be arranged to allow urine pregnancy tests to be performed 
by the patients at home in-between clinic visits.  
In addition, parts of the protocol inadvertently state that a separate informed consent form should 
be used for heterozygous familial hypercholesterolemia (heFH) genotyping. However, the consent 
for heFH genotyping is actually part of the core study information and informed consent form 
(CSICF), therefore relevant sections in the protocol are being revised accordingly for clarification 
purpose. Also in the description of the two-step analysis in the Section 6.3 and Section 11.5, 
revision of the text is done with removal of the sentence “The results of the first step analysis will 
not be used to change the conduct of the ongoing study in any aspect”. In the context of the design 
of the study (double-blind period followed by an open label treatment period) this sentence is not 
appropriate since the double-blind period will be completed at the time of the first step analysis 
with the final comparison between the 2 treatment groups, therefore there will be no bias in this 
comparison. 


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Protocol amendment summary of changes table 
Section # and name 
Description of change 
Brief rationale 
Clinical Trial Summary- Study Design 
Removed the word “academic” and 
added a sentence to specify that the 
independent physician is not part of the 
EFC14643 study team and any 
alirocumab activities. 
This revision is to clarify that the 
independent physician is not necessarily 
an academic physician but nevertheless 
is external to the EFC14643 study team 
and any alirocumab activities. 
6.3 and 11.5 Two-step analysis 
Removed the sentence “The results of 
the first step analysis will not be used to 
change the conduct of the ongoing 
study in any aspect”. 
This sentence is not appropriate in the 
context of the design of the study 
(double-blind period followed by an 
open label treatment period). 
6.4.2 Data monitoring committee 
Description of how the independent 
physician will have access to patient 
treatment information during the 
double-blind treatment period. 
To better assure that the study team 
members will be blinded to the data that 
the independent physician reviews. 
8.3.1.2 Lipid parameters 
Clarification with regard to the Sponsor, 
that the EFC14643 study team is 
blinded for lipid parameters. 
To better assure that the study team 
members will be blinded to the data that 
the independent physician reviews. 
10.1.1.1 Visit 1 (Week 6, run in) and 
12.2 Informed consent 
Specifying that the optional consent for 
genotyping is part of the main informed 
consent form. 
Clarification that the heFH consent is 
not a separate document from the 
informed consent form. 
10.1.3 Twenty-four week double-blind 
treatment period 
Removed the word “academic” and 
added a sentence to specify that the 
independent physician is not part of the 
EFC14643 study team and any 
alirocumab activities. 
This revision is to clarify that the 
independent physician is not necessarily 
an academic physician but nevertheless 
is external to the EFC14643 study team 
and any alirocumab activities. 
10.6.2.3 Independent physician 
monitoring for patients reaching LDLC 
levels <50 mg/dL (1.30 mmol/L) during 
the double-blind treatment period and 
recommendations for the Investigator in 
case of an alert 
Clarification on how the independent 
physician will have access to patient 
treatment information during the 
double-blind period and Sponsor’s 
EFC14643 study team will not have 
access to. 
To better assure that the study team 
members will be blinded to the data that 
the independent physician reviews. 
17. Appendices- Appendix J Country 
Specific Requirements and 1.2 Study 
flowchart-footnote “bb” 
Monthly urine pregnancy tests to be 
performed at home added as country 
specific changes. 
Added as Appendix J for Norway and 
Argentina, in keeping with the clinical 
trials facilitation group (CTFG) 
guidelines. 
Throughout 
Minor editorial revisions to reflect the 
rationale stated above. 
Minor, therefore have not been 
summarized. 
 


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Page 1
STATISTICAL ANALYSIS PLAN 
A randomized, double-blind, placebo-controlled study followed by an open-label 
treatment period to evaluate the efficacy and safety of alirocumab in children and 
adolescents with heterozygous familial hypercholesterolemia 
SAR236553/RGN727-EFC14643 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 19-Feb-2021 
Total number of pages: 
102 
NCT03510884


Statistical Analysis Plan  
19-Feb-2021 
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Version number: 2 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................. 10 
1.2.1 
Primary objectives .......................................................................................................................... 10 
1.2.2 
Secondary objectives ..................................................................................................................... 10 
1.2.3 
Other Objectives ............................................................................................................................ 11 
1.2.4 
Exploratory objective of the FMD sub-study ................................................................................... 11 
1.3 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 11 
1.4 
STUDY PLAN ................................................................................................................................. 13 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 14 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN...................... 16 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 17 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 17 
2.1.1 
Demographic and baseline characteristics .................................................................................... 17 
2.1.2 
Prior or concomitant medications and post-treatment medications ............................................... 20 
2.1.3 
Efficacy endpoints .......................................................................................................................... 21 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 22 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 22 
2.1.4 
Safety endpoints ............................................................................................................................. 23 
2.1.4.1 
Adverse events variables ............................................................................................................... 25 
2.1.4.2 
Deaths ............................................................................................................................................ 27 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 27 
2.1.4.4 
Vital signs variables ........................................................................................................................ 28 
2.1.4.5 
Electrocardiogram variables ........................................................................................................... 29 
2.1.4.6 
Tanner stage measurement ........................................................................................................... 29 
2.1.4.7 
Cogstate battery test ...................................................................................................................... 30 
2.1.5 
Other endpoints .............................................................................................................................. 30 
2.1.6 
Anti-alirocumab antibodies variables ............................................................................................. 31 


Statistical Analysis Plan  
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2.1.7 
Pharmacokinetic variables ............................................................................................................. 32 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 32 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 34 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 35 
2.3.1 
Efficacy populations ....................................................................................................................... 35 
2.3.1.1 
Intent-to-treat population ................................................................................................................ 35 
2.3.1.2 
Modified Intent to treat population .................................................................................................. 35 
2.3.1.3 
FMD sub-study population ............................................................................................................. 35 
2.3.2 
Safety population ............................................................................................................................ 36 
2.3.3 
Anti-alirocumab antibody population .............................................................................................. 36 
2.3.4 
Pharmacokinetics population ......................................................................................................... 36 
2.3.5 
Open-label population .................................................................................................................... 36 
2.3.6 
Population without trial impact/disruption due to COVID-19 .......................................................... 36 
2.4 
STATISTICAL METHODS ............................................................................................................. 37 
2.4.1 
Demographics and baseline characteristics .................................................................................. 37 
2.4.2 
Prior or concomitant medications ................................................................................................... 38 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 38 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 39 
2.4.3.2 
Compliance .................................................................................................................................... 41 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 42 
2.4.4.1 
Analysis of primary efficacy endpoint ............................................................................................. 43 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 48 
2.4.4.3 
Multiplicity issues ............................................................................................................................ 51 
2.4.4.4 
Exploratory efficacy analyses ......................................................................................................... 52 
2.4.5 
Analyses of safety data .................................................................................................................. 52 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 54 
2.4.5.2 
Deaths ............................................................................................................................................ 57 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 57 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 59 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 60 
2.4.5.6 
Analysis of Tanner stages measurement ....................................................................................... 60 
2.4.5.7 
Analyses of Cogstate Battery test .................................................................................................. 60 
2.4.6 
Analyses of other endpoints ........................................................................................................... 61 
2.4.7 
Analyses of anti-alirocumab antibodies variables .......................................................................... 62 
2.4.8 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 63 
2.4.9 
Analyses of quality of life variables ................................................................................................ 63 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 63 
2.5.1 
General conventions ...................................................................................................................... 63 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 64 


Statistical Analysis Plan  
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2.5.3 
Missing data ................................................................................................................................... 64 
2.5.4 
Windows for time points ................................................................................................................. 66 
2.5.5 
Unscheduled visits ......................................................................................................................... 68 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 68 
2.5.7 
Statistical technical issues ............................................................................................................. 68 
3 
INTERIM ANALYSIS ..................................................................................................................... 69 
4 
DATABASE LOCK ........................................................................................................................ 71 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 72 
6 
REFERENCES ............................................................................................................................... 73 
7 
LIST OF APPENDICES ................................................................................................................. 74 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES FOR CHILDREN ............. 75 
APPENDIX B 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES FOR ADULTS ................. 86 
APPENDIX C 
DETAILED STATISTICAL METHODOLOGY FOR PATTERN MIXTURE MODEL ............ 91 
APPENDIX D 
LIST OF MEDDRA TERMS FOR CMQS ............................................................................ 95 
APPENDIX E 
Z-SCORE CALCULATION FORMULA FOR COGSTATE BATTERY TEST ...................... 98 
APPENDIX F 
COGSTATE NORMATIVE DATA ........................................................................................ 99 
APPENDIX G 
EFFECT SIZE CALCULATION FORMULA FOR COGSTATE DATA .............................. 101 
APPENDIX H 
PEDIATRIC FORMULA FOR EGFR AND CREATININE CLEARANCE ........................... 102 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACTH: 
adenocorticotrophic hormone 
ADA: 
anti-alirocumab antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransaminase 
ANCOVA: 
analysis of covariance 
Apo A-1: 
apolipoprotein A-1 
Apo B: 
apolipoprotein B 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic chemical 
BMI: 
body mass index  
BW: 
body weight 
CMQ: 
customized MedDRA queries 
CPK: 
creatine phosphokinase 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DET: 
Detection test 
DHEAS: 
dehydroepiandrosterone sulfate 
e-CRF: 
electronic case report form 
eDISH: 
evaluation of drug-induced serious hepatotoxicity 
eGFR: 
estimated glomerular filtration rate 
GML: 
Groton maze learning task test 
HbA1c: 
glycated haemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
heFH: 
heterozygous familial hypercholesterolemia 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
IDN: 
Identification test 
IMP: 
Investigational Medicinal Product 
ITT: 
intent-to-treat 
LDH: 
lactate dehydrogenase 
LDL-C: 
low-density lipoprotein cholesterol 
LLN: 
lower limit of normal 
LLOQ: 
lower limit of quantification 
LLT: 
lowest level term 
LMT: 
lipid modifyng therapy 
LOCF: 
last observation carried forward 
Lp[a]: 
lipoprotein (a) 


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LS: 
least square 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
myocardial infarction 
NMAR: 
not-missing-at-random 
non-HDL-C: 
non-high density lipoprotein cholesterol 
OCL: 
One card learning test 
OL: 
open-label 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PK: 
pharmacokinetics 
PT: 
preferred term 
Q1: 
first quartile 
Q2W: 
every 2 weeks 
Q3: 
third quartile 
Q4W: 
every 4 weeks 
QQ-plot: 
Quantile Quantile plot 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SC: 
subcutaneous 
SMQ: 
standardised MedDRA queries 
SOC: 
system organ class 
TGs: 
triglycerides 
Total-C: 
total-cholesterol 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
US: 
United States of America  
WHO-DD: 
World Health Organization-Drug Dictionary  
γGT: 
gamma-glutamyl transferase 
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
This Statistical Analysis Plan (SAP) is intended to be a detailed description of the definitions and 
statistical techniques to be used for the analyses of data collected in the EFC14643 study. This 
SAP will be finalized prior to the first step analysis. This first step analysis would be conducted 
after the completion of the double-blind treatment period. 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This study is a randomized, 24-week double-blind, placebo-controlled, parallel-group, multi-
national, multi-center study followed by an open-label treatment period of 80 weeks.  
Approximately 150 children and adolescents 8 to 17 years of age with heterozygous familial 
hypercholesterolemia (heFH) and low-density lipoprotein cholesterol (LDL-C) ≥130 mg/dL 
(3.37 mmol/L) at the screening visit, despite stable lipid modifying therapies (LMTs), are 
randomized to alirocumab or placebo using a 2:1 ratio (alirocumab: placebo). Two dosing 
regimens, administration every 2 weeks (Q2W) and every 4 weeks (Q4W), will be evaluated with 
approximately 75 patients in each dosing regimen cohort. Recruitment in the Q4W dosing regimen 
cohort started once recruitment in the Q2W dosing regimen cohort was completed and the 
protocol amendment was approved. 
A Flow Mediated Dilation (FMD) exploratory sub-study is also planned to involve a subset of 
30-39 patients at selected sites. 
Note: Patients who had previously participated in the DFI14223 study and had received 
alirocumab administration during the open-label extension of the DFI14223 study required a 
wash-out period of at least 10 weeks between the last injection of alirocumab and the screening 
lipid assessment at the entry of the screening period. However, as these patients had already met 
the LDL-C requirement of at least 130 mg/dL (3.37 mmol/L) when they were screened for the 
DFI14223 study, they were not excluded based on the LDL-C value obtained during the screening 
for the EFC14643 study. 
Randomization is stratified according to previous participation (yes or no) in the Phase 2 
DFI14223 study and baseline body weight (BW) (<50 or ≥50 kg). 
The study is comprised of 4 periods as described below: 
• 
A run-in period (if needed) up to 4 weeks (+2 days) in duration. 
• 
A screening period up to 2 weeks (+5 days) in duration. 
• 
A 24-week double-blind treatment period. 
• 
A 80-week open-label treatment period. 
The total study duration may be up to 110 weeks (+7 days). 


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Double-blind treatment period: 
Two dosing regimens will be evaluated, Q2W and Q4W. Patients will be included in them in a 
sequential manner, ie, the first half of the patients in the Q2W dosing regimen cohort then the 
second half of patients in the Q4W dosing regimen cohort. Patients will be blinded to study 
treatment and randomized to either alirocumab or placebo using a 2:1 ratio for each dosing 
regimen cohort. 
Q2W dosing regimen cohort: 
The first half of the total patient population (approximately 75 patients) will be randomized to 
receive Q2W subcutaneous (SC) injections of either alirocumab or placebo, starting at the 
randomization Visit (Week 0) and continuing up to the end of the double-blind period. 
For patients randomized to receive alirocumab the following doses based on BW will be initially 
administered: 
• 
40 mg for BW <50 kg or, 
• 
75 mg for BW ≥50 kg. 
At Week 12 patients randomized to alirocumab will either, in a blinded manner: 
• 
Continue alirocumab 40 mg or 75 mg Q2W, if the Week 8 LDL-C is <110 mg/dL 
(2.85 mmol/L) OR 
• 
Have a dose up-titration to alirocumab 75 mg Q2W (for patients initially on 40 mg Q2W) 
or 150 mg Q2W (for patients initially on 75 mg Q2W) if the Week 8 LDL-C is 
≥110 mg/dL (2.85 mmol/L). 
Q4W dosing regimen cohort: 
The second half of the patient population (ie, approximately 75 patients) will be enrolled in a 
Q4W dosing regimen cohort. During the first 12 weeks of the double-blind period, all patients will 
receive SC injection(s) Q4W of alirocumab or placebo. After Week 12, with regard to the possible 
dose-adjustment in some patients and the need for maintaining the double-blind until the end of 
the double-blind period, all patients will receive SC injection(s) Q2W.  
For patients randomized to alirocumab the following doses based on BW will be initially 
administered: 
• 
150 mg Q4W for BW <50 kg or,  
• 
300 mg Q4W for BW ≥50 kg. 
At Week 12, patients randomized to alirocumab will either, in a blinded manner: 
• 
Continue alirocumab 150 mg or 300 mg Q4W, if the Week 8 LDL-C is <110 mg/dL 
(2.85 mmol/L) alternating with Q4W placebo injection (“sham” Q2W regimen) OR 


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• 
Have a dose adjustment to 75 mg Q2W (for patients on 150 mg Q4W) or 150 mg Q2W 
(for patients on 300 mg Q4W) if the Week 8 LDL-C is ≥110 mg/dL (2.85 mmol/L) 
(“actual” Q2W regimen). 
Note: participants enrolled in the placebo Q4W group will receive injection of placebo of 
alirocumab Q4W for the first 12 weeks, then injection of placebo of alirocumab Q2W until the 
end of the double-blind period. 
Open-label treatment period 
The open-label (OL) treatment period consists of 80 weeks of open-label alirocumab SC Q2W or 
Q4W depending on the frequency of the dosing regimen initiated at randomization. 
At the first open-label treatment period visit (corresponding to Week 24 of the double-blind 
period), depending on whether subjects were randomized  in the Q2W or Q4W dosing regimen 
cohort, both alirocumab and placebo treated patients will receive alirocumab either 40 mg Q2W or 
150 mg Q4W if BW <50 kg, and 75 mg Q2W or 300 mg Q4W if BW ≥50 kg, based on the weight 
obtained at the Week 24 visit (dosing frequency assigned at the start of the open-label treatment 
period was to maintain the same dosing frequency to which the patient was randomized for the 
double-blind treatment period). 
After Week 24, change in the dose and dosing regimen can be based on either change in BW or 
LDL-C levels. 
Therefore, the Investigator can manage, based on his/her own judgment, adjustment of alirocumab 
dose based on changes in BW: 
• 
If the patient is currently on 40 mg Q2W but the BW has changed from <50 kg to ≥50 kg, 
then the Investigator can adjust the dose to 75 mg Q2W. 
• 
If the patient is currently on 150 mg Q4W but the BW has changed from <50 kg to ≥50 kg, 
then the Investigator can adjust the dose to 300 mg Q4W. 
Note: For patients whose weight oscillates around 50 kg the dose must be adjusted only once 
during the open-label treatment period. 
Lipid levels will be communicated to the Investigator during the OL treatment period from the 
second visit (ie, Week 32) onwards. From this visit, the Investigator is responsible, based on 
his/her own judgment related to the patient’s LDL-C levels and the safety profile, to up-titrate, 
down-titrate, maintain the dose of alirocumab or discontinue alirocumab throughout the study. 
From Week 32 onwards: 
For Q2W dosing regimen cohort: 
The following up-titration or down-titration of alirocumab doses will be possible: 


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Up-titration: 
• 
40 mg to 75 mg Q2W if BW <50 kg.  
• 
75 mg to 150 mg Q2W if BW ≥50 kg. 
Down-titration: 
• 
75 mg to 40 mg Q2W if BW <50 kg. 
• 
150 mg to 75 mg Q2W if BW ≥50 kg. 
For Q4W dosing regimen cohort: 
Dose adjustment will be possible, as follows: 
• 
150 mg Q4W to 75 mg Q2W if BW <50 kg. 
• 
300 mg Q4W to 150 mg Q2W if BW ≥50 kg. 
Note: A patient for whom the dose has been adjusted to a Q2W dosing regimen can only have 
subsequently a dose modification following the rule that applies for the Q2W dosing regimen 
cohort. 
Approximately 150 patients (approximately 75 patients in each dosing regimen cohort) from 
approximately 70 sites will be randomized. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
To evaluate the efficacy of alirocumab administered Q2W and Q4W versus placebo after 
24 weeks of double-blind treatment on LDL-C levels in patients with heFH 8 to 17 years of age on 
optimal stable daily dose of statin therapy ± other LMTs or a stable dose of non-statin LMTs in 
case of intolerance to statins. 
1.2.2 Secondary objectives 
• 
To evaluate the efficacy of alirocumab versus placebo on LDL-C levels after 12 weeks of 
double-blind treatment. 
• 
To evaluate the effects of alirocumab versus placebo 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 12 and 24 weeks of 
treatment. 
• 
To evaluate the safety and tolerability of alirocumab after 24 weeks of treatment in 
comparison with placebo. 


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• 
To evaluate the efficacy, safety and tolerability of alirocumab after 80 weeks of open-label 
treatment. 
• 
To evaluate the development of anti-alirocumab antibodies after 24 weeks of treatment 
during the double-blind treatment period. 
1.2.3 Other Objectives 
• 
To evaluate the development of anti-alirocumab antibodies after 80 weeks of open-label 
treatment. 
• 
To evaluate the pharmacokinetics (PK) of alirocumab. 
1.2.4 Exploratory objective of the FMD sub-study 
To explore the effect of alirocumab versus placebo on endothelial function after 24 weeks of 
treatment in heFH patients aged of 8 to 17 years on optimal stable daily dose of statin therapy ± 
other LMTs or a stable dose of non-statin LMTs in case of intolerance to statins. 
1.3 
DETERMINATION OF SAMPLE SIZE 
Each alirocumab dosing regimen group will be compared to its contemporaneously randomized 
placebo group (ie, of the same dosing regimen cohort) as follows: 
• 
alirocumab Q2W versus placebo Q2W  
• 
alirocumab Q4W versus placebo Q4W 
Of note, Q2W and Q4W refer to the dosing regimens initiated at randomization. 
Multiplicity will be controlled using Bonferroni adjustment, hence using a two-sided alpha level 
of 0.025 for each comparison. 
With a randomization ratio of 2:1 (alirocumab: placebo) for each dosing regimen cohort, a total 
sample size of 90 patients (30 in each alirocumab dosing regimen group and 15 in each placebo 
dosing regimen group) will have 92% power to detect a difference in mean percent change in 
LDL-C of 30% in any comparison between each alirocumab dosing regimen group and its 
contemporaneously randomized placebo dosing regimen group with a 0.025 two-sided 
significance level and assuming a common standard deviation (SD) of 25%. 
Nevertheless, to have a sufficient number of pediatric patients for properly assessing the safety 
and tolerability of alirocumab, sample size was increased to 150 patients in total (50 in each 
alirocumab dosing regimen group and 25 in each of the placebo dosing regimen group). The 
enrollment of 150 patients will allow for a safety assessment over 2 years in approximately 
128 patients, assuming a discontinuation rate of 15%. 
Calculations were made using nQuery 7.0 Advisor software. 


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Sample Size Determination for the FMD sub-study: 
Assuming that 30 to 39 patients (regardless of the dosing regimen cohort: 20 to 26 in the 
alirocumab group and 10 to 13 in the placebo group) will participate in the sub-study, the 
statistical power to demonstrate superiority of alirocumab versus placebo at a 0.05 two-sided 
significance level is provided in Table 1. This sample size calculation is based on several 
assumptions for the mean difference and standard deviation (SD) of the absolute change from 
baseline to Week 24 in flow mediated dilatation of the brachial artery that are enumerated in 
Table 1. 
Table 1 - Statistical power according to mean difference and SD of the FMD absolute change from 
baseline to Week 24 
Expected number 
of patients  
(2:1 ratio) 
Standard 
deviation  
(%) 
Delta mean (%) 
2 
2.5 
3 
30 
2.5 
51% 
70% 
84% 
 
4 
23% 
34% 
46% 
39 
2.5 
63% 
81% 
93% 
 
4 
29% 
43% 
57% 


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1.4 
STUDY PLAN 
The following figures present the graphical study design: 
Figure 1 - Graphical study design for Q2W dosing regimen cohort 
 
 


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Figure 2 - Graphical study design for Q4W dosing regimen cohort 
 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section. 


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Table 2 - Protocol amendment statistical changes 
Amendment 
Number 
Rationale 
Description of statistical changes 
2 
Revision of the statistical section in 
accordance with the addition of the 
Q4W regimen 
- 
Sample size considerations adapted to the addition of 
the Q4W regimen 
- 
In the efficacy analyses, addition of alirocumab Q4W 
and placebo Q4W to the treatment groups used in the 
statistical modelling, as well as description of the main 
comparison (each alirocumab regimen compared to the 
combined placebo group) 
- 
Addition of an analysis exploring the difference in terms 
of percent change from baseline in LDL-C between the 
2 alirocumab dosing regimens  
- 
Safety analyses: the summary of safety results will be 
presented in each alirocumab regimen, in the combined 
alirocumab group (ie, regardless of the regimen), and in 
the combined placebo group.  
 
 
- 
Description of the duration of exposure added for the 
Q4W dosing regimen 
- 
Revision of the handling of multiplicity. 
3 
Revision of the statistical sections in 
order to specify analyzing each of 
the two randomized dosing regimen 
cohorts separately 
- 
Revision of the 2 main comparisons: in each dosing 
regimen cohort, the alirocumab group will be compared 
to its contemporaneously randomized placebo group 
(ie, of the same dosing regimen cohort). The study 
power has been updated accordingly. Revision of the 
statistical models (a separate model will be run for each 
dosing regimen cohort) 
Revision of the treatment groups to be displayed in 
result summaries for safety and other endpoints: 
alirocumab and placebo within each dosing regimen 
cohort, and regardless of the dosing regimen cohort 
(pooled across cohorts) 
To be consistent with the 
significance level that will be used 
for tests (2.5% two-sided), 97.5% CI 
will be computed instead of 95% CI.  
- 
Since two-sided test with a significance level of 2.5% 
will be performed, 97.5%CI will be computed instead of 
95%CI for primary and secondary efficacy endpoints. 
Information omitted by error in the 
previous version 
- 
Addition of the definition of the treatment period for the 
Q4W dosing regimen cohort  
- 
For the FMD sub-study: addition of the dosing regimen 
cohort and the treatment-by-dosing regimen cohort 
effects in the statistical model.  
Revision of the statistical analysis 
for the FMD sub-study due to its 
very exploratory nature 
- 
Removal of the multiple imputations process 


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1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Changes already incorporated in a protocol amendment are listed in Table 2. The statistical 
analysis plan history table below gives the timing, rationale, and key details for major changes to 
the statistical analysis features in this amended version of the statistical analysis plan (version 2) 
compared to the initial version (version 1) of 8 January 2021. 
Table 3 - Statistical analysis plan statistical changes 
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
This version  
Per protocol, safety assessments 
(laboratory data, vital signs etc..) at 
Week 24 are measured on the same 
day as the administration of first open-
label injection (just before)  
For patients proceeding into the open-label 
period, the double-blind TEAE period is 
truncated at the first open-label injection and 
not the day before (Section 2.1.4) 
2 
This version 
As per regulatory agency’s feedback   
Unequal variances by treatment group will be 
implemented for ANCOVA analyses 
(Section 2.4.4.1.4, Section 2.4.4.4 and 
Section 2.4.5.7). Consistently, a correlation 
matrix by treatment group to model within-
patients error will be used for the MMRM 
models (Section 2.4.4.1.1) 
2 
This version  
As per regulatory agency’s feedback   
In the pattern mixture model (Section 2.4.4.1.4), 
post-treatment missing values for patients who 
discontinued the treatment due to the COVID-
19 pandemic will be imputed under missing at 
random assumption, ie. based on on-treatment 
values in the same treatment group 
2 
This version  
Simplification 
Removal of a sensitivity analysis in 
Section 2.4.4.1.5 as a similar analysis is 
already included in Section 2.4.4.1.4 
2 
This version  
As per regulatory agency’s feedback   
Pattern Mixture Model for key secondary 
continuous efficacy endpoints normally 
distributed will be implemented 
(Section 2.4.4.2.1) 
2 
This version  
As per regulatory agency’s feedback   
For binary efficacy endpoints, in the situation of 
data dependent case, post-treatment missing 
values will be considered as failure (except for 
patients who discontinue due to the COVID-19 
pandemic) (Section 2.4.4.2.3)  
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last available value obtained before or equal to the date and 
time of the first double-blind Investigational Medicinal Product (IMP) injection in the EFC14643 
study. In case of missing time of the first double-blind IMP injection and/or time of assessment, 
the baseline value is defined as the last available value obtained before or equal to the date of the 
first double-blind IMP injection. 
For patients randomized and not treated, the baseline value is defined as the last available value 
obtained before or equal to the date and time of randomization. In case of missing time of 
assessment, the baseline value is defined as the last available value obtained before or equal to the 
date of the randomization. 
All baseline safety and efficacy parameters are presented along with the summary statistics in the 
safety and efficacy sections (Section 2.4.4 and Section 2.4.5). 
Demographic characteristics 
Demographic variables include: 
• 
Gender (Male, Female). 
• 
Age in years (quantitative and categorical variable: <12 and ≥12 to <18 years, as well as 
<10, ≥10 to <12, and ≥12 to <18 years). 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, other). 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino). 
• 
Weight in kilograms (quantitative and categorical variable: <50 and ≥50 kg). 
• 
Height in centimeters (quantitative variable). 
• 
Body mass index (BMI) in kg/m² (quantitative and categorical variable: <P5: Underweight, 
≥P5 to <P85: Healthy weight, ≥P85 to <P95: Overweight and ≥P95: Obesity, using the 
World Health Organization [WHO] growth reference 5-19 years (1, 2, 3). 
Medical or surgical history 
Medical or surgical history includes medical history of specific interest such as cardiovascular 
(CV) history and cardiovascular risk factors, subject medical allergic history and family medical 
allergic history, and relevant medical or surgical history other than hypercholesterolemia, CV/CV 


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Risk and allergies. Medical and surgical history will be described using all pre-printed terms 
collected in the dedicated medical history e-CRF pages. 
CV history and CV Risk factors history will be based on items pre-listed in the dedicated medical 
history e-CRF page and include: 
• 
Family history of Myocardial Infarction (MI) (below 50 years of age in 2nd degree relative 
or below 60 years of age in 1st degree relative). 
• 
Family history of raised cholesterols (>7.5 mmol/L [290 mg/dL] in adult 1st or 2nd degree 
relative or >6.7 mmol/L [260 mg/dL] in child or sibling under 16 years of age). 
• 
Tendon xanthoma in family (in 1st or 2nd degree relative). 
• 
Familial defective apo B-100. 
• 
DNA-based evidence of an LDL receptor mutation (of the subject). 
• 
Tendon xanthoma (of the subject). 
• 
Subject history of raised Total-C: Total-C >6.7 mmol/l (260 mg/dL) in a child under 
16 years of age OR >7.5 mmol/l (290 mg/dL) above 16; Levels either pre-treatment or 
highest on treatment. 
• 
Subject history of raised LDL cholesterol: LDL cholesterol > 4.0 mmol/l (155 mg/dL) in a 
child under 16 years OR > 4.9 mmol/l (190 mg/dL) above 16; Levels either pre-treatment 
or highest on treatment. 
• 
Hypertension (of the subject). 
• 
Type 1 Diabetes (of the subject). 
• 
Type 2 Diabetes (of the subject). 
Subject medical allergic history and family medical allergic history will be described using all pre-
printed terms collected in the dedicated medical history e-CRF page. 
All medical history information pre-listed or not in the e-CRF, will be coded using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time 
of database lock. 
Smoking status and alcohol habits 
Smoking status and alcohol habits include: 
• 
Smoking status (Never, Former and Current). 
• 
Frequency of alcoholic drinks in the last 12 months (Never/Occasional/At least monthly/At 
least weekly/At least daily). 
• 
Number of standard drinks (1 or 2/Greater than 2) per day when drinking alcohol. 


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Disease Characteristics and relevant medical data 
Specific disease characteristic includes: 
• 
Diagnosis of heFH made by Clinical Simon Broome Criteria (Definite/Possible). 
• 
Diagnosis of heFH made by genotyping at any time prior to or during the study (Yes [Prior 
to screening/ At baseline with centralized genotyping], No). 
• 
Time to diagnosis (in years). 
• 
Statin intolerant status, as per protocol definition (Yes, No): 
- 
If Yes, reason the subject is statin intolerant: [Subject is not receiving a daily regimen 
of statin/Not tolerating daily dose, Subject unable to tolerate statins, having tried at 
least 2 statins: one statin at the lowest daily starting dose, AND another statin at any 
dose, due to skeletal muscle-related symptoms]. 
- 
If Not statin intolerant: [Subject treated with maximal dose of statin he can tolerate due 
to adverse event (AE) at higher dose [Yes, No]]. 
- 
If Yes, AE(s) encountered at higher doses: [Skeletal muscle related events, Liver 
function test abnormalities, Co-morbid conditions such as impaired glucose 
tolerance/impaired fasting glucose, Other]. 
- 
If No, reason of no statin intensification: [Regional practice or local guideline, 
Patient/parent’s refusal, Other]. 
• 
Subjects, age of 8 to less than 10 years, have had other available interventions to lower 
calculated LDL-C, but these have been insufficient [Yes, No, NA]. 
• 
Type of lipid-modifying therapy ever taken: Statin, fibrates, bile acid sequestrant, 
cholesterol absorption inhibitor, nicotinic acid and derivates, omega 3 fatty acids 
≥1000 mg/day) as reported in the “History of Hyperlipoproteinemia” e-CRF page. 
• 
Background LMT at randomization, as reported in the dedicated prior & concomitant 
medications e-CRF pages. 
- 
Any statin  
- 
Atorvastatin daily dose in mg (<10, 10, 20, 40, 80, Other), 
- 
Rosuvastatin daily dose in mg (<5, 5, 10, 20, 40, Other), 
- 
Simvastatin daily dose in mg (<10, 10, 20, 40, >40, Other), 
- 
Pravastatin daily dose in mg (<10, 10, 20, 40, >40, Other), 
- 
Lovastatin daily dose in mg (<10, 10, 20, 40, >40, Other), 
- 
Fluvastatin daily dose in mg (<20, 20, 40, 80, >80, Other), 
- 
Pitavastatin (at any dose) 


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- 
Any LMT other than statins: 
- 
Ezetimibe, 
- 
Any other LMT other than nutraceuticals (by chemical class and drug name). 
This includes fenofibrate and other non-Statin LMT eg, niacin. 
- 
Nutraceuticals (Omega 3 fatty acids (<1000mg/day), Phytosterols, 
Psyllium/plantago, Policosanol, Other nutraceuticals). 
Other baseline characteristics  
Other baseline characteristics include: 
• 
Glycated haemoglobin A1c (HbA1c) (quantitative and qualitative variable: <5.7%, ≥5.7% 
to <6.5%, ≥6.5%), and efficacy lipid parameters (quantitative variables for all efficacy 
parameters and the following categorical variables) will be also summarized at baseline 
(see definition in Section 2.1.3): 
• 
LDL-C: <130, ≥130 to <160, ≥160 to <190, ≥190 mg/dL (ie, <3.37, ≥3.37 to <4.14, 
≥4.14 to <4.91, ≥4.91 mmol/L). 
• 
HDL-C: <40, ≥40 mg/dL (ie, <1.04, ≥1.04 mmol/L). 
• 
Non-HDL-C: <160, ≥160 to <190, ≥190 to <220, ≥220 mg/dL (ie, <4.14, ≥4.14 to <4.91, 
≥4.91 to 5.69, ≥5.69 mmol/L). 
• 
Fasting TGs: <150, ≥150 to <200, ≥200 mg/dL (ie, <1.7, ≥1.7 to <2.3, ≥2.3 mmol/L). 
• 
Lp(a): <30, ≥30 to <50, ≥50 mg/dL (ie, <0.3, ≥0.3 to <0.5, ≥0.5 g/L).  
• 
Apo B: <75, ≥75 to <90, ≥90 mg/dL (ie, <0.75, ≥0.75 to <0.9, ≥0.9 g/L). 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5. 
2.1.2 Prior or concomitant medications and post-treatment medications 
All medications taken within 12 weeks prior to screening and until the end of the study, including 
LMTs are to be reported in one of the following specific case report form pages: 
• 
Previous and concomitant statin drugs. 
• 
Previous and concomitant lipid lowering drugs (other than statins). 
• 
Other Previous and concomitant medications (other than statin, lipid lowering drugs).   
• 
Topical anesthetic for IMP injection. 


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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• 
Prior medications are those the patient used within 12 weeks prior to screening visit and 
prior to first double-blind IMP administration. Prior medications can be discontinued 
before first administration or can be ongoing during treatment phase. 
• 
Double-blind concomitant medications are any treatments received by the patient 
concomitantly with the IMP, from first double-blind IMP to the last double-blind IMP 
injection +70 days (for patients choosing not to continue into the OL period). For patients 
entering in the OL period, concomitant medications will be truncated at the day before first 
open-label IMP injection in the extension period. A given medication can be classified 
both as a prior medication and as a concomitant medication. Double-blind concomitant 
medications do not include medications started during the double-blind post-treatment 
period (as defined in the observation period in Section 2.1.4). 
• 
Post-treatment double-blind medications are those the patient took in the period starting 
from 71 days after the last double-blind IMP injection and ending when the patient 
terminates the study (for patients choosing not to continue into the OL period). 
• 
Open-label concomitant medications are defined as any treatments received by the patient 
concomitantly with the open-label IMP, from the first open-label IMP injection to the last 
open-label IMP injection +70 days. 
• 
Post-treatment open-label medications are those the patient took in the period starting from 
71 days after the last open-label IMP injection. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5 
2.1.3 Efficacy endpoints 
Efficacy endpoints include lipid parameters (ie, Total-C, LDL-C, HDL-C, fasting TG, 
non-HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp[a]). All these parameters are measured or 
calculated by a central laboratory, for both scheduled and unscheduled time points. Calculated 
LDL-C is obtained using the Friedewald formula. However if TG values exceed 400 mg/dL 
(4.52 mmol/L), the LDL-C should be measured by the Central Laboratory (via beta quantification 
method) and used as the reference value for LDL-C rather than calculated LDL-C. Non-HDL-C is 
calculated by subtracting HDL-C from the Total-C. 
Unless otherwise specified, all lipid values (scheduled or unscheduled, fasting or not fasting) may 
be used to provide a value for the primary and secondary efficacy endpoints. All measurements, 
scheduled or unscheduled, fasting or not fasting, will be assigned to analysis windows defined in 
Section 2.5.4, Table 5 and Table 6 in order to provide an assessment for time points when the lipid 
values were to be collected as per protocol. For TG, only fasting measurements will be used and 
measurements with missing fasting status will be excluded from the analyses. 


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For all time points post-baseline, the value used for the analyses at a given time point 
(eg, at Week 24) is the value obtained within the corresponding analysis window. 
The baseline definition described in Section 2.1.1 will be used for the analyses of the double-blind 
and OL periods. 
The analysis of primary and key secondary endpoints consists of the comparison of each 
alirocumab dosing regimen group versus its contemporaneously randomized placebo group 
(ie, alirocumab Q2W versus placebo Q2W; alirocumab Q4W versus placebo Q4W) for endpoints 
listed in primary endpoint and secondary endpoints. A sequential inferential approach will be used 
within each regimen (refer to Section 2.4.4.3). 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the percent change in LDL-C from baseline to Week  24 in the 
intent-to-treat (ITT) population (defined in Section 2.3.1.1), using LDL-C values regardless of 
adherence to treatment (ITT estimand). Primary endpoint is defined as: 100x (LDL-C value at 
Week 24 - LDL-C value at baseline) / LDL-C value at baseline. 
The LDL-C at Week 24 will be the LDL-C level obtained within the Week 24 analysis window. 
All calculated and measured LDL-C values (scheduled or unscheduled, fasting or not fasting) may 
be used to provide a value for the primary efficacy endpoint if appropriate according to the above 
definition. In case both calculated and measured LDL-C values are provided for the same 
sampling, the measured LDL-C will be considered. 
2.1.3.2 Secondary efficacy endpoint(s) 
2.1.3.2.1 Key secondary efficacy endpoints 
The key secondary efficacy endpoints are: 
• 
Percent change in LDL-C from baseline to Week 12 (ITT estimand). 
• 
Percent change in Apo B from baseline to Week 24 (ITT estimand). 
• 
Percent change in non-HDL-C from baseline to Week 24 (ITT estimand). 
• 
Percent change in Total-C from baseline to Week 24 (ITT estimand). 
• 
Percent change in Apo B from baseline to Week 12 (ITT estimand). 
• 
Percent change in non-HDL-C from baseline to Week 12 (ITT estimand). 
• 
Percent change in Total-C from baseline to Week 12 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 130 mg/dL (3.37 mmol/L) at 
Week 24 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 130 mg/dL (3.37 mmol/L) at 
Week 12 (ITT estimand). 


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• 
Proportion of patients achieving a LDL-C level lower than 110 mg/dL (2.84 mmol/L) at 
Week 24 (ITT estimand). 
• 
Proportion of patients achieving a LDL-C level lower than 110 mg/dL (2.84 mmol/L) at 
Week 12 (ITT estimand). 
• 
Percent change in Lp (a) from baseline to Week 24 (ITT estimand). 
• 
Percent change in Lp (a) from baseline to Week 12 (ITT estimand). 
• 
Percent change in HDL-C from baseline to Week 24 (ITT estimand). 
• 
Percent change in fasting TG from baseline to Week 24 (ITT estimand). 
• 
Percent change in Apo A-1 from baseline to Week 24 (ITT estimand). 
• 
Percent change in HDL-C from baseline to Week 12 (ITT estimand). 
• 
Percent change in fasting TG from baseline to Week 12 (ITT estimand). 
• 
Percent change in Apo A-1 from baseline to Week 12 (ITT estimand). 
2.1.3.2.2 Other secondary efficacy endpoints 
• 
All primary and key secondary endpoints in the modified ITT (mITT) population (defined 
in Section 2.3.1.2), using LDL-C values during the treatment period (on-treatment 
estimand). 
• 
Absolute change in Apo B/Apo A-1 ratio to Week 12 and Week 24 (ITT and on-treatment 
estimands). 
• 
Proportion of patients achieving at least 30% reduction, 50% reduction in LDL-C at 
Week 24 (ITT and on-treatment estimands). 
• 
Proportion of patients achieving at least 30% reduction, 50% reduction in LDL-C at 
Week 12 (ITT and on-treatment estimands). 
• 
Percent change in LDL-C from baseline to Week 104 (ITT and on-treatment estimands). 
2.1.3.2.3 Exploratory endpoint of the FMD sub-study 
The exploratory endpoint of the FMD sub-study is the absolute change from baseline to Week 24 
in flow mediated dilatation of the brachial artery (as determined by the central reading laboratory) 
regardless of adherence to treatment. The analysis will consist of the comparison of alirocumab to 
placebo, regardless of the dosing regimen cohort. 
On-treatment analysis will be also conducted. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported AEs and other safety information, such as 
clinical laboratory data, vital signs, Tanner stage and Cogstate battery (neurocognitive functions) 
test assessment. 


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Observation period for the Q2W dosing regimen cohort, 
The observation of safety data will be as follows: 
• 
The pre-treatment period is defined from the signed informed consent up to the first dose 
of double-blind IMP.  
• 
Double-blind treatment-emergent adverse event (TEAE) period is defined as: 
- 
the time from the first dose of double-blind IMP to the last dose of double-blind IMP 
injection +70 days (10 weeks) as residual effect of alirocumab is possible until 10 
weeks after the stop of treatment IMP injection. This period will be truncated at the 
first dose of open-label IMP for patients proceeding into the OL treatment period. 
The double-blind TEAE period will include: 
- 
The double-blind treatment period defined as the time from the first dose of double-
blind IMP injection up to the day of last dose of double-blind IMP injection +21 days. 
• 
The double-blind post-treatment period is defined as the time starting the day after the end 
of the double-blind TEAE period (truncated at the first dose of open-label IMP for patients 
proceeding into the open-label treatment period). 
• 
The open-label TEAE period is defined as the time from the first dose of open-label IMP 
injection up to the day of last dose of open-label IMP injection +70 days. 
- 
The open-label TEAE period will include the open-label treatment period defined as 
the time from the first dose of open-label IMP injection up to the day of last dose of 
open-label IMP injection + 21 days. 
• 
The open-label post-treatment period is defined as the time starting the day after the end of 
the open-label TEAE period (ie, 71 days after the day of last dose of open-label IMP 
injection). 
Observation period for the Q4W dosing regimen cohort, 
The observation of safety data will be as follows: 
• 
The pre-treatment period is defined from the signed informed consent up to the first dose 
of double-blind IMP. 
- 
Double-blind treatment-emergent adverse event (TEAE) period is defined as:  the time 
from the first dose of double-blind IMP to the last dose of double-blind IMP injection 
+70 days (10 weeks) as residual effect of alirocumab is possible until 10 weeks after 
the stop of treatment IMP injection. This period will be truncated at the first dose of 
open-label IMP for patients proceeding into the OL treatment period. 
The double-blind TEAE period will include: 
- 
The double-blind treatment period defined as the time from the first dose of double-
blind IMP injection up to the day of last dose of double-blind IMP injection +35 days 


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for patients who stopped definitively the IMP before the switch to Q2W regimen 
(actual or sham) at Week 12 
- 
The double-blind treatment period defined as the time from the first dose of double-
blind IMP injection up to the day of last dose of double-blind IMP injection +21 days, 
otherwise. 
• 
The double-blind post-treatment period is defined as the time starting the day after the end 
of the double-blind TEAE period (truncated at the first dose of open-label IMP for patients 
proceeding into the open-label treatment period). 
• 
The open-label TEAE period is defined as the time from the first dose of open-label IMP 
injection up to the day of last dose of open-label IMP injection +70 days. 
The open-label TEAE period will include the open-label treatment period defined as: 
- 
the time from the first dose of open-label IMP injection up to the day of last dose of 
open-label IMP injection +35 days, for patients still under Q4W regimen at the end of 
the open-label treatment period. 
- 
the time from the first dose of open-label IMP injection up to the day of last dose of 
open-label IMP injection + 21 days, otherwise. 
• 
The open-label post-treatment period is defined as the time starting the day after the end of 
the open-label TEAE period (ie, 71 days after the day of last dose of open-label IMP 
injection). 
2.1.4.1 Adverse events variables 
Adverse events (including serious adverse events (SAEs) and adverse events of special interest 
(AESIs) are recorded from the time of signed informed consent until the end of study (definition 
of AESIs is provided in the study protocol). All AEs diagnosed by the Investigator will be 
reported and described. 
All AEs will be coded to a “lowest level term (LLT)”, “preferred term (PT)”, “high level term 
(HLT)”, “high level group term (HLGT)” and associated primary “system organ class (SOC) using 
the version of MedDRA currently in effect at Sanofi at the time of database lock. 
Adverse event observation period  
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the pre-
treatment period. 
• 
For double-blind period: 
- 
Double-blind treatment-emergent adverse events are AEs that developed or worsened 
or became serious during the double-blind TEAE period. 
- 
Double-blind post-treatment AEs are AEs that developed or worsened or became 
serious during the double-blind post-treatment period. 
• 
For open-label period: 


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- 
Open-label treatment-emergent adverse events are AEs developed or worsened or 
became serious during the open-label TEAE period. 
- 
Open-label post-treatment AEs are AEs that developed or worsened or became serious 
during the open-label post-treatment period. 
Groupings of adverse events  
Grouping of adverse events include the following: 
• 
Local injection site reactions (AESIs or not), selected using e-CRF specific tick box on the 
adverse event page. 
• 
General allergic events (AESIs or not), selected using SMQ “hypersensitivity” (broad and 
narrow) excluding the preferred terms linked to local injection site reactions (ie, preferred 
terms containing “injection site” or “infusion site”). 
• 
ALT >3 ULN (if baseline ALT < ULN), or ALT ≥2 times  the baseline value (if baseline 
ALT ≥ ULN), selected using laboratory data. 
• 
Neurologic events (AESIs or not), selected using a CMQ based on SMQs “demyelination” 
(broad and narrow), “peripheral neuropathy” (broad and narrow), and “Guillain-Barre 
syndrome” (broad and narrow) excluding the following preferred terms “acute respiratory 
distress syndrome”, “asthenia”, “respiratory arrest” and “respiratory failure” and including 
selected PTs from SMQ "optic nerve disorders" (see Table 8 for the list of terms). 
• 
Neurocognitive events: 
- 
Selected using a CMQ, based on the following 5 HLGTs: “deliria (including 
confusion)”, “cognitive and attention disorders and disturbances”, “dementia and 
amnestic conditions”, “disturbances in thinking and perception”, and “mental 
impairment disorders”. 
- 
A second grouping of terms for neurocognitive events was defined based on 
Regulatory Agency request (see Table 9 for the list of terms). 
• 
Symptomatic overdose of IMP selected using appropriate MedDRA codes and the tick 
boxes “Overdose of Alirocumab” and “Symptomatic Overdose” in the overdose adverse 
event form. 
• 
Pregnancy (including male patient’s partner) selected using eCRF tick box. 
In addition, the following additional grouping of events will be provided: 
• 
Hepatic disorder events using SMQ “Hepatic disorder”. 
• 
Diabetes mellitus or diabetic complications using 1/HLGT “diabetes complications” 
(including PTs pertaining to the secondary SOC included in the HLGT), 2/ the HLT 
“diabetes mellitus”, 3/ the HLT “carbohydrate tolerance analyses (including diabetes)” 
excluding PTs “blood glucose decreased” and “glycosylated haemoglobin decreased” and 
4/  from the HLT "hyperglycaemic conditions NEC" only the following PTs 
“hyperglycaemia”, “hyperglycaemic unconsciousness” and “hyperglycaemic seizure”. 


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• 
Cataract using HLT “Cataract conditions”. 
Of note, groupings are based on the version of MedDRA currently in effect at Sanofi at the time of 
this SAP version (Version 23.1) and may be updated if appropriate, based on a more recent 
version available at time of database lock. 
2.1.4.2 Deaths 
The deaths observation periods are per the observation periods defined above.  
For double-blind period: 
• 
Death on-treatment: deaths occurring during the double-blind TEAE period, 
• 
Death post-treatment: deaths occurring during the double-blind post-treatment period 
For open-label period: 
• 
Death on-treatment: deaths occurring during the open-label TEAE period, 
• 
Death post-treatment: deaths occurring during the open-label post-treatment period 
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consist of blood analysis, including hematology and clinical chemistry. 
Clinical laboratory values will be analyzed into international units. International units will be used 
in all listings and tables. Clinical laboratory values converted into conventional (US) units will be 
also available in the database. Analyses can be provided upon request. 
Unless otherwise specified below, blood samples for clinical laboratories (eg, hematology, clinical 
chemistry) were to be collected during: 
• 
Screening at Visit 2 (up to Week -2). 
• 
The double-blind period at Visit 4 (Week 0 / Day 1), Visit 6 (Week 12) and Visit 7 (Week 
24) /or early termination.   
• 
The OL period at Visit 8 (Week 32), Visit 9 (Week 44), Visit 11 (Week 68) and Visit 14 
(Week 104)/or early termination, for patients proceeding into OL period. 
Adrenal gland hormones, gonadal and pituitary hormones, fat soluble vitamins, were to be 
collected during: 
• 
The double-blind period at Visit 4 (Week 0 / Day 1) and Visit 7 (Week 24)/or early 
termination  
• 
The OL period at Visit 9 (Week 44), Visit 11 (Week 68) and Visit 14 (Week 104)/or early 
termination, for patients proceeding into OL period. 


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The following laboratory parameters (excluding those considered as efficacy parameters) will be 
classified as follows: 
• 
Hematology:  
- 
Red blood cells and platelets: hemoglobin, hematocrit, red blood cell count, platelet 
count and hematocrit 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. 
• 
Clinical chemistry: 
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase (CPK), 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphorus, bicarbonate, 
- 
Renal function: creatinine, eGFR, creatinine clearance, blood urea nitrogen, uric acid, 
- 
Liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), gamma glutamyl transferase (γGT), lactate dehydrogenase 
(LDH),  total bilirubin, and in case of total bilirubin values above the normal range, 
must include conjugated and non-conjugated bilirubin (used for describing individual 
cases only). 
• 
Adrenal gland hormones: cortisol (with reflexive adrenocorticotrophic hormone (ACTH) 
levels if cortisol < lower limit of normal [LLN]) and dehydroepiandrosterone sulfate 
(DHEAS). 
• 
Gonadal hormones: testosterone (males) and estradiol (females).  
• 
Pituitary hormones: luteinizing hormone (LH) and follicle-stimulating hormone (FSH). 
• 
Fat soluble vitamins: A (retinol), D (25 hydroxy vitamin D), E (alpha-tocopherol), and K 
(phylloquinone). 
• 
Serum pregnancy test: blood test at screening visit and local urine pregnancy test for all 
other tests. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital Signs parameters include Heart Rate (HR), Systolic and Diastolic Blood Pressure (SBP and 
DBP) in sitting position, as well as weight, height and BMI. 
Body weight was to be measured during: 
• 
Run-in (if applicable) at Visit 1 (up to Week -6) or Screening at Visit 2 (up to Week -2). 
• 
The double-blind period at Visit 4 (Week 0/Day 1), Visit 6 (Week 12), Visit 7 
(Week 24)/or early termination.  


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• 
The OL period at Visit 8 (Week 32), Visit 9 (Week 44), Visit 11 (Week 68), Visit 13 
(Week 92) and Visit 14 (Week 104)/or early termination for patients proceeding into OL 
period. 
Height was to be measured during: 
• 
Run-in (if applicable) at Visit 1 (up to Week -6) or Screening at Visit 2 (up to Week -2). 
• 
The double-blind period at Visit 7 (Week 24)/or early termination. 
• 
The OL period at Visit 9 (Week 44), Visit 11 (Week 68) and Visit 14 (Week 104)/or early 
termination for patients proceeding into OL period. 
BMI and height percentiles will be calculated (1, 2, 3). 
Heart rate and blood pressure were to be measured during: 
• 
Screening at Visit 2 (up to Week -2).  
• 
The double-blind period at Visit 4 (Week 0/Day 1), Visit 6 (Week 12), Visit 7 (Week 24) 
/or early termination. 
• 
The OL period at Visit 8 (Week 32), Visit 9 (Week 44), Visit 11 (Week 68) and Visit 14 
(Week 104)/or early termination for patients proceeding into OL period. 
2.1.4.5 Electrocardiogram variables 
Not applicable 
2.1.4.6 Tanner stage measurement 
Tanner stages measurement include assessments of boys–development of external genitalia, girls 
breast development, boys/girls –pubic hair, performed if possible, by the same 
investigator/designee trained to assess pubertal development, during: 
• 
Run-in (if needed) at Visit 1 (up to Week -6) or Screening at Visit 2 (up to Week -2). 
• 
The double-blind period at Visit 7 (Week 24)/or early termination. 
• 
The OL period at Visit 9 (Week 44), Visit 11 (Week 68) and Visit 14 (Week 104)/or early 
termination for patients proceeding into OL period. 
In addition, a global Tanner puberty classification as Prepubescent [Tanner stage = 1], Pubescent 
[Tanner stage ≥2 to 4] and Postpubescent [Tanner stage = 5]) will be derived,  based on breast 
development stage for girls and external genitalia stage for boys as it is commonly reported in the 
literature that in most children the first signs of puberty is breast development for girls and 
external genitalia for boys (4, 5, 6). 


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2.1.4.7 Cogstate battery test 
Cogstate battery test was to be administered during: 
• 
The double-blind period at Visit 4 (Week 0/Day 1) and Visit 7 (Week 24)/or early 
termination 
• 
The OL period at Visit 11 (Week 68) and Visit 14 (Week 104)/or early termination 
Cogstate battery test consists of identification test (IDN), detection test (DET), one card learning 
test (OCL), and Groton maze learning test (GML). The results (ie, scores) will be automatically 
calculated. The change from baseline to Week 24 will be calculated for each score. 
Z-scores will be also computed for each test based on patient’s age at baseline for the 24-week DB 
period, or based on patient’s age at the visit when the test is performed for the OL period (see 
Appendix E and Appendix F for details). 
A composite score will be calculated as the mean of the Z-scores equally weighted, provided that 
at least three of the four tests are available AND if all the following cognitive domains are 
covered: 
• 
Attention, through either DET or IDN 
• 
Visual learning, through OCL 
• 
Executive function, through GML 
Then change from baseline to Week 24 will be computed for the composite score. 
2.1.5 Other endpoints 
Other endpoints listed below are defined using same definitions and rules as for LDL-C, when 
applicable (see Section 2.1.3) and include: 
• 
The absolute change in HbA1c (%) from baseline to Week 24 in the double-blind period, as 
well as change from baseline to Week 68 and Week 104 in the OL period. PCSA criteria 
for HbA1c will be also used (see Appendix A). 
• 
The proportion of patients with  2 consecutives results, spaced out by at least 21 days, of 
LDL-C <50 mg/dL (<1.30 mmol/L), LDL-C <25 mg/dL (<0.65 mmol/L) , LDL-C 
<15 mg/dL( 0.39 mmol/L) during each treatment period (double-blind or open-label) and 
the time to the first LDL-C <50 mg/dL (<25 mg/dL, <15mg/dL respectively) for these 
patients within the relevant treatment period. 
• 
Cardiac function: CPK-MB and cardiac troponin (at Visit 4 [Week 0 / Day 1] and Visit 7 
[Week 24]/or early termination) and in case of any clinically relevant cardiovascular effect 
observed in patients. 
• 
The percent change in hs-CRP from baseline to Week 24 in the double-blind period. 
Hs-CRP values greater or equal to 10 mg/L will be excluded from analyses in a second 
approach, since these are suggestive of concurrent infections (1). PCSA (potentially 


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clinically significant abnormalities) criteria for hs-CRP will be also used (see  
Appendix A). 
• 
Urine test at Visit 4 (Week 0 / Day 1) and Visit 7 (Week 24)/or early termination. 
Macroscopy will be performed at the central laboratory. If abnormal, then a standard 
microscope assessment will be conducted. 
2.1.6 Anti-alirocumab antibodies variables 
Anti-alirocumab antibodies (ADA) are assessed: 
• 
During the double-blind period at Visit 4 (Week 0/Day 1, before the first IMP injection), at 
Visit 6 (Week 12) and Visit 7 (Week 24)/or early termination for patients not proceeding 
into OL period. 
• 
During the OL period at Visit 11 (Week 68) and Visit 14 (Week 104) /or early termination 
for patients proceeding into OL period. 
ADA measurements will be assigned to the same analysis windows as defined for efficacy 
endpoints (Table 5 and Table 6).The following variables will be described for both double-blind 
and open-label periods: 
• 
ADA response (Positive or Negative). 
For ADA positive: 
- 
Titer levels.  
- 
Neutralizing status (Positive or Negative). 
• 
Pre-existing positive ADA defined as patients with positive ADA response at baseline with 
less than 4-fold increase in titer in the post-baseline period. 
• 
Treatment-emergent positive ADA response defined as: 
- 
Patients with no ADA positive response at baseline but with any positive response in 
the post-baseline period (for double-blind period: up to Visit 7 (Week 24)/ early 
termination  visit for patients not proceeding into open-label period or first open-label 
IMP injection for patient proceeding into open-label period, for open-label period: up 
to Visit 14 (week 104)/early termination.  
OR  
- 
Patients with a positive ADA response at baseline and at least a 4-fold increase in titer 
in the post-baseline period (for double-blind period: up to Visit 7 (Week 24)/early 
termination  for patients not proceeding into OL period or first open-label IMP 
injection for patient proceeding into OL period, for OL period: up to Visit 14 (week 
104)/early termination. 


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For treatment-emergent positive ADA, the following categories for ADA duration will be 
applied: 
- 
A persistent positive response is a treatment-emergent ADA positive response detected 
in at least 2 consecutive post-baseline samples separated by at least a 12-week period. 
- 
An indeterminate duration positive response is defined as ADA present only at the last 
sampling time point.  
- 
A transient positive response is defined as any treatment-emergent positive ADA 
response that is neither considered persistent nor indeterminate.  
In addition, potential ADA samples to be collected for patients who do not enter into OL period or 
who prematurely discontinue the double-blind period and have a titer≥240 at their end of 
treatment visit will be listed. 
2.1.7 Pharmacokinetic variables  
Concentrations of total alirocumab, total and free PCSK9 in serum are assessed during the double-
blind period at  Visit 4 (Week 0/Day 1), Visit 5 (Week 8), Visit 6 (Week 12) and Visit 7 
(Week 24). 
Pharmacokinetic variable is the total alirocumab concentration at each time point. Depending on 
the timing of the sample versus the previous injection, Ctrough, will be defined as follows: 
• Ctrough for Q2W regimen: alirocumab concentration sample taken between 8 and 21 days 
after previous injection of alirocumab (ie, just prior the next injection). 
• Ctrough for Q4W regimen: alirocumab concentration sample taken between 22 and 35 days 
after previous injection of alirocumab (ie, just prior the next injection). 
Total alirocumab concentration and total and free PCSK9 concentration will be described 
following time windows as defined in Section 2.5.4 in Table 7. 
Of note, for patients with a dose adjustment from Q4W dosing regimen to Q2W dosing regimen, 
the Ctrough will be defined according to the regimen received at the time of the sample collection. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patient who signed the informed consent. 
Randomized patients consist of all screened patients, with a double-blind treatment kit number 
allocated and recorded in the IVRS/IWRS database, regardless of whether the treatment kit was 
used or not. Patients treated without being randomized or treated with a double-blind treatment kit 


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before the randomization will not be considered as randomized and will not be included in any 
analysis population. 
For patient study status in the double-blind period, the total number of patients in each of the 
following categories will be presented in the clinical study report using a flowchart diagram or 
summary table: 
• 
Screened patients. 
• 
Screen failure patients and reasons for screen failure. 
• 
Non-randomized but treated patients, if any. 
• 
Randomized patients. 
• 
Randomized but not treated patients and reason for not being treated. 
• 
Randomized and treated patients. 
• 
Patients who completed the double-blind study treatment period as per protocol (as per 
eCRF end of double-blind treatment form). 
• 
Patients who did not complete the double-blind study treatment period as per protocol (as 
per eCRF end of double-blind treatment form). 
• 
Patients who discontinued the double-blind study treatment by main reason for permanent 
treatment discontinuation (as per eCRF end of double-blind treatment form). 
• 
Status at last study contact for patients not entering in the open-label treatment extension. 
• 
Patients participating in the open-label treatment extension period.  
For all above categories of patients (except for the screened and non-randomized categories) 
percentages will be calculated using the number of randomized patients as denominator and 
summaries will be presented by treatment group as described in Section 2.4. 
For patient study status in the open-label period, the total number of patients in each of the 
following categories will be presented in the clinical study report using a flowchart diagram or 
summary table: 
• 
Patients treated during the OL period (all patients who received at least one open-label 
injection during the OL period). 
• 
Patients who completed the OL treatment period as per protocol (as per eCRF end of open-
label treatment form). 
• 
Patients who did not complete the OL treatment period as per protocol (as per eCRF end of 
open-label treatment form). 
• 
Patients who discontinued OL treatment by main reason for permanent treatment 
discontinuation. 


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For patient study status in the open-label period, percentages will be calculated using the number 
of patients in the OL population (defined in Section 2.3.5) as denominator and summaries will be 
presented by treatment group as described in Section 2.4. 
Reasons for treatment discontinuation will be supplied in tables giving numbers and percentages. 
The incidence of premature treatment discontinuation during the double-blind period (irrespective 
of the reason) and premature treatment discontinuation due to AEs will be presented graphically 
on randomized and treated patients (as randomized), using Kaplan-Meier method. 
Any critical or major protocol deviations (automatic or manual) will be summarized by deviation 
category in the randomized population for the double-blind period and in the OL population for 
open-label period. This description will also be performed distinguishing patients with trial impact 
due to Covid-19 from those who were not (see definition in Section 2.3). In addition, the number 
(%) of patients by country/site and the listing of patients with at least one critical or major 
deviation will be provided. 
Additionally, the following populations will be summarized: 
• 
Randomized population. 
• 
Efficacy populations: ITT and mITT populations. 
• 
Exploratory efficacy population: FMD sub-study population. 
• 
Safety population. 
• 
Pharmacokinetics population. 
• 
Anti-alirocumab antibody population. 
• 
Open-label population. 
• 
Population without trial impact/disruption due to COVID-19. 
Definitions of the study populations are provided in Section 2.3. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) a patient is randomized based on an incorrect stratum, or b) a patient is 
randomized twice. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a non-
randomized patient is treated with IMP reserved for randomized patients. 


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Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. These irregularities will be summarized on the randomized population.  Non-randomized, 
treated patients will be described separately.  
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any analysis population.  The safety experience of patients treated and not randomized 
will be reported separately, and these patients will not be in the safety population. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Efficacy populations 
The primary efficacy analysis population will be the ITT population. 
2.3.1.1 Intent-to-treat population  
The ITT population is defined as all randomized patients. 
Patients in the ITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
2.3.1.2 Modified Intent to treat population 
The mITT population is defined as all randomized patients who took at least one dose or part of a 
dose of the double-blind IMP injection. 
Patients in the mITT population will be analyzed according to the treatment group allocated by 
randomization (ie, as-randomized treatment group). 
2.3.1.3 FMD sub-study population 
The analysis of the FMD will be performed on randomized patients included in the sub-study with 
a baseline and a post-baseline FMD assessment available. Patients in the FMD sub-study 
population will be analyzed according to the treatment group allocated by randomization 
(ie, as-randomized treatment group). 


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2.3.2 Safety population 
The Safety population considered for safety analyses will be the randomized patients who actually 
received at least one dose or part of a dose of the double-blind IMP injection. Patients will be 
analyzed according to the treatment actually received (ie, as-treated treatment group). 
In addition, randomized patients for whom it is unclear whether they took the study medication 
will be included in the safety population in the treatment group as randomized. 
Within each dosing regimen cohort, for patients receiving mistakenly both placebo and 
alirocumab (regardless of the dose) IMP injection during the double-blind  period (cases reported 
as protocol deviation), the treatment group used for as-treated analysis will be defined according 
to the treatment (alirocumab or placebo) of which the patient received highest number of 
injections. In case of the same number of injections of each treatment is received, the as-treated 
treatment group will be the as-randomized group. Of note, placebo injections allocated by 
IVRS/IWRS to maintain the blind for the alirocumab Q4W group (“sham Q2W”) will not be taken 
into account in the derivation of the “as-treated treatment group”. 
2.3.3 Anti-alirocumab antibody population 
The ADA analysis will be performed on all randomized and treated patients (safety population) 
with an available ADA sample at Week 0 (baseline) and at least one non-missing ADA sample 
post first double-blind IMP injection and up to Week 24/early termination or up to first open-label 
IMP injection for patient proceeding into open-label period. 
2.3.4 Pharmacokinetics population 
The PK analysis will be performed on all randomized and treated patients (safety population) with 
at least one non-missing  drug concentration value (including BLQ values) post first double-blind 
IMP injection and up to Week 24/early termination visit or up to first injection in the open-label 
period, for patients proceeding into the open-label period. 
2.3.5 Open-label population 
The OL population considered for all analyses in the OL treatment period will be all randomized 
patients who received at least one dose or part of dose of IMP during the OL treatment period. 
2.3.6 Population without trial impact/disruption due to COVID-19 
The population without trial impact/disruption due to COVID-19 will be defined as any patient 
without any of the following: 
• 
Major or critical deviation related to COVID-19 
• 
Permanent treatment discontinuation related to COVID-19 
• 
Permanent study discontinuation related to COVID-19. 


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2.4 
STATISTICAL METHODS 
General rules 
Analyses will be performed separately for the double-blind and the OL periods, unless otherwise 
noted. 
Double-blind period 
Unless otherwise specified, the analyses will be performed by treatment group (placebo, 
alirocumab) within each dosing regimen cohort. 
In addition, for disposition, populations, demographic/baseline characteristics, safety and other 
endpoints (refer to Section 2.1.5), analyses will be provided by treatment group (placebo, 
alirocumab) regardless of the dosing regimen cohorts (pooled across cohorts). 
Of note, an Overall column will be displayed for populations, demographics and baseline 
characteristics. 
 OL period 
The summaries will be displayed according to the treatment group (placebo, alirocumab) received 
in the double-blind period and Overall within each dosing regimen cohort (dosing regimen 
initiated at the randomization). 
For disposition, populations, demographic/baseline characteristics, safety and other endpoints, 
analyses will be also provided by treatment group received in the double-blind period regardless of 
the dosing regimen cohorts, and Overall.  
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized using descriptive statistics. 
Continuous data will be summarized using the number of available data, mean, SD, median, 
minimum and maximum for each treatment group. First quartile (Q1) and third quartile (Q3) will 
be also provided for baseline lipid parameters and HbA1c. Categorical and ordinal data will be 
summarized using the number and percentage of patients. 
Parameters will be summarized on the randomized population analyzed in the as-randomized 
treatment group.  Similar analyses will be done on safety population in the as-treated treatment 
group and will be included in the appendices if the size of the safety population is different 
(>10%) from the size of the randomized population for any dosing regimen/treatment group. In the 
randomized population, parameters will also be summarized within each randomization stratum as 
per IVRS/IWRS. 
All reported patient’s medical and surgical history will be presented by primary SOC and HLT. 
The tables will be sorted by SOC internationally agreed order and decreasing frequency of HLT 


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based on the overall incidence across treatment groups. In addition, all medical history of specific 
interest (see Section 2.1.1) will be summarized. 
These parameters will be also summarized in the OL population. 
P-values on demographic and baseline characteristic data will not be calculated. 
No specific description of safety parameters will be provided at baseline. If relevant, the baseline 
values will be described along with each safety analysis. 
2.4.2 Prior or concomitant medications  
Double-blind period 
The prior, concomitant and post-treatment medications will be presented for the safety population. 
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomical therapeutic chemical (ATC) class (anatomic category) and the first 3 digits of 
the ATC class (therapeutic category). All ATC codes corresponding to a medication will be 
summarized, and patients will be counted once in each ATC category (anatomic or therapeutic) 
linked to the medication. Therefore, patients may be counted in several categories for the same 
medication. 
The table for prior medications will be sorted by decreasing frequency of ATC followed by 
therapeutic class based on the overall incidence across treatment groups.  In case of equal 
frequency across anatomic or therapeutic categories, alphabetical order will be used. 
The tables for concomitant and post-treatment medications will be sorted by decreasing frequency 
of ATC followed by therapeutic class based on the incidence in the combined alirocumab group. 
In case of equal frequency across anatomic or therapeutic categories, alphabetical order will be 
used. 
In addition, concomitant LMT medications will be summarized by pre-specified categories, 
chemical class or therapeutic class and standardized medication name. 
OL period 
All concomitant and post-treatment medications recorded during the OL period will be 
summarized in the OL population according to the WHO-DD dictionary. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance for the double-blind period will be assessed and 
summarized for the safety population; for the OL period, it will be assessed on the OL population. 
In addition, a description will be performed distinguishing patients with trial impact due to 
COVID-19 from those who were not.  


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2.4.3.1 Extent of investigational medicinal product exposure 
Double-blind period 
• 
Q2W dosing regimen cohort 
The exposure during the double-blind period will be assessed using descriptive statistics for: 
- 
The total number of double-blind IMP administrations by patient. 
- 
Duration of IMP exposure in weeks defined as (last dose of double-blind IMP injection 
date – first dose of double-blind IMP injection date + 14 days)/7, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of 
missing or incomplete data). 
• 
Q4W dosing regimen cohort 
The exposure during the double-blind period will be assessed using descriptive statistics for: 
- 
The total number of double-blind IMP administrations by patient. 
- 
Duration of IMP exposure in weeks defined as: 
- 
(last dose of double-blind IMP injection date – first dose of double-blind IMP 
injection date + 28 days)/7, for patients who stopped definitively the IMP before 
the switch to Q2W regimen (actual or sham) at Week 12, regardless of unplanned 
intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data). 
- 
(last dose of double-blind IMP injection date – first dose of double-blind IMP 
injection date + 14 days)/7, otherwise, regardless of unplanned intermittent 
discontinuations (see Section 2.5.3 for calculation in case of missing or incomplete 
data). 
Non-integer values will be rounded to one decimal place. 
All quantitative parameters above will be summarized using number, mean, SD, median, 
minimum and maximum. In addition, the durations of treatment exposure will be summarized 
according to the following categories: ≥1 day and <4 weeks, ≥4 weeks and <8 weeks, ≥8 weeks 
and <12 weeks, ≥12 weeks and <16 weeks, ≥16 weeks and <22 weeks, ≥22 weeks. 
OL period 
• 
Q2W dosing regimen cohort 
The duration of IMP exposure (in weeks) during the OL period will be defined as (last dose of 
open-label IMP injection date – first dose of open-label IMP injection date + 14 days)/7, 
regardless of unplanned intermittent discontinuations. 
• 
Q4W dosing regimen cohort 


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The duration of IMP exposure (in weeks) during the OL period will be defined as: 
- 
(last dose of open-label IMP injection date – first dose of open-label IMP injection date 
+ 28 days)/7, for patients still under Q4W regimen at the end of the open-label 
treatment period, regardless of unplanned intermittent discontinuations.  
- 
(last dose of open-label IMP injection date – first dose of open-label IMP injection date 
+ 14 days)/7, otherwise, regardless of unplanned intermittent discontinuations. 
Duration of IMP exposure will be summarized using number, mean, SD, median, minimum and 
maximum and according to the following categories: ≥1 day and <24 weeks, ≥24 weeks and 
<52 weeks, ≥ 52 weeks and <78 weeks, ≥ 78 weeks. 
Combined period (double-blind and OL periods) 
In each dosing regimen cohort, study treatment exposure variables combining double-blind and 
open-label periods are listed below for all patients who received alirocumab in the double-blind 
period and entered in the OL period: 
• 
Combined duration of alirocumab exposure in weeks, regardless of unplanned intermittent 
discontinuations. 
• 
The following categories will be used for treatment exposure intervals: ≥1 day and 
<24 weeks, ≥24 weeks and <52 weeks, ≥ 52 weeks and <78 weeks, ≥ 78 weeks and 
<102 weeks, ≥ 102 weeks. 
Titration/dose-adjustment 
For the double-blind period, the number and percentage of patients with an up-titration/dose-
adjustment in the alirocumab group during the double-blind period will be described for each 
dosing regimen cohort. 
• 
In the Q2W dosing regimen cohort, patients with an up-titration are defined as up-titrated 
patients according to IVRS/IWRS Week 12 transaction with at least 1 injection of 
alirocumab 75 mg Q2W for patients with baseline BW<50 kg and 150 mg Q2W for 
patients with baseline BW≥50 kg afterwards. 
• 
In the Q4W dosing regimen cohort, patients with a dose-adjustment are defined as dose-
adjusted patients according to IVRS/IWRS Week 12 transaction with at least 1 injection of 
alirocumab 75 mg Q2W for patients with baseline BW<50 kg and 150 mg Q2W for 
patients with baseline BW≥50 kg afterwards. 
For the OL period, the number and percentage of patients with an up-titration/dose-adjustment at 
Week 32 or thereafter will be described for each dosing regimen cohort, as well as the number and 
percentage of patients down-titrated at least once. A summary of titration status will be provided 
by visit. Reasons for up- or down-titration and LDL-C used to up/down-titrate will be 
summarized, overall and by visit. LDL-C will be summarized quantitatively and with the 
following categories: <25, ≥25 and <50, ≥50 and <110, ≥110 and <130, ≥ 130 mg/dL. 


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2.4.3.2 Compliance 
For the Q2W dosing regimen cohort, compliance for the double-blind period will be assessed 
using the following parameters: 
• 
The mean administration frequency of IMP double-blind injections will be defined for 
each patient as the average number of days between 2 consecutive double-blind 
administrations, that is: (last double-blind administration date – first double-blind 
administration date)/ (number of double-blind administrations -1) for patients receiving at 
least 2 administrations. 
• 
The overall compliance for double-blind injections will be defined for each patient as: 100- 
(%days with under-planned dosing + %days with above-planned dosing). Under-planned 
and above-planned dosing will be defined as follows, considering that administrations 
should be performed every 2 weeks (±3 days as per protocol): 
- 
The % days with under-planned dosing will be defined for each patient as the number 
of days with no IMP administration within the previous 17 days divided by the 
duration of IMP exposure in days. For example, if a patient takes a dose 18 days after 
his/her previous administration, then 1 day is counted as a day under-planned dosing. 
- 
The % days with above-planned dosing will be defined for each patient as the number 
of days with more than one administration within the 11 days before divided by the 
duration of IMP exposure in days. For example, if a patient takes a dose 9 days after 
his/her previous administration, then 2 days are counted as days above-planned dosing. 
For the Q4W dosing regimen cohort, compliance for the double-blind period will be assessed 
using the following parameters: 
• 
The mean administration frequency of IMP double-blind injections will be defined for 
each patient as the average number of days between 2 consecutive double-blind 
administrations, that is: (last double-blind administration date – first double-blind 
administration date)/ (number of double-blind administrations -1) for patients receiving at 
least 2 administrations. 
• 
The overall compliance for double-blind injections will be defined for each patient as: 100- 
(% days with under-planned dosing + %days with above-planned dosing). Under-planned 
and above-planned dosing will be defined as follows, considering that administrations 
should be performed every 4 weeks (±3 days as per protocol) during the first 12 weeks and 
every 2 weeks (±3 days) afterwards: 
- 
The % days with under-planned dosing will be defined for each patient as: 
▪  the number of days with no IMP administration within the previous 31 days 
divided by the duration of IMP exposure in days, for the first 12 weeks. 
▪  the number of days with no IMP administration within the previous 17 days 
divided by the duration of IMP exposure in days, after the first 12 weeks.  
- 
The % days with above-planned dosing will be defined for each patient as: 


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▪  the number of days with more than one administration within the 25 days before 
divided by the duration of IMP exposure in days within the first 12 weeks.  
▪ the number of days with more than one administration within the 11 days before 
divided by the duration of IMP exposure in days after the first 12 weeks.  
If appropriate, for the Q4W dosing regimen cohort, mean administration frequency and 
compliance could be also provided separately for the first 12 weeks and the period after. 
For the OL period, only mean administration frequency will be assessed for compliance. 
• 
The mean administration frequency of IMP open-label injections will be defined for each 
patient as the average number of days between 2 consecutive open-label administrations, 
that is: (last open-label administration date – first open-label administration date)/(number 
of administration -1) for patients receiving at least 2 administrations (or partial 
administration) 
These parameters will be summarized descriptively (N, Mean, SD, Median, Minimum and 
Maximum). 
The percentage of patients whose overall compliance for injections is <80% will be also 
summarized as well as numbers and percentages of patients with 0%, >0% and ≤5%, >5% and 
≤10%, >10% and ≤20%, and >20% days with above-planned dosing and numbers and percentages 
of patients with 0%, >0% and ≤5%, >5% and ≤10%, >10% and ≤20%, and >20% days with under-
planned dosing. 
According to protocol, cases of overdose are reported in the AE e-CRF pages and will be 
described in the AE analysis (see Section 2.1.4.1 and Section 2.4.5.1). More generally, dosing 
irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
For statistics where international and conventional units do not impact the results (eg, means and 
least square (LS) means for percent changes from baseline, p-values for both percent and absolute 
changes from baseline, rates of patients below a threshold), derivations will be done and statistical 
models will be run using conventional units. For other statistics (eg, descriptive statistics at 
baseline and over time, absolute changes from baseline), derivations will be done with both 
international and conventional units. 
Double-blind period 
Statistical analyses for the primary and secondary efficacy endpoints will be conducted in the 
double-blind period and will compare each alirocumab dosing regimen group versus its 
contemporaneously randomized placebo group (ie, of the same dosing regimen cohort): 
• 
alirocumab Q2W versus placebo Q2W 
• 
alirocumab Q4W versus placebo Q4W 


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Of note, Q2W and Q4W refer to the dosing regimens initiated at randomization. 
Efficacy endpoints analyzed with the ITT estimand will be analyzed in the ITT population. 
Efficacy endpoints analyzed with the on-treatment estimand will be analyzed in the mITT 
population. 
OL period 
With respect to efficacy data collected during the OL period, only descriptive summaries for each 
lipid parameter will be provided in the OL population. 
Formal testing is not planned due to the absence of control group in the OL period. 
Combined period (double-blind and OL periods) 
For patients receiving alirocumab in the double-blind period, a combined summary including both 
the double-blind and open-label period assessments may be considered, referencing the double-
blind baseline for variable calculations. 
2.4.4.1 Analysis of primary efficacy endpoint 
2.4.4.1.1 Primary efficacy analysis 
Within each dosing regimen cohort, the percent change from baseline in LDL-C to Week 24 as 
defined in Section 2.1.3.1 will be analyzed in the ITT population using a mixed-effect model with 
repeated measures (MMRM) model. All post-baseline data available within Week 8 to Week 24 
analysis windows will be used and missing data will be accounted for by the MMRM model. 
For the Q2W dosing regimen cohort, the model will include the fixed categorical effects of 
treatment group (alirocumab, placebo), randomization strata (previous participation [yes or no] to 
DFI14223 study, baseline body weight [<50 or ≥50 kg]), time point (Week 8, Week 12, Week 24), 
treatment-by-time point interaction, and strata-by-time point interaction, as well as the continuous 
fixed covariates of baseline LDL-C value and baseline value-by-time point interaction. Model 
assumptions for normality will be explored prior to the analysis testing. 
For the Q4W dosing regimen cohort, the model will include the fixed categorical effects of 
treatment group (alirocumab, placebo), randomization strata (baseline body weight [<50 or 
≥50 kg]), time point (Week 8, Week 12, Week 24), treatment-by-time point interaction, and strata-
by-time point interaction, as well as the continuous fixed covariates of baseline LDL-C value and 
baseline value-by-time point interaction. Model assumptions for normality will be explored prior 
to the analysis testing. 
Of note, the stratum related to the previous participation in the DFI14223 Phase 2 study will not 
be included in the model for the Q4W dosing regimen cohort, as too few patients from this Phase 
2 study are enrolled in this cohort due to the late start of enrollment in the Q4W regimen. 


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These 2 separate models will be run using SAS Mixed procedure with an unstructured correlation 
matrix by treatment group (in case of convergence issue, a common unstructured correlation 
matrix for both groups will be used) 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. 
Throughout MMRM models, least-square (LS) mean and standard error (SE) at Week 24 will be 
provided for each treatment group within each dosing regimen cohort. 
LS means difference at Week 24 will be provided for the comparison of each alirocumab dosing 
regimen group versus its contemporaneously randomized placebo group (ie, of the same dosing 
regimen cohort) as follows: 
• 
alirocumab Q2W versus placebo Q2W 
• 
alirocumab Q4W versus placebo Q4W, 
with the SE, 97.5% confidence intervals (CI) and p-value, using appropriate contrasts. Statistical 
testing will be evaluated at a 2-sided significance level of 0.025 per comparison. 
 Within group least-squares means and standard errors will be provided, using weights equal to the 
observed proportion of patients in strata variable levels in the study population (ie, “population 
weight”) rather than equal weights. Population weights are considered more appropriate than 
equal coefficients due to unbalances observed in the study population between levels of the 
randomization stratification factors. 
Let µ0, µ1 be the population means of the percent change from baseline in calculated LDL-C at 
Week 24 under placebo and alirocumab in the Q2W dosing regimen cohort, and respectively µ0’, 
µ1’ the corresponding population means in the Q4W dosing regimen cohort. The hypotheses that 
will be tested are: 
• 
For Q2W dosing regimen cohort: “H0: µ0 =µ1 versus “H1: µ0≠µ1 
• 
For Q4W dosing regimen cohort: “H0: µ0’ =µ1’ versus “H1: µ0’≠µ1’ 
The MMRM models relies on the “missing-at-random” (MAR) assumption. As we can never 
exclude the possibility for a not-missing-at-random (NMAR) missingness mechanism, sensitivity 
analyses to explore the impact of non-ignorable missingness on the primary efficacy analysis will 
be conducted (pattern mixture model approach using mixed imputation defined in 
Section 2.4.4.1.4).  
2.4.4.1.2 Model assumption checks 
Homogeneity of treatment effect across baseline LDL-C levels 
In order to check the homogeneity of treatment effect versus baseline LDL-C, the following 
interaction terms will be added in the two primary MMRM models: 
• 
Treatment group * baseline LDL-C. 


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• 
Treatment group * time-point * baseline LDL-C. 
Within the framework of this model with interaction terms, for each dosing regimen cohort, a 
graph presenting the LS means difference versus the placebo group at Week 24 and the 
corresponding 97.5% CI will be provided by baseline LDL-C value. 
Analysis of residuals: 
The analysis of the residuals of the MMRM (for each dosing regimen cohort separately) will be 
primarily based on studentized residuals. It will include: 
• 
Normality of studentized residuals, presented graphically using histogram and QQ-plot. 
• 
Plot of studentized residuals versus predicted values. 
• 
Distribution of studentized residuals, presented graphically using boxplots, within each 
category of the fixed categorical effects of the MMRM: 
- 
treatment group (alirocumab and placebo). 
- 
time point (Week 8, Week 12, Week 24). 
- 
treatment-by-time point interaction. 
- 
randomization strata. 
- 
randomization strata-by time point interaction. 
2.4.4.1.3 Sensitivity to randomization strata 
In order to assess the robustness of the primary analysis to randomization stratum mistakes (ie, the 
stratum recorded in IVRS differs from the actual one), the MMRM model for each dosing regimen 
cohort for the primary efficacy endpoint will be re-run including the actual stratum as per the 
eCRF instead of the stratum recorded in IVRS. 
In addition, for each dosing regimen cohort, a sensitivity analysis excluding patients who 
previously participated in the Phase 2 DFI14223 study will be conducted for the primary efficacy 
endpoint. 
2.4.4.1.4 Sensitivity to handling of missing data 
Sensitivity analyses will be conducted to assess the robustness of primary efficacy analysis with 
regards to handling of missing data (7) (for each dosing regimen cohort separately). 
Visual examination: 
• 
In order to explore the missing data pattern, post-baseline LDL-C observations (in the ITT 
population) will be described by visit according to the following groups:  
1. LDL-C available at Week 24* (ie, primary efficacy endpoint available), 
2. LDL-C available at Week 12* but missing at Week 24*, 


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3. LDL-C available at Week 8* but missing from Week 12*, 
4. LDL-C missing from Week 8 
(*): as defined in Section 2.5.4 in Table 5 
• 
Then, a graph of mean LDL-C levels (respectively percent change from baseline in 
LDL-C) ± SE at baseline, Week 8, Week 12 and Week 24 will be provided by missing data 
pattern, for each treatment group. 
In the ITT population, demographic and baseline characteristics will be described within the 
missing data pattern number 1 versus the pooled others. P-values from Fisher exact test for 
categorical data and from asymptotic one-way ANOVA test for Wilcoxon scores (Kruskal-Wallis 
test) for continuous data, will be also provided, for descriptive purposes. 
Multiple Imputations (under MAR assumption): 
In addition to the MMRM method, for each dosing regimen cohort separately, the multiple 
imputation method will be used to address missing values, in the randomized population, followed 
by the testing of alirocumab versus placebo group, using an analysis of covariance (ANCOVA) 
model, with unequal variances by treatment group (except if convergence issue), with the intent to 
evaluate the robustness of the primary analysis using a different statistical method. The imputation 
model described in Section 2.4.4.2.2 will be used but without log transformation. In addition, for 
each simulation leading to negative imputed value, another value will be redrawn using 
MINIMUM option of MI SAS procedure. 
Pattern mixture model (see Appendix C for more details) 
For the Q2W dosing regimen cohort, multiple imputations will be used with different imputation 
strategies applied to LDL-C values missing during the on-treatment period (ie, within the time 
period from the first double-blind IMP injection up to the day of last double-blind injection 
+21 days) versus LDL-C values missing after treatment discontinuation (ie, after the day of last 
double-blind injection +21 days) based on the following assumptions: 
• 
Patients within 21 days of their last double-blind IMP injection would continue to show 
benefit from treatment similar to that observed at the scheduled time point. Therefore, 
LDL-C values missing during the on-treatment period (eg, samples obtained out-side the 
specified window, no blood sample available although visit was performed, etc.) should be 
considered “Missing At Random” and imputed based on other on-treatment measurements. 
• 
Patients who stopped taking their study treatment no longer benefited from it after 
discontinuation, and thus tended to have LDL-C values returning to baseline.  Therefore, 
LDL-C values missing more than 21 days after treatment discontinuation should be 
imputed based on patient’s own baseline value. 
For patients who permanently discontinued the treatment due to the COVID-19 pandemic, missing 
post-treatment data will be considered “Missing at Random” and imputed based on other on-
treatment measurements in the same treatment group. 


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Missing LDL-C values will be imputed 100 times to generate 100 complete data sets.  The percent 
change from baseline to Week 24 will be derived from observed and imputed LDL-C at this time 
point.  The completed data sets will be analyzed using an ANCOVA model, with unequal 
variances by treatment group (except if convergence issue),  with treatment group (alirocumab, 
placebo) and randomization strata (previous participation [yes or no] to DFI14223 study, baseline 
body weight [<50 or ≥50 kg]) as fixed effects, and the baseline LDL-C value as continuous 
covariate.  The results from the 100 analyses will be combined using Rubin’s formulae (8). 
For the Q4W dosing regimen cohort, the same approach will be taken with the following 
differences: 
• 
The on-treatment period will be defined as the time period from the first IMP injection up 
to the day of the last double-blind injection +35 days for patients with a last double-blind 
injection before the switch to Q2W regimen (actual of sham), +21 days otherwise. 
• 
The ANCOVA model will include treatment group (alirocumab, placebo) and 
randomization strata (baseline body weight [<50 or ≥50 kg]) as fixed effects, and the 
baseline LDL-C value as continuous covariate. 
2.4.4.1.5 Sensitivity to the impact of COVID-19 
To estimate what would have been the treatment effect had the COVID-19 pandemic not occurred, 
the MMRM model used for the primary analysis will be executed on the population without trial 
impact/disruption due to COVID-19 (See definition in Section 2.3.6). 
2.4.4.1.6 Subgroup analyses 
To assess the homogeneity of the treatment effect across various subgroups, treatment-by-
subgroup factor, time point-by-subgroup factor and treatment-by time point-by subgroup factor 
interaction terms and a subgroup factor term will be added in the two primary MMRM models 
(except for the subgroup “Body weight”). 
LS means difference at Week 24 will be provided, as well as the corresponding SE and 97.5% CIs, 
within each subgroup for each alirocumab dosing regimen group versus its contemporaneously 
randomized placebo dosing regimen group (ie, of the same dosing regimen cohort): 
• 
alirocumab Q2W versus placebo Q2W,  
• 
alirocumab Q4W versus placebo Q4W, 
The significance level of the treatment-by-subgroup factor interaction term for each alirocumab 
dosing regimen group versus its contemporaneously randomized placebo group (ie, of the same 
dosing regimen cohort) at Week 24 will be also provided for each factor group for descriptive 
purpose. Forest plots will be provided. In order to handle unbalances between randomization 
stratification factors levels, population weights will be used as for the primary analysis model. 
Only subgroups for which we anticipate having enough patients in each level are evaluated. 


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Subgroups of interest are: 
• 
Body Weight stratum as par IVRS/IWRS (<50 kg, ≥50 kg), 
• 
Gender (Female, Male), 
• 
Age (<12 years, ≥12 years), 
• 
Baseline LDL-C: < 160 mg/dl; ≥160 mg/dL. 
2.4.4.2 Analyses of secondary efficacy endpoints 
2.4.4.2.1 Continuous endpoints anticipated to have a normal distribution 
Continuous secondary efficacy endpoints defined in Section 2.1.3.2 analyzed with the ITT 
estimand and anticipated to have a normal distribution [ie, lipids other than TG and Lp(a)] will be 
analyzed using the same MMRM models as for the primary endpoint with the corresponding 
baseline and post-baseline values in the ITT population. 
Continuous secondary efficacy endpoints analyzed with the on-treatment estimand and anticipated 
to have a normal distribution will be analyzed using the same MMRM models but only including 
on-treatment values in the mITT population. 
• 
For the Q2W dosing regimen cohort, the treatment period is defined as the time period 
from the first double-blind IMP injection up to the day of last double-blind injection 
+21 days. 
• 
For the Q4W dosing regimen cohort, the treatment period is defined as the time period 
from the first double-blind IMP injection up to the day of last double-blind injection 
+35 days for patients who stopped IMP before the switch to Q2W regimen (actual or 
sham), +21 days otherwise. 
In addition, key continuous secondary efficacy endpoints anticipated to have a normal distribution 
will be analyzed using the same ITT estimand and Pattern Mixture Model for missing data as 
described for the primary efficacy endpoint in Section 2.4.4.1.4. 
2.4.4.2.2 Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy endpoints defined in Section 2.1.3.2 analyzed with the ITT 
estimand and anticipated to have a non-normal distribution (ie, TG and Lp(a)), will be analyzed 
using multiple imputation approach for handling of missing values in the ITT population. The 
percent change from baseline at time point of interest will be derived from observed and imputed 
lipid values at this time point. 
For the Q2W dosing regimen cohort, multiple imputation will be followed by robust regression 
model (9) with endpoint of interest as response variable using M-estimation (using SAS 
ROBUSTREG procedure) with treatment group (alirocumab, placebo), randomization strata 
(previous participation [yes or no] to DFI14223 study, baseline body weight [<50 or ≥50 kg]) and 
corresponding baseline value(s) as effects to compare treatment effects. Combined means 


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estimates for each treatment group will be provided. The differences of these estimates with their 
corresponding SEs, 97.5% CIs and p-value will be provided through the SAS MIANALYZE 
procedure for the comparison of the alirocumab group versus the placebo group. 
For the Q4W dosing regimen cohort, the same strategy will be conducted, using a robust 
regression model with endpoint of interest as response variable using M-estimation with treatment 
group (alirocumab, placebo) and randomization strata (baseline body weight [<50 or ≥50 kg]) as 
main effects and corresponding baseline value as covariate. 
For both dosing regimen cohorts, continuous secondary efficacy endpoints analyzed with the on-
treatment estimand and anticipated to have a non-normal distribution will be analyzed using the 
same imputation and analysis models but only including on-treatment values (see 
Section 2.4.4.2.1) in these models in the mITT population. 
Multiple imputation model 
Since in general the missing pattern is anticipated to be not monotone, a two-step approach will be 
used: 
• 
Step 1: The MCMC method will be used in conjunction with the IMPUTE=MONOTONE 
option to create an imputed data set with a monotone missing pattern; 
• 
Step 2: Using the monotone data set from step 1, missing data will be imputed using the 
regression method. 
The imputation model for step 1 will include the treatment group and the values of the analyzed 
parameter at baseline and time-points up to Week 24. 
The imputation model for step 2 will include the same variables as in step 1 with the following 
additional variables: 
• 
the randomization strata; 
• 
age and gender (age included as continuous variables). 
Data will be log-transformed before imputation process and then back-transformed to create the 
imputed data sets using the TRANSFORM statement of SAS MI procedure. 
2.4.4.2.3 Binary endpoints 
Binary secondary efficacy endpoints defined in  in Section 2.1.3.2 (ie, proportion of patients 
achieving at least 30% reduction, 50% reduction in LDL-C at Week 12 or Week 24) will be 
analyzed using multiple imputation approach for handling of missing values as described for non-
normally distributed endpoints but without log-transformation (see Section 2.4.4.2.2 for details 
about multiple imputation). 
For each simulation leading to negative imputed value, another value will be redrawn using 
MINIMUM option of MI SAS procedure. 


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For the Q2W dosing regimen cohort, the binary endpoint at time point of interest will be derived 
from observed and imputed lipid values at this time point. Multiple imputation will be followed 
by stratified logistic regression with treatment group (alirocumab, placebo) as main effect and 
corresponding baseline value(s) as covariate, stratified by randomization factors (as per IVRS, 
previous participation [yes or no] to DFI14223 study, baseline body weight [<50 or ≥50 kg]) 
Combined estimates of odds ratio 97.5% CIs, and p-value will be obtained through the SAS 
MIANALYZE procedure, for the alirocumab group versus the placebo group. 
For the Q4W dosing regimen cohort, the same strategy will be conducted using a stratified logistic 
regression with treatment group (alirocumab, placebo) as main effect and corresponding baseline 
value(s) as covariate, stratified by randomization factors (as per IVRS, baseline body weight [<50 
or ≥50 kg]). 
In the data dependent case such logistic regression is not applicable (eg, the response rate is zero 
in one treatment arm and thus the maximum likelihood estimate may not exist), a stratified exact 
conditional logistic regression would be performed to compare treatment effects. LDL-C values 
missing during the on-treatment period will be imputed using the last observation carried forward 
(LOCF) approach, as well as post-treatment missing values for patients who discontinued due to 
the COVID-19 pandemic. The LOCF imputation method will consist of using the last value 
obtained up to the Week 24 analysis window (Week 12 respectively) to impute the missing Week 
24 value (Week 12 respectively). Other post-treatment missing values will be considered as 
failure. 
In case of computing issues with exact logistic regression, the baseline level(s) will be entered in 
the model as a categorical variable(s) using quartiles. In case the model would not converge with 
stratification variables, an unstratified exact logistic regression will be performed. Exact odds ratio 
versus placebo, 97.5% CIs, and p-value will be provided. 
Binary secondary efficacy endpoints analyzed with the on-treatment estimand will be analyzed 
using the same imputation model, but only including on-treatment values (see Section 2.4.4.2.1)  
in this model in the mITT population. 
2.4.4.2.4 Summary of results per time point 
Double-blind period 
Central laboratory values (in conventional (US) and international units), percent change from 
baseline, and/or when appropriate absolute change from baseline (in conventional and 
international units), for LDL-C, Total-C, HDL-C, fasting TG, non-HDL-C, at Week 8, Week 12 
and Week 24 time points, for Lp(a), Apo-B, Apo-A1 and ratio Apo-B/Apo-A1 (absolute change 
from baseline) at Week 12 and Week 24 time points will be summarized in the ITT population 
and in the mITT population using: 
• 
For lipids other than TG and Lp(a): LS mean and SE, obtained from the same MMRM 
models as used for endpoints above and including planned time points (see 


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Section 2.4.4.2.1) and with raw values, changes from baseline, or percent change from 
baseline as response variable in the model as appropriate. 
• 
For TG and Lp(a): mean and SE obtained from multiple imputation approach followed by 
the robust regression models as used for endpoints above and including planned time 
points (see Section 2.4.4.2.2) and with raw values or percent changes from baseline as 
response variable in the model as appropriate. 
In addition, quantitative descriptive summaries by time point (value at visit and % change from 
baseline) will be presented for all lipids using observed (ie, non-missing) data. In addition, binary 
variables for LDL-C will be also described by time point. For LDL-C, these summaries will be 
also provided according to BW stratum as per IVRS/IWRS, and according to up-titration/dose 
adjustment status at Week 12. 
OL period  
Quantitative descriptive summaries by time point will be presented for LDL-C, Total-C, HDL-C, 
fasting TG, and non- HDL-C, Lp(a), Apo-B, Apo-A1 and ratio Apo-B/Apo-A1 using observed 
data in the OL population. LDL-C will be also described by category over time. 
Combined period 
In each dosing regimen cohort, for patients receiving alirocumab in the double-blind period, 
central laboratory values (in conventional (US) and international units) including both the double-
blind and open-label period assessments, percent change from baseline, and/or when appropriate 
absolute change from baseline (in conventional and international units), LDL-C, Total-C, HDL-C, 
fasting TG, and non- HDL-C, Lp(a), Apo-B, Apo-A1 and ratio Apo-B/Apo-A1 (absolute change 
from baseline) at all planned time points (Week 8 to Week 104) will be summarized by patient 
counts, mean and SD by all patients. 
2.4.4.3 Multiplicity issues 
The Bonferroni adjustment will be applied to handle multiplicity for the comparison of each 
alirocumab dosing regimen group versus its contemporaneously randomized placebo group 
(ie, alirocumab Q2W versus placebo Q2W; alirocumab Q4W versus placebo Q4W) for the 
primary efficacy endpoint (two-sided 0.025 alpha level will apply for each comparison). 
In order to handle multiple key secondary endpoints, the overall type-I error will be controlled by 
the use of a sequential inferential approach applied independently within each dosing regimen 
cohort (Q2W and Q4W). Statistical significance of the primary parameter at the two-sided 0.025 
alpha level is required before drawing inferential conclusions for that dosing regimen cohort about 
first key secondary parameter (refer to order of list in Section 2.1.3.2.1. Inferential conclusions 
about successive key secondary parameters for a given dosing regimen cohort require statistical 
significance of the prior one in that dosing regimen cohort. 
The Bonferroni adjustment and this fixed hierarchical approach will ensure a strong control of the 
overall type-I error rate at the two-sided 0.05 level. 


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No further adjustments will be made for other secondary endpoints for which p-values will be 
provided for descriptive purpose only (no claim). 
In addition, no further multiplicity adjustment is needed for multiple analyses (ie, first step and 
second step analyses, if applicable, see Section 3). All primary and key secondary efficacy 
endpoints will be fully evaluable at the time of the first step analysis. Analyses of lipid parameters 
beyond Week 24 will be descriptive. 
2.4.4.4 Exploratory efficacy analyses 
Difference in percent change in LDL-C between the 2 alirocumab Q2W and Q4W dosing regimen 
cohorts 
The difference in terms of percent change in LDL-C between the 2 alirocumab dosing regimen 
groups will be explored in the ITT population and in the mITT population. 
FMD sub-study 
The absolute change from baseline in FMD at Week 24 in the FMD sub-study population will be 
analyzed using an ANCOVA model, with unequal variances by treatment group (except if 
convergence issue). The model will include the fixed categorical effects of treatment group 
(alirocumab, placebo), the dosing regimen cohort (Q2W, Q4W) the treatment-by-dosing regimen 
cohort interaction and the continuous fixed covariate of baseline FMD value. Model assumptions 
for normality will be explored prior to the analysis testing. Throughout the ANCOVA model, 
least-square (LS) mean and standard error (SE) will be provided, regardless of the dosing regimen 
cohort, for the alirocumab group and the placebo group. LS means difference will be provided for 
the comparison of the alirocumab group versus the placebo group regardless of the dosing regimen 
cohorts with the 95% CI, using appropriate contrasts. 
All Week 24 FMD values will be included in the analysis regardless of individual patient 
adherence to treatment. 
In addition, the same statistical approach as described above will be applied but only including on-
treatment values in the model (on-treatment analysis). 
2.4.5 Analyses of safety data 
No formal inferential testing will be performed for either study period. Summaries will be 
descriptive in nature. All summaries of safety results described below will be presented for each 
study period respectively, unless otherwise noted. 


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General common rules 
All safety analyses will be performed on the safety population for the double-blind period and on 
the OL population for the OL period, as defined in Section 2.3.2 unless otherwise specified, using 
the following common rules: 
• 
Safety data in patients who do not belong to the safety population (ie, exposed but not 
randomized) will be listed separately. 
• 
The baseline value for both double-blind and OL periods is defined as the last available 
value obtained up to the date and time of the first double-blind IMP injection in EFC14643 
study, except otherwise specified.  
• 
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 in children [Appendix A] 
and PCSA in adults version dated May 2014 [Appendix B]). Considering that the threshold 
defined in the PCSA list for monocytes and basophils can be below the ULN, the 
following PCSA criteria will be used for the PCSA analysis of monocytes and basophils: 
- 
PCSA criterion for monocytes: >0.7 Giga/L or > ULN (if ULN ≥0.7 Giga/L) 
- 
PCSA criterion for basophils: >0.1 Giga/L or > ULN (if ULN ≥0.1 Giga/L) 
• 
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 
nonscheduled or repeated evaluations. 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter at least once during the TEAE 
period. 
• 
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to 
analysis windows defined in Section 2.5.4, Table 5 and Table 6 in order to provide an 
assessment for Week 4 to Week 104 time points. 
• 
In both the double-blind and the OL periods, for quantitative safety parameters based on 
central laboratory/reading measurements, descriptive statistics will be used to summarize 
results and change from baseline values by visit using analysis windows. Summaries will 
also include the last on-treatment value and the worst on-treatment value. The last on-
treatment value is defined as the last value collected during the treatment period of each 
study period (see Section 2.1.4). The worst on-treatment value is defined as the nadir and 
/or the peak value during the treatment period of each study period according to the 
direction (minimum or maximum) of the abnormality as defined in the PCSA list. 
• 
For exploratory purposes, key safety analyses for the double-blind period could also be 
provided according to up-titration/dose-adjustment status, ie, according to whether the 
patients remained on their initial dose or whether the dose was up-titrated/dose-adjusted.  
These analyses will be exploratory and descriptive (no formal comparison per dose) as it is 
expected that there could be inherent differences in the baseline characteristics between 
those patients up-titrating and those remaining on their initial dose. In order to reduce the 


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bias of this analysis, the period before the up-titration/dose-adjustment time point (planned 
at Week 12) will be analyzed separately since the early events occurring before Week 12 
can only be attributed to the initial dose regimen (40 mg Q2W, 75 mg Q2W, 150 mg Q4W 
or 300 mg  Q4W). Therefore the descriptive analysis per dose will include any safety 
events occurring from the first injection post Week 12 IVRS/IWRS transaction to the end 
of the TEAE period. Baseline characteristics of patients receiving each dose will be 
summarized. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs.  Pre-treatment and post-treatment AEs will 
be described separately. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment. The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment emergent unless there is definitive information to determine it is 
pre-treatment or post-treatment.  Details on classification of AEs with missing or partial onset 
dates are provided in Section 2.5.3. 
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC, HLGT (when applicable), HLT (when applicable), and PT. Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment phase. For tables presenting severity of events, the worst severity will be chosen for 
patients with multiple instances of the same event. 
Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the table of all 
TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and decreasing 
frequency of PTs within SOCs (in the overall population) will define the presentation order for all 
other tables unless otherwise specified. The tables of AEs by SOC, HLGT, HLT and PT will be 
sorted by the SOC internationally agreed order and the other levels (HLGT, HLT, PT) will be 
presented in alphabetical order, unless otherwise specified. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated: 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE. 
- 
Serious TEAE. 
- 
TEAE leading to death. 
- 
TEAE leading to permanent treatment discontinuation. 


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- 
Treatment-related TEAE. 
• 
All TEAEs by primary SOC, HLGT, HLT, and PT. 
• 
Number (%) of patients experiencing common TEAE(s) presented by primary SOC, HLT 
and PT (HLT incidence ≥5 % in any treatment group), sorted by SOC internationally 
agreed order and by alphabetic order for the other levels (HLT and PT); 
• 
All TEAEs by primary SOC and PT, sorted by the internationally agreed SOC order and by 
decreasing incidence of PTs within each SOC (in the combined alirocumab group for the 
double-blind period and overall for the open-label period). This sorting order will be 
applied to all other tables by SOC and PT of TEAEs, unless otherwise specified. 
• 
All TEAEs regardless of relationship in one column and, in the same table, a second 
column with TEAEs related to alirocumab according to investigator’s opinion by primary 
SOC, HLGT, HLT and PT. 
• 
All TEAEs by maximal intensity (ie, mild, moderate or severe), presented by primary SOC 
and PT, sorted by the sorting order defined above. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All serious TEAEs by primary SOC, HLGT, HLT, and PT and by SOC/PT. 
• 
All serious TEAEs by dose regardless of relationship in one column and, in the same table, 
a second column with TEAEs related to alirocumab according to investigator’s opinion, by 
primary SOC, HLGT, HLT, and PT. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT 
and by SOC/PT. 
Analysis of groupings of adverse events including selected adverse events of special interest 
All groupings of TEAEs including adverse events of special interest as listed in Section 2.1.4.1 
will be analyzed using selections defined in Section 2.1.4.1 and will be presented by SMQ/CMQ 
and PT (when selection is based on SMQs/CMQs) and by SOC and PT (when selection is based 
on the e-CRF tick box or HLGT/HLT). The summaries will be sorted by decreasing incidence of 
PT within each SOC/SMQ (in the alirocumab group) for the double-blind period and overall for 
the open-label period. 
In addition, the following variables will be tabulated for the local injection site reactions TEAEs: 
• 
Intensity of the event (mild, moderate, severe). 
• 
Number of events divided by the number of IMP injections. 
• 
Time from first IMP injection to first injection site reaction. 
• 
Description of the highest intensity of each symptom recorded in the specific e-CRF page. 
• 
The use of the topical anesthetic will be assessed with regards to the occurrence of pain. 


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Besides, description of symptoms and possible etiologies for General Allergic Reaction TEAE 
reported by investigator (using the tick box), will be presented. 
Analysis of pre-treatment and post-treatment adverse events  
• 
All pre-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab group) within each SOC; 
• 
All pre-treatment AEs leading to treatment discontinuation by primary SOC and PT, sorted 
by the sorting order defined above; 
• 
All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the alirocumab group) within each SOC; 
• 
All post-treatment SAEs by primary SOC and PT, sorted by the sorting order defined 
above; 
Analysis of treatment emergent adverse events related to COVID-19 
The number of patients who experienced at least one TEAE related to COVID-19 will be 
described by primary SOC and PT (terms selected using the SMQ “COVID-19” narrow). 
Analysis according to patients’ status with regards to trial impact/disruption due to COVID-19 
All TEAEs by primary SOC and PT will be presented according to trial impact/disruption due to 
COVID-19. 
Subgroup of patients with two consecutive LDL-C <50 mg/dL or two consecutive LDL-C 
<25 mg/dL or two consecutive LDL-C <15 mg/dL   
If applicable, summaries of TEAEs by SOC and PT and by SOC,HLGT,HLT and PT will be also 
provided on the safety subgroup population of patients with two consecutive results of LDL-C <50 
mg/dL (and also those respectively <25 mg/dL, <15 mg/dL) (as defined in Section 2.1.5). Only 
TEAE for which it will be confirmed or unclear that they occurred, worsened or became serious 
the day or after the first level of LDL-C <50 mg/dL (respectively <25 mg/dl, <15 mg/dL) will be 
considered. 
Analysis according to IVRS/IWRS BW strata 
A summary of TEAEs, serious TEAE, TEAE leading to treatment discontinuation and local 
injection site reaction will be provided according to the baseline BW stratum (as per IVRS/IWRS) 
for the double-blind period. 
Analysis according to previous participation to the Phase 2 DFI14223 study 
A summary of TEAEs by SOC and PT and General allergic events will be provided on the safety 
population according to previous participation to the Phase 2 DFI14223 study. 
Additional analysis for the OL period 


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The following summary tables will be added: 
• 
The event rate per patient year (the number of patients with an event in question divided by 
total patient-years) will be provided for all TEAEs by SOC and PT. For a patient with 
event, patient year is censored at time of first event; for patient without event, it 
corresponds to length of the open-label TEAE period 
2.4.5.2 Deaths 
The following summaries of deaths will be generated separately for double-blind and OL periods: 
• 
Number (%) of patients from the safety population who died by period (on-treatment, post-
treatment). 
• 
TEAEs leading to death (death as an outcome on the AE as reported by the Investigator) by 
primary SOC, HLGT, HLT, and PT sorted by internationally agreed SOC order, with 
HLGT, HLT, and PT presented in alphabetical order within each SOC. TEAEs leading to 
death are TEAEs that led to death regardless of timing of death in relation to IMP injection 
(ie, death occurring in the TEAE period or during the post-treatment period). 
• 
In addition, deaths in nonrandomized patients or randomized but not treated patients will 
be summarized. 
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, Q1, Q3, SD, minimum and maximum) 
of all laboratory variables (central laboratory values and changes from baseline) will be calculated 
for each visit or study assessment (baseline, each post-baseline value of the treatment period, last 
on-treatment and worst on-treatment value). In addition, for some parameters of interest, mean 
changes from baseline with the corresponding SE could be plotted over time (at same time points). 
This section will be organized by biological function as specified in Section 2.1.4.3. For glucose, 
only fasting samples will be summarized. 
The incidence of PCSAs (list provided in Appendix A and Appendix B), as well as ALT increase 
as defined as AESI, at any time during the TEAE period will be summarized by biological 
function irrespective of the baseline level and/or according to the following baseline status 
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. 
For clinical laboratory parameters during the OL period, summary tables as described for the 
double-blind period above will be used with the exceptions of the analyses by visit (unless data 
warrants further investigation) 


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Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity.  The proportion of patients with PCSA values or ALT increase as 
defined in the section grouping of adverse events (see Section 2.1.4.1) during TEAE period by 
baseline status will be displayed for each parameter. 
An evaluation of drug-induced serious hepatotoxicity (eDISH) with the graph of distribution of 
peak values of ALT versus peak values of total bilirubin will also be presented using post-baseline 
values during TEAE period. Note that the ALT and total bilirubin values are presented on a 
logarithmic scale. The graph will be divided into 4 quadrants with a vertical line corresponding to 
3 x ULN for ALT and a horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (ie, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN, concomitantly or not) with 
ALT, AST, ALP, total bilirubin, and if available direct and indirect bilirubin will be provided. 
The incidence of liver related TEAEs will be summarized. The selection of PTs will be based on 
SMQ Hepatic disorder (see Section 2.1.4.1). 
Gonadal hormones and pituitary hormones 
Girls and boys will be described separately. 
• 
For girls 
The following analyses will be provided only in post-menarchal girls for at least 1 year at 
baseline and without receiving any oral contraceptive throughout the study. 
- 
Changes from baseline will be tabulated by time point for estradiol and pituitary 
hormones (FSH and LH) during treatment period.  
- 
Similar table as for PCSA will be provided using normal range during the TEAE 
period. The number (%) of patients with at least one estradiol value <LLN and LH 
>ULN, estradiol value<LLN and FSH >ULN, estradiol value <LLN and LH>ULN and 
FSH >ULN) during the TEAE period will be presented. 
In addition, a listing of estradiol, LH, FSH values over time along with the tanner stage and 
date of last menses (if any) will be displayed for all girls.  
• 
For boys 
The following analyses will be provided only in boys with at least a Tanner stage 2 
- 
Changes from baseline will be tabulated by time point for testosterone and pituitary 
hormones (FSH and LH) during treatment period.  
- 
Similar table as for PCSA will be provided using the normal range. The number (%) of 
patients with at least one testosterone value <LLN and LH >ULN, testosterone 


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value<LLN and FSH >ULN, testosterone value<LLN and LH>ULN and FSH >ULN) 
during the TEAE period will be presented. 
In addition, a listing of testosterone, LH, FSH values over time along with the tanner stage 
will be displayed for all boys.  
Adrenal gland hormones 
DHEAS:  
Girls and boys will be described separately. 
• 
Changes from baseline will be tabulated by time point.  
• 
Similar table as for PCSA will be provided using the normal range during the TEAE 
period. 
These summaries will be provided in post-menarchal girls for at least 1 year at baseline and 
without receiving any oral contraceptive throughout the study, and in boys with at least a tanner 
stage 2. 
In addition, a listing of all values over time along with normal range will be provided. 
Cortisol and ACTH 
Girls and boys will be analyzed together. Samples not drawn between ≥6:00 AM and <11:00 AM 
will be excluded. 
• 
Changes from baseline will be tabulated by time point for cortisol during treatment period. 
• 
Similar table as for PCSA will be provided using the normal range during the TEAE 
period. The number (%) of patients with at least one cortisol <LLN, cortisol <LLN and 
ACTH >ULN will be presented. 
Although the summaries for gonadal and pituitary hormones and DHEA will be provided as 
planned for safety endpoints (ie, by treatment groups within each dosing regimen cohort, and by 
treatment groups regardless of the dosing regimen cohorts), the analyses by treatment regardless of 
the dosing regimen cohorts (ie, pooled across the cohorts) appears the most relevant, due to the 
restriction of the population involved in those analyses (post-menarchal girls for at least 1 year at 
baseline and without receiving any oral contraceptive throughout the study, and in boys with at 
least a tanner stage 2). 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (heart rate, diastolic and systolic blood pressure in sitting 
position) , height, height percentile, weight, BMI and BMI percentile (value and change from 
baseline) will be calculated for each visit or study assessment (baseline, each post-baseline value 
of the treatment period, last on-treatment, worst on-treatment value).  For weight, percent change 


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from baseline will also be presented. In addition, summaries by gender will be provided for height, 
weight and BMI. Heart rate and blood pressure without position filled in will only be used for the 
PCSA analysis described below. 
The incidence of PCSAs for heart rate and blood pressure at any time during the TEAE period will 
be summarized. 
For OL vital signs parameters, summary tables as described for the double-blind period above will 
be used with the following exceptions: 
• 
Analyses by visit (unless data warrants further investigation) 
2.4.5.5 Analyses of electrocardiogram variables 
Not Applicable. 
2.4.5.6 Analysis of Tanner stages measurement 
Boys–development of external genitalia, girls-breast development, boys/girls –pubic hair stages as 
well as a global Tanner puberty classification (Prepubescent, Pubescent and Postpubescent) will 
be described by analysis visit using count and percentage. 
The change from baseline in Tanner stage based on development of external genitalia for boys, 
and breast development for girls by analysis visits will be assessed (No change in Tanner stage, 
change in Tanner stage ≥1). 
In addition, number of post-menarchal girls at baseline and during the study will be summarized. 
2.4.5.7 Analyses of Cogstate Battery test  
Cognitive scores (including by domains: DET [Psychomotor Function], IDN [Attention]; [OCL; 
Visual Learning]; GML [Executive Function]) and composite score will be described on the safety 
population by treatment for the double-blind period. 
The change from baseline will be described for each score and the composite score. 
The absolute change from baseline in the composite score at Week 24 will be analyzed using an 
ANCOVA model, with unequal variances by treatment group (except if convergence issue). The 
model will include the fixed categorical effects of treatment group (alirocumab, placebo), the 
dosing regimen cohort (Q2W, Q4W), the treatment-by-dosing regimen cohort interaction, the 
randomization strata and the continuous fixed covariate of baseline composite score value. Model 
assumptions for normality will be explored prior to the analysis testing. Throughout the ANCOVA 
model, least-square (LS) mean and standard error (SE) will be provided for each treatment group 
(placebo, alirocumab) regardless of the dosing regimen cohorts. LS means difference will be 
provided for the comparison of the alirocumab group versus the placebo group regardless of the 
dosing regimen cohorts, with the SE, 95% confidence intervals (CI) for descriptive purpose, using 


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appropriate contrasts. The corresponding effect sizes will be computed using Cohen’s formulae 
(see Appendix G). 
For the OL period, the results will be described overall in the OL population. 
2.4.6 Analyses of other endpoints 
All analyses/summaries for other endpoints will be performed on the safety population for the 
double-blind period and on the OL population for the OL period.  
All measurements, scheduled or unscheduled, fasting or not fasting, will be assigned to analysis 
windows defined in Section 2.5.4, Table 5 and Table 6 in order to provide an assessment for Week 
4 to Week 104 time points. 
HsCRP and HbA1c 
Hs-CRP and HbA1c parameters will be summarized by analysis visit using number of available 
data, mean, SD, median, minimum, and maximum (for hs-CRP, Q1 and Q3 will be also provided) 
during the treatment period. The time profile of each parameter will be also plotted with the means 
and the corresponding SEs for HbA1c and the medians with (Q1-Q3) for hs-CRP. The incidence of 
PCSA at any time during the TEAE period will be also summarized using descriptive statistics. 
Patients with low LDL-C 
Binary endpoints defined in Section 2.1.5 will be described using count and percentage. Kaplan-
Meier curves will be provided for the “Time to” variables in the double-blind treatment period. 
Patient without event will be censored at the end of the treatment period. For the analysis of the 
time to the first of the two consecutive LDL-C as defined in Section 2.1.5, patients without post-
baseline LDL-C result or with only one post-baseline LDL-C result will not be included. 
Creatine phosphokinase-MB and cardiac troponin 
Creatine phosphokinase-MB parameter will be summarized at Week 24 on the safety population 
using number of available data, mean, SD, median, Q1, Q3, minimum, and maximum. In addition, 
similar tables as for PCSA will be provided using the normal range. This table will summarize the 
number (%) of patients with value >ULN during the TEAE period irrespective of the baseline 
level and/or according to the following baseline status categories ≤ULN, >ULN. 
Cardiac troponin at Week 24 will be summarized on the safety population according to the 
following categories: 
• 
<LLOQ; 
• 
≥LLOQ. 
Urinalysis 


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The proportion of patients with at least one finding of proteinuria, hematuria or an abnormality on 
urine microscopy during the TEAE period will be summarized using descriptive statistics. 
2.4.7 Analyses of anti-alirocumab antibodies variables 
The summary of ADA variables will be presented on the ADA population, taking into account all 
samples regardless of timing in relation to injections but within each study period separately. 
Within each dosing regimen cohort, the double-blind period will be presented by treatment group, 
as well as, according to baseline body weight (as per IVRS/IWRS stratum) and by up-titration / 
dose-adjustment status. 
The OL period will be presented also within each dosing regimen cohort, according to the 
treatment received in the double-blind period (placebo or alirocumab) and overall. 
 All summaries described below will be presented for each study period respectively. 
ADA results (negative or positive) by time point; 
• 
Neutralizing status (negative or positive) by time point for positive ADA; 
• 
ADA titers using descriptive statistics (median, minimum and maximum) for positive 
ADA by time point; 
• 
Number (%) of patients with pre-existing ADA and number (%) of patients with treatment-
emergent ADA positive response; 
• 
Number (%) of patients with persistent/indeterminate/transient treatment-emergent ADA 
positive response; 
• 
Time to onset of treatment-emergent ADA positive response using descriptive statistics, 
beginning from the first IMP administration within the relevant period (double-blind or 
OL). 
• 
Number (%) of patients with at least one neutralizing ADA. 
If appropriate, correlations between ADA parameters (eg, titers, treatment-emergent ADA positive 
status, neutralizing status) and PK, safety and/or efficacy endpoints will be also explored (eg, 
scatter plot, summary of TEAEs for ADA positive patients). 
In addition, the following summaries will be also presented on ADA population according to 
previous participation in the DFI14223 study: 
• 
Number (%) of patients with pre-existing ADA and number (%) of patients with treatment-
emergent ADA positive response; 
• 
Number (%) of patients with persistent/indeterminate/transient treatment-emergent ADA 
positive response. 


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2.4.8 Analyses of pharmacokinetic and pharmacodynamic variables 
Within each dosing regimen cohort, concentrations of total alirocumab in serum (Ctrough), free and 
total PCSK9 concentrations will be summarized on the PK population by treatment group and up-
titration/dose-adjustment status using descriptive statistics. These summaries will be also provided 
by baseline BW (as per IVRS/IWRS) in the treatment groups. 
Time profiles for Ctrough concentration, total and free PCSK9 will be also provided by group using 
graphs (mean ± SE or Median, as appropriate). 
Additional plots will be prepared, as deemed necessary (eg, to explore the relationship with some 
safety or efficacy endpoints of interest).  
Concentrations of total alirocumab in serum as well as concentrations of free and total PCSK9 
might be used for population PK modeling if considered necessary and the results of population 
PK modeling will be reported separately from the study report. 
2.4.9 Analyses of quality of life variables 
Not applicable. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters: 
Time from diagnosis of heFH  
Time from diagnosis (years) = (Date of informed consent – Date of diagnosis*) / 365.25. 
(*): In case the month of diagnosis would be missing, it will be put equal to 1st JANUARY if the year of diagnosis 
equals the year of informed consent; it will be put equal to 1st JUNE otherwise. In case only the day of diagnosis 
would be missing, it will be put equal to the 1st of the month. 
Date of last dose of IMP (for double-blind and for open-Label) 
The date of the last injection in the double-blind period is equal to the last date of administration 
reported on injection administration case report form page in double-blind period or missing if the 
last administration date is unknown.  
The date of the last injection in the open-label period is equal to the last date of administration 
reported on injection administration case report form page in open-label period or missing if the 
last administration date is unknown. 
Renal function formulas  


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Creatinine clearance value will be derived using the modified Schwartz equation presented in 
Appendix H. 
Lipids variables, laboratory safety variables, Hs-CRP  
For data below the lower limit of quantification (LLOQ) / limit of linearity, half of the lower limit 
value (ie, LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification (ULOQ) / limit of linearity, the upper limit value (ie, ULOQ) will be used for 
quantitative analyses. 
The above rules will not be applied for the calculated LDL-C and non-HDL-C when HDL-C value 
is below the LLOQ. The value of LLOQ/2 for HDL-C will be used to obtain the non-HDL-C and 
calculated LDL-C used for quantitative analyses. 
Below is an example of data for a “dummy” patient, with the values that will be used in 
quantitative analyses for each parameter. 
Table 4 - Example of lipid data for a “dummy” patient 
Parameter 
Value recorded in the 
database 
Value used in the analysis 
TC 
255 mg/dL 
255 mg/dL 
HDL-C 
<10 mg/dL 
5 mg/dL 
Calculated LDL-Ca 
<221 mg/dL 
216 mg/dL 
NON-HDL-C 
<255 mg/dL 
250 mg/dL 
TG 
172 mg/dL 
172 mg/dL 
a Friedewald formula for calculated LDL-C (when lipid expressed in mg/dL: LDL-C=NON-HDL-C-0.2*TG) 
Pharmacokinetic variables 
Data below the LLOQ are set to zero. 
2.5.2 Data handling conventions for secondary efficacy variables 
See Section 2.1.3.2. 
2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Handling of baseline definition if time of first double-blind administration or time of 
assessment at Week 0 visit is missing 


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If the time of the first double-blind administration or the time of assessment at Week 0 visit is 
missing, then the baseline value is defined as the last available value obtained before or on the day 
of the first double-blind IMP administration 
Handling of computation of treatment duration and compliance if investigational medicinal 
product first or end of treatment date is missing  
If the last or first injection date is missing, the exposure duration and compliance will be left as 
missing. 
Handling of safety and efficacy analysis periods and survival analysis if investigational 
medicinal product end of treatment date is missing 
If the last injection date of double-blind period or open-label period is missing, then this date is 
imputed to the earliest between: 
• 
the last day of the month and year, when applicable or else the 31st of December of the 
year,  
• 
the date of the end of treatment visit of the period (Double-blind period: Week 24 visit for 
patients who completed the double-blind study treatment period as per protocol, early end 
of treatment visit for patients who prematurely discontinued the IMP; open-label period: 
Week 104 for patients who completed the open-label study treatment period as per 
protocol, early end of treatment visit for patients who prematurely discontinued the IMP), 
• 
and the date of the last contact, 
for the purpose of safety and efficacy analysis period start and/or end. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial AE dates and times will be imputed so that if the partial AE date/time 
information does not indicate that the AE started prior to treatment or after the TEAE period, the 
AE will be classified as treatment emergent. These data imputations are for categorization purpose 
only and will not be used in listings. No imputation is planned for date/time of AE resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all AEs that occurred on or 
after the day of randomization will be considered as TEAEs.  


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When the time of the first double-blind IMP administration is missing, all AEs that occurred on 
the day of the first double-blind IMP administration will be considered as treatment-emergent 
AEs. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or >ULN if 
ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
2.5.4 Windows for time points 
Data analyzed by time point (including efficacy, laboratory safety data, vital signs, ADA) will be 
summarized using the analysis windows given in Table 5, Table 6 and Table 7. These analysis 
windows will be applicable for all analyses, and they are defined to provide more homogeneous 
data for time point-specific analyses. 
Table 5 - Analysis windows definition for double-blind period 
Time point 
Targeted study day 
Analysis window in study days 
Week 8 
57 
43 to 70 
Week 12 
85 
71 to minimum (98; study day corresponding to the first  
injection with IMP from kit allocated at Week 12 re-supply 
IVRS contact) 
Week 24 
169 
155 to 182a 


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Time point 
Targeted study day 
Analysis window in study days 
Study days are calculated from the day of first double-blind IMP injection, the day of first double-blind IMP injection being Day 1. For randomized 
but not treated patients, Day 1 is the day of randomization.  
a 155 to 182 for patients not entering the OL period or minimum of 182 or study day corresponding to the first OL injection for patients entering the 
open-label extension  
Table 6 - Analysis windows definition for OL period 
Time point 
Targeted study day 
Analysis window in study days 
Week 32 
57 
36 to 77 
Week 44 
141 
120 to 161 
Week 56 
225 
204 to 245  
Week 68  
309 
 288 to 329  
Week 80 
393 
372 to 413 
Week 92 
477 
456 to 497 
Week 104 
561 
540 to 581 
 Study days are calculated from the day of first OL IMP injection, the day of first OL IMP injection being Day 1. 
If multiple valid values of a variable exist within an analysis window, the value collected at the 
scheduled visit will be used if within the analysis window. Otherwise the nearest from the targeted 
study day or time will be selected. If the difference is a tie, the value after the targeted study day or 
time will be used 
For all endpoints except PK, if multiple valid values of a variable exist within a same day, then the 
first value of the day will be selected when time is available, else the scheduled visit will be 
selected. 
PK Concentration will be analyzed following time windows as defined below in Table 7. If the 
date of the previous injection is unknown, the alirocumab concentration will not be considered for 
the analysis. 
Table 7  Time windows for PK variables definition 
PK variables 
Time window (D1 = day of previous injection or day of last injection for 
Cfollow-up) 
 
Q2W regimen 
Q4W regimen 
 
 
 
Ctrough 
Day 9 to Day 22 
Day 23 to Day 36 
 
 
 
If multiple valid values satisfy the Ctrough criteria, the nearest from the targeted study day (ie, Day 
15/32 for Cthrough, Day 1 being the day of previous injection) will be selected. If the difference is a 
tie, the value after the targeted study day will be used. 


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2.5.5 Unscheduled visits 
For all parameters, unscheduled visit measurements may be used to provide a measurement for a 
time point, a baseline, a last or a worst value, if appropriate according to their definitions. The 
measurements may also be used to determine abnormal/PCSA. 
2.5.6 Pooling of centers for statistical analyses 
Not Applicable. 
2.5.7 Statistical technical issues 
Not Applicable. 


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3 
INTERIM ANALYSIS 
The analyses will be conducted in 2 steps. The first analysis will not be conducted before 
completion of the double-blind treatment period. Since analysis of double-blind primary and key 
secondary efficacy endpoints will have been concluded at the time of the first step analysis 
described below, no multiplicity adjustment for multiple analyses is needed (see Section 2.4.4.3), 
and the overall significance level remains at 0.05 for the study. 
• 
First step analysis: Analysis of the completed double-blind treatment period and first step 
analysis of the open-label treatment period 
- 
This analysis will be conducted when all patients have been randomized and have at 
least all their lipid data up to Week 24 analysis window (double-blind period) collected 
and validated. 
- 
The efficacy analyses of the double-blind period will consist in the final analysis of the 
primary and secondary efficacy endpoints (except those measured during open-label 
period). Analysis of lipid data collected during the OL period will be descriptive.  
- 
The safety analyses of the double-blind period will not be fully final at the time of this 
analysis since the double-blind TEAE period will be truncated at the cut-off date for 
some patients. The safety analyses of the double-blind and open-label treatment 
periods will be performed on all safety data collected up to the common cut-off date. 
The common cut-off date is defined as date of the last patient included completed 
Week 24 visit.  
• 
Final analysis of the open-label treatment period 
- 
This analysis will be conducted at the end of the study with the data of the open-label 
treatment period and will consist in the final analysis of the safety and efficacy 
measures of the open-label treatment period.  
Analyses methods and conventions described in the other sections of this SAP will be applied for 
all analyses as applicable. The following additional rules will apply for analyses performed at first 
analysis: 
• 
Any lipid assessments within analysis windows up to Week 24 will be taken into account 
(may include few unscheduled lipid data soon after the cut-off date).  
• 
Open-label period: Patients without end of treatment visit performed at the time of the cut-
off date will be considered as ongoing and exposed up to the cut-off date. Therefore: 
- 
Patients who did not complete treatment period nor prematurely discontinued the study 
treatment at cut-off date will be analyzed as “ongoing” in the disposition summary. 
- 
Their open-label TEAE period, open-label treatment period and open-label on-study 
observation period will end at the cut-off date. 
- 
Their treatment duration for the open-label period will be derived by considering date 
of cut-off as last injection date. 


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• 
Open-label period: Analyses of number of injections, mean injection frequency, percentage 
of days with under/above-planned dosing and compliance will be performed up to the last 
injection reported in the e-CRF up to the cut-off date.  
• 
Double-blind period and open-label period: AEs occurring, worsening or becoming serious 
after the cut-off date will not be included in the analyses. However, any available outcome 
before database lock, regardless of timing in relation to the cut-off date, of an adverse 
event starting prior to the cut-off date will be taken into account. Medications, treatment 
discontinuations/completions and deaths occurring after the cut-off date will not be 
included in the analyses. 
• 
Open-label period: Post-treatment period and post-study period are not applicable for 
ongoing patients. Analyses of post-treatment AEs, post-study deaths and post-treatment 
medications will be performed for patients who either completed or prematurely 
discontinued the treatment before or at the cut-off date.  
• 
Analysis of status at last study contact will be provided for patients who prematurely 
discontinued the study treatment before or at the cut-off date. 


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4 
DATABASE LOCK 
As the analysis will be conducted in two-steps, two database locks will be done: 
• 
First database lock (for first step analysis): will include all available data on all 
randomized patients up to the common cut-off date as defined in Section 3. This database 
lock is planned to be done approximately 4 weeks after the common cut-off date. 
• 
Final database lock (for final analysis): will include all data of the open-label treatment 
period, for all patients entered in the OL period. This database lock is planned to be done 
approximately 4 weeks after last patient last visit. 


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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
 


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6 
REFERENCES 
1. Cole TJ, Green PJ. Smoothing reference centile curves: the LMS method and penalized 
likelihood. Stat Med. 1992;11(10):1305-19. 
2. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: 
Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass 
index-for-age: Methods and development. Geneva: World Health Organization; 2006. 
3. Rigby RA, Stasinopoulos DM. Smooth centile curves for skew and kurtotic data modelled 
using the Box-Cox power exponential distribution. Stat Med. 2004;23(19):3053-76. 
4. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291-303. 
5. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45(239):13-23. 
6. Shi L, Jiang F, Ouyang F, Zhang J, Shen X. Using physical examinations to estimate age in 
elementary school children: A Chinese population-based study. J Sport Health Sci. 
2017;6(3):352-8. 
7. Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The 
prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367(14):1355-
60. 
8. SAS/STAT® 9.2 User’s Guide. 2nd ed. Cary (NC): SAS Institute Inc; 2009. 
9. Mehrotra DV, Li X, Liu J, Lu K. Analysis of longitudinal clinical trials with missing data 
using multiple imputation in conjunction with robust regression. Biometrics. 2012;68(4):1250-
9.  
 


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7 
LIST OF APPENDICES 
Appendix A: 
Potentially clinically significant abnormalities for children 
Appendix B: 
Potentially clinically significant abnormalities for adults 
Appendix C: 
Detailed statistical methodology for pattern mixture model  
Appendix D: 
List of MedDRA terms for CMQs  
Appendix E: 
Z-score calculation formula for Cogstate Battery test 
Appendix F: 
Cogstate normative data 
Appendix G: 
Effect size calculation formula for Cogstate data 
Appendix H: 
Pediatric formula for eGFR and creatinine clearance 


Statistical Analysis Plan  
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Appendix A 
Potentially clinically significant abnormalities for children 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
ECG parameters 
Ref.: Rijnbeek P.R. et al., 
Eur Heart J 2001; 
Davignon A. et al., Ped 
Cardiol 1979/1980; 
Semizel E.et al., Cardiol 
Young 2008; Mulberg AE 
et al. Pediatric Drug 
Development Concepts 
and applications. John 
Wiley & sons, Inc. 2009 
HR 
Birth/0 to 27 days 
old (Neonates) 
90 bpm and decrease from baseline 20 bpm 
190 bpm and increase from baseline 20 bpm 
 
28 days/1 month 
to 23 months old 
(Infants) 
80 bpm and decrease from baseline 20 bpm 
175 bpm and increase from baseline 20 bpm 
24 months/2 years 
to <6 years old 
(Children) 
75 bpm and decrease from baseline 20 bpm 
140 bpm and increase from baseline 20 bpm 
6 to <12 years old 
(Children) 
50 bpm and decrease from baseline 20 bpm 
120 bpm and increase from baseline 20 bpm 
12 to 16/18 years 
old (Adolescents) 
50 bpm and decrease from baseline 20 bpm  
120 bpm and increase from baseline 20 bpm 
PR 
Birth/0 to 27 days 
old (Neonates) 
120 ms 
 
28 days/1 month 
to 23 months old 
(Infants) 
140 ms 
24 months/2 years 
to <6 years old 
(Children) 
160 ms 
6 to <12 years old 
(Children) 
170 ms 
12 to 16/18 years 
old (Adolescents) 
180 ms 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
QRS 
Birth/0 to 27 days 
old (Neonates) 
85 ms 
 
28 days/1 month 
to 23 months old 
(Infants) 
85 ms 
2 to <6 years old 
(Children) 
95 ms 
6 to <12 years old 
(Children) 
100 ms 
12 to 16/18 years 
old (Adolescents) 
110 ms 
QTc  
Birth/0 to 
<12 years old  
(Neonates, 
Infants, Children) 
Absolute values (ms)  
Borderline: 431-450 ms  
Prolonged*: >450 ms  
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms 
To be applied to QTcF 
 
*QTc prolonged and 
QTc >60 ms are the 
PCSA to be identified in 
individual subjects/patients 
listings. 
 
12 to 16/18 years 
old (Adolescents) 
Borderline: 431-450 ms (Boys); 451-470 ms (Girls) 
Prolonged*: >450 ms (Boys); >470 ms (Girls) 
Additional: ≥500 ms 
 
AND 
 
Increase from baseline  
Borderline: Increase from baseline 30-60 ms 
Prolonged*: Increase from baseline >60 ms  


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Page 77 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
Vital Signs 
Ref.: Kidney Disease 
Outcomes Quality 
Initiatives (KDOQI) 
Guideline 13; 1996; The 
fourth report on the 
diagnosis, evaluation, and 
treatment of high blood 
pressure in children and 
adolescents, Pediatrics 
2004; Bowman E & Fraser 
S Neonatal Handbook 
2012; Mulberg AE et al. 
Pediatric Drug 
Development Concepts 
and applications. John 
Wiley & sons, Inc. 2009; 
Pediatric respiratory rates 
http://www.health.ny.gov/ 
SBP  
Birth/0 to 27 days 
old (Neonates) 
60 mmHg and decrease from baseline 20 mmHg  
85 mHg and increase from baseline 20 mmHg 
Based on definition of 
Hypertension as average 
SBP or DBP ≥95th 
percentile for gender, age, 
and height on 
≥3 occasions 
28 days/1 month 
to 23 months old 
(Infants) 
70 mmHg and decrease from baseline 20 mmHg  
98 mmHg and increase from baseline 20 mmHg 
24 months/2 years 
to <6 years old 
(Children) 
70 mmHg and decrease from baseline 20 mmHg  
101 mHg and increase from baseline 20 mmHg 
6 to <12 years old 
(Children) 
80 mmHg and decrease from baseline 20 mmHg  
108 mmHg and increase from baseline 20 mmHg 
12 to 16/18 years 
old (Adolescents) 
90 mmHg and decrease from baseline 20 mmHg  
119 mmHg and increase from baseline 20 mmHg 
DBP 
Birth/0 to 27 days 
old (Neonates) 
34 mmHg and decrease from baseline 10 mmHg  
50 mHg and increase from baseline 10 mmHg 
 
28 days/1 month 
to 23 months old 
(Infants) 
34 mmHg and decrease from baseline 10 mmHg  
54 mHg and increase from baseline 10 mmHg 
24 months/2 years 
to <6 years old 
(Children) 
34 mmHg and decrease from baseline 10 mmHg  
59 mHg and increase from baseline 10 mmHg  
6 to <12 years old 
(Children) 
48 mmHg and decrease from baseline 10 mmHg  
72 mHg and increase from baseline 10 mmHg  


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
12 to 16/18 years 
old (Adolescents) 
54 mmHg and decrease from baseline 10 mmHg  
78 mHg and increase from baseline 10 mmHg  
Orthostatic 
hypotension 
All age ranges 
SBP: St − Su ≤ -20 mmHg  
DBP: St − Su ≤ -10 mmHg  
 
Temperature 
All age ranges 
Rectal, ear or temporal artery: >100.4°F/38.0°C 
Oral or pacifier: >99.5°F/37.5°C 
Axillary or skin infrared: >99°F/37.2°C 
Ear temperature not 
accurate below 6 months 
of age 
Respiratory rate 
Birth/0 to 27 days 
old (Neonates) 
<30 per minutes  
>60 per minutes 
Based on normal range 
 
28 days/1 month 
to 23 months old 
(Infants) 
<24 per minutes  
>40 per minutes 
24 months/2 years 
to <6 years old 
(Children) 
<22 per minutes  
>34 per minutes 
6 to <12 years old 
(Children) 
<18 per minutes  
>30 per minutes 
12 to 16/18 years 
old (Adolescents) 
<12 per minutes  
>20 per minutes 
Sa02 
All age ranges 
<95% 
 
Weight 
All ranges 
>5% weight loss from baseline 
Based on identification of 
trends in the child’s growth 
with a series of visits 
WHO Multicentre 
Reference Study Group, 
2006; Center for Disease 
Control. Growth chart 2007 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
Clinical Chemistry  
Ref Molleston JP et al. 
JPGN 2011; Moritz et al., 
Pediatrics 1999; Moritz et 
al., Pediatr Nephrol 2005; 
Sedlacek et al., Seminars 
in Dialysis 2006) Gong G 
et al. Clinical Biochemistry 
2009; Masilamani et al. 
Arch Dis Children 2012; 
Mulberg AE et al. Pediatric 
Drug Development 
Concepts and applications. 
John Wiley & sons, Inc. 
2009 
ALT/SGPT 
All age ranges 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be 
expressed in ULN, not in 
IU/L.  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. 
Rows following one 
mentioning zero can be 
deleted.  
AST/SGOT 
All age ranges 
By distribution analysis: 
>3 ULN    
>5 ULN   
>10 ULN  
>20 ULN 
Enzymes activities must be 
expressed in ULN, not in 
IU/L.  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. 
Rows following one 
mentioning zero can be 
deleted.  
Alkaline Phosphatase 
All age ranges 
>1.5 ULN 
Enzymes activities must be 
expressed in ULN, not in 
IU/L. 
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008  


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
Total Bilirubin 
All age ranges 
>1.5 ULN  
>2 ULN 
Enzymes activities must be 
expressed in ULN, not in 
IU/L. 
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
All age ranges 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed 
on a case-by-case basis.  
ALT and Total 
Bilirubin 
All age ranges  
ALT >3 ULN and Total Bilirubin > 2 ULN  
Concept paper on DILI – 
FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a 
same treatment phase, 
whatever the interval 
between measurement. 
CPK 
All age ranges 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. 
Rows following one 
mentioning zero can be 
deleted. 
Creatinine 
Birth/0 to <6 years 
old (Neonates, 
Infants, Children) 
>53 µmol/L or 0.6 mg/dL   
CF = mg x 8.8 = µmol 
Based on normal ranges: 
<0.6 mg/dL (0-1 year), 
0.5 to 1.5 mg/dL (1 to 
16/18 years) 
6 years to 
<12 years old 
(Children) 
≥ 90 µmol/L or 1.1 mg/dL 
12 years to 
16/18 years old 
(Adolescents) 
≥ 132 µmol/L or 1.5 mg/dL 
Creatinine Clearance  
All age ranges 
50% of normal  
<60 mL/min/1.73 m2 (After 1 year old) 
Based on GFR Bedside 
Schwartz Formula 
Based on normal ranges: 
20 to 50 (<8 days), 25 to 
80 (8 days to 1 month), 
30 to 90 (1-6 months), 
40 to 115 (6-12 months), 
60 to 190 (12-23 months), 
90 to 165 (2-12 years), 
80-120 (After 12 years)  


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
Uric Acid  
All age ranges 
≤ 2.0 mg/dL or 119 µmol/L 
≥ 8.0 mg/dL or 476 µmol/L 
CF = mg x 5.95 = µmol 
Based on normal ranges: 
2.4 to 6.4 mg/dL  
Blood Urea Nitrogen 
(BUN) 
Birth/0 to 27 days 
old (Neonates) 
≥4.3 mmol/L or 12 mg/dL 
CF = g x 16.66 = mmol 
Based on normal ranges: 
3 to 12 mg/dL (NN; 5 to 
18 mg/dL (other classes of 
age) 
28 days/1 month 
to 16/18 years old 
(Infants, Children, 
Adolescents) 
≥6.4 mmol/L or 18 mg/dL 
Chloride 
All age ranges 
≤80 mmol/L or 80 mEq/L 
≥115 mmol/L or 115 mEq/L 
CF = 1 
Based on normal range: 
98 to 106 
Sodium 
All age ranges 
≤129 mmol/L or 129 mEq/L 
≥150 mmol/L or 150 mEq/L 
CF = 1 
Based on normal range: 
134 to 146 
Potassium 
Birth/0 to 27 days 
old (Neonates) 
≤3.0 mmol/L or 3.0 mEq/L 
≥7.0 mmol/L or 7.0 mEq/L 
CF = 1 
Based on normal ranges: 
3.0 to 7.0 (NN); 3.5 to 
6.0 (Infants); 3.5 to 
5.0 (> Infants) 
28 days/1 month 
to 23 months old 
(Infants) 
≤3.5 mmol/L or 3.5 mEq/L 
≥6.0 mmol/L or 6.0 mEq/L 
24 months/2 years 
to 16/18 years old 
(Children, 
Adolescents) 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
Bicarbonate 
All age ranges 
≤16 mmol/L or 16 mEq/L 
>ULN 
CF = 1 
Based on normal range: 
18 to 26 
Calcium total 
All age ranges 
≤2.0 mmol/L or 8.0 mg/dL 
≥2.9 mmol/L or 11.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 
8.4 to 10.9 mg/dL 
Calcium ionized 
All age ranges 
≤1.0 mmol/L or 4.0 mg/dL 
≥1.4 mmol/L or 5.6 mg/dL 
CF = mg x 0.025 = mmol 
Based on normal range: 
4.0 to 5.1 mg/dL 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
Total Cholesterol 
All age ranges  
≥6.20 mmol/L or 240 mg/dL  
CF = g x 2.58 = mmol 
Based on normal ranges: 
45 to 182 mg/dL 
(1-3 years), 109 to 
189 mg/dL (4-6 years), 
126 to 191 mg/dL (Boys 
6-9 years), 122 to 
209 mg/dL (Girls 
6-9 years), 130 to 
204 mg/dL (Boys 
10-14 years), 
124-217 mg/dL (Girls 
10-14 years), 114 to 
198 mg/dL (Boys 
15-19 years), 125 to 
212 mg/dL (Girls 
14-19 years) 
Triglycerides 
All age ranges 
≥4.0 mmol/L or 350 mg/dL  
After >12 hours of fast) 
CF = g x 1.14 = mmol 
Based on normal ranges: 
30 to 86 mg/dL (Boys 
0-5 years), 32 to 99 mg/dL 
(Girls 0-5 years), 
31-108 mg/dL (Boys 
6-11 years), 35 to 
114 mg/dL (Girls 
6-11 years), 36 to 
138 mg/dL (Boys 
12-15 years), 43 to 
138 mg/dL (Girls 
12-15 years), 40 to 
163 mg/dL (Boys 
16-19 years), 
40-128 mg/dL (Girls 
16-19 years) 
Lipasemia 
All age ranges 
≥2 ULN 
Based on normal ranges: 
3 to32 U/L (1-18 years) 
Amylasemia 
All age ranges 
≥2 ULN 
Based on normal ranges: 
10 to 30 U/L (NN), 10 to 
45 U/L (1-18 years) 
Glucose 
All age ranges 
Hypoglycaemia <2.7 mmol/L or 50 mg/dL 
Hyperglycaemia >7 mmol/L or 120 mg/dL (fasted 
after >12 hours of fast); >10.0 mmol/L or 180 mg/dL 
(unfasted) 
CF = g x 5.55 = mmol 
Based on normal ranges: 
50 to 90 mg/dL (NN), 60 to 
100 mg/dL (Child) 
Albumin 
All age ranges 
≤25 g/L 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
CRP 
All age ranges 
>2 ULN or 
>10 mg/L (if ULN not provided) 
Based on normal ranges: 
<6 mg/L FDA Sept 2005. 
Hematology 
Common Terminology 
Criteria for Adverse Events 
v3.0 (CTCAE), 2006; 
Division of Microbiology 
and Infections Diseases 
Pediatric Toxicity Tables, 
2007; Division of AIDS 
Table for Grading the 
Severity of Adult and 
Pediatric Adverse Events, 
2004; Mulberg AE et al. 
Pediatric Drug 
Development Concepts 
and applications. John 
Wiley & sons, Inc. 2009; 
Family Practice Notebook, 
LLC, 2012; Tietz NW et al. 
Clinical Guide to 
Laboratory Testing, 3rd 
edition 1995 
WBC 
Birth/0 to 27 days 
old (Neonates) 
<4.0 GIGA/L or 4 000/mm3 
>25.0 GIGA/L or 25 000/mm3 
To be used if no differential 
count available 
Based on normal ranges: 
9 000 to 30 000/mm3 
(birth), 9 400 to 
38 000/mm3 (0-1 day), 
5 000 to 21 000/mm3 
(1 day-1 month), 6 000 to 
17 500/mm3 (1 month-
2 years), 5 000 to 
17 000/mm3 (2-6 years), 
4 500 to 15 500/mm3 
(6-11 years), 4 500 to 
13 500/mm3 (11-18 years) 
28 days/1 month 
to 23 months old 
(Infants) 
<4.0 GIGA/L or 4 000/mm3 
>20.0 GIGA/L or 20 000/mm3 
24 months/2 years 
to <6 years old 
(Children) 
<3.0 GIGA/L or 3 000/mm3 
>16.0 GIGA/L or 16 000/mm3 
6 to <12 years old 
(Children) 
<5.0 GIGA/L or 5 000/mm3  
>17.0 GIGA/L or 17 000/mm3  
12 to 16/18 years 
old (Adolescents) 
<4,5 GIGA/L or 5 000/mm3 
>13.5 GIGA/L or 17 000/mm3  
Lymphocytes (ALC) 
Birth/0 to 27 days 
old (Neonates) 
<1.2 GIGA/L or 1 200/mm3 
>17.0 GIGA/L or 17 000/mm3 
Based on normal ranges: 
2 000 to 11 500/mm3 
(0-1 days), 2 000 to 
17 000 /mm3 (2 days-
1 month), 3 000 to 
13 500 /mm3 (1 month-
2 years), 1,500 to 
9 500/mm3 (2-6 years), 
1 500 to 8 000/mm3 
28 days/1 month 
to 23 months old 
(Infants) 
<2.0 GIGA/L or 2 000/mm3 
>13.5 GIGA/L or 13 500/mm3 
24 months/2 years 
to <6 years old 
(Children) 
<1.0 GIGA/L or 1 000/mm3 
>9.5 GIGA/L or 9 500/mm3 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
6 to <12 years old 
(Children) 
<1.0 GIGA/L or 1 000/mm3 
>8.0 GIGA/L or 8 000/mm3 
(6-10 years), 1 200 to 
5 200/mm3 (10-18 years) 
12 to 16/18 years 
old (Adolescents) 
<0.6 GIGA/L or 600/mm3 
>6.0 GIGA/L or 6 000/mm3 
Absolute Neutrophil 
Count (ANC) 
Birth/0 to 27 days 
old (Neonates) 
<4.0 GIGA/L or 4 000/mm3 (1 day old) 
<1.5 GIGA/L or 1 500/mm3 (2-7 days old) 
<1.25 GIGA/L or 1 250/mm3 (>7 day-1month old) 
>1 ULN 
Based on normal ranges: 
5 000 to 28 000 /mm3 
(0-1 day), 1 000 to 
10 000 (1 day-1 month), 
1 000 to 8 500 
(1-12 months), 1 500 to 
8 500 (1 to 6 years), 
1 500 to 8 000 (6 to 
10 years), 1 800 to 
8 000 (10 to 18 years)  
28 days/1 month 
to 23 months old 
(Infants) 
<1.0 GIGA/L or 1 000/mm3 (1-3 months) 
<1.2 GIGA/L or 1 200/mm3 (3-24 months) 
>1 ULN 
24 months/2 years 
to <6 years old 
(Children) 
<1.2 GIGA/L or 1 200/mm3 
>1 ULN 
6 to <12 years old 
(Children) 
<1.2 GIGA/L or 1 200/mm3 
>1 ULN 
12 to 16/18 years 
old (Adolescents)  
<1.2 GIGA/L or 1 200/mm3 
>1 ULN 
Eosinophils 
All age ranges 
>0.5 GIGA/L or 500/mm3  
Or > ULN if ULN >0.5 GIGA/L or 500/mm3 
Based on normal ranges: 
0 to 500 /mm3 (0-1 month), 
0 to 300 /mm3 (1 month-
18 years) 
Hemoglobin 
Birth/0 to 27 days 
old (Neonates) 
<86 mmol/L or 12.0 g/dL or any decrease 
≥0.31 mmol/L or 2 g/dL 
CF = g x 1.55 = mmol 
Based on normal ranges: 
15 to 20 g/dL (0-3 days), 
12.5 to 18.5 g/dL 
(1-2 weeks), 10.0 to 
13.0 g/dL (1-6 months), 
10.5 to 13.0 g/dL 
(7 months-2 years), 11.5 to 
13.0 g/dL (2-5 years), 
11.5 to 14.5 (5-8 years), 
12.0 to 15.2 g/dL 
(13-18 years)   
28 days/1 month 
to 23 months old 
(Infants) 
<1.40 mmol/L or 9.0 g/dL or any decrease 
≥0.31 mmol/L or 2 g/dL 
24 months/2 years 
to <16/18 years 
old (Children, 
Adolescents) 
<1.55 mmol/L or10.0 g/dL or any decrease 
≥0.31 mmol/L or 2 g/dL 
Hematocrit 
Birth/0 to 27 days 
old (Neonates) 
<0.39 l/l or 40% 
>0.61 l/l or 47% 
CF = % x 0.01 = l/l 
Based on normal ranges: 
45% to 61% (0-3 days), 
39% to 57% (1-2 weeks), 
29% to 42% (1-6 months), 
28 days/1 month 
to 23 months old 
(Infants) 
<0.29 l/l or 29% 
>0.42 l/l or 42% 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
For studies in children 
Parameter 
Age range 
PCSA 
Comments 
24 months/2 years 
to <12 years old 
(Children) 
<0.32 l/l or 32% 
>0.47 l/l or 47% 
33% to 38% (7 months-
2 years), 34% to 39% 
(2-5 years), 35% to 42% 
(5-8 years); 36% to 47% 
(13-18 years) 
 
≥12 years 
(Adolescents) 
≤0.37 l/l or 37% (Male)  
 ≤0.32 l/l or 32% (Female) 
≥0.55 l/l or 55% (Male)  
 ≥0.5 l/l or 50% (Female) 
Platelets 
All age ranges 
<100 GIGA/L or 100 000/mm3 
>700 GIGA/L or 700 000/mm3 
Based on normal ranges: 
250 000 to 450 000/mm3 
(NN); 300 000 to 
700 000/mm3 
(1-6 months), 250 000 to 
600 00/mm3 (7 months-
2 years), 250 000 to 
550 000/mm3 (2-12 years), 
150 000 to 450 000/mm3 
(13-18 years) 
Urinalysis 
Patel HP, Pediatr Clin N 
Am, 2006 
Ketonuria 
All age ranges 
Presence 
Semi-quantitative methods 
Glycosuria 
All age ranges 
Presence 
Semi-quantitative methods 
Hematuria 
All age ranges 
≥1+ 
Semi-quantitative methods 
Proteinuria 
All age ranges 
≥1+ 
Semi-quantitative methods 
End of Document 
 


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Appendix B 
Potentially clinically significant abnormalities for adults 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L.  
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 
Alkaline 
Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not in 
IU/L. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin >35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurement. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning 
zero can be deleted. 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
CLcr (mL/min) 
(Estimated 
creatinine clearance 
based on the 
Cokcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR 
(mL/min/1.73m2) 
(Estimate of GFR 
based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are more 
relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic 
Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A (2012), 
and Cardiac Safety Research Consortium White Paper 
on PR and QRS (Nada et al. Am Heart J. 2013; 165(4) 
: 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual subjects/patients 
listings. 
 


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Appendix C 
Detailed statistical methodology for pattern mixture model 
For the Q2W dosing regimen cohort, as a sensitivity analysis of the primary efficacy endpoint 
(ie, percent change from baseline to Week 24 in LDL-C), a pattern-mixture model approach will 
be used, with a different imputation strategy applied for missing LDL-C values during the on-
treatment period (ie, within the time period from the first IMP injection up to the day of the last 
double-blind injection +21 days) and missing LDL-C values after treatment discontinuation 
(ie, after the day of last double-blind  injection +21 days as described above) based on the 
following assumptions: 
• 
Patients within 21 days (see above) of their last double-blind IMP injection would continue 
to show benefit from treatment similar to that observed at the scheduled time point. 
Therefore, LDL-C values missing during the on-treatment period will be considered 
“Missing at Random” and imputed using a model estimated using all samples collected on 
treatment. 
• 
Patients who stopped taking their study treatment no longer benefited from it in the future, 
and thus tended to have LDL-C values returning to baseline. Thus LDL-C values missing 
after treatment discontinuation will be imputed based on patient’s own baseline value. 
For patients who permanently discontinued the treatment due to the COVID-19 pandemic, missing 
post-treatment data will be considered “Missing at Random” and imputed based on other on-
treatment measurements in the same treatment group. 
For the Q4W dosing regimen cohort, the same approach will be taken except that the on-treatment 
period will be defined as the time period from the first double-blind IMP injection up to the day of 
the last double-blind injection +35 days for patients with a last double-blind injection before the 
switch to Q2W regimen (actual of sham), +21 days otherwise. The two assumptions made for the 
Q2W dosing regimen cohort prevail for the Q4W dosing regimen cohort as well. 
The assumptions for this approach are based on the following considerations: 
• 
Missing values during the on-treatment period are mostly consecutive to: 
- 
Visits performed outside of the pre-specified time-window, 
- 
No blood sample available although visit was done, 
- 
LDL-C not measurable due to technical reasons. 
In addition, these missing data are often intermittent, ie, followed by LDL-C values 
collected at subsequent visits. It is therefore considered reasonable to assume that these 
missing data were “At Random”. 
• 
Phase 2 studies DFI11565 and R727-CL-1003 included a prospective assessment of 
calculated LDL-C during the follow-up period after a 12-week treatment period. These 
studies showed that after treatment discontinuation, the average calculated LDL-C returned 


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to baseline level within 4 weeks after ceasing alirocumab treatment (See Figure 3 and 
Figure 4). 
Figure 3 - Study DFI11565: calculated LDL-C mean (+/- SE) percent change from baseline 
 
Figure 4 - Study R-727-CL-1003: calculated LDL-C mean (+/- SE) percent change from baseline 
 
For each dosing regimen cohort, missing LDL-C values will be imputed 100 times to generate 100 
complete data sets. The percent change from baseline to Week 24 will be derived from observed 
and imputed LDL-C at this time point. The completed data sets will be analyzed using a linear 


Statistical Analysis Plan  
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regression model with the baseline LDL-C value as continuous covariate. Combined mean with 
their corresponding standard errors (SEs) and 97.5% CIs will be provided through the SAS 
MIANALYZE procedure using Rubin’s formulae (8). 
Imputation of missing data during the on-treatment period 
Missing LDL-C values during the on-treatment period will be imputed from other on-treatment 
measurements assuming Missing At Random, using SAS MI procedure. 
Only LDL-C values collected during the on-treatment period will be included in the imputation 
model. This way, missing LDL-C values during the on-treatment period will be imputed based 
solely on observed on-treatment LDL-C values. 
The imputation model will include the baseline LDL-C value and all LDL-C values at 
pre-specified visits. Since the pattern of missing data is necessarily non-monotone, a Monte-Carlo 
Markov Chain (MCMC) method is used. A minimum value of 0 will be specified in order to avoid 
negative imputed LDL-C values. 
A sample SAS code is provided below: 
proc mi data=DATAIN out=DATAOUT nimpute=100 minimum=0; 
var LDL_BASE   LDL_W8   LDL_W12   LDL_W24  ; 
run; 
As stated above, the input dataset DATAIN will include only LDL-C values collected during the 
on-treatment period. Any LDL-C values collected during the post-treatment period will be 
excluded from the input dataset. In practice, the MI procedure generates imputed values for all 
missing values (whether on-treatment or post-treatment), but only imputed values during 
the-on-treatment period will be kept in the final datasets that will be described using means and 
their corresponding. Imputed values during the post-treatment period will be discarded and 
replaced by imputed values described in the next paragraph. 
Imputation of missing data after treatment discontinuation 
Missing LDL-C values during the post-treatment period will be imputed assuming LDL-C values 
would on average return to baseline values. 
For each patient, missing post-treatment LDL-C values will be imputed 100 times, using a random 
draw from a normal distribution, with mean equal to patient’s own baseline value and variance 
equal to the conditional variance at the specific time-point, given the baseline value. 
Let Y0 and Y1 denote the LDL-C at baseline and at the specific time-point respectively. Since Y0 
and Y1 are assumed to have a bivariate normal distribution, the conditional variance of Y1 given 
Y0 is: 
Var(Y1|Y0 = y0) = σ12(1 - ρ2) 
Where σ12 denotes the variance of Y1 and ρ the coefficient of correlation between Y0 and Y1.  


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The conditional variance will be estimated from observed data at the specific time-point. 
During the random generation process, a minimum value of 0 will also be applied in order to 
avoid negative imputed LDL-C values. 


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Appendix D 
List of MedDRA terms for CMQs 
Table 8 - Selected PTs from SMQ “Optic nerve disorders” including in the CMQ for neurologic 
events 
MedDRA Term Label 
Preferred Term Code 
Benign neoplasm of optic nerve 
10057424 
Optic atrophy 
10030910 
Optic discs blurred 
10030923 
Optic nerve disorder 
10061322 
Optic nerve injury 
10030938 
Optic nerve neoplasm 
10053645 
Optic nerve operation 
10053272 
Optic neuropathy 
10061323 
Papillitis 
10033708 
Pseudopapilloedema 
10037141 
Subacute myelo-opticoneuropathy 
10058009 
Toxic optic neuropathy 
10044245 
Visual evoked potentials abnormal 
10047549 
Amaurosis fugax 
10001903 
Blindness 
10005169 
Blindness unilateral 
10005186 
Colour blindness acquired 
10010051 
Colour vision tests abnormal 
10010056 
Cranial nerve injury 
10061094 
Delayed myelination 
10076456 
Fundoscopy abnormal 
10017520 
Hemianopia 
10019452 
Hemianopia heteronymous 
10019455 
Hemianopia homonymous 
10019456 
Loss of visual contrast sensitivity 
10064133 
Neuro-ophthalmological test abnormal 
10029256 
Night blindness 
10029404 
Ophthalmological examination abnormal 
10056836 
Optic pathway injury 
10030949 
Optical coherence tomography abnormal 
10073561 


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MedDRA Term Label 
Preferred Term Code 
Quadrantanopia 
10077820 
Visual acuity reduced 
10047531 
Visual acuity reduced transiently 
10047532 
Visual acuity tests abnormal 
10047534 
Visual field defect 
10047555 
Visual field tests abnormal 
10047567 
Visual impairment 
10047571 
Visual pathway disorder 
10061411 
 
Table 9 - CMQ “Neurocognitive disorders – FDA’s recommendation” 
MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD 
10001949 
Amnesia 
PTCD 
10061423 
Amnestic disorder 
PTCD 
10002711 
Anterograde Amnesia 
PTCD 
10078497 
Neuropsychiatric symptoms  
PTCD 
10008398 
Change in sustained attention 
LLTCD 
10009843 
Cognitive Deterioration 
PTCD 
10057668 
Cognitive Disorder 
LLTCD 
10010300 
Confusion 
LLTCD 
10048321 
Confusion Aggravated 
PTCD 
10010305 
Confusional State 
PTCD 
10012218 
Delirium 
PTCD 
10012267 
Dementia 
PTCD 
10012271 
Dementia Alzheimer's type 
LLTCD 
10012290 
Dementia Nos 
LLTCD 
10012291 
Dementia Nos Aggravated 
LLTCD 
10012292 
Dementia of the Alzheimer's type NOS 
PTCD 
10067889 
Dementia with Lewy Bodies 
PTCD 
10013395 
Disorientation 
PTCD 
10013496 
Disturbance in attention 
PTCD 
10070246 
Executive dysfunction 
PTCD 
10068968 
Frontotemporal Dementia 
LLTCD 
10058669 
Global Amnesia 
PTCD 
10021402 
Illogical Thinking 


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MedDRA level 
MedDRA Code 
MedDRA Term Label 
PTCD 
10071176 
Impaired reasoning 
PTCD 
10021630 
Incoherent 
PTCD 
10023236 
Judgement impaired 
PTCD 
10027175 
Memory Impairment 
PTCD 
10027374 
Mental Impairment 
LLTCD 
10027376 
Mental Impairment Nos 
LLTCD 
10048345 
Mental State Abnormal Aggravated 
PTCD 
10048294 
Mental Status Changes 
PTCD 
10065424 
Mini Mental Status Examination Abnormal 
PTCD 
10036631 
Presenile Dementia 
PTCD 
10038965 
Retrograde Amnesia 
PTCD 
10039966 
Senile Dementia 
LLTCD 
10039967 
Senile Dementia Nos 
LLTCD 
10040602 
Short-term Memory Loss 
PTCD 
10043431 
Thinking Abnormal 
LLTCD 
10043438 
Thinking Slowed 
PTCD 
10044380 
Transient Global Amnesia 
PTCD 
10057678 
Vascular Dementia 
 
 


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Appendix E 
Z-score calculation formula for Cogstate Battery test 
 


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Appendix F 
Cogstate normative data 
 
 


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Appendix G 
Effect size calculation formula for Cogstate data 
 
 
 


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Appendix H 
Pediatric formula for eGFR and creatinine clearance 
 
 


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