Clinical trial NCT03510715
Conditions: Hypercholesterolemia
Keywords: Pediatrics, Homozygous Familial Hypercholesterolemia, Alirocumab, PCSK9 inhibitor, Low-density Lipoprotein Cholesterol (LDL-C)
Sponsor: Sanofi
Start date: 2018-08-31; Completion date: 2020-02-17
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To evaluate the efficacy of alirocumab (75 or 150 milligrams \[mg\] depending on body weight \[BW\]), administered every 2 weeks (Q2W), on low-density lipoprotein cholesterol (LDL-C) levels at Week 12 of treatment in children and adolescents with homozygous familial hypercholesterolemia (hoFH) of 8 to 17 years of age on top of background treatments.

Secondary Objectives:

* To evaluate the efficacy of alirocumab after 24 and 48 weeks of treatment on LDL-C levels.
* To evaluate the effects of alirocumab on other lipid parameters (eg, apolipoprotein B \[Apo B\], non-high density lipoprotein cholesterol \[non-HDL-C\], total cholesterol \[Total-C\], high density lipoprotein cholesterol \[HDL-C\], lipoprotein a \[Lp (a)\], triglycerides \[TG\], apolipoprotein A-1 \[Apo A-1\] levels) after 12, 24, and 48 weeks of treatment.
* To evaluate the safety and tolerability of alirocumab up to 48 weeks of treatment.

Detailed description:
The study duration was up to 62 weeks, which included (if needed) a run-in period of up to 4 weeks, a screening period of up to 2 weeks, a treatment period of up to 48 weeks, and a follow-up of 8 weeks.

Arms: arm 1: Participants with BW less than (\<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to \[\>=\] 50 kg.

Participants with BW \>=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.
Interventions: intervention 1: Alirocumab SAR236553 (REGN727) intervention 2: Atorvastatin intervention 3: Simvastatin intervention 4: Fluvastatin intervention 5: Pravastatin intervention 6: Lovastatin intervention 7: Rosuvastatin intervention 8: Ezetimibe intervention 9: Cholestyramine intervention 10: Nicotinic acid intervention 11: Fenofibrate intervention 12: Omega-3 fatty acids
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection in pre-filled syringe,

Route of administration: subcutaneous (SC) intervention 2: Pharmaceutical form: tablet,

Route of administration: oral intervention 3: Pharmaceutical form: tablet,

Route of administration: oral intervention 4: Pharmaceutical form: capsule,

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: tablet,

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

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity
According to template: QSD-002579 VERSION N°16.0 (31-JUL-2017)
Page 1
AMENDED CLINICAL TRIAL PROTOCOL NO. 02
COMPOUND: alirocumab / SAR236553-REGN727
An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in 
Children and Adolescents with Homozygous Familial Hypercholesterolemia
STUDY NUMBER: EFC14660
VERSION DATE / STATUS: 11-Sep-2018 / Approved
Version Number:
1
EudraCT 
2017-002297-39
IND Number
105574
WHO universal trial number
U1111-1200-2046
Date:
11-Sep-2018
Total number of pages:
112
(electronic 2.0)
NCT03510715


Amended Clinical Trial Protocol NO. 02
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EFC14660 - alirocumab
Version number: 1
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Page 2
NAMES AND ADDRESSES OF
COORDINATING 
INVESTIGATOR
Name:
Address:
Tel:
Fax:
E-mail:
MONITORING TEAM’S 
REPRESENTATIVE
Name:
Address:
Tel:
Fax:
E-mail:
SPONSOR
Company:
Address:
OTHER EMERGENCY 
TELEPHONE NUMBERS
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Amended Clinical Trial Protocol NO. 02
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
DOCUMENT HISTORY
Document
Country/countries impacted by 
amendment
Date, version
Amended Clinical Trial Protocol 02
All
11-Sep-2018, version 1 (electronic 2.0)
Amended Clinical Trial Protocol 01
All
20-Feb-2018, version 1 (electronic 1.0)
Original Protocol
21-Dec-2017, version 1 (electronic 1.0)
Amended protocol 02 (11-Sep-2018)
This amended protocol (amendment 02) 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
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 a separate informed consent form should be 
used for homozygous familial hypercholesterolemia (hoFH) genotyping. However, the consent for 
hoFH 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.
Protocol amendment summary of changes table
Section#
and Name
Description of Change
Brief Rationale
12.2 Informed consent
Specifying that the optional consent for 
genotyping is part of the main informed 
consent form.
Clarification that the homozygous familial 
hypercholesterolemia consent is not a 
separate document from the informed 
consent form.
17. Appendices- Appendix I. Country 
Specific Requirements and 1.2 Study 
flowchart-footnote “u"
Monthly urine pregnancy tests to be 
performed at home added as country 
specific changes.
Added as Appendix I 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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CLINICAL TRIAL SUMMARY
COMPOUND: alirocumab
STUDY No.: EFC14660
TITLE
An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in 
Children and Adolescents with Homozygous Familial Hypercholesterolemia
INVESTIGATOR/TRIAL LOCATION
Worldwide
PHASE OF DEVELOPMENT
Phase 3
STUDY OBJECTIVE(S)
Primary objective:

To evaluate the efficacy of alirocumab (75 or 150 mg depending 
on body weight [BW]), administered every 2 weeks (Q2W), on 
low-density lipoprotein cholesterol (LDL-C) levels at Week 12 of 
treatment in children with homozygous familial 
hypercholesterolemia (hoFH) 8 to 17 years of age on top of 
background treatments.
Secondary objectives:

To evaluate the efficacy of alirocumab after 24 and 48 weeks of 
treatment on LDL-C levels.

To evaluate the effects of alirocumab on other lipid parameters 
(eg, apolipoprotein B [Apo B], non-high density lipoprotein 
cholesterol [non-HDL-C], total-cholesterol [total-C], high-density 
lipoprotein cholesterol [HDL-C], lipoprotein (a) [Lp (a)], triglycerides 
[TG], apolipoprotein A-1 [Apo A-1] levels) after 12, 24, and 
48 weeks of treatment.

To evaluate the safety and tolerability of alirocumab up to 
48 weeks of treatment.
Other objectives:

To evaluate the development of anti-alirocumab antibodies (ADA) 
during 48 weeks of treatment.

To evaluate the pharmacokinetics (PK) of alirocumab.
STUDY DESIGN
This study is a multi-national, multi-center, open-label study with a treatment 
period of 48 weeks.
Children and adolescents aged 8 to 17 years with hoFH confirmed by 
genetic testing and LDL-C ≥130 mg/dL (3.37 mmol/L) at screening visit, 
despite treatment with stable lipid modifying therapy (LMT)* at optimal 
doses**, will be selected to enter the screening period.
*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 LDL-C being obtained.
**The optimal dose of statin is defined as the dose prescribed based on local 
guidelines or practice, 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 
entry in this study in order to ensure that the addition of a non-statin 
LDL-C lowering therapy (ie, alirocumab) would be the next appropriate step 
in the management of the patient’s hypercholesterolemia. The highest dose 
of statin should not exceed the maximum labeled dose of statin for pediatric 
patients as per the local prescribing information.
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A statin-intolerant patient is defined as one with the documented 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 approved 
regimen of a statin (eg, 1 to 3 times weekly) are also considered as not able 
to tolerate a daily dose.
The study will consist of a run-in period (as needed), a screening period, an 
open-label treatment period, and a follow-up period.
Run-in period (as needed, up to Week -6):
The run-in period will be 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. Patients, who 
have initiated apheresis procedure (every week or every other week) at least 
6 months prior to giving informed consent to the study, can enter the run-in 
period.
Another possible situation requiring the run-in period includes patients with 
suspected hoFH based on clinical criteria but without confirmation by 
previous genetic testing. Such patients will be asked to undergo centralized 
genetic testing during the run-in period.
Screening period:
For all patients regardless of their participation in a run-in period, the 
screening period will be up to 2 weeks (+5 days) in duration.
The injection training will occur during the screening period after the eligibility 
criteria have been checked and it is confirmed that the patient is likely to be 
included. Patients aged ≥12 years (or another designated person such as 
parent, etc) will be trained to self-inject/inject with placebo for alirocumab. 
Patients 8 to 11 years old will be assigned a parent or another designated 
person who will be trained during the injection training visit or an alternative 
arrangement. In all cases, alternative arrangements for this required injection 
training may be allowed as needed, regardless of age. Please note that this 
visit (injection training visit) can take place at the same visit as D1 as per the 
site or patient preference.
Prior to the injection, a local topical anesthetic may be utilized as per the 
Investigator’s judgment. Investigators will have the option of providing a 
second placebo kit for alirocumab for patients/parents who require additional 
injection training prior to enrollment.
Patients can be enrolled after the injection training visit and as soon as all 
inclusion and no exclusion criteria are met.
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Treatment period:
The overall treatment period is 48 weeks in duration.
All patients will receive subcutaneously (SC) either 75 or 150 mg alirocumab 
Q2W at entry depending on their BW, without any dose adjustment up to 
Week 12. After Week 12, the dose of alirocumab can be adjusted in case of 
weight change after baseline, such that the dose corresponds to the patient’s 
BW:

75 mg for BW <50 kg.

150 mg for BW ≥50 kg.
For patients treated with apheresis, the frequency will be fixed to the 
individual patient’s established schedule up to Week 12. After Week 12, the 
frequency of apheresis can be adapted following Investigator judgment.
The first investigational medicinal product (IMP) injection from the study 
treatment kit allocated by interactive response technology (IRT) will be 
administered at the site on the day of entry and as close as possible after 
their entry into the study. Patients will be monitored at the investigational site 
for at least 30 minutes after this first injection. The subsequent injections will 
be performed at a patient-preferred location (eg, home). All of the IMP 
injections can be performed by trained patient (self-injection if aged 
≥12 years), parent, or another designated person, or alternative 
arrangements for injection administration will be allowed as needed (eg, 
return to the investigational site). Prior to any injection, a local topical 
anesthetic may be utilized as per the Investigator’s judgment. 
Injection training:

Further injection training can be provided at the enrollment visit 
Week 0/Day 1 when the patient/parent or a trained designated 
person injects the first IMP.

Additional training can be offered at scheduled or unscheduled 
visits with the scheduled open-label treatment, as per
patient/parent or Investigator’s judgment.
The laboratory measurement of lipid parameters will be performed by a 
central laboratory. The results will be communicated to the sites. 
Patients will be instructed to follow a diet to treat their hypercholesterolemia 
in accordance with local guidelines or treatment practice and they should be 
on this diet throughout the entire study duration.
The Investigator will be responsible, based on his/her own judgment related 
to the patients’ LDL-C levels and the safety profile, to continue or discontinue 
alirocumab throughout the study. The statin dose or other LMT should not be 
modified to adjust to the degree of LDL-C lowering before Week 12, unless 
otherwise indicated. Even if it is unlikely in this hoFH population, further 
recommendations for the management and monitoring of patients who will 
have achieved LDL-C level <50 mg/dL (1.30 mmol/L) on one or more 
occasion are provided in this protocol.
Follow-up period:
A follow-up call will be planned 10 weeks after the last IMP injection, ie,
8 weeks after the end of treatment (EOT) visit, for the patients who complete 
the study and for patients who discontinue early for any reason.
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STUDY POPULATION 
Main selection criteria
Inclusion criteria:
I 01.
Male and female children and adolescents aged 8 to 17 years 
genetically diagnosed with homozygous familial 
hypercholesterolemia* inadequately controlled (see threshold 
mentioned in exclusion criterion E 02) 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.
I 02.
A signed informed consent indicating parental permission with or 
without patient assent, depending on capacity for understanding 
based on developmental maturity. In cases involving emancipated 
or mature minors with adequate decision-making capacity, or when 
otherwise permitted by law, a signed informed consent directly 
from patients.
I 03.
For patients on apheresis, currently undergoing stable LDL 
apheresis therapy for at least 4 weeks prior to the screening visit 
(Week -2) and have initiated apheresis treatment for at least 
6 months (see Appendix A).
* Diagnosis of hoFH must be made either by previous genotyping (true 
homozygotes, compound heterozygotes, or double heterozygotes) or 
current genotyping performed after having been suspected by clinical 
criteria according to European Atherosclerosis Society (EAS) Consensus 
Panel recommendations for diagnosis of HoFH. Previous genotyping 
refers to documented results that are available from prior genotyping 
testing supporting a diagnosis of hoFH. Current centralized genotyping 
refers to patients electing to undergo genotyping during the run-in period 
with results supporting a diagnosis of hoFH (see Appendix B). 
** The optimal dose of statin is defined as the stable daily dose prescribed 
based on local guidelines or practice, or is the dose that is maximally 
tolerated due to adverse effects of higher doses. For patients not 
receiving the maximally tolerated dose of statin, statin intensification 
should be carefully considered prior to inclusion in this study in order to 
ensure that the addition of a non-statin LDL-C lowering therapy (ie, 
alirocumab) would be the next appropriate step in the management of the 
patient’s hypercholesterolemia. The highest dose of statin should not 
exceed the maximum labeled dose of statin for pediatric patients as per 
the local prescribing information.
*** A statin-intolerant patient is defined as a patient with the documented
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 approved regimen of a statin (eg, 1 to 3 times weekly) will also be 
considered as not able to tolerate a daily dose.
Exclusion criteria:
Key Exclusion criteria (additional details are in Section 7.2):
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 8 to less than 10 years who have not had previous 
attempts to lower LDL-C by other means will be excluded.
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E 02.
Patients with LDL-C (pre-apheresis, if applicable) less than 
130 mg/dL (3.37 mmol/L) obtained during the screening period 
after the patient has been on stable apheresis procedure or 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.
E 03.
Patients with null low-density lipoprotein receptor (LDLR) mutations 
in both alleles.
E 04.
Patients with BW less than 25 kg.
E 05.
Patients aged 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.
E 06.
Daily dose of statin that is above the maximum recommended dose 
for pediatric patients as per the local prescribing label.
E 07.
Patients who will receive statin de novo during the run-in period.
E 08.
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 09.
Patients not previously instructed on a cholesterol-lowering diet
prior to the screening visit.
E 10.
Mipomersen in the last 5 months.
E 11.
Patients with uncontrolled (ie, HbA1c >9% at the screening visit) 
Type 1 or 2 diabetes mellitus.
E 12.
Patients with known uncontrolled thyroid disease 
(ie, thyroid-stimulating hormone levels outside of the laboratory’s 
reference range within the past 6 months, or with elevated free T3 
or T4 and with clinical symptoms of hyperthyroidism).
E 13.
Patients who use systemic corticosteroids.
E 14.
Patients with uncontrolled (ie, systolic blood pressure or diastolic 
blood pressure above local guidelines or equivalent) hypertension.
E 15.
Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening 
visit.
E 16.
Severe renal impairment (ie, estimated glomerular filtration rate 
[eGFR] <30 mL/min/1.73 m2) at the screening visit.
E 17.
ALT (alanine aminotransferase) or AST (aspartate 
aminotransferase) >2 x upper limit of normal (ULN) (1 repeat 
laboratory allowed per patient) at the screening visit.
E 18.
CPK (creatine phosphokinase) >3 x ULN (1 repeat laboratory
allowed per patient) at the screening visit.
Total expected number of patients:
Expected number of sites:
Approximately 18 patients enrolled.
Approximately 20 sites.
STUDY TREATMENT(s)
Investigational medicinal product(s)
Alirocumab
Formulation:
Prefilled syringes (PFS) with finger grip, to be replaced by PFS with safety 
system (PFS-S) as soon as available: 
Alirocumab 75 or 150 mg/mL solution as described below:

BW <50 kg: 1.0 mL of alirocumab 75 mg/mL solution.

BW ≥50 kg: 1.0 mL of alirocumab 150 mg/mL solution.
Route(s) of administration:
Subcutaneous (SC) injections in the abdomen, thigh, or outer area of upper 
arm.
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Dose regimen:
Alirocumab Q2W
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 
product (NIMP) because the medication is a potential background therapy 
that will not be provided by the Sponsor:

Statins.

Cholesterol absorption inhibitors (ezetimibe).

Bile acid-binding sequestrants (such as cholestyramine, colestipol, 
colesevelam).

Nicotinic acid.

Fenofibrate.

Omega-3 fatty acids (≥1000 mg daily).
ENDPOINT(S)
Primary endpoint:

Percent change in LDL-C (pre-apheresis, if applicable) from 
baseline to Week 12 in the intent-to-treat (ITT) population, using all 
LDL-C values (pre-apheresis, if applicable) regardless of 
adherence to treatment (ITT estimand).
Secondary efficacy endpoints:

Percent change in LDL-C (pre-apheresis, if applicable) from 
baseline to Week 12 in the ITT population, using all LDL-C values 
during the treatment period (on-treatment estimand).

Percent change in LDL-C (pre-apheresis, if applicable) from 
baseline to Weeks 24 and 48 (ITT and on-treatment estimands).

Percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, 
fasting TG, and Apo A-1 (pre-apheresis, if applicable) from 
baseline to Weeks 12, 24, and 48 (ITT and on-treatment 
estimands).

Proportion of patients with ≥15% reduction in LDL-C 
(pre-apheresis, if applicable) at Weeks 12, 24, and 48 (ITT and 
on-treatment estimands).

The absolute change in LDL-C from baseline to Weeks 12, 24, and 
48 (ITT and on-treatment estimands).
Safety endpoints:

Main safety parameters: adverse events (AEs), serious AEs
(SAEs), and AEs of special interest (AESIs), assessed throughout 
the study.

Other safety parameters: laboratory data, vital signs, body weight, 
height, and Tanner stage, assessed throughout the study.
Other endpoints:

Anti-alirocumab antibodies (ADA) assessed throughout the study.

Alirocumab and PCSK9 concentrations assessed throughout the 
study.
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ASSESSMENT SCHEDULE
Run-in period (as needed):
The run-in period will be up to 4 weeks (+2 days), with 1 visit. Patients can 
enter the screening period as soon as the criterion for stable LMT is met 
and/or centralized genotyping data (if no previous genotyping) is available. 
Screening period:
The screening period will be up to 2 weeks (+5 days) in duration. The 
injection training will occur during the screening period after the eligibility 
criteria have been checked and it is confirmed that the patient is likely to be 
included. Patients aged ≥12 years (or another designated person such as 
parent, etc) will be trained to self-inject/inject with placebo for alirocumab.  
Patients 8 to 11 years old will be assigned a parent or another designated 
person who will be trained during the injection training visit or an alternative 
arrangement. In all cases, alternative arrangements for this required injection 
training may be allowed as needed, regardless of age. Patients can be 
enrolled after the injection training visit and as soon as eligibility is 
confirmed.
Treatment period:
The overall treatment period will be 48 weeks in duration. Visits will be 
scheduled as follows: enrollment visit (Day 1, Week 0), Weeks 4, 12, 24, 36,
and 48 (end of the treatment period visit). 
Follow-up period:
A follow-up call will be planned 10 weeks after the last IMP injection, ie,
8 weeks after the EOT visit, for the patients who will complete the study and 
for the patients who discontinue early for any reason.
STATISTICAL CONSIDERATIONS
Sample size determination:
No sample size calculation was performed. Eighteen patients are planned to 
be enrolled to have at least 15 evaluable patients considering the 
recruitment constraints in this rare disease population.
Analysis population:
The primary efficacy analysis population will be the ITT population, defined 
as the patients receiving at least one dose or partial dose of IMP.
Safety analyses will be performed on the safety population, which will consist
of patients receiving at least one dose or partial dose of IMP.
Primary analysis:
The percent change from baseline in LDL-C at Week 12 will be analyzed in 
the ITT population using a mixed-effect model with repeated measures 
(MMRM) approach. All post-baseline data available within the Week 4 to
Week 48 analysis windows will be used and missing data will be accounted 
for by the MMRM model. The model will include the fixed categorical effect 
of time point (Weeks 4, 12, 24, and 48), as well as the continuous fixed 
covariate of baseline LDL-C value.
Safety analysis:
Safety analyses (AEs, laboratory data, and vital signs) will be descriptive, 
based on the safety population.
DURATION OF STUDY PERIOD (per 
patient) 
A study duration of up to 62 weeks (run-in period, as needed): up to 
4 weeks, screening period: up to 2 weeks, treatment period: 48 weeks and 
follow-up of 8 weeks.
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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 Data Monitoring Committee (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
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Page 13
1.2
STUDY FLOW CHARTS
Study Flow chart
Run-in (as
needed)a
Screening
Open-Label Treatment Period
Follow-up
Phone call
VISIT
1 
2 
3
4
5
6
7
8
9
10
Week
Up to W-6
Up to W-2 
Up to W-1b
W0/D1
W4
W12
W24
W36
W48c
W56
Visit Window (+/- days)
+2
+5
+/- 7
+/- 7
+/- 3
+/- 7
+/- 7
+/- 3
+/- 7
Informed consent
Xd
hoFH Genotyping Informed Consent (if 
needed)e f
X
Inclusion criteria
X
X
X
Exclusion criteria
X
X
X
Patient demography
Xf
Medical/surgical/family medical history
Xf
Alcohol/smoking habits
Xf
Prior medication history
Xf, g
Physical examination
Xf
X
X
X
Measured body weight
Xf
X
X
X
X
X
X
Measured height
Xf
X
X
X
X
X
Tanner stageh
Xf
X
X
X
IRT contact
X
X
X
X
X
X
X
X
X
Inclusion
X
Treatment:
Injection training
Xi, j
Xj, k
IMP administration Q2W regimenj, l
------------------------------------------------------------------------------------------
Open-label IMP kit dispensationm
X
X
X
X
Compliance check of IMP and data 
collection on IMP administration
X
X
X
X
X
Concomitant medication recording
X
X
X
X
X
X
X
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Study Flow chart
Run-in (as
needed)a
Screening
Open-Label Treatment Period
Follow-up
Phone call
VISIT
1 
2 
3
4
5
6
7
8
9
10
Week
Up to W-6
Up to W-2 
Up to W-1b
W0/D1
W4
W12
W24
W36
W48c
W56
Visit Window (+/- days)
+2
+5
+/- 7
+/- 7
+/- 3
+/- 7
+/- 7
+/- 3
+/- 7
Check of stability of background LMT, 
including apheresis frequency, if applicable
X
X
X
X
X
X
X
X
X
Review of dietn
Xf
X
X
X
X
X
X
Efficacy:
Total-C, LDL-C, HDL-C, TG, non-HDL-Co, p
X
X
X
X
X
X
Apo B, Apo A-1, ratio Apo B/Apo A-1, and 
Lp (a)o, p
X
X
X
X
Safety:
AE/SAE recording
X
X
X
X
X
X
X
X
X
X
Vital signsq
X
X
X
X
X
X
X
Laboratory testing:
hoFH genotypinge, o
X
Hematology and chemistryr, o
X
X
X
X
X
X
HbA1c o
X
X
X
X
CPK-MB and cardiac troponins, o
X
X
Creatine phosphokinase (CPK)o
X
X
X
X
X
Liver panelt, o
X
X
X
X
X
X
Pregnancy testu, o
X
X
X
X
X
X
Anti-alirocumab antibodies (ADA)v, o
X
X
X
X
Serum alirocumab concentration 
(pharmacokinetics) and PCSK9 
concentrationsw, o
X
X
X
X
AE = adverse event; Apo A-1 = apolipoprotein A 1; Apo B = apolipoprotein B; CPK-MB = creatine phosphokinase-MB; HDL-C = high-density lipoprotein cholesterol; hoFH = homozygous familial hypercholesterolemia; 
IMP = investigational medicinal product; IRT = interactive response technology; IVRS = Interactive Voice Response System; LDL-C = low-density lipoprotein cholesterol; LMT = lipid modifying therapy; 
Lp (a) = lipoprotein (a); non-HDL-C = non-high density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; Q2W = every 2 weeks; SAE = serious adverse event; total-C = total cholesterol; 
TG = triglycerides
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a
Patients who have not been on stable LMT 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 hoFH but without confirmation by previous genetic testing 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-treatment period visit.
d
Informed consent should be obtained only once. If the patient enters the run-in period then informed consent will be obtained prior to entry into the run-in period. If the patient does not require a run-in period, then
informed consent will be obtained prior to entry into the screening period.
e
Genotyping for hoFH 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 previously documented genotyping. For non-mandatory genotyping, the sample should preferably be taken during the screening period, but can be done at any visit during the 
treatment period.
f
The corresponding assessment should be obtained only once. If the patient enters the run-in period then the corresponding assessment will be obtained during the run-in period. If the patient does not require a 
run-in period, then the corresponding assessment will be obtained during the screening period.
g
Document prior medication history within the previous 12 weeks, especially for lipid modifying therapy (including statins) and nutraceutical products that may affect lipids (eg, omega-3 fatty acids, plant stanols such 
as those found in Benecol, flax seed oil, and psyllium).
h
See Appendix C for Tanner stage evaluation.
i
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 enrollment.
j
Prior to the injection, a local topical anesthetic may be utilized as per the Investigator’s judgment.
k
Further injection training can be provided at the enrollment visit Week 0/Day 1 when the patient/parent or a trained designated person injects the first dose of IMP from the open-label study treatment kit allocated 
by IVRS. Additional training can be offered at scheduled or unscheduled visits with the scheduled open-label treatment, as per patient/parent or Investigator’s judgment. 
l
The first IMP injection during the treatment period will be done at the site on the day of enrollment and as close as possible after enrollment in the study. Subsequent injections will be done at a patient-preferred 
location (eg, home). These injections can be performed by a trained patient (self-injection) for patients ≥12 years old or parent, or another designated person, or alternative arrangements for injection administration 
will be allowed as needed for all patients whatever their age. 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.
m 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.
n
Patients/parents will be instructed to follow a diet to treat their hypercholesterolemia in accordance with local guidelines or treatment practice.
o
Prior to any laboratory testing, the site may utilize a local topical anesthetic as per the Investigator’s judgment. 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 91 mL for the entire study; 124 mL for patients on apheresis); see Section 10. Lipid panel 1 (Total-C, LDL-C, HDL-C, TG, and non-HDL-C) should take 
highest priority, followed by safety parameters, and then other parameters.
p
The lipid levels will be communicated to the Investigator during the treatment period.
q
Vital signs include: heart rate, systolic and diastolic BP in a sitting position.
r
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 gamma-glutamyl transferase (γGT).
s
CPK-MB and troponin levels will be assayed at baseline and at Week 12 and in case of any clinically relevant cardiovascular effect observed in patients.
t
Liver panel: ALT, AST, alkaline phosphatase (ALP), and total bilirubin.
u
Pregnancy test should be done on females of childbearing potential who are sexually active or females who have experienced menarche (they must have a confirmed test at screening). Pregnancy tests may be 
performed more frequently in some countries due to local legislations related to women of childbearing potential enrolled in clinical trials. See Appendix I. The screening (Week -2) pregnancy test should be a blood 
test. All other pregnancy tests will be with a local urine pregnancy test.
v
Patient who prematurely discontinue 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 taken at 6 to 12 months after the 
last alirocumab administration and thereafter, at about every 3 to 6 months until the titer returns to below 240.
w Blood samples should be collected before IMP injection and apheresis, if applicable. The PK samples will also be used for free and total PCSK9 analyses.
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2
TABLE OF CONTENTS
1
FLOW CHARTS.............................................................................................................................12
1.1
GRAPHICAL STUDY DESIGN ......................................................................................................12
1.2
STUDY FLOW CHARTS................................................................................................................13
2
TABLE OF CONTENTS ................................................................................................................16
2.1
LIST OF TABLES...........................................................................................................................22
3
LIST OF ABBREVIATIONS ..........................................................................................................23
4
INTRODUCTION AND RATIONALE.............................................................................................25
5
STUDY OBJECTIVES ...................................................................................................................30
5.1
PRIMARY.......................................................................................................................................30
5.2
SECONDARY ................................................................................................................................30
5.3
OTHER...........................................................................................................................................30
6
STUDY DESIGN ............................................................................................................................31
6.1
DESCRIPTION OF THE STUDY...................................................................................................31
6.2
DURATION OF STUDY PARTICIPATION ....................................................................................32
6.2.1
Duration of study participation for each patient .............................................................................32
6.2.2
Determination of end of clinical trial (all patients) ..........................................................................32
6.3
INTERIM ANALYSIS......................................................................................................................32
6.4
STUDY COMMITTEES..................................................................................................................32
6.4.1
Steering Committee .......................................................................................................................32
6.4.2
Data Monitoring Committee ...........................................................................................................33
7
SELECTION OF PATIENTS..........................................................................................................34
7.1
INCLUSION CRITERIA..................................................................................................................34
7.2
EXCLUSION CRITERIA ................................................................................................................35
7.2.1
Exclusion criteria related to study methodology ............................................................................35
7.2.2
Exclusion criteria related to the active comparator and/or mandatory background therapies.......37
7.2.3
Exclusion criteria related to the current knowledge of sanofi compound.......................................37
8
STUDY TREATMENTS .................................................................................................................38
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8.1
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................38
8.2
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................39
8.3
BLINDING PROCEDURES............................................................................................................39
8.3.1
Methods of blinding........................................................................................................................39
8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................40
8.5
INVESTIGATIONAL MEDICINAL PRODUCT PACKAGING AND LABELING .............................40
8.6
STORAGE CONDITIONS AND SHELF LIFE................................................................................40
8.7
RESPONSIBILITIES ......................................................................................................................41
8.7.1
Treatment accountability and compliance......................................................................................41
8.7.2
Return and/or destruction of treatments ........................................................................................42
8.8
CONCOMITANT MEDICATION.....................................................................................................42
8.8.1
Management of background lipid modifying therapy .....................................................................42
8.8.2
Contraception.................................................................................................................................43
8.8.3
Prohibited concomitant medications ..............................................................................................43
9
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................44
9.1
PRIMARY ENDPOINT ...................................................................................................................44
9.1.1
Primary efficacy endpoint...............................................................................................................44
9.2
SECONDARY ENDPOINTS ..........................................................................................................44
9.2.1
Secondary efficacy endpoints........................................................................................................44
9.2.2
Efficacy assessment method .........................................................................................................45
9.2.2.1
Lipid parameters ............................................................................................................................45
9.2.3
Safety endpoints ............................................................................................................................45
9.2.3.1
Observation period.........................................................................................................................45
9.2.3.2
Adverse events ..............................................................................................................................45
9.2.3.3
Laboratory safety variables............................................................................................................46
9.2.3.4
Vital signs.......................................................................................................................................46
9.2.3.5
Tanner stages measurement.........................................................................................................47
9.3
OTHER ENDPOINTS.....................................................................................................................47
9.3.1
Pharmacokinetics...........................................................................................................................47
9.3.1.1
Sampling time ................................................................................................................................47
9.3.1.2
Pharmacokinetics handling procedure...........................................................................................47
9.3.1.3
Bioanalytical method......................................................................................................................47
9.3.2
Anti-alirocumab antibody assessments .........................................................................................48
9.3.2.1
Sampling time ................................................................................................................................48
9.3.2.2
Sampling procedure.......................................................................................................................48
9.3.2.3
Bioanalytical method......................................................................................................................48
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9.3.3
Pharmacogenetic assessment.......................................................................................................48
9.3.4
Pharmacodynamic variables..........................................................................................................48
9.3.5
Creatine phosphokinase-MB and cardiac troponin........................................................................49
9.4
FUTURE USE OF SAMPLES ........................................................................................................49
9.5
APPROPRIATENESS OF MEASUREMENTS ..............................................................................49
10
STUDY PROCEDURES ................................................................................................................50
10.1
VISIT SCHEDULE..........................................................................................................................52
10.1.1
Run-in period (as needed, up to Week -6).....................................................................................53
10.1.1.1 Visit 1 (Week -6, Run-in)................................................................................................................53
10.1.2
Screening period............................................................................................................................54
10.1.2.1 Visit 2 (Up to Week -2, Screening visit) .........................................................................................54
10.1.2.2 Visit 3 (Week -1, Injection training) ................................................................................................56
10.1.3
Treatment period............................................................................................................................56
10.1.3.1 Visit 4 (Day 1, Week 0, Enrollment visit)........................................................................................57
10.1.3.2 Visit 5 (Week 4)..............................................................................................................................58
10.1.3.3 Visit 6 (Week 12)............................................................................................................................59
10.1.3.4 Visit 7 (Week 24)............................................................................................................................60
10.1.3.5 Visit 8 (Week 36)............................................................................................................................61
10.1.3.6 Visit 9 (Week 48, end of the treatment period visit).......................................................................61
10.1.4
Follow-up........................................................................................................................................62
10.2
DEFINITION OF SOURCE DATA..................................................................................................62
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................63
10.3.1
Temporary treatment discontinuation with investigational medicinal product(s) ...........................63
10.3.2
Permanent treatment discontinuation with investigational medicinal product(s) ...........................64
10.3.3
List of criteria for permanent treatment discontinuation.................................................................64
10.3.4
Handling of patients after permanent treatment discontinuation ...................................................64
10.3.5
Procedure and consequence for patient withdrawal from study....................................................65
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................65
10.4.1
Definitions of adverse events.........................................................................................................65
10.4.1.1 Adverse event ................................................................................................................................65
10.4.1.2 Serious adverse event ...................................................................................................................66
10.4.1.3 Adverse event of special interest...................................................................................................67
10.4.1.4 Local injection site reactions..........................................................................................................68
10.4.2
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................68
10.4.3
General guidelines for reporting adverse events ...........................................................................68
10.4.4
Instructions for reporting serious adverse events ..........................................................................69
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10.4.5
Guidelines for reporting adverse events of special interest...........................................................70
10.4.6
Guidelines for management of specific laboratory abnormalities ..................................................70
10.4.7
Guidelines for reporting product complaints (IMP/NIMP) ..............................................................71
10.5
OBLIGATIONS OF THE SPONSOR .............................................................................................72
10.6
SAFETY INSTRUCTIONS .............................................................................................................72
10.6.1
Local tolerability (local injection site reactions)..............................................................................72
10.6.2
Allergic adverse events..................................................................................................................72
10.6.2.1 Allergic adverse event with cutaneous involvement ......................................................................73
10.6.2.2 Acute allergic injection reactions....................................................................................................73
10.6.3
Recommendations for managing and monitoring patients reaching LDL-C levels (ie, LDL-C 
<50 mg/dL [1.30 mmol/L]) during the treatment period .................................................................74
10.7
ADVERSE EVENTS MONITORING..............................................................................................74
11
STATISTICAL CONSIDERATIONS..............................................................................................75
11.1
DETERMINATION OF SAMPLE SIZE...........................................................................................75
11.2
DISPOSITION OF PATIENTS .......................................................................................................75
11.3
ANALYSIS POPULATIONS...........................................................................................................75
11.3.1
Efficacy population.........................................................................................................................75
11.3.2
Safety population ...........................................................................................................................75
11.3.3
Other analysis populations.............................................................................................................75
11.4
STATISTICAL METHODS .............................................................................................................76
11.4.1
Extent of study treatment exposure and compliance.....................................................................76
11.4.1.1 Extent of investigational medicinal product exposure....................................................................76
11.4.1.2 Compliance ....................................................................................................................................76
11.4.2
Analyses of efficacy endpoints.......................................................................................................76
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................76
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................77
11.4.2.3 Multiplicity considerations ..............................................................................................................77
11.4.3
Analyses of safety data..................................................................................................................78
11.4.3.1 Adverse events ..............................................................................................................................79
11.4.3.2 Laboratory data and vital signs......................................................................................................79
11.4.4
Other endpoints..............................................................................................................................79
11.4.4.1 Pharmacokinetics...........................................................................................................................80
11.4.4.2 Anti-alirocumab antibody assessments .........................................................................................80
11.4.4.3 LDL-C less than 50 mg/dL (1.30 mmol/L)......................................................................................80
11.4.4.4 Creatine phosphokinase-MB and cardiac troponin........................................................................80
11.5
INTERIM ANALYSIS......................................................................................................................80
12
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................81
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12.1
ETHICAL AND REGULATORY STANDARDS ..............................................................................81
12.2
INFORMED CONSENT .................................................................................................................81
12.3
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................82
13
STUDY MONITORING...................................................................................................................83
13.1
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................83
13.2
RESPONSIBILITIES OF THE SPONSOR.....................................................................................83
13.3
SOURCE DOCUMENT REQUIREMENTS....................................................................................84
13.4
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................84
13.5
USE OF COMPUTERIZED SYSTEMS..........................................................................................84
14
ADDITIONAL REQUIREMENTS...................................................................................................85
14.1
CURRICULUM VITAE....................................................................................................................85
14.2
RECORD RETENTION IN STUDY SITES ....................................................................................85
14.3
CONFIDENTIALITY .......................................................................................................................85
14.4
PROPERTY RIGHTS.....................................................................................................................86
14.5
DATA PROTECTION.....................................................................................................................86
14.6
INSURANCE COMPENSATION....................................................................................................87
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................87
14.8
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................87
14.8.1
By the Sponsor...............................................................................................................................87
14.8.2
By the Investigator .........................................................................................................................88
14.9
CLINICAL TRIAL RESULTS ..........................................................................................................88
14.10
PUBLICATIONS AND COMMUNICATIONS .................................................................................88
15
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................89
16
BIBLIOGRAPHIC REFERENCES.................................................................................................90
17
APPENDICES................................................................................................................................92
APPENDIX A.
MANAGEMENT OF PATIENTS TREATED WITH LDL APHERESIS THERAPY IN
THE EFC14660 STUDY ................................................................................................................92
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APPENDIX B.
CRITERIA FOR THE DIAGNOSIS OF HOMOZYGOUS FAMILIAL 
HYPERCHOLESTEROLAEMIA - EAS CONSENSUS PANEL RECOMMENDATIONS FOR 
DIAGNOSIS OF HOFH..................................................................................................................95
APPENDIX C.
TANNER STAGE................................................................................................................96
APPENDIX D.
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................98
APPENDIX E.
PEDIATRIC FORMULAE FOR EGFR AND CREATININE CLEARANCE .......................102
APPENDIX F.
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................103
APPENDIX G.
SUMMARY OF AE REPORTING INSTRUCTIONS.........................................................108
APPENDIX H.
ASSESSMENT OF LOCAL INJECTION SITE REACTIONS...........................................110
APPENDIX I.
COUNTRY SPECIFIC REQUIREMENTS..........................................................................111
APPENDIX J.
PROTOCOL AMENDMENT HISTORY.............................................................................112
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2.1
LIST OF TABLES
Table 1 - Pharmacokinetics handling for alirocumab ....................................................................................47
Table 2 - Summary of adverse event reporting instructions..........................................................................71
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3
LIST OF ABBREVIATIONS
ADA:
anti-alirocumab (drug) antibodies
ADR:
adverse drug reaction
AE:
adverse event
ALP:
alkaline phosphatase
Apo A-1:
apolipoprotein A-1
Apo B:
apolipoprotein B
AST:
aspartate aminotransferase
BP:
blood pressure
BW:
body weight
CI:
confidence interval
CPK:
creatine phosphokinase
CPK-MB:
creatine phosphokinase-MB
CRF:
case report form
CVD:
cardiovascular disease
DBP:
diastolic blood pressure
DMC:
Data Monitoring Committee
DRF:
discrepancy resolution form
DTP:
direct-to-patient
EAS:
European Atherosclerosis Society
eCRF:
electronic case report form
eGFR:
estimated glomerular filtration rate
ELISA:
enzyme-linked immunosorbent assay
EOT:
end of treatment
ER:
emergency room
FH:
familial hypercholesterolemia
FSH:
follicle stimulating hormone, follicle stimulating hormone
GCP:
Good Clinical Practice
HbA1c:
hemoglobin A1c
HDL-C:
high-density lipoprotein cholesterol
heFH:
heterozygous familial hypercholesterolemia
hoFH:
homozygous familial hypercholesterolemia
HRT:
hormone replacement therapy
IEC:
independent ethics committee
IMP:
investigational medicinal product
IRB:
institutional review board
IRT:
interactive response technology
ITT:
intent-to-treat
IVRS:
interactive voice response system
IWRS:
interactive web response system
LDL-C:
low-density lipoprotein cholesterol
LDLR:
low-density lipoprotein receptor
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LDLRAP1:
LDL receptor adaptor protein 1
LLQ:
lower limit of qualification
LMT:
lipid modifying therapy
Lp (a):
lipoprotein (a)
LS:
least-square
MedDRA:
medical dictionary for regulatory activities
MMRM:
mixed-effect model with repeated measures
NIMP:
noninvestigational medicinal product
non-HDL-C:
non-high density lipoprotein cholesterol
PCSA:
potentially clinically significant abnormality
PCSK9:
proprotein convertase subtilisin/kexin type 9
PFS:
pre-filled syringes
PFS-S:
PFS with safety system
PK:
pharmacokinetic(s)
PT:
preferred term
Q2W:
every 2 weeks
Q4W:
every 4 weeks
SAE:
serious adverse event(s)
SAP:
statistical analysis plan
SBP:
systolic blood pressure
SC:
subcutaneous
SD:
standard deviation
SE:
standard error
SOC:
system organ class 
TG:
triglyceride
Total-C:
total cholesterol
ULN:
upper limit of normal
WOCBP:
women of childbearing potential
γGT:
gamma-gutamyl transferase
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4
INTRODUCTION AND RATIONALE
Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism, characterized by 
severely elevated levels of low-density lipoprotein cholesterol (LDL-C) that lead to premature 
atherosclerosis and cardiovascular disease (CVD) (1). It can be either an autosomal dominant or 
an autosomal recessive disease that results from mutations in the low-density lipoprotein receptor 
(LDLR), apolipoprotein B (Apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), or in 
the LDL receptor adaptor protein 1 (LDLRAP1). The latter is a rare mutation in LDLRAP1, a 
protein which interacts with the LDL receptor or signal transducing adaptor family member 
1 (STAP1) gene with a recessive mode of transmission, since carrier parents have normal lipid 
profiles. In all cases, these result in an accumulation of LDL-C in the plasma from birth, and 
subsequent development of tendon xanthomas, xanthelasmas, atheromata, and CVD (2).
Homozygous familial hypercholesterolemia (hoFH) is a rare, serious condition genetically defined 
to include individuals with the same mutation(s) in either LDLR, Apo B, or PCSK9 alleles (true 
homozygotes) or defined to include individuals with different mutations in each allele (compound 
heterozygotes). Rarely, hoFH patients may have mutations in 2 different FH-causing genes, one 
within the LDLR gene and one in another gene (double heterozygotes). Historically thought to 
affect 1 in a million people, new research indicates that hoFH prevalence is likely to be higher, 
with as many as 1 in 160 000 to 300 000 people affected (2). Phenotypically, the severity of hoFH 
depends on the amount of residual LDLR activity, historically categorized as either 
receptor-negative (<2% of normal LDLR activity) or receptor-defective (2% to 25% of normal 
LDLR activity) based on the amount of activity in skin fibroblasts. The genetic definition used in 
the current study will include all individuals considered to be either true homozygotes or 
compound heterozygotes. However, those individuals with null LDLR mutations in both alleles 
will be excluded because it is expected that alirocumab will not be efficacious in those patients, as 
already shown with another PCSK9 inhibitor, evolocumab (3, 4).
Homozygous FH is characterized by drastically increased levels of LDL-C from early childhood 
onwards. Patients with hoFH have severe hypercholesterolemia (500 to 1000 mg/dL, 12.95 to 
25.9 mmol/L), resulting in lifelong exposure to high levels of plasma LDL-C and increased risk of 
developing atherosclerosis at a highly accelerated rate, often manifesting within the first 2 decades 
of life. In children, the only clinical symptom is xanthoma tuberosum, typically occurs 
predominantly on the knees, elbows, and Achilles tendon. If left untreated, it is common that 
affected subjects die at an early age, due to CVDs (5).
Familial hypercholesterolemia including both heterozygous and homozygous forms may be 
suspected in a child, adolescent, or young adult (<20 years of age) if he/she has an untreated 
fasting LDL-C level ≥160 mg/dL (or non-high density lipoprotein cholesterol [non-HDL-C], 
≥190 mg/dL) (6). 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 heterozygous familial hypercholesterolemia 
(heFH). An LDL-C level of <130 mg/dL (3.4 mmol/L) is considered acceptable and <110 mg/dL 
(2.85 mmol/L) ideal for children with heFH (6), or the achievement of ≥50% reduction in LDL-C. 
Since LDL-C levels are only indicative of hoFH, especially in children, and do not exclude hoFH 
diagnosis, a similar LDL-C threshold to that used for heFH will be used to trigger a 
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genotyping determination. Thus, the protocol will include patients with a screening LDL-C 
≥130 mg/dL (3.4 mmol/L) despite being treated with stable lipid modifying therapy (LMT). 
The LDL-C targets recommended in the European Atherosclerosis Society (EAS) Consensus 
Panel statement related to hoFH were <2.5 mmol/L (<100 mg/dL), <3.5 mmol/L (<135 mg/dL) in 
children, or <1.8 mmol/L (<70 mg/dL) in adults with clinical CVD (2). These targets are similar 
to those for patients at high cardiovascular risk; however, it is well recognized that these targets 
are ambitious because they are very difficult to achieve with current lipid modifying treatments. 
After initiation of diet (including dietary adjuncts of plant sterols/stanols and soluble fiber), statins 
are the preferred initial pharmacologic treatment in children with FH. Consideration should be 
given to starting medical treatment at the age of 8 years or older. In special cases, such as those 
with homozygous FH, treatment might need to be initiated at earlier ages, including mechanical 
removal of LDL-C by lipoprotein apheresis (7), which is an important adjunct treatment in hoFH 
that can help in LDL-C goal attainment. Ideally, treatment should be started by the age of 5 and 
not later than 8 years, although the Panel recognizes that practical feasibility and cost also 
influence decisions regarding treatment (2, 8).
Six statins (rosuvastatin, atorvastatin, simvastatin, pravastatin, lovastatin, and fluvastatin) are 
FDA approved as an adjunct to diet to lower markedly elevated LDL-C levels in children 10 years 
of age and older (ages 8 years and older for pravastatin) (6). In general, statins reduce LDL-C 
levels in children with FH by 23% to 50% (9, 10, 11, 12). Adverse event (AE) profiles for statins 
in children are similar to those reported in adult studies and include rare instances of myopathy 
and hepatic enzyme elevation. Despite severely reduced LDLR level/activity in hoFH patients, 
high doses of statins may be somewhat effective in lowering LDL-C concentrations. Limited data 
are available for the combination of ezetimibe and simvastatin (13) 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. Taken together, this information supports the 
age of patients included in this study as well as the definition of stable LMTs as provided in the 
inclusion criteria of the protocol and its mandatory use as background therapy. Stable LMTs 
include stable optimal doses of statin based on pediatric guidelines, which will be followed by the 
site (14).
Novel therapeutic approaches in hoFH, including the recently licensed treatments lomitapide 
(adults only) and mipomersen (from 12 years old), as well as high dose PCSK9 monoclonal 
antibody therapy, offer the potential for further substantial LDL-C lowering by 25% to 50% on
top of current standards of care, including maximal statin therapy (2). Another PCSK9 inhibitor, 
evolocumab, was evaluated at a dose of 420 mg every 4 weeks (Q4W) in a hoFH population, 
including patients from 12 years old (4). In the open-label TAUSSIG trial, evolocumab 
420 mg Q4W demonstrated a favorable benefit/risk profile in all 106 patients, including 
14 adolescents aged from 12 to less than 18 years old. Mean reductions in LDL-C were -24% for 
LDLR defective, -6% for LDLR negative/negative,-51% for PCSK9 gain of function/LDLR 
negative and -43% for Autosomal Recessive Hypercholesterolemia (ARH) (15). Owing to the 
potential risk for hepatic toxicity, lomitapide and mipomersen have been approved for restricted 
use and will not be authorized in this study.
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Alirocumab is a fully human monoclonal antibody that targets PCSK9 (16) approved in adults but 
not yet approved in the pediatric population. A clinical development program is ongoing in the 
pediatric population, including a Phase 2 study conducted in heFH children and adolescents from
8 to 17 years old (NCT02890992) which will be followed by a Phase 3 study in the same heFH 
pediatric population. Since in the adult clinical development program body weight (BW) was 
identified as a significant covariate affecting alirocumab exposure and pharmacokinetics (PK)
with however a limited impact on alirocumab PK, the dose to be used in the pediatric population 
was defined according to BW categories, ie, BW <50 kg or BW ≥50 kg. The Phase 2 DFI14223 
study, conducted in 31 pediatric heFH patients in 3 cohorts, evaluated a fixed dosage according to 
BW categories, with staggered doses of 30 mg every 2 weeks (Q2W) (Cohort 1), and 40 mg Q2W 
(Cohort 2), or 75 mg 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 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 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 
(least-square [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), compared with Cohort 1, which also used a 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). For Cohort 3, the overall 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 dose 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 alirocumab doses (40 mg Q2W/75 mg Q2W) as per 
BW category (<50 kg/≥50 kg) used Cohort 2. Overall, for the combined doses, the proportion of 
patients who achieved a LDL-C value <110 mg/dL (2.85 mmol/L) was 76.4%. There were no 
patients with treatment-emergent serious adverse events, treatment-emergent adverse events 
(TEAEs) leading to death, or TEAEs leading to permanent treatment discontinuation. There were 
no adverse events of special interest (AESIs) including, neurological events, neurocognitive 
events, increase in alanine aminotransferase (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.
In addition to the pediatric program, the efficacy and safety of the alirocumab dose of 150 mg
Q2W is currently being investigated in the ongoing study R727-CL-1628 (NCT03156621),
conducted in hoFH adult patients. Based on the totality of this information, the doses for the 
EFC14660 study were established for hoFH children and adolescents. In this study, conducted in 
even more severe patients with confirmed hoFH genotyping, the alirocumab doses of 75 mg Q2W 
for BW <50 kg and 150 mg Q2W for BW ≥50 kg were selected to allow the greatest benefit 
associated with a good safety profile in hoFH patients known to have a very high baseline LDL-C 
despite optimal treatment with LMTs, including statins, and other LMTs.
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Very little information is available on statin intolerance in the pediatric population but this cannot 
be ruled out. This is acknowledged by the NICE guidance that recommends healthcare 
professionals consider offering non-statin LMT for lowering LDL-C levels in children and young 
people with FH who are intolerant of statins (17). Presently available non-statin LMTs commonly 
prescribed in the pediatric population, in particular ezetimibe and colesevelam, appear less 
effective than statins in lowering LDL-C, 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 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 75 mg Q2W for 
BW <50 kg and 150 mg Q2W for BW ≥50 kg in a pediatric population with hoFH. It is a 48 week 
uncontrolled, open-label treatment period study. The assessment of the primary endpoint of 
LDL-C at Week 12 represents the time point at which stable efficacy should be achieved based on 
the data from the large adult alirocumab program and should provide a reasonable duration of 
efficacy in this rare disease patient population who are expected to ultimately derive a potential 
benefit from the drug. 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. Patients who have initiated apheresis treatment 
for at least 6 months prior to screening and are currently undergoing stable LDL apheresis therapy 
as described in Appendix A are also eligible for the study.
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 cholesterol 
(Total-C), Apo B, non-HDL-C, a decrease in lipoprotein (a) [Lp (a)], and a favorable trend for 
high-density lipoprotein cholesterol (HDL-C), and triglycerides. Maximum efficacy was observed 
as early as 4 weeks after the initial dose, and efficacy was well sustained up to 2 years. In the 
DFI14223 pediatric study, treatment with alirocumab over 8 weeks demonstrated a significant and 
sustained LDL-C lowering effect in Cohort 2.
Alirocumab administration to date in clinical trials has been associated with a favorable safety and 
tolerability profile.
Immunogenicity and systemic hypersensitivity are considered as important identified risks.
The following safety information is based on the adult clinical trials. Injection site reactions 
(including erythema/redness, itching, swelling, pain, and tenderness), upper respiratory tract signs 
and symptoms (including mainly oropharyngeal pain, rhinorrhea, and sneezing), pruritus, 
hypersensitivity, eczema nummular, urticaria, and hypersensitivity vasculitis are identified as 
adverse drug reactions (ADRs) for alirocumab. The 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.
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In addition, in adults, there was no safety signal observed with neurologic events, 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 with 0.8% of alirocumab-treated patients who 
did not achieve such low levels. Although the limitations of this postrandomization comparison 
have to be considered, and there were no statistically significant differences in the incidence of 
cataracts in this subgroup of patients when compared to control groups, cataracts in patients with 
very low LDL-C levels are 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 AESI in this study.
Monitoring for, and collection of, all AEs will occur in this study conducted in pediatric patients.
In the DFI14223 pediatric study, treatment with alirocumab over 8 weeks and during the 
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.
This specific study is undertaken to demonstrate the efficacy and safety of alirocumab in the 
hoFH pediatric population. Due to the rapid clinical progression of atherosclerotic disease in 
children and adults with FH, pediatric guidelines (14, 15, 16, 17, 18, 19) recommend LDL-C 
lowering intervention starting with statins. However, in this particular population with very high 
LDL-C levels, and where achieving target LDL-C reductions with currently available LMTs 
appears very ambitious, adding alirocumab to the LDL-C lowering therapies can improve the 
condition of this hoFH population.
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5
STUDY OBJECTIVES
5.1
PRIMARY
To evaluate the efficacy of alirocumab (75 or 150 mg depending on BW), administered every 
2 weeks (Q2W), on low-density lipoprotein cholesterol (LDL-C) levels at Week 12 of treatment 
in children with homozygous familial hypercholesterolemia (hoFH) 8 to 17 years of age on top of 
background treatments.
5.2
SECONDARY

To evaluate the efficacy of alirocumab after 24 and 48 weeks of treatment on LDL-C 
levels.

To evaluate the effects of alirocumab on other lipid parameters (eg, Apo B, non-HDL-C, 
total-C, HDL-C, Lp (a), triglycerides [TG], apolipoprotein A-1 [Apo A-1] levels) after 12, 
24, and 48 weeks of treatment.

To evaluate the safety and tolerability of alirocumab up to 48 weeks of treatment.
5.3
OTHER

To evaluate the development of anti-alirocumab antibodies (ADA) during 48 weeks of 
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, multi-national, multi-center, open-label study with a treatment period of 
48 weeks.
Children and adolescents aged 8 to 17 years with hoFH confirmed by genetic testing and 
LDL-C ≥130 mg/dL (3.37 mmol/L) at the screening visit, despite treatment with stable LMTs at 
optimal doses, will be selected to enter the screening period. 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 LDL-C being 
obtained. The optimal dose of statin is defined as the dose prescribed based on local guidelines or 
practice, 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 entry 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.
A statin-intolerant patient is defined as one with the documented 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 approved regimen of a statin (eg, 1 to 3 times weekly) 
are also considered as not able to tolerate a daily dose.
Patients who have been on a stable apheresis1 schedule prior to the screening visit (Week -2), and 
stable background medical LMT for at least 4 weeks prior to the screening visit (Week -2), will 
enter a 2-week screening period.
Genotyping for hoFH 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 previously documented genotyping. 
For non-mandatory genotyping, the sample should preferably be taken during the screening 
period, but can be done at any visit during the treatment period.
The study will consist of a run-in period (as needed), a screening period, an open-label treatment 
period, and a follow-up period.
                                                
1 Stable apheresis is defined as 4 apheresis procedures performed during a 4 week period, approximately 
1 week apart, or 4 apheresis procedures performed during an 8 week period, approximately 2 weeks apart 
(see Appendix A).
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The initial dose of alirocumab will be based on BW (75 mg Q2W for patient <50 kg, 150 mg 
Q2W for patients ≥50 kg). After Week 12, if there is a change in BW, the dose of alirocumab can 
be adjusted such that the dose corresponds to the patient’s BW.
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 1.2, 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 48-week open-label treatment period.

A follow-up of 8 weeks (±3 days).
The total duration of the study will be up to 62 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
INTERIM ANALYSIS
No formal interim analysis is planned.
Interim analyses might be performed if requested by Health Authorities or if needed for the 
purpose of scientific communication.
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 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.
Detailed activities and responsibilities of the Steering Committee are described in the 
Steering Committee charter.
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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 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 10.6.3) in conjunction with the independent physician.
Detailed activities and responsibilities of the DMC are described 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 genetically diagnosed with 
homozygous familial hypercholesterolemia2 inadequately controlled (see threshold 
mentioned in exclusion criterion E 02) 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 weeks.
I 02.
A signed informed consent indicating parental permission with or without patient assent, 
depending on capacity for understanding based on developmental maturity. In cases 
involving emancipated or mature minors with adequate decision-making capacity, or when 
otherwise permitted by law, a signed informed consent directly from patients.
I 03.
For patients on apheresis, currently undergoing stable LDL apheresis therapy for at least 4 
weeks prior to the screening visit (Week -2) and have initiated apheresis treatment for at 
least 6 months (see Appendix A).
                                                
2 Diagnosis of hoFH must be made either by previous genotyping (true homozygotes, compound 
heterozygotes, or double heterozygotes) or current genotyping performed after having been suspected by 
clinical criteria according to EAS Consensus Panel recommendations for diagnosis of HoFH. Previous
genotyping refers to documented results that are available from prior genotyping testing supporting a 
diagnosis of hoFH. Current centralized genotyping refers to patients electing to undergo genotyping 
during the run-in period with results supporting a diagnosis of hoFH (see Appendix B).
3 The optimal dose of statin is defined as the stable daily dose prescribed based on local guidelines or 
practice, or is the dose that is maximally tolerated due to adverse effects of higher doses. For patients not 
receiving the maximally tolerated dose of statin, statin intensification should be carefully considered 
prior to inclusion in this study in order to ensure that the addition of a non-statin LDL-C lowering 
therapy (ie, alirocumab) would be the next appropriate step in the management of the patient’s 
hypercholesterolemia. The highest dose of statin should not exceed the maximum labeled dose of statin 
for pediatric patients as per the local prescribing information.
4 A statin-intolerant patient is defined as a patient with the documented 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 approved regimen of a statin (eg, 1 to 3 times weekly) will 
also be considered as not able to tolerate a daily dose.
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7.2
EXCLUSION CRITERIA
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 3 subsections: 
7.2.1
Exclusion criteria related to study methodology
E 01. 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 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 (pre-apheresis, if applicable) less than 130 mg/dL (3.37 mmol/L) 
obtained during the screening period after the patient has been on stable apheresis 
procedure or 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.
E 03. Patients with null LDLR mutations in both alleles.
E 04. Patients with BW less than 25 kg.
E 05. Patients aged 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 C).
E 06. Daily dose of statin that is above the maximum recommended dose for pediatric patients as 
per the local prescribing label.
E 07. Patients who will receive statin de novo during the run-in period.
E 08. 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 09. Patients not previously instructed on a cholesterol-lowering diet prior to the screening 
visit.
E 10. Mipomersen in the last 5 months.
E 11. Patients with uncontrolled (ie, hemoglobin A1c [HbA1c] >9% at the screening visit) Type 1 
or 2 diabetes mellitus.
E 12. Patients with known uncontrolled thyroid disease (ie, thyroid-stimulating hormone levels 
outside of the laboratory’s reference range within the past 6 months, or with elevated free 
T3 or T4 and with clinical symptoms of hyperthyroidism).
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E 13. Patients who use systemic corticosteroids.
Note: Topical, intra-articular, nasal, inhaled, and ophthalmic steroid therapies are not 
considered as ‘systemic’ and are allowed.
E 14. Patients with uncontrolled (ie, systolic blood pressure [SBP] or diastolic blood pressure 
[DBP] above local guidelines or equivalent) hypertension.
E 15. Fasting triglycerides >350 mg/dL (3.95 mmol/L) at the screening visit.
E 16. Severe renal impairment (ie, estimated glomerular filtration rate [eGFR]
<30 mL/min/1.73 m2) at the screening visit.
E 17. ALT or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN) (1 repeat 
laboratory allowed per patient) at the screening visit.
E 18. Creatine phosphokinase (CPK) >3 x ULN (1 repeat laboratory allowed per patient) at the 
screening visit.
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 19. Patient/parents who withdraws consent during the run-in or screening period (patient who 
is not willing to continue or fails to return).
E 20. 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 Subinvestigator would preclude safe completion of the 
study or constrain endpoints assessment such as major systemic diseases.

Patients considered by the Investigator or any Subinvestigator 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/parent 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 21. Known or suspected alcohol and/or drug abuse.
E 22. Patients who have previously received evolocumab.
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E 23. Treatment with any investigational medicinal product (IMP) within 8 weeks or 5 half-lives 
prior to the screening period, whichever is longer.
Note: If half-life is not known, then 8 weeks should be applied for non-biological IMP and 
6 months for biological IMP.
7.2.2
Exclusion criteria related to the active comparator and/or mandatory background 
therapies 
E 24. 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 sanofi compound 
E 25. Hypersensitivity to alirocumab or to any of the ingredients of alirocumab injections.
E 26. 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 legislation related to women of childbearing potential (WOCBP) 
randomized in clinical trials. See Appendix I for further details.
E 27. Positive pregnancy test in females who have experienced menarche.
E 28. Females who are breast-feeding.
E 29. 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 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
Formulation: Prefilled syringes (PFS) with finger grip, to be replaced by PFS with safety system 
(PFS-S) as soon as available: alirocumab 75 or 150 mg/mL solution as described below:

BW <50 kg: 1.0 mL of alirocumab 75 mg/mL solution.

BW ≥50 kg: 1.0 mL of alirocumab 150 mg/mL solution.
Route of administration: Subcutaneous (SC) injections in the abdomen, thigh, or outer area of 
upper arm.
Dose regimen: Alirocumab Q2W: 75 mg for BW <50 kg or 150 mg for BW ≥50 kg.
After Week 12, the dose of alirocumab can be adjusted in case of weight change after baseline, 
such that the dose corresponds to the patient’s BW.
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 will be able to 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 put in a safe location at room temperature for about 30 to 40 minutes. Thereafter, the 
IMP should be administered as soon as possible. If LDL apheresis coincides with study drug 
administration, study drug will be administered immediately after completion of the 
LDL apheresis procedure.
During the treatment period, alirocumab will be administered Q2W SC, starting at Week 0 and 
continuing up to the end of the open-label treatment period (last injection on Week 46).
Administration of IMP will start as soon as possible after the treatment kit numbers have been 
provided by the Interactive Response Technology (IRT). If at all possible, the first injection 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 injection. The IMP should ideally be administered Q2W 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. 
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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’s judgment.
Provision of IMP:
In exceptional cases, 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 the study Sponsor. For this reason, 
the IMP delivery will be managed by the service provider. The clinical site will instruct the 
patient, as appropriate, on how the DTP process operates before it starts.
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 product (NIMP) because the medication is a potential background 
therapy that will not be provided by the Sponsor:

Statins.

Cholesterol absorption inhibitors (ezetimibe).

Bile acid-binding sequestrants (such as cholestyramine, colestipol, and colesevelam).

Nicotinic acid.

Fenofibrate.

Omega-3 fatty acids (≥1000 mg daily).
8.3
BLINDING PROCEDURES
8.3.1
Methods of blinding
Not applicable – this is an open-label study.
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8.4
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP
This is an open-label study and every patient will receive alirocumab.
The lists of treatment kit numbers will be generated centrally by sanofi. 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 and
allocate the treatment kits to the patients.
Before allocating a treatment kit to the patient, the Investigator or designee will have to contact 
the centralized treatment allocation system.
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
Each kit will contain PFS 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°F to 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 sanofi compound 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 Investigational Site and Sponsor (eg, patient 
unable to attend an Investigational Site 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 
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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 DTP 
process will be described in detail in a separate document and will be implemented after 
appropriate training of Monitoring Teams and Investigational Sites.
8.7
RESPONSIBILITIES
The Investigator, 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) must be promptly notified 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 (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), 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
The IMP administration data will be recorded by the Investigator on the electronic case report 
form (eCRF) 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 
the patient’s diary.

The Investigator or designee will enter data in the appropriate eCRF pages, according to 
data recorded in the Treatment Log Form.
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
The monitor will check the data consistency between eCRF pages, Treatment Log Forms 
using the patient’s diary, and returned unused syringes of a corresponding kit.
For any background LMT that is supplied by the sponsor (eg, via a local warehouse), tracking and 
reconciliation will be conducted in accordance with the Sponsor’s directives.
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 has to be 
achieved by the Investigator according to the system proposed by the Sponsor.
8.8
CONCOMITANT MEDICATION
A concomitant medication is any treatment received by the patient concomitantly with 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 eCRF 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, and during the screening period. 
During the 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 those found in 
Benecol, flax seed oil, and psyllium.
Any adjustment will be documented in the eCRF.
8.8.1
Management of background lipid modifying therapy
Patients must have been on stable LMTs, 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 LDL-C being obtained.
During the treatment period, lipid levels will be communicated to the Investigator.
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Patients will be instructed to follow a diet to treat their hypercholesterolemia in accordance with 
local guidelines or treatment practice, and they should be on this diet throughout the entire study 
duration.
The Investigator will be responsible, based on his/her own judgment related to the patients’ 
LDL-C levels and the safety profile, to continue or discontinue alirocumab throughout the study. 
The statin dose or other LMT should not be modified to adjust for the degree of LDL-C lowering
before Week 12, unless otherwise indicated.
8.8.2
Contraception
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 IMP injection
(see Appendix D).
8.8.3
Prohibited concomitant medications
Prohibited concomitant medications from the initial screening visit until the end of treatment 
(EOT) period visit include the following:

Oral and injectable corticosteroids.

Fibrates (except fenofibrate).

Mipomersen.

Immunosuppressants.

Other PCSK9 inhibitor, evolocumab.
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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 (pre-apheresis, if applicable) from baseline to Week 12 in the 
intent-to-treat (ITT) population, using all LDL-C values (pre-apheresis, if applicable) regardless 
of adherence to treatment (ITT estimand).
The LDL-C at Week 12 will be the LDL-C level obtained within the Week 12 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 are provided for the same sampling, the 
measured LDL-C will be considered. For patients undergoing apheresis, pre-apheresis values will 
be considered. The analysis window used to allocate a time point to a measurement will be 
defined in the statistical analysis plan (SAP).
9.2
SECONDARY ENDPOINTS
9.2.1
Secondary efficacy endpoints

Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Week 12 in the 
ITT population, using all LDL-C values during the treatment period (on-treatment 
estimand).

Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Weeks 24 and 48 
(ITT and on-treatment estimands).

Percent change in Apo B, non-HDL-C, Total-C, Lp (a), HDL-C, fasting TG and Apo A-1 
(pre-apheresis, if applicable) from baseline to Weeks 12, 24, and 48 (ITT and on-treatment 
estimands).

Proportion of patients with ≥15% reduction in LDL-C (pre-apheresis, if applicable) at 
Weeks 12, 24, and 48 (ITT and on-treatment estimands).

The absolute change in LDL-C from baseline to Weeks 12, 24, and 48 (ITT and 
on-treatment estimands).
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9.2.2
Efficacy assessment method
9.2.2.1
Lipid parameters
Total-C, HDL-C, TG, Apo B, Apo A-1, and Lp (a) will be directly measured by the central 
laboratory as per the schedule in Section 1.2. LDL-C will be calculated using the Friedewald 
formula by the central laboratory as per the schedule in Section 1.2. If TG values exceed 
400 mg/dL (4.52 mmol/L), then the central laboratory will reflexively measure (via the beta
quantification method) the LDL-C rather than calculating it. Non-HDL-C will be calculated by 
subtracting HDL-C from the Total-C. Ratio Apo B/Apo A-1 will be calculated. Detailed 
procedures of sample preparation, storage, and shipment will be described in the specific 
laboratory manual which will be provided to sites. Information on the processing, methodology 
and other relevant information will be available upon request, in the Reference Laboratory 
Manual.
Efficacy endpoints will not be considered as AEs, such as those involving abnormalities in lipid 
levels, unless meeting the criteria in Section 10.4.
9.2.3
Safety endpoints
Main safety parameters: AEs, serious AEs (SAE), and AESIs, assessed throughout the study.
Other safety parameters: laboratory data, vital signs, body weight, height, and Tanner stage,
assessed throughout the study.
The AESIs are defined in Section 10.4.1.3.
9.2.3.1
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 IMP.

TEAE period: The TEAE observation period is defined as the time from the first dose of 
IMP to the last dose of IMP + 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 TEAE period up to the end of the study for each 
patient.
9.2.3.2
Adverse events
Refer to Section 10.4 to Section 10.7 for details.
All AEs reported by the Investigator, will be described.
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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 Medical Dictionary for Regulatory Activities (MedDRA) 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 AEs (AESIs or not, see Section 10.4.1.3).

Neurocognitive events.

Symptomatic overdose with IMP:
-
An overdose (accidental or intentional) is an event suspected by the Investigator or 
spontaneously notified by the patient (not based on systematic injection counts) and 
defined as at least twice of the intended dose within the intended therapeutic interval 
(ie, 2 or more injections from the treatment kit are administered in <7 calendar days to 
be reported using the corresponding screens in the eCRF using the term “symptomatic 
overdose (accidental or intentional)”. The patient should be monitored and appropriate 
symptomatic treatment instituted, if needed.

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, 
“poststudy” 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).
9.2.3.3
Laboratory safety variables
The clinical laboratory data consist of blood analysis (including hematology and clinical 
chemistry). Clinical laboratory values will be analyzed after conversion into standard international 
units. International units will be used in all listings and tables.
9.2.3.4
Vital signs
Vital signs include: heart rate, systolic and diastolic blood pressure (BP) in sitting position.
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9.2.3.5
Tanner stages measurement
The Tanner stages will be measured (see Appendix C) throughout the study according to the 
schedule in Section 1.2. The Tanner stages assessment for each patient at each site should be 
performed, if possible by the same Investigator/designee trained to assess pubertal development.
9.3
OTHER ENDPOINTS
9.3.1
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) 
(pre-apheresis and post-apheresis, if applicable) at Weeks 0, 12, 24, and 48 per the study 
flowchart (see Section 1.2).
Exact date and time of last IMP administration and PK sampling are to be recorded.
Pharmacokinetics handling for alirocumab are presented in Table 1.
9.3.1.2
Pharmacokinetics handling procedure
Table 1 - Pharmacokinetics handling for alirocumab
Sample type
Alirocumab
Matrix
Serum
Blood sample volume
3 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. The 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 PK samples will also be analyzed for the determination of the total and free PCSK9 levels 
using validated ELISA. 
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9.3.2
Anti-alirocumab antibody assessments
Anti-alirocumab antibodies include the antibody status (positive/negative), antibody titers, and 
neutralizing activity for positive ADA. Samples should be collected pre-apheresis, if applicable.
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 1.2. All scheduled samples will 
be obtained before IMP injection (predose).
9.3.2.2
Sampling procedure
Details 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 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 ADA 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
For the purposes of verifying participant eligibility, patients with suspected hoFH based on 
clinical criteria, but without confirmation by previous genetic testing, will be asked to undergo 
centralized hoFH genotyping.
No other pharmacogenetic testing will be done in this study.
9.3.4
Pharmacodynamic variables
The pharmacodynamic 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).
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9.3.5
Creatine phosphokinase-MB and cardiac troponin
Creatine phosphokinase-MB (CPK-MB) and cardiac troponin levels will be assessed at baseline 
and at Week 12 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 (enrollment visit), a timeframe of a certain number of days will 
be allowed. The window period for the visits at Weeks 4, 24, 36, and 56 is ±7 days, and the 
window period for the visits at Weeks 12 and 48 is ±3 days.
For all visits after Day 1/Week 0, if one visit date is changed, then the next visit should take place 
according to the original schedule as outlined in Section 1.2.
Blood sampling:
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, and 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. 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 maximum blood volume of 38.0 mL/day or 50.9 mL/month 
[20, 21, 22]). Lipid panel 1 (Total-C, LDL-C, HDL-C, TG, and non-HDL-C) should take highest 
priority, followed by safety parameters, and then other parameters.
Laboratory tests:
The laboratory data are collected in accordance with the study schedule in Section 1.2 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-glutamyl transferase (γGT).
Note: eGFR and creatinine clearance will be calculated at screening; creatinine clearance will be 
calculated for all subsequent visits where chemistry laboratory testing is performed. The formula 
for calculating eGFR and creatinine clearance is provided in Appendix E.

Lipid panel 1: Total-C, calculated LDL-C, HDL-C, TG, and 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).

CPK.

HbA1c.

CPK-MB and cardiac troponin.

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. Refer to 
Appendix I for further details.
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 F.
Pharmacogenetic samples:
Blood samples for hoFH genotyping will be obtained during the run-in period for patients with 
suspected hoFH not confirmed by previous genetic testing.
Pharmacokinetic samples:
Serum samples for assessment of alirocumab concentration will be obtained periodically 
throughout the study as per schedule note in study flowchart of Section 1.2. Blood samples should 
be collected before IMP injection. The 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 1.2. If a new clinically significant abnormality or worsening from 
baseline is detected after enrollment, then an AE should be reported and the patient should be 
considered for further clinical investigations and/or specialist consultation as per the 
Investigator’s medical judgment.
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Blood pressure/heart rate:
Blood pressure 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 
eCRF; both SBP and DBP should be recorded. At the first screening visit, BP should be measured 
in both arms. The arm with the highest DBP 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 eCRF.
Heart rate will be measured in sitting position at the time of the measurement of BP.
Tanner stages:
The Tanner stages (18, 19) should be measured by the Investigator at the time points indicated in 
the study schedule flowchart Section 1.2. Tanner stages are provided in Appendix C. 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.
10.1
VISIT SCHEDULE
The visit schedule and procedures/assessments are listed in the study flow chart in Section 1.2.
The aim of this section is to provide details on how some of the procedures/assessments have to 
be performed. The study consists of 8 or 9 on-site visits and 1 telephonic visit (follow-up).
If patients are treated with LDL apheresis, the visits from Day 1/Week 0, Week 4 and Week 12 
must coincide with an LDL apheresis procedure as well as with study drug administration; study 
drug will be administered immediately after completion of the LDL apheresis procedure. After 
Week 12, it is strongly recommended to conduct further visits Week 24 and Week 48 the same 
day as an LDL apheresis procedure, if these procedures are maintained.
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Only patients who meet/are likely to meet the inclusion criteria as noted in Section 7.1 should be 
screened.
10.1.1 Run-in period (as needed, 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. 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. Patients who have initiated apheresis procedure (every 
week or every other week) at least 6 months prior to giving informed consent to the study, can 
enter the run-in period.
Another possible situation requiring the run-in period includes patients with suspected hoFH 
based on clinical criteria but without confirmation by previous genetic testing. Such patients will 
be asked to undergo centralized genotyping testing during the run-in period.
The run-in period is up to 4 weeks (+2 days) in duration, with 1 visit.
Patients can enter the screening period as soon as the criterion for stable LMT is met and/or 
centralized genotyping data (if no previous genotyping) are available.
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 hoFH Genotyping Informed Consent from the dedicated section in the main 
ICF (if needed, ie, if no previous result of genotyping is available).

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.

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 those found in Benecol, flax seed oil, and psyllium).

Check of stability of background LMT, including apheresis schedule (see Appendix A).

Review of diet.

Physical examination including vital signs (heart rate, SBP and DBP in sitting position) in 
both arms.

Body weight measurement.
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
Height without shoes.

Tanner stage.

Collect AEs from this point onward:
-
All AEs and SAEs will be collected from the time of informed consent signature and 
throughout the study.

Sampling for hoFH genotyping (if needed).

IRT will be contacted for notification of screening and for patient number allocation.
10.1.2 Screening period
For all patients regardless of their participation in a run-in period, the screening period is up to 
2 weeks (+5 days) in duration.
The injection training will occur during the screening period after the eligibility criteria have been 
checked and it is confirmed that the patient is likely to be included. Patients aged ≥12 years (or 
another designated person such as parent, etc) will be trained to self-inject/inject with placebo for 
alirocumab. Patients 8 to 11 years old will be assigned a parent or another designated person who 
will be trained during the injection training visit or an alternative arrangement. In all cases, 
alternative arrangements for this required injection training may be allowed as needed, regardless 
of age. Please note that this visit (injection training visit) can take place at the same visit as D1 as 
per the site or patient preference. Prior to the injection, a local topical anesthetic may be utilized 
as per the Investigator’s judgment. Investigators will have the option of providing a second 
placebo kit for alirocumab for patients/parents who require additional injection training prior to 
enrollment.
All laboratory tests measured at the central laboratory needed for checking the exclusion criteria 
of the patients will be performed during the screening period.
The screening period may include more than one site visit for patients for whom not all screening 
procedures can be done at the first 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, including 
apheresis) for at least 4 weeks.
Patients can be enrolled after the injection training visit and as soon as all inclusion and no 
exclusion criteria are met.
Patients will be instructed to follow a diet to treat their hypercholesterolemia in accordance with 
local guidelines or treatment practice and they should be on this diet throughout the entire study 
duration.
10.1.2.1 Visit 2 (Up to 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 1.2 and for detailed description of assessments 
Section 9 and Section 10.6.
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The following procedures/assessments will be performed at the Screening visit:

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.

Check of stability of background LMT, including apheresis schedule (if applicable)

If not collected before:
-
Collection of demographic data (age, gender, race, and ethnic origin).
-
Collection of genotyping results.
-
Medical/surgical/family medical history.
-
Record habits: alcohol habits (during the last 12 months), smoking status.
-
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 those found in Benecol, flax seed oil, and psyllium).
-
Review of diet.
-
Physical examination including vital signs (heart rate, SBP and DBP in sitting
position) in both arms.
-
Body weight measurement.
-
Height without shoes.
-
Tanner stage.

Collect AEs.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Hematology and chemistry.
-
HbA1c.
-
CPK.
-
Liver panel.
-
Pregnancy test.
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10.1.2.2 Visit 3 (Week -1, Injection training)
The injection training will occur during the screening period after the eligibility criteria have been 
checked and it is confirmed that the patient is likely to be included. Patients aged ≥12 years (or 
another designated person such as parent, etc) will be trained to self-inject/inject with placebo for 
alirocumab. Patients 8 to 11 years old will be assigned a parent or another designated person who 
will be trained during the injection training visit or an alternative arrangement. In all cases, 
alternative arrangements for this required injection training may be allowed as needed, regardless 
of age.
Prior to the injection, a local topical anesthetic may be utilized as per the Investigator’s judgment. 
Investigators will have the option of providing a second placebo kit for patients/parents who 
require additional injection training prior to enrollment.
Patients can be enrolled after the injection training visit and as soon as eligibility is confirmed.
The injection training visit at Week -1 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:

IRT contact.

Check of stability of background LMT, including apheresis schedule (if applicable).

Collect AEs.
10.1.3 Treatment period
The overall treatment period is 48 weeks in duration.
All patients will receive subcutaneously (SC) either 75 or 150 mg alirocumab Q2W at entry,
depending on their BW, without any dose adjustment up to Week 12. After Week 12, the dose of 
alirocumab can be adjusted in case of weight change after baseline, such that the dose corresponds 
to the patient’s BW:

75 mg for BW <50 kg.

150 mg for BW ≥50 kg.
For patients treated with apheresis, the frequency will be fixed to the individual patient’s 
established schedule up to Week 12. After Week 12, the frequency of apheresis can be adapted 
following Investigator judgment.
For dosing and timing of injection details, see Section 8.1.
The first IMP injection from the study treatment kit allocated by IRT will be administered at the 
site on the day of entry and as close as possible after their entry into the study. Patients will be 
monitored at the investigational site for at least 30 minutes after this first injection. Subsequent 
injections will be performed at a patient-preferred location (eg, home). All of the IMP injections 
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can be performed by a trained patient (self-injection if aged ≥12 years), parent, or another 
designated person, or alternative arrangements for injection administration will be allowed as 
needed (eg, return to the investigational site). 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’s recommendation.
The laboratory measurement of lipid parameters will be performed by a central laboratory. 
The results will be communicated to the sites.
Statin and other LMT, including apheresis, (if applicable) should be stable during the treatment 
period barring exceptional circumstances whereby overriding concerns (including but not limited 
to triglyceride alert posted by the central laboratory) warrant such changes, as per the 
Investigator’s judgment.
10.1.3.1 Visit 4 (Day 1, Week 0, Enrollment visit)
The following procedures/assessments will be performed:

Assessment of inclusion/exclusion criteria.

Concomitant medication recording.

Check of stability of background LMT, including apheresis (if applicable).

Review of diet.

Vital signs.

Body weight.

Body height.

IRT contact.

Inclusion in study.

Collect AEs.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) (pre-apheresis, if applicable).
-
Hematology and chemistry.
-
CPK-MB and cardiac troponin.
-
CPK.
-
Liver panel.
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-
Anti-alirocumab antibodies (ADA) (pre-apheresis, if applicable).
-
Serum alirocumab concentration (PK) and PCSK9 concentrations (pre-apheresis and 
post-apheresis, if applicable).

Pregnancy test (urine).

IMP administration; patients will remain under observation at the site for 30 minutes 
post-injection.

IMP kit dispensation (including treatment administration package, patient diary, and 
injection instruction manual, as needed).
Injection training: Further injection training can be provided at the enrollment visit 
Week 0/Day 1 when the patient/parent or a trained designated person injects the first dose of IMP
allocated by IRT. Additional training can be offered at scheduled or unscheduled visits within the 
scheduled treatment period, as per patient/parent or Investigator’s judgment.
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.
10.1.3.2 Visit 5 (Week 4)
The following procedures/assessments will be performed:

Compliance check of IMP and data collection on IMP administration.

Concomitant medication recording.

Check of stability of background LMT, including apheresis (if applicable).

Review of diet.

Collect AEs.

Vital signs.

Body weight.

Body height.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Hematology and chemistry.
-
Liver panel.

IMP administration.
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10.1.3.3 Visit 6 (Week 12)
The following procedures/assessments will be performed:

Compliance check of IMP and data collection on IMP administration

Concomitant medication recording.

Check of stability of background LMT, including apheresis (if applicable).

Review of diet.

Collect AEs.

Vital signs.

Physical examination.

Body weight.

Body height.

IRT contact.

Tanner stage.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) (pre-apheresis, if applicable).
-
Hematology and chemistry.
-
HbA1c.
-
CPK-MB and cardiac troponin.
-
CPK.
-
Liver panel.
-
Anti-alirocumab antibodies (ADA) (pre-apheresis, if applicable).
-
Serum alirocumab concentration (PK) and PCSK9 concentrations (pre-apheresis and 
post-apheresis, if applicable).

Pregnancy test (urine).

IMP kit dispensation (including treatment administration package, patient diary, and 
injection instruction manual, as needed).

IMP administration.
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10.1.3.4 Visit 7 (Week 24)
The following procedures/assessments will be performed:

Compliance check of IMP and data collection on IMP administration.

Concomitant medication recording.

Check of stability of background LMT, including apheresis (if applicable).

Review of diet.

Collect AEs.

Vital signs.

Physical examination.

Body weight.

Body height.

Tanner stage.

IRT contact.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) (pre-apheresis, if applicable).
-
Hematology and chemistry.
-
HbA1c.
-
CPK.
-
Liver panel.
-
Anti-alirocumab antibodies (ADA) (pre-apheresis, if applicable).
-
Serum alirocumab concentration (PK) and PCSK9 concentrations (pre-apheresis and 
post-apheresis, if applicable).

Pregnancy test (urine).

IMP kit dispensation (including treatment administration package, patient diary, and 
injection instruction manual, as needed).

IMP administration.
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10.1.3.5 Visit 8 (Week 36)
The following procedures/assessments will be performed:

Compliance check of IMP and data collection on IMP administration.

Concomitant medication recording.

Check of stability of background LMT, including apheresis (if applicable).

Review of diet.

Collect AEs.

Vital signs.

Body weight.

IRT contact.

Pregnancy test (urine).

IMP kit dispensation (including treatment administration package, patient diary, and 
injection instruction manual, as needed).

IMP administration.
10.1.3.6 Visit 9 (Week 48, end of the treatment period visit)
The following procedures/assessments will be performed:

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.

Physical examination.

Body weight.

Body height.

Tanner stage.

IRT contact.

Fasting blood sampling for:
-
Total-C, LDL-C, HDL-C, TG, and non-HDL-C (pre-apheresis and post-apheresis, if 
applicable).
-
Apo B, Apo A-1, ratio Apo B/Apo A-1, and Lp (a) (pre-apheresis, if applicable).
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-
Hematology and chemistry.
-
HbA1c.
-
CPK.
-
Liver panel.
-
Anti-alirocumab antibodies (ADA) (pre-apheresis, if applicable).
-
Serum alirocumab concentration (PK) and PCSK9 concentrations (pre-apheresis and 
post-apheresis, if applicable).

Pregnancy test (urine).
10.1.4 Follow-up
A follow-up call will be planned 10 weeks after the last IMP injection, ie. 8 weeks after the EOT 
visit, for the patients who complete the study and for the patients who discontinue early for any
reason.
The following procedures/assessments will be performed remotely:

Concomitant medication recording.

Collect AEs.

IRT contact.
10.2
DEFINITION OF SOURCE DATA
Evaluations that are reported in the eCRF must be supported by appropriately signed identified 
source documentation related but not limited to the following:

Agreement, date, and signature of informed consent mentioning the study identification.

Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology.

Genotyping result, if available.

Contraception methods for females of childbearing potential who are sexually active.

Previous and concomitant medication (including LMT).

Study identification.

Treatment number and dates of administration.

Dates of visits and assessments including the examination report.

Vital signs, height, BW, and Tanner stage.

Faxed central laboratory reports (dated and signed by the Investigator or Subinvestigator)
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
IRT confirmation fax (screening, screen failure, discontinuation, EOT period, end of 
follow-up period, and end of study).

Adverse events and follow-up:
-
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports documenting the 
follow-up of the SAE.

Date of premature study discontinuation (if any) and reason.
Source documentation may be found in the following:

Patient’s identity.

Medical history.

Hospital records.

Nursing notes.

Physician’s notes.
10.3
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation must be fully documented in the eCRF. 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. Reinitiation of treatment with the IMP 
will be done under close and appropriate clinical/and or laboratory monitoring once the 
Investigator will have considered according to his/her best medical judgment that the 
responsibility of the IMP(s) in the occurrence of the concerned event was unlikely and if the 
selection criteria for the study are still met (refer to Section 7.1 and Section 7.2).
For all temporary treatment discontinuations, duration must be recorded by the Investigator in the 
appropriate pages of the eCRF.
Treatment interruption is defined as one or more scheduled injections that are not administered to 
the patient as decided by the Investigator.
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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 reason(s) for treatment discontinuation and this should be documented in the eCRF.
Patients should discontinue the IMP for the following reasons:

Pregnancy, intention for pregnancy, or no longer using an 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 allergic 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.
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.
All cases of permanent treatment discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed.
10.3.4 Handling of patients after permanent treatment discontinuation
Patients will be followed up according to the study procedures specified in this protocol up to the 
scheduled date of study completion, or up to recovery or stabilization of any AE to be followed up 
as specified in this protocol, whichever comes last.
Patients who prematurely discontinue study treatment (regardless of the reason) should undergo 
the following visits:

At the time of treatment discontinuation, the patient should have, as soon as possible, an 
unscheduled visit with assessments normally planned at the EOT period visit. 

Week 12 and Week 48 visits, as described in Section 1.2, should be performed regardless 
of the timing of the last alirocumab injection.
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In case of permanent treatment discontinuation, the recommendation is to limit data collection to 
critical data, ie, primary endpoint/main secondary endpoint and safety endpoints. All cases of 
permanent treatment discontinuation must be recorded by the Investigator in the appropriate pages 
of the eCRF when considered as confirmed.
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.
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 eCRF
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 reallocated (treated) in the study. Their 
inclusion and treatment numbers must not be reused.
10.4
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING
10.4.1 Definitions of adverse events
10.4.1.1 Adverse event
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
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10.4.1.2 Serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death, or

Is life-threatening, or
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization, or

Results in persistent or significant disability/incapacity, or

Is a congenital anomaly/birth defect.

Is a medically important event.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above.
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered 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.
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10.4.1.3 Adverse event of special interest
An 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. The AESIs may be added, modified, or removed during a study 
by protocol amendment.
The AESI are AEs (serious or nonserious) that need to be monitored, documented, and managed 
in a prespecified manner described in the protocol. Please see Appendix G for additional 
information.
For these AEs, the Sponsor will be informed immediately (ie, within 24 hours), as per SAEs 
notification described in Section 10.4.1.2 even if not fulfilling a seriousness criterion, using the 
corresponding screens in the eCRF.
AESIs in this study will include:

ALT >3 x 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 F 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 eCRF 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 eCRF screen 
(see Section 10.6.2).

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.

Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP;
-
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2).
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-
In the event of pregnancy in a female participant, IMP should be discontinued.
-
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined.

Symptomatic overdose (serious or nonserious) with IMP/NIMP:
-
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic pills 
count) and defined as at least twice 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 eCRF 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.
Of note, asymptomatic overdose has to be reported as a standard AE.
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 eCRF screens will need to be completed. If such an AE was to occur, then do not report 
the individual components of the reaction but rather the term “local injection site reaction”, the 
individual components being described in the specific eCRF screen.
If a local topical anesthetic is used before alirocumab injection, the time of local anesthetic 
administration, the time of alirocumab administration, and the time of AE will be recorded in the 
eCRF.
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities
Not applicable.
10.4.3 General guidelines for reporting adverse events

All AEs, regardless of seriousness or relationship to IMP/NIMP, 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 eCRF.
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
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 or by the study procedure(s).

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.

Laboratory or vital signs abnormalities are to be recorded as AEs only if: 
-
Symptomatic and/or 
-
Requiring either corrective treatment or consultation, and/or 
-
Leading to IMP discontinuation or modification of dosing, and/or 
-
Fulfilling a seriousness criterion, and/or 
-
Defined as an AESI.
Instructions for AE reporting are summarized in Table 2.
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 eCRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the eCRF or after a standard delay.

SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges.

All further data updates should be recorded in the eCRF, as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification.
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
A back-up plan (using a paper case report form [CRF] process) is available and should be 
used when the eCRF system does not work.
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team.
10.4.5 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 eCRF.
Instructions for AE reporting are summarized in Table 2 and Appendix G.
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 F.
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices:

Neutropenia.

Thrombocytopenia.

ALT increase.

Acute renal insufficiency.

Increase in CPK and suspicion of rhabdomyolysis.
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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 x 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
No
Neurocognitive events
Yes
Yes
No 
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.
Noninvestigational medicinal products 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.
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10.5
OBLIGATIONS OF THE SPONSOR
During the course of the study, the Sponsor will report in an expedited manner:

All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]), to the 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 x 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.
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 eCRF screens are to be filled in to assess allergic AEs or allergic-like AEs 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.
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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 AE 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 AE
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 1 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 
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 AE that occurs during or shortly after injection of the IMP 
(characterized by but not limited to hypotension, bronchoconstriction, urticaria, edema, 
angioedema, nausea, and vomiting). Emergency equipment and medication for the treatment of 
these potential adverse effects (eg, antihistamines, bronchodilators, intravenous saline, 
corticosteroids, acetaminophen, and epinephrine) must be available for immediate use for the 
injections at the site visits.
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Patients will be observed at the investigational site for at least 30 minutes following the injection 
that takes place at the enrollment visit. Patients should be treated symptomatically if any AEs are 
observed. Patients are to remain at the site until any acute injection reaction is assessed as stable, 
per the Investigator’s discretion. General Allergic Reaction and/or Local Injection Site Reaction 
Complementary Form will have to be completed.
10.6.3 Recommendations for managing and monitoring patients reaching LDL-C levels 
(ie, LDL-C <50 mg/dL [1.30 mmol/L]) during the treatment period 
If a patient achieves a low LDL-C level (ie, LDL-C <50 mg/dL [1.30 mmol/L] on one or more 
occasion) during the treatment period, then the Investigator will:

Call the patient/parent as soon as possible to inquire about interval occurrence of AEs.

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.
10.7
ADVERSE EVENTS MONITORING
All AEs 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
No sample size calculation was performed. Eighteen patients are planned to be enrolled to have at 
least 15 evaluable patients considering the recruitment constraints in this rare disease population.
11.2
DISPOSITION OF PATIENTS
Screened patients are defined as any patient who originally met all the inclusion criteria and none 
of the exclusion criteria and signed the informed consent.
Enrolled patients consist of all screened patients, with a treatment kit number allocated and 
recorded in the IVRS/IWRS database, regardless of whether treatment kit was used or not.
11.3
ANALYSIS POPULATIONS
11.3.1 Efficacy population
The efficacy analysis population will be the ITT population defined as the patients receiving at 
least one dose or partial dose of IMP.
11.3.2 Safety population
Safety analyses will be performed on the safety population, which will consist of patients 
receiving at least one dose or partial dose of IMP.
In addition: 

Patients for whom it is unclear whether they took the study medication will be included in 
the safety population.
11.3.3Other analysis populations
The ADA 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 IMP 
injection.
The PK analysis will be performed on all treated patients (safety population) with at least one 
available PK sample post first IMP injection.
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11.4
STATISTICAL METHODS
11.4.1 Extent of study treatment exposure and compliance
The extent of study treatment exposure and compliance will be assessed and summarized by dose 
and overall 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: (last dose of IMP injection date – first dose 
of IMP injection date + 14 days)/7, regardless of unplanned intermittent discontinuations.

The total number of injections by patient.
11.4.1.2 Compliance
Compliance will be assessed using the following parameters:

The injection frequency will be defined for each patient as the average number of days 
between 2 injections, that is: (last dose date – first dose date)/(number of injections -1).
This parameter will be summarized descriptively (N, mean, standard deviation [SD], median, 
minimum [Min] and maximum [Max]).
11.4.2 Analyses of efficacy endpoints
Efficacy endpoints analyzed with the ITT and on-treatment estimands will be analyzed in the ITT 
population.
11.4.2.1 Analysis of primary efficacy endpoint(s)
The percent change from baseline in LDL-C at Week 12 (see Section 9.1.1) will be analyzed in 
the ITT population using a mixed-effect model with repeated measures (MMRM) approach. All 
post-baseline data available within the Week 4 to Week 48 analysis windows will be used and 
missing data will be accounted for by the MMRM model. The model will include the fixed 
categorical effect of time point (Weeks 4, 12, 24, and 48), as well as the continuous fixed 
covariate of baseline LDL-C value.
This model will be run using SAS mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation. Throughout the MMRM model, LS mean and standard error 
(SE) at Week 12 will be provided with the SE and 95% confidence interval (CI).
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).
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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 
(eg, percent change in LDL-C), continuous measurements expected to have a non-normal 
distribution (eg, TG), and binary measurements (eg, proportion of patients with ≥15% reduction in 
LDL-C).
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 using the same 
MMRM model 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 model but only including 
on-treatment values. The treatment period is defined as the time period from the first IMP 
injection up to the day of last injection + 21 days.
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) with baseline value as effect. 
Missing values will be addressed using a multiple imputation approach, which will be described 
in the SAP. The combined means will be provided with respective SE estimates and 95% CI.
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 in these models.
Binary endpoints
Binary secondary efficacy endpoints analyzed with the ITT estimand will be analyzed with 
multiple imputation approach for handling of missing values, which will be described in the SAP. 
Combined proportions will be provided with corresponding 95% CI.
Binary secondary efficacy endpoints analyzed with the on-treatment estimand will be analyzed 
using the same imputation model, but only including on-treatment values in this model.
11.4.2.3 Multiplicity considerations
Not applicable.
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11.4.3 Analyses of safety data
The summary of safety results (see Section 9.2.3) will be presented by dose and overall. 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 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.

The PCSA criteria will determine which patients had at least 1 PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
unscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the PCSA percentage.

Treatment period: the treatment period used for quantitative analysis is defined as the time 
from first dose of IMP injection to the last dose of IMP injection +21 days.
Adverse event definition:

Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period.

Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious 
during the TEAE period.

Post-treatment AEs are AEs that developed or worsened or became serious during the 
POST-TREATMENT period.
Drug-induced liver injury
Liver function tests, namely ALT, AST, ALP, and total bilirubin, are used to assess possible 
drug-induced liver toxicity. The proportion of patients with PCSA values at any post-baseline visit 
by baseline status will be displayed 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. The selection of PT will be based on 
standardized MedDRA query (SMQ) hepatic disorder.
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11.4.3.1 Adverse events
Adverse event incidence tables will present the number (n) and percentage (%) of patients 
experiencing an AE by SOC (sorted by internationally agreed order), HLGT, HLT, and PT sorted 
in alphabetical order. Multiple occurrences of the same event in the same patient will be counted 
only once in the tables within a treatment phase. The denominator for computation of percentages 
is the safety population.
Adverse event incidence table will be provided for all types of TEAEs: all TEAEs, all 
treatment-emergent AESI 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, poststudy) 
summarized on the safety population.

Death in non-treated patients.

TEAE leading to death (death as an outcome on the AE eCRF page as reported by the 
Investigator) by primary SOC, HLGT, HLT, and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and 
PT.
11.4.3.2 Laboratory data and vital signs
The summary statistics (including mean, median, Q1, Q3, standard error, minimum, and 
maximum) of all laboratory variables, all vital signs parameters (raw data and changes from 
baseline) will be calculated for each visit, last and worst value assessed during the treatment 
period.
The incidence of PCSAs at any time during the TEAE period (on-treatment PCSAs) will be 
summarized whatever the baseline level and/or according to the following baseline categories:

Normal/missing.

Abnormal according to PCSA criterion or criteria.
For laboratory parameters for which PCSA criterion is not defined, similar table(s) using the 
normal range could be provided.
11.4.4 Other endpoints
For definitions see Section 9.3.
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11.4.4.1 Pharmacokinetics
Serum total alirocumab concentrations, and total and free PCSK9 concentrations will be 
summarized by visit using descriptive statistics by dose and overall. Serum concentration time 
profiles will be provided by dose and overall. Further details will be provided in the SAP.
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 visit using 
descriptive statistics by dose and overall.
11.4.4.3 LDL-C less than 50 mg/dL (1.30 mmol/L)
The number and percentage of patients with 2 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
(<25 mg/dL, <15 mg/dL respectively), will be provided by dose and overall.
11.4.4.4 Creatine phosphokinase-MB and cardiac troponin
Creatine phosphokinase-MB and cardiac troponin (value and percent change from baseline) at 
Week 12 will be summarized on the safety population using number of available data, mean, SD, 
median, Q1, Q3, minimum, and maximum for each dose and overall. In addition, the incidence of 
PCSA at any time during the TEAE period will be summarized by dose and overall using 
descriptive statistics.
11.5
INTERIM ANALYSIS
No interim analysis is planned (see Section 6.3).
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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 Subinvestigator, 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, should fully inform the patient (and the parent[s] or guardian[s]) of all pertinent 
aspects of the clinical trial including the written information given approval/favorable opinion by 
the ethics committee (IRB/IEC). All participants should be informed to the fullest extent possible 
about the study in language and terms they are able to understand.
Prior to a patient’s participation in the clinical trial, the informed consent form should be signed, 
name filled in, and personally dated by the patient’s parent(s) or by the patient’s legally 
acceptable representative, and by the person who conducted the informed consent discussion. 
Local law must be observed in deciding whether 1 or both parents/guardians consent is required. 
If only 1 parent or guardian signs the consent form, the Investigator must document the reason for 
only 1 parent or guardian’s signature.
In addition, participants will assent as detailed below or will follow the IRB/IEC approved 
standard practice for pediatric participants at each participating center (age of assent to be 
determined by the IRBs/IECs or be consistent with the local requirements):
Participants who can read the assent form will do so before writing their name and 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.
Prior to collection of blood for genotyping for hoFH 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.
A copy of the signed and dated written informed consent form(s) will be provided to the patient or 
legal representative.
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, etc],
Investigator’s curriculum vitae), 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 
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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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 eCRF, Discrepancy Resolution Form [DRF], or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives.
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred.
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information.
13.2
RESPONSIBILITIES OF THE SPONSOR
The Sponsor of this clinical trial is responsible to 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 eCRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical, and regulatory quality in all aspects of the clinical trial.
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use, and quality of 
data.
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13.3
SOURCE DOCUMENT REQUIREMENTS
According to the ICH GCP, the monitoring team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient’s medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules).
13.4
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All 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 eCRF overwriting 
the initial information. An audit trail allows identifying the modification. 
Data are available within the system to the Sponsor as soon as they are entered in the eCRF.
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the eCRF.
13.5
USE OF COMPUTERIZED SYSTEMS
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor’s trial master file.
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ADDITIONAL REQUIREMENTS
14.1
CURRICULUM VITAE
A current copy of the curriculum vitae describing the experience, qualification, and training of 
each Investigator and Subinvestigator will be signed, dated, and provided to the Sponsor prior to 
the beginning of the clinical trial.
14.2
RECORD RETENTION IN STUDY SITES
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents.
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial.
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required.
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation.
If the Investigator’s personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee. 
14.3
CONFIDENTIALITY
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator’s Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor.
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality.
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial.
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account.
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14.4
PROPERTY RIGHTS
All information, documents, and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor.
The Investigator and delegated Investigator staff/Subinvestigator shall not mention any 
information or the Product in any application for a patent or for any other intellectual property 
rights.
All the results, data, documents, and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor.
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market, or otherwise use the results of the clinical trial.
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents.
14.5
DATA PROTECTION
The patient’s personal data, which are included in the Sponsor 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
Subject 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.
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14.6
INSURANCE COMPENSATION
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document. 
14.7
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities.
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information.
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents.
As soon as the Investigator is notified of a planned inspection by the authorities, he/she 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.
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
Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP.

The total number of patients are included earlier than expected.
In any case the Sponsor will notify the Investigator of its decision by written notice.
14.8.2 By the Investigator
The Investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial. 
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements.
14.9
CLINICAL TRIAL RESULTS
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator.
14.10 PUBLICATIONS AND COMMUNICATIONS
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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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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BIBLIOGRAPHIC REFERENCES
1. 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. 8 ed. 
New York, NY: McGraw-Hill. 2001:2863-913.
2. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, et al. Homozygous 
familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection 
and clinical management. A position paper from the Consensus Panel on Familial 
Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 
2014;35(32):2146-57.
3. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein 
convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial 
hypercholesterolemia. Circulation. 2013;128(19):2113-20.
4. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with 
evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, 
double-blind, placebo-controlled trial. Lancet. 2015;385:341-50.
5. Widhalm K, Benke IM, Fritz M, Geiger H, Helk O, Fritsch M, et al. Homozygous familial 
hypercholesterolemia: Summarized case reports. Atherosclerosis. 2017;257:86-9.
6. 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;5:30-7.
7. 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;5:133-40.
8. Stock J. EAS Consensus Panel statement on homozygous FH. Atherosclerosis. 2015 
;242(1):323-6.
9. 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(14):1948–67.
10. 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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11. 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.
12. 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(11):1121–6.
13. Van der Graaf A, Cuffie-Jackson C, Vissers MN, Gagné C, Shi G, Veltri E, et al. Efficacy and 
safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous 
familial hypercholesterolemia. J Am Coll Cardiol. 2008;52(17):1421-9.
14. Eiland LS, Luttrell  PK. Use of statins for dyslipidemia in the pediatric population. J Pediatr 
Pharmacol Ther. 2010;15(3):160-72.
15. Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, and al. Long-term 
treatment with evolocumab added to conventional drug therapy, with or without apheresis, in 
patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the 
open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017;5(4):280-90.
16. 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.
17. NICE clinical guideline. Identification and management of familial hypercholesterolemia. 
London: National Institute for Health and Clinical Excellence, 2008.
18. Marshall WA, Tanner JM. Variations in the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45(239):13–23.
19. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child. 
1969;44(235):291–303.
20. hhs.gov. OHRP Expedited Review Categories (1998) [Internet]. HHS.gov. 2016.
21. WHO | Blood sample volumes in child health research: review of safe limits [Internet].
22. European Union. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. Eur J Health Law. 2008;15(2):223–50.
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17
APPENDICES
Appendix A.
Management of patients treated with LDL apheresis therapy in the 
EFC14660 study
Introduction
Despite effective available treatments that can also be used in combination, many high-risk 
patients fail to reach their guideline target LDL-C level. For these patients who are still unable to 
achieve guideline target level for LDL-C, despite available lipid modifying therapy (LMT), 
mechanical removal of LDL-C by LDL apheresis is an option.
However, LDL apheresis is a costly procedure that is invasive and burdensome for patients, 
especially in children. Because of the sparsity of apheresis centers, many patients must travel a 
significant distance for this procedure, which is administered over 3 hours and must be given 
every week to every 4 weeks, depending on the patient’s LDL-C level and cardiovascular risk. 
Low-density lipoprotein apheresis is generally well tolerated, but may result in hypotension, 
hypocalcemia, allergic reactions, and an acute decrease in serum protein levels.
An average reduction of the LDL-C value ranges from 30% to 75% depending on the technique 
and duration of apheresis (1). With weekly or bi-weekly treatment, the LDL-C levels can be 
reduced by 40% to 50%. The LDL-C levels rise towards baseline after each apheresis procedure, 
but do not reach the original levels; with repeated weekly or bi-weekly apheresis, the baseline 
levels continue to fall until a plateau is reached (2). Alirocumab may offer a significant 
therapeutic advancement for patients with HoFH who require LDL apheresis by decreasing the 
frequency or removing the need for apheresis procedures.
Screening and inclusion in EFC14660
Patients diagnosed with hoFH confirmed by genotyping, who are undergoing stable5 LDL 
apheresis therapy every 1 or 2 weeks, are allowed to be enrolled in this study, and their 
background treatment with LMT will be maintained throughout the study.
Screening
Patients who have been on a stable apheresis schedule prior to the screening visit (Week -2) and 
stable background medical LMT for at least 4 weeks prior to the screening visit (Week -2) will 
enter a 2-week screening period.
                                                
5 Stable apheresis is defined as 4 apheresis procedures performed during a 4 week period, approximately 
1 week apart, or 4 apheresis procedures performed during an 8 week period, approximately 2 weeks apart.
Note: Acceptable apheresis techniques are: double membrane filtration, immunoadsorption, 
heparin-induced LDL precipitation, direct adsorption of lipids, dextran sulfate adsorption (plasma), dextran 
sulfate adsorption (whole blood).
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Inclusion criteria
For patients on apheresis, currently undergoing stable LDL apheresis6 therapy prior to the 
screening visit (Week -2) and have initiated apheresis treatment for at least 6 months.
Exclusion criteria
LDL apheresis schedule/apheresis settings that have not been stable for at least 4 weeks prior to 
the screening visit (Week -2) for patients undergoing apheresis weekly, and at least 8 weeks prior 
to the screening visit (Week -2) for patients undergoing apheresis bi-weekly.
During the course of the study
If patients are treated with LDL apheresis, the visits from Day 1/Week 0, Week 4 and Week 12 
must coincide with an LDL apheresis procedure as well as with study drug administration; study 
drug will be administered immediately after completion of the LDL apheresis procedure.
Treatment injections during the treatment period will be administered at the site, starting on the 
day of enrollment (Week 0 [Day 1]/Visit 3). The patient will be monitored at the clinical site for 
30 minutes after the first dose after this first injection. For this visit as well as visits Week 4 and 
Week 12, LDL apheresis must coincide with study visit; study drug will be administered 
immediately after completion of the LDL apheresis procedure.
From Day 1 to Week 12, the apheresis frequency will be fixed to the individual patient’s 
established schedule.
After Week 12, at the Investigator’s discretion, patients may continue to undergo apheresis 
procedures, as needed and the frequency of apheresis procedures can be adapted to their needs. If 
these procedures are maintained, it is strongly recommended to conduct the visits Week 24 and 
Week 48 the same day as an LDL apheresis procedure, in order to collect appropriately the 
investigational blood samples.
Blood sample collection and overall study assessment throughout the study
All samples for clinical laboratory (lipid and specialty lipid panels) and PK evaluations must be 
obtained immediately prior to and immediately after the LDL apheresis procedure, therefore LDL 
apheresis has to be administered at that visit and before study drug administration.

Lipid panel 1 (Total-C, calculated LDL-C, HDL-C, TG, and non-HDL-C): samples should 
be drawn immediately prior to and immediately following the apheresis procedure.
                                                
6 Stable apheresis is defined as 4 apheresis procedures performed during a 4 week period, approximately 
1 week apart, or 4 apheresis procedures performed during an 8 week period, approximately 2 weeks apart.
Note: Acceptable apheresis techniques are: double membrane filtration, immunoadsorption,
heparin-induced LDL precipitation, direct adsorption of lipids, dextran sulfate adsorption (plasma), 
dextran sulfate adsorption (whole blood).
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
Alirocumab, and free and total PCSK9 levels: PK samples should be drawn immediately 
prior to and immediately following the apheresis procedure.

Specialty lipid panel (lipid panel 2: Apo B, Apo A-1, and Lp (a)): samples should be 
drawn immediately prior to apheresis (where applicable).

ADA assessment: samples should be drawn prior to apheresis (where applicable).
Study assessments such as vital signs, BP etc, have to be done before apheresis, and alirocumab is 
to be administered after apheresis.
REFERENCES
1.
Bambauer R, Bambauer C, Lehmann B, et al. LDL Apheresis: Technical and Clinical 
Aspects. Scientific World Journal 2012;2012:1-19.
2.
Thompsen J, Thompson PD. A systematic review of LDL apheresis in the treatment of 
cardiovascular disease. Atherosclerosis 2006;189:31-38.
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Appendix B.
Criteria for the diagnosis of homozygous familial 
Hypercholesterolaemia - EAS Consensus Panel recommendations 
for diagnosis of hoFH

Genetic conﬁrmation of 2 mutant alleles at the LDLR, APO B, PCSK9, or LDLRAP1 
gene locus.
OR

An untreated LDL-C >13 mmol/L (500 mg/dL) or treated LDL-C 7.8 mmol/L 
(300 mg/dL)* together with either:
-
Cutaneous or tendon xanthoma before age 10 years or,
-
Untreated elevated LDL-C levels consistent with heterozygous FH in both parents.
* These LDL-C levels are only indicative, and lower levels, especially in children or in treated 
patients, do not exclude HoFH.
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Appendix C.
Tanner stage
The Tanner stages (1, 2) assessment for each patient at each site should be performed, if possible 
by the same Investigator/designee trained to assess pubertal development.
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.
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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.
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 the pattern of pubertal changes in boys. Arch Dis 
Child. 1970;45:13-23.
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Appendix D.
Contraceptive guidance and collection of pregnancy information
DEFINITIONS
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
Premenarchal
Premenopausal female with 1 of the following:
-
Documented hysterectomy.
-
Documented bilateral salpingectomy.
-
Documented bilateral oophorectomy.
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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CONTRACEPTION GUIDANCE
Sexual counseling should be provided to patients when indicated.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 3 –
Highly effective contraceptive methods.
Table 3 - Highly effective contraceptive methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb
Oral.
Intravaginal.
Transdermal.

Progestogen-only hormone contraception associated with inhibition of ovulation
Oral.
Injectable.
Highly Effective Methods That Are User Independenta

Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
Intrauterine device (IUD).
Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.
Vasectomized partner
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. 
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 treatment. 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 
participant.
NOTES:
a
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 participants participating in clinical studies.
b
Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case TWO highly effective methods of contraception should be utilized during the treatment period and for at least 10 weeks 
after the last dose of study treatment.
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See guidance below:
Clinical Facilitation Group (September 2014) - Recommendations related to contraception and 
pregnancy testing in clinical trials
COLLECTION OF PREGNANCY INFORMATION
Male participants with partners who become pregnant

The Investigator will attempt to collect pregnancy information on any male participant’s
female partner who becomes pregnant while the male participant is in this study. This
applies only to male participants 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. The
female 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, the 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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Female participants who become pregnant

The Investigator will collect pregnancy information on any female participant 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. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information 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.
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 poststudy pregnancy-related SAE 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 participants, he or she may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.
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Appendix E.
Pediatric formulae for eGFR and creatinine clearance
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Appendix F.
General guidance for the follow-up of laboratory abnormalities by 
Sanofi
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met.
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Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Section 10.4.3 is met.
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INCREASE IN ALT
ALT 3 ULN (if baseline ALT <ULN) 
Or, ALT 2 times the baseline value 
(if baseline ALT ULN)
ALT 5 ULN
(if baseline ALT < ULN)
Or, ALT 3 times the baseline 
value
(If baseline ALT ULN)
ALT > 5 ULN
(if baseline ALT < ULN)
Or, ALT > 3 times the 
baseline value
(if baseline ALT ULN)
Total bilirubin 2 ULN
Total bilirubin > 2 ULN
DISCONTINUE 
ADMINISTRATION OF 
INVESTIGATIONAL 
MEDICINAL PRODUCT
In ANY CASE, FOLLOW the instructions #1 to 7 listed in the box below. 
1. INVESTIGATE THE CLINICAL CONTEXT in the previous 72 hours, specifically for malaise with or without 
loss of consciousness, dizziness, and/or hypotension and/or episode of arrhythmia; rule out muscular injury
2. PERFORM the following tests: 
- LFTs : AST, ALT, Alkaline Phosphatase, Total and Conjugated Bilirubin and Prothrombin Time / INR 
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM, anti-HCV and HCV RNA , anti-CMV IgM and anti-HEV IgM antibodies, and 
depending on the clinical context, check for recent infections, eg, EBV, Herpes viruses and toxoplasma 
- Hepatobiliary ultrasonography (can be completed by other imaging investigations if needed)
3. CONSIDER auto-antibodies: anti-nuclear, anti-DNA, anti-smooth muscle, anti-LKM
4. CONSIDER consultation with hepatologist
5. CONSIDER patient hospitalization if INR>2 (or PT<50%) and/or central nervous system disturbances suggesting 
hepatic encephalopathy
6. MONITOR LFTs
- If investigational medicinal product is continued: every 48 hours until return to normal (<2ULN) or 
baseline. If ALT elevation persists beyond 2 weeks then perform LFTs every 2 weeks and 15 to 30 days after 
the last dose according to the study protocol.
- If investigational medicinal product is discontinued: as closely as possible to every 48 hours until 
stabilization then every 2 weeks until return to normal (<2ULN) or baseline or for at least 3 months, whichever 
comes last.
7. COLLECT/STORE one sample following handling procedures described in PK sections (for studies with PK 
sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of investigational medicinal product).
COMPLETE the 
specific CRF form for 
“ALT increase” 
And INFORM the 
Monitoring Team 
within 24 hours
Monitor LFTs 
every 48 hours
If Not Possible
Investigational Medicinal Product 
administration can be continued, as 
long as – under close monitoring –
conditions for stopping are not met
NOTE: ALT ≥3 ULN (IF BASELINE ALT < ULN) OR ALT ≥2 TIMES THE BASELINE VALUE (IF BASELINE ALT ≥ULN) SHOULD BE 
NOTIFIED WITHIN 24 HOURS TO THE MONITORING TEAM (SEE Section 10.4.1.3, Section 10.4.5, AND Section 10.4.6). IN ADDITION, 
IF ALT <3 ULN MEETS A SERIOUSNESS CRITERION, THE EVENT SHOULD BE NOTIFIED WITHIN 24 HOURS TO THE MONITORING 
TEAM.
(electronic 
 
 
 
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Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Section 10.4.3 is met.
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If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie, stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE investigational 
medicinal product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
INCREASE IN CPK SUSPECTED TO BE OF NON-CARDIAC ORIGIN 
AND NOT RELATED TO INTENSIVE PHYSICAL ACTIVITY
Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs in Section 10.4.3 is met.
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Appendix G.
Summary of AE 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 F.
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 10.4.1.3).
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 10.4.1.3.
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
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Event 
t
Reporting 
ti
f
Specific events in this category
Case report form completion
Laboratory, vital 
sign, (non-SAE, 
non-AESI) that is: 
- Symptomatic
- Requiring 
corrective 
treatment or 
consultation
- Leading to IMP 
discontinuation 
or dose regimen 
modification 
Routine
Neutropenia (per Appendix F).
Yes
No
No
Thrombocytopenia (per Appendix F).
Yes
No
No
Acute renal insufficiency (per Appendix F).
Yes
No
No
Increase in CPK and suspicion of 
rhabdomyolysis (per Appendix F).
Yes
No
No
Death from any 
cause
Expedited
Yes
Yes
Yes
AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; CPK = creatine phosphokinase; 
IMP = investigational medicinal product; SAE = serious adverse event; ULN = upper limit of normal
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.
(electronic 
 
 
 
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Appendix H.
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/Rednessa
2.5 – 5 cm
5.1 – 10 cm
>10 cm
Necrosis or 
exfoliative 
dermatitis
Swellingb
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)
ER visit or 
hospitalization
Other (Please specify)c
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.
ER visit or 
hospitalization
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable
b
Swelling should be evaluated and graded using the functional scale as well as the actual measurement
c
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 I.
Country Specific Requirements
AMENDMENT FOR NORWAY AND ARGENTINA
For Norway and Argentina, 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 10, during clinical 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 8, 16, 20, 28, 32, 40, 44, and 52.
Sexual counseling should be provided to patients when indicated. In the event of a pregnancy test 
performed at home 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 J.
Protocol amendment history
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amended protocol 01 (20-Feb-2018)
The main reason for this amendment is the addition of the IRT contact to Visit 3 (the intermediate
visit for injection training) of the screening period with clarifications made regarding this visit.

Addition of the IRT contact to be performed during Visit 3 (intermediate visit).
In section(s): Tabulated clinical trial summary, Section 1.2, Section 7.1, and Section 10 of the
protocol.
Overall Rationale for the Amendment
Injection training kits will be allocated via the IXRS system during the intermediate visit of the 
screening period for the purposes of injection training. Patients aged ≥12 years (or another 
designated person such as parent, etc) will be trained to self-inject/inject with placebo for 
alirocumab. Patients 8 to 11 years old will be assigned a parent or another designated person who 
will be trained during the injection training visit or an alternative arrangement. However, it was 
observed that this IRT/allocation of training kits was neither checked in the flowchart in Section 
1.2 with an “X” in the “IRT contact” row (that corresponds with the Visit 3 column) nor described 
in Section 10 (study procedures). This amendment corrects this omission and clarifies the 
procedures that occur during this visit during the screening period. In addition, several 
inconsistencies, typographical errors, and other grammatical errors are corrected as well, with 
some made in the amended protocol only.
(electronic 
 
 
 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC14660 16.1.1 Amended Protocol 02
Clinical Approval
Clinical Approval

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
An open-label study to evaluate the efficacy and safety of alirocumab in children 
and adolescents with homozygous familial hypercholesterolemia  
SAR236553/REGN727-EFC14660 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 27-Jan-2020 
Total number of pages: 
70 
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Statistical Analysis Plan  
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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 ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Other objectives ............................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN........................ 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 12 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 12 
2.1.1 
Demographic and baseline characteristics .................................................................................... 12 
2.1.2 
Prior or concomitant medications ................................................................................................... 15 
2.1.3 
Efficacy endpoints .......................................................................................................................... 16 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 16 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 16 
2.1.4 
Safety endpoints ............................................................................................................................. 17 
2.1.4.1 
Adverse events variables ............................................................................................................... 17 
2.1.4.2 
Deaths ............................................................................................................................................ 19 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 19 
2.1.4.4 
Vital signs variables ........................................................................................................................ 20 
2.1.4.5 
Electrocardiogram variables ........................................................................................................... 20 
2.1.4.6 
Tanner stages measurement ......................................................................................................... 21 
2.1.5 
Other endpoints .............................................................................................................................. 21 
2.1.6 
Anti-alirocumab antibodies variables ............................................................................................. 21 
2.1.7 
Pharmacokinetic variables ............................................................................................................. 22 
2.1.8 
Pharmacodynamic/genomics endpoints ........................................................................................ 23 
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2.1.9 
Quality-of-life endpoints .................................................................................................................. 23 
2.1.10 
Health economic endpoints ............................................................................................................ 23 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 23 
2.2.1 
Enrollment and drug dispensing irregularities ................................................................................ 24 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 25 
2.3.1 
Efficacy populations ....................................................................................................................... 25 
2.3.2 
Safety population ............................................................................................................................ 25 
2.3.3 
Anti-alirocumab antibody population .............................................................................................. 25 
2.3.4 
Pharmacokinetics population ......................................................................................................... 25 
2.4 
STATISTICAL METHODS ............................................................................................................. 25 
2.4.1 
Demographics and baseline characteristics .................................................................................. 25 
2.4.2 
Prior or concomitant medications ................................................................................................... 26 
2.4.3 
Extent of investigational medicinal product exposure and compliance .......................................... 26 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 27 
2.4.3.2 
Compliance .................................................................................................................................... 27 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 28 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 28 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 30 
2.4.4.3 
Multiplicity issues ............................................................................................................................ 32 
2.4.4.4 
Additional efficacy analysis(es) ...................................................................................................... 32 
2.4.5 
Analyses of safety data .................................................................................................................. 32 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 33 
2.4.5.2 
Deaths ............................................................................................................................................ 35 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 35 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 36 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 37 
2.4.5.6 
Analyses of Tanner stages measurement ..................................................................................... 37 
2.4.6 
Analyses of other endpoints ........................................................................................................... 37 
2.4.7 
Analyses of anti-alirocumab antibodies variables .......................................................................... 37 
2.4.8 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 38 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 38 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 38 
2.5.1 
General conventions ...................................................................................................................... 38 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 39 
2.5.3 
Missing data ................................................................................................................................... 39 
2.5.4 
Windows for time points ................................................................................................................. 41 
2.5.5 
Unscheduled visits ......................................................................................................................... 42 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 42 
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2.5.7 
Statistical technical issues ............................................................................................................. 42 
3 
INTERIM ANALYSIS ..................................................................................................................... 43 
4 
DATABASE LOCK ........................................................................................................................ 44 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 45 
6 
REFERENCES ............................................................................................................................... 46 
7 
LIST OF APPENDICES ................................................................................................................. 47 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES FOR CHILDREN ............. 48 
APPENDIX B 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES FOR ADULTS ................. 59 
APPENDIX C 
DETAILED STATISTICAL METHODOLOGY FOR PATTERN MIXTURE MODEL ............ 64 
APPENDIX D 
LIST OF MEDDRA TERMS FOR CMQS ............................................................................ 68 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-alirocumab (drug) antibodies 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransaminase 
Apo A-1: 
apolipoprotein A-1 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic chemical 
BMI: 
body mass index 
BW: 
body weight 
CI: 
confidence intervals 
CMQ: 
customized MedDRA queries 
CPK: 
creatine phosphokinase 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
e-CRF: 
electronic case report form 
eDISH: 
evaluation of drug-induced serious hepatotoxicity 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end-of-treatment 
HbA1c: 
glycated haemoglobin A1c 
HDL-C: 
high density lipoprotein cholesterol 
HLGT: 
high level group term 
HLT: 
high level term 
hoFH: 
homozygous familial hypercholesterolemia 
HR: 
heart rate 
ie: 
id est = that is 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
LDH: 
lactate dehydrogenase 
LDL-C: 
low-density lipoprotein cholesterol 
LLOQ: 
lower limit of quantification 
LLT: 
lowest level term 
LMT: 
lipid modifying therapy 
Lp (a): 
lipoprotein a 
LS: 
least square 
MAR: 
missing-at-random 
MedDRA: 
medical dictionary for regulatory activities 
MI: 
myocardial infarction 
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MMRM: 
mixed-effect model with repeated measures 
NMAR: 
not missing-at-random 
PCSA: 
potentially clinically significant abnormality 
PCSK9: 
proprotein convertase subtilisin/kexin type 9 
PK: 
pharmacokinetics 
PT: 
preferred term 
Q2W: 
every 2 weeks 
QQ-plot: 
quantile-quantile plot 
SAE: 
serious adverse event 
SAS: 
statistical analysis software 
SBP: 
systolic blood pressure 
SC: 
subcutaenous 
SE: 
standard error 
SMQ: 
standardised MedDRA queries 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
TG: 
triglyceride 
ULN: 
upper limit of normal 
ULOQ: 
upper limit of quantification 
WHO-DD: 
World Health Organization-Drug Dictionary 
γGT: 
gamma-glutamyl transferase 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This study is a Phase 3, multi-national, multi-center, open-label study with a treatment period of 
48 weeks to evaluate the efficacy and safety of alirocumab in children and adolescents aged 8 to 
17 years with homozygous familial hypercholesterolemia (hoFH) confirmed by genetic testing and 
LDL-C ≥130 mg/dL (3.37 mmol/L) at screening visit, despite treatment with stable lipid 
modifying therapy (LMT) at optimal doses. Patients who have initiated apheresis treatment for at 
least 6 months prior to screening and are currently undergoing stable LDL apheresis therapy are 
also eligible for the study. 
The study comprises 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 48-week open-label treatment period. 
 A follow-up of 8 weeks (±3 days). 
The total duration of the study will be up to 62 weeks for each patient. 
During the treatment period, alirocumab will be administered every 2 weeks (Q2W) 
subcutaneously (SC), starting at Week 0 and continuing up to the end of the open-label treatment 
period (last injection at Week 46). 
The dose of alirocumab will be based on body weight (BW) (75 mg Q2W for BW<50 kg, 150 mg 
Q2W for BW ≥50 kg). After Week 12, if there is a change in BW, the dose of alirocumab can be 
adjusted such that the dose corresponds to the patient’s BW. 
A follow-up call will be planned 10 weeks after the last Investigational medicinal product (IMP) 
injection, ie, 8 weeks after the end-of-treatment (EOT) visit, for the patients who completed the 
treatment and for patients who prematurely discontinued for any reason. 
Approximately 18 patients are to be enrolled from approximately 20 sites. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to evaluate the efficacy of alirocumab (75 or 150 mg 
depending on BW), administered every 2 weeks (Q2W), on low-density lipoprotein cholesterol 
(LDL-C) levels at Week 12 of treatment in children with HoFH 8 to 17 years of age on top of 
background treatments. 
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1.2.2 Secondary objectives 
The secondary objectives of this study are: 
 To evaluate the efficacy of alirocumab after 24 and 48 weeks of treatment on LDL-C 
levels. 
 To evaluate the effects of alirocumab on other lipid parameters (eg, Apo B, non-HDL-C, 
total-C, HDL-C, Lp (a), triglycerides [TG], apolipoprotein A-1 [Apo A-1] levels) after 
12, 24, and 48 weeks of treatment. 
 To evaluate the safety and tolerability of alirocumab up to 48 weeks of treatment. 
1.2.3 Other objectives 
The other objectives of this study are: 
 To evaluate the development of anti-alirocumab antibodies (ADA) during 48 weeks of 
treatment. 
 To evaluate the pharmacokinetics (PK) of alirocumab. 
1.3 
DETERMINATION OF SAMPLE SIZE 
No sample size calculation was performed. Eighteen patients are planned to be enrolled to have at 
least 15 evaluable patients considering the recruitment constraints in this rare disease population. 
1.4 
STUDY PLAN 
The following figure presents the graphical study design:
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Figure 1 - Graphical study design 
 
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). 
As of the date of approval of this statistical analysis plan, the statistical section of the protocol has 
not been changed in any amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
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 30 May 2018. 
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Table 1 - Statistical analysis plan statistical changes 
SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
This version  
Genotyping data has been collected in 
order to document the diagnosis of 
HoFH and verify that patients do not 
have null mutations on both LDLR 
alleles.   
Description of genotyping data related to HoFH 
diagnosis added in Section 2.1.1 
2 
This version 
For cardiac troponin T, since expected 
values should be mainly below the 
lower limit of quantification (LLOQ) 
and since no reference ranges are 
available for healthy children in the 
central laboratory, quantitative 
description and description according 
to normal ranges are replaced by a 
description by category (<LLOQ, 
≥LLOQ) at baseline and Week 12.  
Cardiac troponin will be described by category 
(<LLOQ, ≥LLOQ) at baseline and Week 12. 
Quantitative analysis and summaries according 
to normal ranges will not be performed (Cf. 
Section 2.1.1 and Section 2.4.5.3). 
2 
This version  
To ensure adequate selections of 
events of interest 
Grouping for events of interest updated in 
Section 2.1.4.1 and in Appendix D based on the 
last MedDRA version currently in effect at 
Sanofi at the time of this amendment 
(version 22.1) 
2 
This version  
To better assess pubertal maturation 
and the growth development during 
the study 
For pubertal maturation:  
 
Definition of global Tanner puberty 
classification added (Section 2.1.4.6) 
 
Analysis of change from baseline in 
Tanner stage based on breast 
development (girls) or external 
genitalia (boys) added 
(Section 2.4.5.6) 
 
Number of post-menarchal girls at 
baseline and during the study will be 
described (Section 2.4.5.6) 
For growth development (Section 2.4.5.4): 
 
description of % change from 
baseline in weight added 
 
description of values and absolute 
change from baseline for BMI added 
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SAP 
version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
This version 
Post-apheresis LDL-C not considered 
in the analysis of patients with 
2 consecutive low LDL-C values due 
to the expected transient status of 
such low values following apheresis. 
In addition, post apheresis LDL-C 
values are not related to the 
administration of the investigational 
product but directly related to the 
strength and the length of the 
apheresis procedure. Therefore they 
do not provide relevant information on 
the effectiveness of the IMP and the 
need to adjust treatment with the IMP. 
The analysis of patients with 2 consecutive low 
LDL-C values (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)) based on post-apheresis LDL-C 
data will not be provided. Only the analysis 
using pre-apheresis data will be presented (cf. 
Section 2.1.5) 
2 
This version 
Clarification that only enrolled patients 
are part of analyses populations.  
 
Description of disposition will be 
performed on enrolled patients 
instead of treated patients 
(Section 2.2). 
 
Definition of populations are modified 
to exclude not enrolled patients from 
any analysis populations (Section 
2.3). 
2 
This version 
Define rule to derive non-HDL-C and 
calculated LDL-C values when HDL-C 
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 
values used for lipid quantitative analyses, in 
case of HDL-C <LLOQ (Section 2.5) 
2 
This version 
Update PCSAs list for children to 
ensure consistency within the program 
with another study conducted in 
children (phase 2 DFI14223 study)  
Update of the list of PCSAs for children 
(Appendix A) 
 
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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 up to the date and time of the 
first open-label IMP administration.  
All baseline efficacy and safety parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in efficacy and safety sections (Section 2.4.4 and 
Section 2.4.5). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (White, Black or African American, 
Asian, American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, other), 
ethnicity (Hispanic or Latino, Not-Hispanic or Latino), age in years (quantitative and qualitative 
variable: <12 and ≥12 to <18 years, as well as  <10, ≥10 to <12, and ≥12 to <18 years).  
Medical or surgical history 
Medical or surgical history includes medical history of specific interest such as cardiovascular 
(CV) history and cardiovascular risk factors other than hypercholesterolemia, subject medical 
allergic history and family medical allergic history, and relevant medical or surgical history other 
than CV, CV 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). 
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 
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). 
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. 
Disease characteristics at baseline   
Specific disease characteristic includes: 
 Time from diagnosis of hoFH (years). 
 Confirmation of diagnosis (genotyping [Yes, No]). 
 HoFH genotype: Mutations affecting LDL receptor function are located on LDLR, 
LDLRAP1, PCSK9 or APOB genes. Patients are classified according to the mutant alleles 
and as either “true homozygote” (patients with the same mutation in both alleles of the 
same gene) , or “compound heterozygote” (patients with different mutation in each allele 
of the same gene), or “double heterozygotes” (patients with mutations in two different 
genes) or “Other” (patients not defined as above) 
 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 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]. 
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 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 lipid modifying therapy at enrollment, as reported in the dedicated prior & 
concomitant medications e-CRF pages. 
 Any statin, eg,  
- 
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) 
- 
Other statin (Yes/No) 
 Any LMT other than statins: 
- 
Any LMT other than nutraceuticals (by chemical class and drug name) including 
fenofibrate and ezetimibe or other non-Statin LMT, 
- 
Nutraceuticals (Omega 3 fatty acids (<1000mg/day), Phytosterols, Psyllium/plantago, 
Policosanol, Other nutraceuticals). 
Other baseline characteristics  
Other baseline characteristics include body mass index (BMI) in kg/m² (quantitative and 
qualitative variable using BMI percentiles defined according to age for boys and girls: 
<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]), weight in kg 
(quantitative and qualitative: <50, ≥50 kg), height in cm, smoking status and alcohol habits. 
Glycated haemoglobin A1c (HbA1c ) (quantitative and qualitative variable: <5.7%, ≥5.7% to 
<6.5%, ≥6.5%), cardiac parameters (quantitative for CPK-MB, by category for cardiac troponin T 
(<LLOQ, ≥LLOQ)) and efficacy lipid parameters (pre-apheresis, if applicable) (quantitative 
variables for all efficacy parameters and the following qualitative 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). 
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 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  
All medications taken within 12 weeks prior to screening and until the end of the study, including 
lipid modifying therapies are to be reported in one of the following specific case report form 
pages: 
 Previous and concomitant statin drugs. 
 Previous and concomitant lipid modifying therapy except Statin. 
 Other Previous and concomitant medications. 
 Medications - Anesthetic for IMP injection. 
 Apheresis procedure. 
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 IMP administration. Prior medications can be discontinued before first 
administration or can be ongoing during treatment phase.  
 Concomitant medications are any treatments received by the patient concomitantly with 
the IMP, from first IMP to the last IMP injection +70 days. A given medication can be 
classified both as a prior medication and as a concomitant medication. Concomitant 
medications do not include medications started during the post-treatment period 
(as defined in the observation period in Section 2.1.4).  
 Post-treatment medications are those the patient took in the period starting from 71 days 
after the last IMP injection and ending when the patient terminates the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
Apheresis procedures: 
 Apheresis history information such as the rate of patients on apheresis treatment, the time 
from the first apheresis procedure to the screening visit in years and the frequency (every 
week/every two weeks/other) for the last 4 apheresis procedures prior to screening.  
 The frequency of the apheresis during the treatment period will be also described. 
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2.1.3 Efficacy endpoints 
Efficacy endpoints include lipid parameters (ie, Total-C, LDL-C (calculated or measured), 
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. Non-HDL-C is 
calculated by subtracting HDL-C from the Total-C. 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) rather than calculated.  
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 3 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. Measurements 
with missing fasting status will be excluded from the analyses.  
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 value is the last available measurement obtained up to the date and time of the 
first IMP injection (pre-apheresis, if applicable). 
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the percent change in LDL-C (pre-apheresis, if applicable) from 
baseline to Week 12 in the ITT population, using all LDL-C values (pre-apheresis, if applicable) 
regardless of adherence to treatment (ITT estimand). Primary endpoint is defined as: 100x (LDL-C 
value at Week 12 - LDL-C value at baseline) / LDL-C value at baseline. 
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. For patients undergoing apheresis, 
pre-apheresis values will be considered. 
2.1.3.2 Secondary efficacy endpoint(s) 
The secondary efficacy endpoints are: 
 Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Week 12 in the 
ITT population, using all LDL C values during the treatment period (on-treatment 
estimand). 
 Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Weeks 24 and 
48 (ITT and on-treatment estimands). 
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 Percent change in Apo B, non-HDL-C, Total-C, Lp (a), HDL-C, fasting TG and Apo A-1 
(pre-apheresis, if applicable) from baseline to Weeks 12, 24, and 48 (ITT and on-treatment 
estimands). 
 Proportion of patients with ≥15% reduction in LDL-C (pre-apheresis, if applicable) at 
Weeks 12, 24, and 48 (ITT and on-treatment estimands). 
 The absolute change in LDL-C from baseline to Weeks 12, 24, and 48 (ITT and 
on-treatment estimands). 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events and other safety information, such 
as clinical laboratory data, vital signs and Tanner stage assessment. 
Observation period  
The period of safety observation starts from the time when the patient gives informed consent and 
is divided into the following periods: 
 The PRE-TREATMENT period is defined from the signed informed consent up to the 
first dose of IMP injection. 
 The TEAE period is defined as the time from the first dose of IMP injection to the last 
dose of IMP injection + 70 days (10 weeks) as residual effect of alirocumab cannot be 
excluded until 10 weeks after the discontinuation of IMP injection. 
The TEAE period will include: 
- 
The TREATMENT period: defined as the time from the first dose IMP injection up to 
the day of last IMP injection +21 days.  
 The POST-TREATMENT period is defined as the time starting the day after the end of the 
TEAE period (ie, 71 days after the day of last dose of 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. 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. 
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 Treatment-emergent AEs 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. 
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 (i.e. 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 5 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 6 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 appropriate MedDRA codes 
In addition, the additional grouping of events will be provided: 
 Hepatic disorder events using SMQ “Hepatic disorder” 
 Diabetes mellitus or diabetic complications using 1/ the HLGT “diabetic complications” 
(including PTs pertaining to the secondary SOC included in the HLGT), 2/ the HLT 
“diabetes mellitus”, 3/ the HLT “carbohydrate tolerance analyses (incl diabetes)” 
excluding PTs “blood glucose decreased” and “glycosylated haemoglobin decreased” and 
4/ from the HLT "Hyperglyceamic 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 amendment (Version 22.1) 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.  
 Death on-study: deaths occurring during the on-study observation period (ie, up to the last 
planned protocol visit). 
 Death on-treatment: deaths occurring during the TEAE period. 
 Death post-study: deaths occurring after the last planned protocol visit. 
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 were to be collected 
during: 
 Screening at Visit 2 (up to Week -2). 
 The Open-Label Treatment Period at Visit 4 (Week 0), Visit 5 (Week 4), Visit 6 
(Week 12), Visit 7 (Week 24) and Visit 9 (Week 48).  
Blood samples for cardiac function were to be collected during: 
 The Open-Label Treatment Period at Visit 4 (Week 0) and Visit 6 (Week 12) and in case 
of any clinically relevant cardiovascular effect observed in patients. 
The 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, 
- 
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, 
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- 
Renal function: creatinine, eGFR, 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). 
 Serum pregnancy test: blood test at screening visit and local urine pregnancy test for all 
other tests. 
 Cardiac function: CPK-MB and cardiac troponin. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital Signs parameters include Height, Weight, BMI, Heart Rate (HR), Systolic and Diastolic 
Blood Pressure (SBP and DBP) in sitting position. 
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 Open-Label Treatment Period at Visit 4 (Week 0), Visit 5 (Week 4), Visit 6 
(Week 12), Visit 7 (Week 24), Visit 8 (Week 36) and Visit 9 (Week 48).   
Body 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 Open-Label Treatment Period at Visit 4 (Week 0), Visit 5 (Week 4), Visit 6 
(Week 12), Visit 7 (Week 24) and Visit 9 (Week 48). 
Heart rate and blood pressure were to be measured during: 
 Run-in (if applicable) at Visit 1(up to Week -6). 
 Screening at Visit 2 (up to Week -2) and Visit 3 (up to Week -1; injection training visit as 
needed). 
 The Open-Label Treatment Period at Visit 4 (Week 0), Visit 5 (Week 4), Visit 6 
(Week 12), Visit 7 (Week 24), Visit 8 (Week 36) and Visit 9 (Week 48).   
2.1.4.5 Electrocardiogram variables 
Not applicable. 
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2.1.4.6 Tanner stages 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 applicable) at Visit 1 (up to Week -6) OR Screening at Visit 2 (up to Week -2).  
 The Open-Label Treatment Period at Visit 6 (Week 12), Visit 7 (Week 24) and Visit 9 
(Week 48).   
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 of kids the first signs of puberty is breast development for girls and external 
genitalia for boys (4, 5, 6). 
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 12, 24 and 48. Out of ranges 
value for HbA1c will also be used. 
 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) (pre-apheresis only). 
 The time to the first LDL-C <50 mg/dL (<25 mg/dL, <15 mg/dL respectively) for these 
patients (pre-apheresis only). 
2.1.6 Anti-alirocumab antibodies variables 
Anti-alirocumab antibodies (ADA) (pre-apheresis, if applicable) are assessed during: 
 The Open-Label Treatment Period at Visit 4 (Week 0), Visit 6 (Week 12), Visit 7 
(Week 24) and Visit 9 (Week 48). 
ADA measurements (pre-apheresis, if applicable) will be assigned to the same analysis windows 
as defined for efficacy endpoints (Table 3). ADA collected post-apheresis (if any) will be 
described separately. 
The following variables will be described: 
 ADA response (Positive or Negative). 
For ADA positive: 
- 
Titer levels, 
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- 
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, 
OR 
- 
Patients with a positive ADA response at baseline and at least a 4-fold increase in titer 
in the post-baseline period. 
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 after the last visit for patients with titer ≥240 at 
their last visit will be listed.  
2.1.7 Pharmacokinetic variables 
Concentrations of total alirocumab, total and free PCSK9 in serum are assessed before IMP 
(pre-dose) (pre apheresis and post-apheresis, if applicable) at baseline (Week 0), Week 12, 
Week 24, and Week 48. Concentrations will be described separately for patients on apheresis and 
for patients not on apheresis. For patients on apheresis, pre and post-apheresis concentrations will 
be analyzed separately.  
Pharmacokinetic variable is the total alirocumab concentration at each time point. Depending on 
the timing of the sample versus the previous injection, Ctrough, Cmax and CFollow-Up will be defined as 
follows: 
 Cmax: alirocumab concentration sample taken 5 days ±2 days after previous injection of 
alirocumab. 
 Ctrough: alirocumab concentration sample taken between 8 and 21 days after previous 
injection of alirocumab (may be just prior the next injection). 
 CFollow-up: alirocumab concentration sample taken more than 21 days after last injection of 
alirocumab and no more than 14 weeks after last injection of alirocumab. 
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Alirocumab concentration and total and free PCSK9 concentrations will be described over time 
following time windows as defined in Section 2.5.4, Table 3. 
2.1.8 Pharmacodynamic/genomics endpoints  
Not Applicable. 
2.1.9 Quality-of-life endpoints  
Not Applicable. 
2.1.10 Health economic endpoints  
Not Applicable. 
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 originally met all the inclusion criteria and none 
of the exclusion criteria and signed the informed consent. 
Enrolled patients consist of all screened patients, with a treatment kit number allocated and 
recorded in the IVRS/IWRS database, regardless of whether treatment kit was used or not. 
For patient study status in the open label treatment period, the total number of patients in each of 
the following categories will be presented: 
 Screened patients. 
 Screen failure patients and reasons for screen failure. 
 Treated and not enrolled 
 Enrolled patients. 
 Enrolled and treated patients. 
 Enrolled and not treated patients and reason for not being treated. 
 Patients who completed the open label treatment period as per protocol (as per e-CRF 
end-of-treatment form).  
 Patients who did not complete the open label treatment period as per protocol (as per 
e-CRF end-of-treatment form).   
 Patients who discontinued the open label treatment by main reason for permanent 
treatment discontinuation.  
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 Patients who completed the open label study period as per protocol (as per e-CRF end-of-
study form).   
 Patients who did not complete the open label study period as per protocol (as per e-CRF 
end-of-study form).   
 Patients who discontinued the open label study by main reason for permanent study 
discontinuation. 
 Status at last study contact.  
For all categories of patients (except for the screened categories) percentages will be calculated 
using the number of enrolled patients as denominator. 
Any critical or major protocol deviations (automatic or manual) will be summarized by deviation 
category in the enrolled population. 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. These deviations 
are listed in the centralized monitoring plan. 
Additionally, the following populations will be summarized:  
 Efficacy population: ITT population.  
 Safety population. 
 Pharmacokinetics population. 
 Anti-alirocumab antibody population. 
Definitions of the study populations are provided in Section 2.3. 
2.2.1 Enrollment and drug dispensing irregularities 
Enrollment and drug-dispensing irregularities occur whenever: 
1. An enrollment is not in accordance with the protocol-defined enrollment method, such as a 
patient is enrolled twice. 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined allocation, such as 
a) a patient at any time in the study is dispensed a different treatment kit than as allocated 
(which may or may not contain the correct-as-allocated IMP dose) or b) a non-enrolled 
patient is treated with IMP reserved for enrolled patients. 
Enrollment and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All enrollment and drug-dispensing irregularities will be documented in the clinical study report.   
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2.3 
ANALYSIS POPULATIONS 
For any patient enrolled more than once, only the data associated with the first enrollment will be 
used in any analysis population. The safety experience associated with any later enrollment will be 
assessed separately. 
2.3.1 Efficacy populations 
The efficacy analysis population will be the ITT population. 
The ITT population is defined as all enrolled patients who received at least one dose or partial 
dose of IMP. 
2.3.2 Safety population 
Safety analyses will be performed on the safety population, which will consist of enrolled patients 
receiving at least one dose or partial dose of IMP. 
In addition, patients for whom it is unclear whether they took the study medication will be 
included in the safety population. 
2.3.3 Anti-alirocumab antibody population 
The anti-alirocumab antibody (ADA) analyses will be performed on all enrolled and treated 
patients (safety population) with a blood sample on Week 0 (baseline) and at least one evaluable 
blood sample for antibodies post first IMP injection. 
2.3.4 Pharmacokinetics population 
The PK analysis will be performed on all enrolled and treated patients (safety population) with at 
least one available PK sample post first IMP injection. 
2.4 
STATISTICAL METHODS 
Unless otherwise specified, analyses will be performed overall and according to the dose received 
at study start (alirocumab 75 mg Q2W and alirocumab 150 mg Q2W).  
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized on the ITT population.  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum. First quartile (Q1) and third quartile (Q3) will 
be also provided for baseline lipid parameters, HbA1c and cardiac parameters. Categorical and 
ordinal data will be summarized using the number and percentage of patients.  
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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 
based on the incidence in the whole population. In addition, all medical history of specific interest 
(see Section 2.1.1) will also be presented. 
2.4.2 Prior or concomitant medications  
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. 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 overall incidence. 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. 
LMT (statins and other LMTs) use after enrollment will be summarized over time graphically by 
LMTs intensity at enrollment using the following categories: 
 Statin.  
 Only LMT other than statin. 
 No LMT. 
The LMTs intensity at enrollment is defined as: 
 Statin. 
 Only LMT other than statin. 
Apheresis procedures will be summarized at baseline and during the treatment period. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be summarized for the safety population.  
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2.4.3.1 Extent of investigational medicinal product exposure 
The total exposure to IMP will be assessed using the following parameters: 
 Duration of IMP injection exposure in weeks defined as (date of last IMP injection 
+ 14 days - date of first IMP injection) / 7, 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.  
 The total number of IMP injections by patient. 
Duration of IMP injection exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum) and categorically using the following 
categories: ≥1 day to <4 weeks, ≥4 to <8 weeks, ≥8 to <12 weeks, ≥12 to <24 weeks, ≥24 to 
<36 weeks, ≥36 to <46 weeks and ≥ 46 weeks.  
In addition, dose adjustments will be described. 
2.4.3.2 Compliance  
Compliance will be assessed using the following parameters: 
 The mean injection frequency of IMP injections will be defined for each patient as the 
average number of days between 2 consecutive injections, that is: (last injection date − first 
injection date) / (number of injections − 1) for patients receiving at least 2 injections. 
 The overall compliance for 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 injections 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 injection administered within the previous 17 days divided by the 
duration of IMP injection exposure in days. For example, if a patient takes a dose 
18 days after his/her previous injection, then 1 day is counted as a day under-planned 
dosing. 
- 
The % days with above-planned dosing will be defined for each patient as the number 
of days with more than one injection administered within the 11 days before divided by 
the duration of IMP injection exposure in days. For example, if a patient takes a dose 
9 days after his/her previous injection, then 2 days are counted as days above-planned 
dosing. 
These parameters will be summarized descriptively (N, Mean, SD, Median, Minimum and 
Maximum). 
The percentage of patients whose overall compliance 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%, 
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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, 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.  
Since there is no control group in this study, there will be no formal statistical test for the efficacy 
endpoints.  
Efficacy endpoints analyzed with the ITT and on-treatment estimands will be analyzed in the ITT 
population. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Unless otherwise specified, efficacy analyses will be performed overall only (all doses combined). 
2.4.4.1.1 Primary efficacy analysis 
The percent change from baseline in LDL-C at Week 12 as defined in Section 2.1.3.1 will be 
analyzed in the ITT population using a mixed-effect model with repeated measures (MMRM) 
approach. All post-baseline data available within the Week 4 to Week 48 analysis windows will 
be used and missing data will be accounted for by the MMRM model. The model will include the 
fixed categorical effect of time point (Weeks 4, 12, 24, and 48), as well as the continuous fixed 
covariate of baseline LDL-C value. 
This model will be run using SAS mixed procedure with an unstructured correlation matrix to 
model the within-patient errors. Parameters will be estimated using restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degrees of freedom will be estimated 
using Satterthwaite’s approximation.  
This model will provide baseline adjusted least-squares means estimates at Week 12 with their 
corresponding standard errors (SEs) and 95% confidence intervals (CI).  
The MMRM model 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 
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be conducted (pattern mixture model approach using mixed imputation defined in 
Section 2.4.4.1.3). 
2.4.4.1.2 Model assumption checks 
The analysis of the residuals of the MMRM 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: 
- 
Time point (Week 4, Week 12, Week 24, week 36, Week 48). 
If the primary endpoint has a non-normal distribution, it will be analyzed using multiple 
imputation approach for handling of missing values as described for non-normally distributed 
endpoints with log-transformation (see Section 2.4.4.2.2 for details about multiple imputations). 
2.4.4.1.3 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).  
Pattern mixture model (see Appendix C for more details): 
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 IMP injection up 
to the day of last injection +21 days) versus LDL-C values missing after treatment discontinuation 
(ie, after the day of last injection +21 days) based on the following assumptions: 
 Patients within 21 days of their last 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. 
Missing LDL-C values will be imputed 100 times to generate 100 complete data sets. The percent 
change from baseline to Week 12 will be derived from observed and imputed LDL-C at this time 
point. The completed data sets will be analyzed using a linear regression model with the baseline 
LDL-C value as continuous covariate. Combined mean with their corresponding standard errors 
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(SEs) and 95% CIs will be provided through the SAS MIANALYZE procedure using Rubin’s 
formulae (8). 
2.4.4.2 Analyses of secondary efficacy endpoints 
2.4.4.2.1 Continuous endpoints anticipated to have a normal distribution 
Continuous secondary variables 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 model as for the primary endpoint with fixed planned post-baseline time 
points up to Week 48, as well as, the continuous fixed covariate of corresponding baseline value.  
Continuous secondary efficacy endpoints analyzed with the on-treatment estimand and anticipated 
to have a normal distribution will be analyzed using the same MMRM model but only including 
on-treatment values.  
2.4.4.2.2 Continuous endpoints anticipated to have a non-normal distribution 
Continuous secondary efficacy variables 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. The percent change from 
baseline at time point of interest will be derived from observed and imputed lipid values at this 
time point. Multiple imputations will be followed by robust regression model (9) with endpoint of 
interest as response variable using M-estimation (using SAS ROBUSTREG procedure) with 
baseline value as effect. Combined means estimates with their corresponding SEs, 95% CIs will 
be provided through the SAS MIANALYZE procedure. 
Multiple imputation model 
Since in general the missing pattern is anticipated not to be 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 models for Step 1 and Step 2 will include the values of the analyzed parameter at 
baseline and time-points up to Week 48.  
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. 
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 in these models. 
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2.4.4.2.3 Binary endpoints  
Binary secondary efficacy endpoints defined in Section 2.1.3.2 (ie, proportion of patients with 
≥15% reduction in LDL-C at Weeks 12, 24, 48)  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 imputations).  
For each simulation leading to negative imputed value, another value will be redrawn using 
MINIMUM option of MI SAS procedure.  
The binary endpoint at time point of interest will be derived from observed and imputed lipid 
values at this time point. Combined proportion with their corresponding 95% CIs will be provided 
through the SAS MIANALYZE procedure. 
Binary secondary efficacy endpoints analyzed with the on-treatment estimand will be analyzed 
using the same imputation model, but only including on-treatment values in this model. 
2.4.4.2.4 Summary of results per time point 
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, non-HDL-C, Total-C, Lp (a), HDL-C, fasting TG, Apo B, 
Apo A-1 and ratio Apo-B/Apo-A1 (absolute change from baseline) (pre-apheresis, if applicable) at 
Week 12, Week 24 and Week 48 time points will be summarized in the ITT population (ITT and 
on-treatment estimands) 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 Section 2.4.4.2.1) and with raw values, absolute changes from baseline, or percent 
changes 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, absolute change from 
baseline and % change from baseline) will be presented for all lipids using observed 
(ie, non-missing) data. Post-apheresis data will be described separately. In addition, binary 
variables for LDL-C will be also described. These analyses will be done overall and by dose.  
Descriptive summaries for value at visit, absolute change from baseline and % change from 
baseline for LDL-C using observed data will also be presented separately for patients on apheresis 
and without apheresis. 
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2.4.4.3 Multiplicity issues 
Not applicable. 
2.4.4.4 Additional efficacy analysis(es) 
Not applicable. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented on the safety population. No formal inferential 
testing will be performed. Summaries will be descriptive in nature. 
General common rules 
All safety analyses will be performed using the following common rules: 
 The baseline value is defined as the last available value obtained up to the date and time of 
the first IMP injection.  
 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], for patients who become 
adults during the study ie, aged 18 years or greater during the study). 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 3 in order to provide an assessment for 
Week 4 to Week 48 time points. 
 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 (see Section 2.1.4). The worst on-treatment value is 
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defined as the nadir and /or the peak value during the treatment period according to the 
direction (minimum or maximum) of the abnormality as defined in the PCSA list. 
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.   
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. 
 All TEAEs by primary SOC, HLGT, 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 overall population).  This sorting 
order will be applied to all other tables by SOC and PT of TEAEs, unless otherwise 
specified. 
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 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 overall population).  
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. 
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 overall population) within each SOC. 
 All pre-treatment AEs leading to treatment discontinuation by primary SOC and PT, sorted 
by the sorting order defined above. 
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 All post-treatment AEs by primary SOC and PT, sorted by the internationally agreed SOC 
order and decreasing incidence of PTs (in the overall population) within each SOC. 
 All post-treatment SAEs by primary SOC and PT, sorted by the sorting order defined 
above. 
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 
Individual data listings of TEAEs in patients with two consecutive results of LDL-C <50 mg/dL 
(respectively LDL-C <25 mg/dL or LDL-C <15 mg/dL) (as defined in Section 2.1.5) will be 
provided.  
Subgroups of patients with treatment-emergent ADA positive response 
Individual data listings of TEAEs in patients with treatment-emergent ADA positive response will 
be provided. 
2.4.5.2 Deaths 
The following summaries of deaths will be generated: 
 Number (%) of patients from the safety population who died by period (on-study, 
on-treatment, post-study);  
 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, for the safety 
population. 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).  
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). This section will be organized by biological function 
as specified Section 2.1.4.3.  
The incidence of PCSAs (list provided in Appendix A and Appendix B), as well as ALT increase 
as defined as AESI, 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. 
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For parameters for which no PCSA criteria are defined for children ie, red blood cell count, 
albumin, monocytes and basophils, similar table(s) using the normal range will be provided. 
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 as AESI 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 (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).  
Creatine phosphokinase-MB and cardiac troponin 
Creatine phosphokinase-MB (value and percent change from baseline) at Week 12 will be 
summarized on the safety population using number of available data, mean, SD, median, Q1, Q3, 
minimum, and maximum. In addition, similar table 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. 
Cardiac troponin at Week 12 will be summarized on the safety population according to the 
following categories:  
 < LLOQ;  
 ≥ LLOQ 
2.4.5.4 Analyses of vital sign variables 
The summary statistics (including number, mean, median, Q1, Q3, SD, minimum and maximum) 
of vital signs variables (heart rate, diastolic and systolic blood pressure in sitting position) , height, 
weight and  BMI (raw 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, worst on-
treatment value and follow-up visit).  For weight, percent change 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. 
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The incidence of PCSAs for heart rate and blood pressure at any time during the TEAE period will 
be summarized. 
2.4.5.5 Analyses of electrocardiogram variables 
Not Applicable. 
2.4.5.6 Analyses 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 time point using count and percentage. 
The change from baseline in Tanner stage based on development of external genitalia for boys, 
and breast development for girls, at Week 12, at Week 24 and Week 48 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 course of the study will be 
summarized. 
2.4.6 Analyses of other endpoints 
HbA1c (value and absolute change from baseline) will be summarized by analysis visit using 
number of available data, mean, SD, median, minimum, and maximum for each dose during the 
treatment period. The time profile will be also plotted with the means and the corresponding SEs. 
Similar table 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. 
Binary endpoints defined in Section 2.1.5 will be described using count and percentage. The 
“Time to” variables will be summarized using number of available data, mean, SD, median, 
minimum, and maximum. 
2.4.7 Analyses of anti-alirocumab antibodies variables 
The following summaries will be performed on the ADA population taking into account all 
samples regardless of timing in relation to injections.  
 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. 
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 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.  
 Time to onset of treatment-emergent persistent ADA positive response using descriptive 
statistics, beginning from the first IMP administration.  
 Number (%) of patients with at least one neutralizing ADA. 
2.4.8  Analyses of pharmacokinetic and pharmacodynamic variables 
Concentrations of total alirocumab in serum (Ctrough, Cmax and Cfollow-up), free and total PCSK9 
concentrations will be summarized on the PK population by visit using descriptive statistics. 
Ctrough,av will be summarized on the PK population using descriptive statistics.  
Time profiles for Ctrough concentration, total and free PCSK9 will be also provided using graphs 
(mean ± SE or Median, as appropriate).  
Concentrations of total alirocumab in serum and PCSK9 levels 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/health economics 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 hoFH  
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 
The date of the last injection is equal to the last date of administration reported on injection 
administration case report form page or missing if the last administration date is unknown.  
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Renal function formulas  
eGFR value will be derived using the Schwartz equation: 
eGFR (mL/min/1.73 m2) = (0.41 × Height in cm) / Creatinine in mg/dL 
Lipids variables, laboratory safety variables 
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 reported in the database, with the values that 
will be used in quantitative analyses for each parameter. 
Table 2 - Example of lipid data for a “dummy” patient 
Parameter 
Value reported 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 
TRIG 
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 will be set to zero. 
2.5.2 Data handling conventions for secondary efficacy variables 
See Section 2.1.3. 
2.5.3 Missing data 
For categorical variables, patients with missing data will not be included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
will be presented. 
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Handling of baseline definition if time of first administration or time of assessment at Week 0 
visit is missing 
If the time of the first 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 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 if investigational medicinal product end of 
treatment date is missing  
If the last injection date 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 (Week 48 visit 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, worsening, seriousness 
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 inclusion will be considered as TEAEs.  
When the time of the first IMP administration is missing, all AEs that occurred on the day of the 
first IMP administration will be considered as treatment-emergent AEs. 
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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 will be 
assumed as possibly related in the frequency tables, but no imputation will be done at the data 
level. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline value, he/she will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value and the other on a 
threshold value or a normal range, 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, physical 
examinations, ADA, PK) will be summarized using the analysis windows given in Table 3. These 
analysis windows will be applicable for all analyses, and they are defined to provide more 
homogeneous data for time point-specific analyses. 
Table 3 - Analysis windows definition for open-label treatment period 
Time point 
Targeted study day 
Analysis window in study days 
Week 4 
29 
8 to 49 
Week 12 
85 
64 to minimum (98; study day corresponding to first the 
injection with IMP from kit allocated at Week 12 re-supply 
IVRS contact) 
Week 24 
169 
148 to 189 
Week 36 
253 
232 to 273 
Week 48 
337 
309 to 364 
Follow-up 
Last IMP + 10 weeks 
Last IMP+10 weeks ±4 weeks 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1. For included but not treated patients, 
Day 1 is the day of enrollment.  
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If multiple valid values of a variable exist within an analysis window, the nearest from the 
targeted study day will be selected. If the difference is a tie, the value after the targeted study day 
will be used. 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 as Cmax, Ctrough or Cfollow-up using definitions as defined in 
Table 4. If the date of the previous injection is unknown, the alirocumab concentration will not be 
considered for the analysis. 
Table 4 - Time windows for PK variables definition 
PK variables 
Time window (D1 = day of previous injection or day of last 
injection for Cfollow-up) 
Cmax 
Day 4 to Day 8 
Ctrough 
Day 9 to Day 22 
Cfollow-up 
Day 23 to last injection + 14 weeks 
Study days are calculated from the day of first IMP injection, the day of first IMP injection being Day 1.  
If multiple valid values satisfy the Cmax, Ctrough or Cfollow-up criteria, the nearest from the targeted 
study day (ie, Day 6 for Cmax, Day 15 for Ctrough and Day 70 for Cfollow-up, 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. 
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. These 
measurements may also be used to determine abnormal/PCSA. 
2.5.6 Pooling of centers for statistical analyses 
No pooling of centers will be performed for safety nor for efficacy analyses. 
2.5.7 Statistical technical issues 
Not Applicable. 
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3 
INTERIM ANALYSIS 
No formal interim analysis for efficacy is planned. 
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4 
DATABASE LOCK 
The database is planned to be locked at 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 9.2 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. 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. 
3. 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. 
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 
Potentially clinically significant abnormalities for children 
Potentially clinically significant abnormalities for adults 
Appendix A: 
Appendix B: 
Appendix C: 
Detailed statistical methodology for pattern mixture model 
Appendix D: 
List of MedDRA terms for CMQs 
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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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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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Page 58 
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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Page 60 
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/1.73 m2) 
(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 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
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. 
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. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for Phase 2/3 studies (oncology excepted) 
Parameter 
PCSA 
Comments 
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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Statistical Analysis Plan  
27-Jan-2020 
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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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Statistical Analysis Plan  
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Appendix C 
Detailed statistical methodology for pattern mixture model 
As a sensitivity analysis of the primary efficacy endpoint (ie, percent change from baseline to 
Week 12 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 injection +21 days) and missing 
LDL-C values after treatment discontinuation (ie, after the day of last injection +21 days) based on 
the following assumptions: 
 Patients within 21 days of their last 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. 
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 
to baseline level within 4 weeks after ceasing alirocumab treatment (See Figure 2 and 
Figure 3). 
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Figure 2 - Study DFI11565: calculated LDL-C mean (+/- SE) percent change from baseline 
 
Figure 3 - Study R-727-CL-1003: calculated LDL-C mean (+/- SE) percent change from baseline 
 
Missing LDL-C values will be imputed 100 times to generate 100 complete data sets. The percent 
change from baseline to Week 12 will be derived from observed and imputed LDL-C at this time 
point. The completed data sets will be analyzed using a linear regression model with the baseline 
LDL-C value as continuous covariate. Combined mean with their corresponding standard errors 
(SEs) and 95% CIs will be provided through the SAS MIANALYZE procedure using Rubin’s 
formulae (8). 
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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_W4   LDL_W12   LDL_W24   LDL_48; 
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.  
The conditional variance will be estimated from observed data at the specific time-point. 
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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 5 - 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 6 - 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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