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Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Study Followed by an Open Label Treatment Period to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous Familial Hypercholesterolemia

Summary
EudraCT number	2017-001903-60
Trial protocol	SE DK FR IT DE AT Outside EU/EEA NL HU SI ES PL FI BG CZ NO
Global end of trial date	05 Aug 2022

Results information
Results version number	v2(current)
This version publication date	24 Jun 2023
First version publication date	22 Feb 2023
Other versions	v1
Version creation reason	Correction of full data set Consistency with CTG

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EFC14643

ISRCTN number

US NCT number

NCT03510884

WHO universal trial number (UTN)

U1111-1193-0721

Sponsor organisation name

Sanofi-aventis Recherche & Développement

Sponsor organisation address

1 Avenue Pierre Brossolette, Chilly-Mazarin, France, 91385

Public contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Scientific contact

Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001169-PIP01-11

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

31 Aug 2022

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

05 Aug 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) and every 4 weeks (Q4W) versus placebo after 24 weeks of double-blind (DB) treatment on low-density lipoprotein cholesterol (LDL-C) levels in subjects with heterozygous familial hypercholesterolemia (heFH) 8 to 17 years of age on optimal stable daily dose of statin therapy ± other lipid modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of intolerance to statins.

Protection of trial subjects

The study was conducted by investigators experienced in the treatment of paediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 May 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 3

Country: Number of subjects enrolled

Finland: 3

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Poland: 12

Country: Number of subjects enrolled

Sweden: 2

Country: Number of subjects enrolled

Argentina: 2

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Lebanon: 5

Country: Number of subjects enrolled

Mexico: 17

Country: Number of subjects enrolled

South Africa: 1

Country: Number of subjects enrolled

Taiwan: 2

Country: Number of subjects enrolled

United States: 13

Country: Number of subjects enrolled

Czechia: 12

Country: Number of subjects enrolled

Italy: 5

Country: Number of subjects enrolled

Bulgaria: 3

Country: Number of subjects enrolled

Netherlands: 18

Country: Number of subjects enrolled

Spain: 9

Country: Number of subjects enrolled

Denmark: 3

Country: Number of subjects enrolled

Hungary: 3

Country: Number of subjects enrolled

Norway: 5

Country: Number of subjects enrolled

Russian Federation: 8

Country: Number of subjects enrolled

Slovenia: 2

Country: Number of subjects enrolled

Turkey: 6

Worldwide total number of subjects

153

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Study was conducted at 43 active sites in 24 countries. A total of 203 subjects were screened between 31-May-2018 and 31-Jul-2020, of whom 50 were screen failures. Screen failures were mainly due to exclusion criteria met. A total of 153 subjects were randomised with a 2:1 ratio to receive study treatment (alirocumab: placebo).

Screening details

Randomisation was stratified according to previous participation (yes or no) in the Phase 2 DFI14223 (EudraCT number: 2015-003766-85) study and Baseline body weight (BW) (less than [<] 50 kilograms (kg) or greater than or equal to [>=] 50 kg).

Period 1 title

Double-blind Period (up to Week 24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer

Are arms mutually exclusive

Yes

DB Period: Placebo Q2W

Arm description

Subjects received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo (matched to alirocumab) SC injection based on BW (<50 kg or >=50 kg) Q2W for 24 weeks with stable LMT.

DB Period: Alirocumab Q2W

Arm description

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) SC injection Q2W for 24 weeks with stable LMT. Up-titrated dose: 75 mg or 150 mg Q2W from Week 12, when LDL-C level was >=110 mg/dL (2.85 mmol/L) at Week 8.

DB Period: Placebo Q4W

Arm description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo (matched to alirocumab) SC injection based on BW (<50 kg or >=50 kg) Q4W for 24 weeks with stable LMT.

DB Period: Alirocumab Q4W

Arm description

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) SC injection Q4W for 24 weeks with stable LMT. Up-titrated dose: 75 mg or 150 mg Q2W from Week 12, when LDL-C level >=110 mg/dL (2.85 mmol/L) at Week 8.

Number of subjects in period 1	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Started	25	49	27	52
Completed	25	45	26	49
Not completed	0	4	1	3
Noncompliance to investigational medicinal product	-	2	-	-
Other - Unspecified	-	-	1	1
Adverse event	-	-	-	2
Subject moved	-	1	-	-
Life events made continuing too difficult	-	1	-	-

Period 2 title

Open Label (OL) Period (up to Week 104)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

OL Period: Placebo/Alirocumab Q2W

Arm description

After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 40 milligrams (mg) (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject low density lipoprotein cholesterol (LDL-C) value, alirocumab dose was either uptitrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

OL Period: Alirocumab Q2W

Arm description

After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

OL Period: Placebo/Alirocumab Q4W

Arm description

After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) Q4W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW <50 kg) or 300 mg Q4W to 150 mg Q2W (for BW >=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW <50 kg) or 150 mg Q2W to 75 mg Q2W (for BW >=50 kg).

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) Q4W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW <50 kg) or 300 mg Q4W to 150 mg Q2W (for BW >=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW <50 kg) or 150 mg Q2W to 75 mg Q2W (for BW >=50 kg).

OL Period: Alirocumab Q4W

Arm description

Arm type

Experimental

Investigational medicinal product name

Alirocumab

Investigational medicinal product code

SAR236553 (REGN727)

Other name

Praluent

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either uptitrated as 150 mg Q4W to 75 mg Q2W (for BW <50 kg) or 300 mg Q4W to 150 mg Q2W (for BW >=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW <50 kg) or 150 mg Q2W to 75 mg Q2W (for BW >=50 kg).

Number of subjects in period 2	OL Period: Placebo/Alirocumab Q2W	OL Period: Alirocumab Q2W	OL Period: Placebo/Alirocumab Q4W	OL Period: Alirocumab Q4W
Started	25	46	25	49
Completed	22	43	24	49
Not completed	3	3	1	0
Other - Unspecified	1	1	-	-
Adverse event	1	-	-	-
Subject moved	1	-	1	-
Life events made continuing too difficult	-	1	-	-
Lack of efficacy	-	1	-	-

Baseline characteristics

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Reporting group title

DB Period: Placebo Q2W

Reporting group description

Subjects received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT.

Reporting group title

DB Period: Alirocumab Q2W

Reporting group description

Reporting group title

DB Period: Placebo Q4W

Reporting group description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT.

Reporting group title

DB Period: Alirocumab Q4W

Reporting group description

Reporting group values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W	Total
Number of subjects	25	49	27	52	153
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	13.2 ( 2.4 )	12.5 ( 2.7 )	12.8 ( 3.0 )	13.1 ( 3.0 )	-
Gender categorical
Units: Subjects
Female	8	30	15	34	87
Male	17	19	12	18	66
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	4	12	16
Asian	1	1	0	0	2
Native Hawaiian or Other Pacific Islander	0	1	0	0	1
Black or African American	0	1	1	1	3
White	23	42	22	38	125
More than one race	1	4	0	0	5
Unknown or Not Reported	0	0	0	1	1
Low-Density Lipoprotein Cholesterol
Calculated LDL-C values were obtained using Friedewald formula: LDL-C = Total cholesterol - High-density lipoprotein cholesterol [HDL-C] - [Triglyceride/5])
Units: mg/dL
arithmetic mean (standard deviation)	175.29 ( 50.23 )	169.69 ( 46.74 )	176.57 ( 49.01 )	176.79 ( 53.93 )	-

End points

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Reporting group title

DB Period: Placebo Q2W

Reporting group description

Subjects received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT.

Reporting group title

DB Period: Alirocumab Q2W

Reporting group description

Reporting group title

DB Period: Placebo Q4W

Reporting group description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT.

Reporting group title

DB Period: Alirocumab Q4W

Reporting group description

Reporting group title

OL Period: Placebo/Alirocumab Q2W

Reporting group description

Reporting group title

OL Period: Alirocumab Q2W

Reporting group description

Reporting group title

OL Period: Placebo/Alirocumab Q4W

Reporting group description

Reporting group title

OL Period: Alirocumab Q4W

Reporting group description

Subject analysis set title

Placebo/Alirocumab Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

Subject analysis set title

Alirocumab Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received SC injection of alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level was >=110 mg/dL (2.85 mmol/L) at Week 8. After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

Subject analysis set title

Placebo/Alirocumab Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW <50 kg) or 300 mg Q4W to 150 mg Q2W (for BW >=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW <50 kg) or 150 mg Q2W to 75 mg Q2W (for BW >=50 kg).

Subject analysis set title

Alirocumab Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects received SC injection of alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level >=110 mg/dL (2.85 mmol/L) at Week 8. After completion of DB treatment period, eligible subjects entered into OL treatment period and received alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on subject LDL-C value, alirocumab dose was either uptitrated as 150 mg Q4W to 75 mg Q2W (for BW <50 kg) or 300 mg Q4W to 150 mg Q2W (for BW >=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW <50 kg) or 150 mg Q2W to 75 mg Q2W (for BW >=50 kg).

Primary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Estimand

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End point title

DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Estimand

End point description

Adjusted least square (LS) means and standard errors (SE) were obtained from mixed-effect model with repeated measures (MMRM) model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population which included all randomised subjects who were analysed according to the treatment group allocated by randomisation. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Primary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	9.7 ( 4.3 )	-33.6 ( 3.4 )	-4.4 ( 3.7 )	-38.2 ( 4.0 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per interactive voice response system (IVRS), time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline LDL-C value and Baseline value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-43.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

-56

upper limit

-30.7

Variability estimate

Standard error of the mean

Dispersion value

5.5

Notes
[1] - Bonferroni adjustment was applied to handle multiplicity for the comparison of each alirocumab dosing regimen group versus its placebo group for the primary efficacy endpoint.
[2] - The threshold for statistical significance was 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline LDL-C value and Baseline value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

< 0.0001 ^[4]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-33.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-46.4

upper limit

-21.2

Variability estimate

Standard error of the mean

Dispersion value

5.5

Notes
[3] - Bonferroni adjustment was applied to handle multiplicity for the comparison of each alirocumab dosing regimen group versus its placebo group for the primary efficacy endpoint.
[4] - The threshold for statistical significance was 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	10.7 ( 3.6 )	-34.8 ( 3.0 )	2.3 ( 3.6 )	-39.2 ( 3.3 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline LDLC value and Baseline value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

< 0.0001 ^[6]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-45.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

-56.3

upper limit

-34.7

Variability estimate

Standard error of the mean

Dispersion value

4.7

Notes
[5] - Hierarchical testing method was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints were reported and independently for each dosing regimen. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level. Statistical significance of the primary endpoint was required before testing the first secondary endpoint for each dosing regimen independently.
[6] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

< 0.0001 ^[8]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-41.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

-52.7

upper limit

-30.2

Variability estimate

Standard error of the mean

Dispersion value

4.9

Notes
[7] - A hierarchical testing method was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported and independently for each dosing regimen. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.025 level. Statistical significance of the primary endpoint was required before testing the first secondary endpoint for each dosing regimen independently.
[8] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)	10.4 ( 2.8 )	-27.4 ( 3.2 )	-3.6 ( 3.9 )	-34.3 ( 2.9 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Apo B value and Baseline Apo B value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

< 0.0001 ^[10]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-37.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-47.5

upper limit

-28.2

Variability estimate

Standard error of the mean

Dispersion value

4.2

Notes
[9] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[10] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Apo B value and Baseline Apo B value by timepoint interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-30.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

-42

upper limit

-19.4

Variability estimate

Standard error of the mean

Dispersion value

4.9

Notes
[11] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[12] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	9.7 ( 3.9 )	-31.0 ( 3.2 )	-3.7 ( 4.0 )	-35.6 ( 3.5 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline non-HDL-C value and Baseline non-HDL-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

< 0.0001 ^[14]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-40.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

-52.2

upper limit

-29.1

Variability estimate

Standard error of the mean

Dispersion value

Notes
[13] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[14] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline non-HDL-C value and Baseline non-HDL-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

< 0.0001 ^[16]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-31.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

-44.1

upper limit

-19.7

Variability estimate

Standard error of the mean

Dispersion value

5.3

Notes
[15] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[16] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	7.4 ( 3.0 )	-23.4 ( 2.5 )	-4.4 ( 3.3 )	-27.7 ( 2.9 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Total-C value and Baseline Total-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

< 0.0001 ^[18]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-30.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-39.8

upper limit

-21.9

Variability estimate

Standard error of the mean

Dispersion value

3.9

Notes
[17] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[18] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Total-C value and Baseline Total-C value by timepoint interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

< 0.0001 ^[20]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-23.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

-33.5

upper limit

-13.1

Variability estimate

Standard error of the mean

Dispersion value

4.4

Notes
[19] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[20] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)	8.9 ( 3.1 )	-30.0 ( 2.5 )	1.1 ( 3.2 )	-31.7 ( 2.9 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Apo B value and Baseline Apo B value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001 ^[22]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-38.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

-48.2

upper limit

-29.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[21] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[22] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Apo B value and Baseline Apo B value by timepoint interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

< 0.0001 ^[24]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-32.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-42.8

upper limit

-22.7

Variability estimate

Standard error of the mean

Dispersion value

4.3

Notes
[23] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[24] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	9.8 ( 3.8 )	-33.0 ( 2.8 )	2.8 ( 3.5 )	-34.7 ( 2.9 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Non-HDL-C value and Baseline Non-HDL-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

< 0.0001 ^[26]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-42.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

-53.8

upper limit

-31.8

Variability estimate

Standard error of the mean

Dispersion value

4.7

Notes
[25] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[26] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline non-HDL-C value and Baseline non-HDL-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

< 0.0001 ^[28]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-37.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

-47.9

upper limit

-27

Variability estimate

Standard error of the mean

Dispersion value

4.5

Notes
[27] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[28] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	7.5 ( 2.9 )	-25.3 ( 2.2 )	0.9 ( 2.5 )	-27.0 ( 2.3 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Total-C value and Baseline Total-C value by time-point interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

< 0.0001 ^[30]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-32.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

-41.3

upper limit

-24.2

Variability estimate

Standard error of the mean

Dispersion value

3.7

Notes
[29] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[30] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

The MMRM model included the fixed categorical effects of treatment group (alirocumab, placebo), randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS, time point, treatment-by-time point interaction, and BW strata-by-time point interaction, as well as the continuous fixed covariates of Baseline Total-C value and Baseline Total-C value by timepoint interaction. Comparison was performed using an appropriate contrast.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

< 0.0001 ^[32]

Method

MMRM

Parameter type

LS mean difference

Point estimate

-27.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

-35.6

upper limit

-20.2

Variability estimate

Standard error of the mean

Dispersion value

3.4

Notes
[31] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[32] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand

End point description

Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 24 were included in the imputation model. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

At Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)	8.0	73.3	22.2	76.3

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

Multiple imputation approach followed by logistic regression model, stratified by randomisation factors (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS included the fixed categorical effect of treatment group and continuous fixed covariate of Baseline LDL-C value. Combined estimate for odds ratio was obtained by combining the logarithm of odds ratio from logistic regression model analyses of different imputed data sets, using Rubin's formulae.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[33]

P-value

= 0.0001 ^[34]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

77.6

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.3

upper limit

960

Notes
[33] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[34] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Multiple imputation approach followed by logistic regression model, stratified by randomisation factors (Baseline BW [<50 or >=50 kg]) as per IVRS included the fixed categorical effect of treatment group and the continuous fixed covariate of Baseline LDL-C value. Combined estimate for odds ratio was obtained by combining the logarithm of odds ratio from logistic regression model analyses of the different imputed data sets, using Rubin’s formulae.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

P-value

< 0.0001 ^[36]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

14.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

3.2

upper limit

69.8

Notes
[35] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[36] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand

End point description

Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 12 were included in the imputation model. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

At Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)	16.4	70.6	12.9	72.6

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

Multiple imputation approach followed by logistic regression model, stratified by randomisation factors (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS included the fixed categorical effect of treatment group and continuous fixed covariate of Baseline LDL-C value. Combined estimate for odds ratio was obtained by combining logarithm of odds ratio from logistic regression model analyses of the different imputed data sets, using Rubin’s formulae.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

< 0.0001 ^[38]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

26.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

upper limit

174.8

Notes
[37] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[38] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

< 0.0001 ^[40]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

40.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

5.7

upper limit

290.9

Notes
[39] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[40] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand

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End point title

DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

At Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)	4.0	57.2	9.0	67.2

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

Multiple imputation approach followed by logistic regression model, stratified by randomisation factors (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS included the fixed categorical effect of treatment group and the continuous fixed covariate of Baseline LDL-C value. Combined estimate for odds ratio was obtained by combining the logarithm of odds ratio from logistic regression model analyses of different imputed data sets, using Rubin’s formulae.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

P-value

= 0.0011 ^[42]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

52.7

Confidence interval

level

97.5%

sides

2-sided

lower limit

3.5

upper limit

804.3

Notes
[41] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[42] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

P-value

= 0.0006 ^[44]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

43.1

Confidence interval

level

97.5%

sides

2-sided

lower limit

3.7

upper limit

498.6

Notes
[43] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[44] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand

Top of page

End point title

DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand

End point description

Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data for Q4W. All available post-baseline data up to Week 12 were included in the imputation model. For Q2W, adjusted percentages at Week 12 were obtained from last observation carried forward approach (LOCF) to handle missing on-treatment LDL-C values as well as missing post-treatment LDL-C values in subjects who discontinued treatment due to the coronavirus disease-2019 pandemic. Other post-treatment missing values were considered as failure. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

At Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)	0.0	61.2	4.3	57.0

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

The LOCF approach followed by exact conditional logistic regression model. The exact conditional logistic regression model stratified by randomisation factors (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS included the fixed categorical effect of treatment group and the quartiles of the Baseline LDL-C value. Odds ratios and confidence intervals estimated from exact conditional logistic regression model.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

P-value

< 0.0001 ^[46]

Method

Exact conditional logistic regression

Parameter type

Odds ratio (OR)

Point estimate

41.3

Confidence interval

level

97.5%

sides

2-sided

lower limit

6.6

upper limit

99999

Notes
[45] - Testing according to hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen). Here, 99999, a space filler = percentage of subjects reaching LDL-C level lower than 110 mg/dL was 0% in placebo arm, as a result it was possible to derive estimated odds-ratio, but estimated confidence interval (CI) was very wide, with upper limit estimated to infinity, therefore upper limit of 97.5% CI was not available to report.
[46] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[47]

P-value

= 0.0005 ^[48]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

104.8

Confidence interval

level

97.5%

sides

2-sided

lower limit

5.2

upper limit

2095.9

Notes
[47] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[48] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand

End point description

Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)	0.5 ( 5.3 )	-14.7 ( 4.1 )	2.5 ( 7.1 )	-22.4 ( 5.0 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

Multiple imputation approach followed by robust regression model, included the fixed categorical effect of treatment group and randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS and the continuous fixed covariate of Baseline lipoprotein (a) value.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

P-value

= 0.0237 ^[50]

Method

Robust regression model

Parameter type

Adjusted mean difference

Point estimate

-15.2

Confidence interval

level

97.5%

sides

2-sided

lower limit

-30.3

upper limit

-0.1

Variability estimate

Standard error of the mean

Dispersion value

6.7

Notes
[49] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[50] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Multiple imputation approach followed by robust regression model. The robust regression model included the fixed categorical effect of treatment group and randomisation strata (Baseline BW [<50 or >=50 kg]) as per IVRS and the continuous fixed covariate of Baseline lipoprotein (a) value.

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

P-value

= 0.0043 ^[52]

Method

Robust regression model

Parameter type

Adjusted mean difference

Point estimate

-24.9

Confidence interval

level

97.5%

sides

2-sided

lower limit

-44.4

upper limit

-5.4

Variability estimate

Standard error of the mean

Dispersion value

8.7

Notes
[51] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[52] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand

End point description

Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)	-7.1 ( 5.9 )	-12.7 ( 3.9 )	-2.5 ( 6.9 )	-16.0 ( 5.1 )

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Statistical analysis description

Multiple imputation approach followed by robust regression model. The robust regression model included the fixed categorical effect of treatment group and randomisation strata (previous participation [yes or no] to DFI14223 study, Baseline BW [<50 or >=50 kg]) as per IVRS and the continuous fixed covariate of Baseline lipoprotein (a) value.

Comparison groups

DB Period: Placebo Q2W v DB Period: Alirocumab Q2W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.4288 ^[54]

Method

Robust regression model

Parameter type

Adjusted mean difference

Point estimate

-5.6

Confidence interval

level

97.5%

sides

2-sided

lower limit

-21.7

upper limit

10.4

Variability estimate

Standard error of the mean

Dispersion value

7.1

Notes
[53] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[54] - Threshold for significance at 0.025 level.

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Statistical analysis description

Comparison groups

DB Period: Placebo Q4W v DB Period: Alirocumab Q4W

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.1148 ^[56]

Method

Robust regression model

Parameter type

Adjusted mean difference

Point estimate

-13.5

Confidence interval

level

97.5%

sides

2-sided

lower limit

-32.7

upper limit

5.7

Variability estimate

Standard error of the mean

Dispersion value

8.6

Notes
[55] - Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the considered dosing regimen).
[56] - Threshold for significance at 0.025 level.

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	-0.8 ( 2.1 )	5.6 ( 1.4 )	-1.1 ( 2.7 )	3.4 ( 2.1 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)	7.7 ( 8.4 )	11.9 ( 6.3 )	12.2 ( 8.2 )	-6.8 ( 5.5 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)	-0.1 ( 2.6 )	1.0 ( 1.5 )	-4.5 ( 2.6 )	4.4 ( 2.0 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)	-2.2 ( 3.2 )	3.5 ( 2.0 )	-3.5 ( 3.2 )	4.0 ( 2.2 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand

End point description

Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. Analysis was performed on ITT population.

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)	6.5 ( 7.4 )	-2.2 ( 5.0 )	7.8 ( 8.4 )	-0.3 ( 6.0 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Week 12

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)	-0.1 ( 1.8 )	-1.7 ( 1.7 )	-0.7 ( 3.1 )	5.0 ( 1.7 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Weeks 12, and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Weeks 12, and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st investigational medicinal product (IMP) injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on modified intent-to-treat (mITT) population which included all randomised subjects who took at least one dose or part of a dose of the IMP injection. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 12	10.7 ( 3.6 )	-34.8 ( 3.0 )	2.3 ( 3.6 )	-39.2 ( 3.3 )
Week 24	9.7 ( 4.3 )	-33.6 ( 3.4 )	-4.4 ( 3.7 )	-38.2 ( 4.0 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein B at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)
Week 12	8.9 ( 3.1 )	-30.0 ( 2.5 )	1.1 ( 3.2 )	-31.7 ( 2.9 )
Week 24	10.4 ( 2.8 )	-27.4 ( 3.2 )	-3.6 ( 3.9 )	-34.3 ( 2.9 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 12	9.8 ( 3.8 )	-33.0 ( 2.8 )	2.8 ( 3.5 )	-34.7 ( 2.9 )
Week 24	9.7 ( 3.9 )	-31.0 ( 3.2 )	-3.7 ( 4.0 )	-35.6 ( 3.5 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Total Cholesterol at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 12	7.5 ( 2.9 )	-25.3 ( 2.2 )	0.9 ( 2.5 )	-27.0 ( 2.3 )
Week 24	7.4 ( 3.0 )	-23.4 ( 2.5 )	-4.4 ( 3.3 )	-27.7 ( 2.9 )

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 130 mg/dL (3.37 mmol/L) at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 130 mg/dL (3.37 mmol/L) at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Analysis was performed on mITT population.

End point type

Secondary

End point timeframe

Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	16.4	70.6	12.9	72.6
Week 24	8.0	73.3	22.2	76.3

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 110 mg/dL (2.84 mmol/L) at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 110 mg/dL (2.84 mmol/L) at Weeks 12 and 24: On-treatment Estimand

End point description

End point type

Secondary

End point timeframe

Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	0.1	61.7	4.3	57.0
Week 24	4.0	57.2	9.0	67.2

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Lipoprotein (a) at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline on-treatment data up to Week 12 and Week 24, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. Analysis was performed on mITT population.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)
Week 12	-7.099 ( 5.923 )	-12.746 ( 3.889 )	-2.545 ( 6.851 )	-16.042 ( 5.139 )
Week 24	0.492 ( 5.254 )	-14.748 ( 4.083 )	2.468 ( 7.135 )	-22.418 ( 5.030 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Apolipoprotein A1 at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM mode, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-Baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: percent change
least squares mean (standard error)
Week 12	-0.1 ( 1.8 )	-1.7 ( 1.7 )	-0.7 ( 3.1 )	5.0 ( 1.7 )
Week 24	-0.1 ( 2.6 )	1.0 ( 1.5 )	-4.5 ( 2.6 )	4.4 ( 2.0 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 day otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 12	-2.2 ( 3.2 )	3.5 ( 2.0 )	-3.5 ( 3.2 )	4.0 ( 2.2 )
Week 24	-0.8 ( 2.1 )	5.6 ( 1.4 )	-1.1 ( 2.7 )	3.4 ( 2.1 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change From Baseline in Fasting Triglycerides at Weeks 12 and 24: On-treatment Estimand

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12, and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percent change
arithmetic mean (standard error)
Week 12	6.5 ( 7.4 )	-2.2 ( 5.0 )	7.8 ( 8.4 )	-0.3 ( 6.0 )
Week 24	7.7 ( 8.4 )	11.9 ( 6.3 )	12.2 ( 8.2 )	-6.8 ( 5.5 )

No statistical analyses for this end point

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: ITT Estimand

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End point title

DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 and Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on subjects with a Baseline value and a post-baseline value for at least one timepoint used in the model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: ratio (Apo B/Apo A-1)
least squares mean (standard error)
Week 12	0.1 ( 0.0 )	-0.2 ( 0.0 )	0.0 ( 0.0 )	-0.3 ( 0.0 )
Week 24	0.1 ( 0.0 )	-0.2 ( 0.0 )	0.0 ( 0.0 )	-0.3 ( 0.0 )

No statistical analyses for this end point

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on subjects with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 12, and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	47	26	49
Units: ratio (Apo B/Apo A-1)
least squares mean (standard error)
Week 12	0.1 ( 0.0 )	-0.2 ( 0.0 )	0.0 ( 0.0 )	-0.3 ( 0.0 )
Week 24	0.1 ( 0.0 )	-0.2 ( 0.0 )	0.0 ( 0.0 )	-0.3 ( 0.0 )

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 30 Percent (%) Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved at Least 30 Percent (%) Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

At Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	0.8	65.8	4.2	70.8
Week 24	4.0	66.7	18.5	72.5

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Achieved at Least 30% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percentage of Subjects Achieved at Least 30% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

End point description

End point type

Secondary

End point timeframe

At Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	0.8	65.8	4.2	70.8
Week 24	4.0	66.7	18.5	72.5

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

End point description

End point type

Secondary

End point timeframe

At Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	0.0	25.2	0.1	31.9
Week 24	0.0	21.6	9.1	32.4

No statistical analyses for this end point

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

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End point title

DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

End point description

End point type

Secondary

End point timeframe

At Weeks 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: percentage of subjects
number (not applicable)
Week 12	0.0	25.2	0.1	31.9
Week 24	0.0	21.6	9.1	32.4

No statistical analyses for this end point

Secondary: DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: ITT Estimand

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End point title

DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: ITT Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 8, Week 12 and Week 24 were used and missing data were accounted for by the MMRM model. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Weeks 8, 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 8	7.1 ( 4.2 )	-35.4 ( 3.6 )	-3.8 ( 3.5 )	-42.0 ( 2.8 )
Week 12	10.7 ( 3.6 )	-34.8 ( 3.0 )	2.3 ( 3.6 )	-39.2 ( 3.3 )
Week 24	9.7 ( 4.3 )	-33.6 ( 3.4 )	-4.4 ( 3.7 )	-38.2 ( 4.0 )

No statistical analyses for this end point

Secondary: DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: On-treatment Estimand

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End point title

DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: On-treatment Estimand

End point description

Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 8, Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint.

End point type

Secondary

End point timeframe

Baseline to Weeks 8, 12 and 24

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	49	26	50
Units: percent change
least squares mean (standard error)
Week 8	7.1 ( 4.2 )	-35.4 ( 3.6 )	-3.8 ( 3.5 )	-42.0 ( 2.8 )
Week 12	10.7 ( 3.6 )	-34.8 ( 3.0 )	2.3 ( 3.6 )	-39.2 ( 3.3 )
Week 24	9.7 ( 4.3 )	-33.6 ( 3.4 )	-4.4 ( 3.7 )	-38.2 ( 4.0 )

No statistical analyses for this end point

Secondary: OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: ITT Estimand

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End point title

OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: ITT Estimand

End point description

Percent Change in LDL-C from Baseline to Week 104 was reported in this endpoint. Analysis was performed on ITT population. Here, number of subjects analysed = subjects with available data for this endpoint. The ITT estimand was analysed by considering all the post-baseline (including both on- and post-treatment) LDL-C values for the analysis.

End point type

Secondary

End point timeframe

Baseline, Week 104

End point values	OL Period: Placebo/Alirocumab Q2W	OL Period: Alirocumab Q2W	OL Period: Placebo/Alirocumab Q4W	OL Period: Alirocumab Q4W
Number of subjects analysed	25	45	23	47
Units: percent change
least squares mean (standard error)	-23.3 ( 4.9 )	-22.2 ( 5.6 )	-27.1 ( 7.0 )	-23.7 ( 4.2 )

No statistical analyses for this end point

Secondary: OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: On-treatment Estimand

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End point title

OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: On-treatment Estimand

End point description

Percent Change in LDL-C from Baseline to Week 104 was reported in this endpoint. Analysis was performed on mITT population. Here, number of subjects analysed = subjects with available data for this endpoint. The on-treatment estimand was analysed using the same imputation model as ITT Estimand, but considered the 'on-treatment' LDL-C values alone for the analysis.

End point type

Secondary

End point timeframe

Baseline, Week 104

End point values	OL Period: Placebo/Alirocumab Q2W	OL Period: Alirocumab Q2W	OL Period: Placebo/Alirocumab Q4W	OL Period: Alirocumab Q4W
Number of subjects analysed	25	45	23	47
Units: percent change
least squares mean (standard error)	-22.8 ( 5.1 )	-25.8 ( 4.9 )	-27.6 ( 7.6 )	-23.4 ( 4.7 )

No statistical analyses for this end point

Secondary: Change From Baseline in Cogstate Battery Test - Overall Composite Score at Weeks 24, 68 and 104

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End point title

Change From Baseline in Cogstate Battery Test - Overall Composite Score at Weeks 24, 68 and 104

End point description

Cogstate battery test (cognitive testing system) consisted of detection test (DET), identification test (IDN), one card learning test (OCL) and Groton maze learning test (GML) to assess processing speed, attention, visual learning and executive functioning, respectively. For each test, Z-scores were computed based on subject's age at Baseline and Weeks 24, 68 and 104. Composite score: mean of Z-scores equally weighted, provided that at least 3 of 4 tests were available and if all of these domains were covered as: attention, through either DET or IDN, visual learning, through OCL and executive function, through GML. There is not minimum/maximum since values were reported as z-score but z-score of 0 means result equals to mean with negative numbers indicating values lower than mean and positive values higher. Positive change in z-score = improvement in cognition (i.e., better outcome) and negative change in z-score = worsening in cognition (i.e., worse outcome). n = subjects with data.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 68 and 104

End point values	Placebo/Alirocumab Q2W	Alirocumab Q2W	Placebo/Alirocumab Q4W	Alirocumab Q4W
Number of subjects analysed	25 ^[57]	49 ^[58]	27 ^[59]	52 ^[60]
Units: Z-score
arithmetic mean (standard deviation)
Week 24 (n = 16, 24, 16, 29)	-0.403 ( 1.008 )	-0.313 ( 0.444 )	-0.218 ( 0.501 )	-0.136 ( 0.637 )
Week 68 (n = 13, 23, 16, 28)	-0.421 ( 1.752 )	-0.334 ( 0.912 )	-0.272 ( 0.814 )	-0.263 ( 0.717 )
Week 104 (n = 13, 21, 15, 22)	-0.601 ( 1.612 )	-0.439 ( 0.917 )	-0.393 ( 0.764 )	-0.638 ( 0.791 )

Notes
[57] - Safety population: randomised population who had actually taken at least 1 dose/partial dose of IMP.
[58] - Analysis was performed on safety population.
[59] - Analysis was performed on safety population.
[60] - Analysis was performed on safety population.

No statistical analyses for this end point

Secondary: Number of Subjects With Tanner Staging at Baseline and Weeks 24, 68 and 104

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End point title

Number of Subjects With Tanner Staging at Baseline and Weeks 24, 68 and 104

End point description

Tanner stage defines physical measurements of development in children and adolescent based on external primary and secondary sex characteristics. Subjects were evaluated for pubic hair distribution, breast development (only females) and genital development (only males) and classified in 3 categories as: Prepubescent (defined as a person just before start of the development of adult sexual characteristics), Pubescent (defined as a person at or approaching the age of puberty), Postpubescent (sexually mature or a person who has completed puberty). Analysis was performed on safety population. Here, 'n' = subjects with available data for each specified category.

End point type

Secondary

End point timeframe

Baseline, Weeks 24, 68 and 104

End point values	Placebo/Alirocumab Q2W	Alirocumab Q2W	Placebo/Alirocumab Q4W	Alirocumab Q4W
Number of subjects analysed	25	49	27	52
Units: subjects
Baseline: Boys - Prepubescent (n=17, 19, 12, 18)	1	4	5	0
Baseline: Boys - Pubescent (n=17, 19, 12, 18)	13	13	4	14
Baseline: Boys - Postpubescent (n=17, 19, 12, 18)	3	2	3	4
Baseline: Girls - Prepubescent (n=8, 30, 15, 34)	1	4	1	7
Baseline: Girls - Pubescent (n=8, 30, 15, 34)	6	16	8	13
Baseline: Girls - Postpubescent (n=8, 30, 15, 34)	1	10	6	14
Week 24: Boys - Prepubescent (n=17, 17, 11, 17)	0	3	1	0
Week 24: Boys - Pubescent (n=17, 17, 11, 17)	13	11	7	12
Week 24: Boys - Postpubescent (n=17, 17, 11, 17)	4	3	3	5
Week 24: Girls - Prepubescent (n=8, 28, 12, 27)	1	4	1	2
Week 24: Girls - Pubescent (n=8, 28, 12, 27)	5	15	6	16
Week 24: Girls - Postpubescent (n=8, 28, 12, 27)	2	9	5	9
Week 68: Boys - Prepubescent (n=11, 16, 9, 15)	0	1	1	0
Week 68: Boys - Pubescent (n=11, 16, 9, 15)	7	9	5	9
Week 68: Boys - Postpubescent (n=11, 16, 9, 15)	4	6	3	6
Week 68: Girls - Prepubescent (n=7, 26, 11, 26)	0	3	1	1
Week 68: Girls - Pubescent (n=7, 26, 11, 26)	6	14	5	16
Week 68: Girls - Postpubescent (n=7, 26, 11, 26)	1	9	5	9
Week 104: Boys - Prepubescent (n=13, 15, 8, 15)	0	1	1	0
Week 104: Boys - Pubescent (n=13, 15, 8, 15)	6	8	5	8
Week 104: Boys - Postpubescent (n=13, 15, 8, 15)	7	6	2	7
Week 104: Girls - Prepubescent (n=6, 21, 11, 29)	0	0	1	1
Week 104: Girls - Pubescent (n=6, 21, 11, 29)	4	10	5	17
Week 104: Girls - Postpubescent (n=6, 21, 11, 29)	2	11	5	11

No statistical analyses for this end point

Secondary: DB Period: Number of Subjects With Treatment-Emergent (TE) Positive Anti-Alirocumab Antibodies (ADA) Response

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End point title

DB Period: Number of Subjects With Treatment-Emergent (TE) Positive Anti-Alirocumab Antibodies (ADA) Response

End point description

ADA samples: analysed using validated non-quantitative, titer-based bridging immunoassay. Number of subjects with positive (+ve) ADA during 24-week treatment period is reported. Treatment-emergent positive ADA response was defined as 1) subjects with no ADA +ve response at Baseline but with any +ve response in post-baseline period or 2) subjects with a +ve ADA response at Baseline and at least a 4- fold increase in titer in the post-baseline period. Persistent +ve response: TE ADA +ve response detected in at least 2 consecutive post-baseline samples separated by at least a 12-week period. Persistent +ve response was only analysed for subjects with +ve TE ADA response. ADA population: all randomised and treated (who actually received at least 1 dose/part of dose of IMP) subjects with available ADA sample at Baseline (Week 0) and at least 1 non-missing ADA sample post first IMP injection and up to Week 24.early termination. 'n'= subject with data and '9999' = no subjects were evaluable.

End point type

Secondary

End point timeframe

Up to 24 weeks

End point values	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W
Number of subjects analysed	25	48	26	49
Units: subjects
TE ADA positive response (n=25, 48, 26, 49)	0	3	0	0
Persistent positive response (n=0, 3, 0, 0)	9999	0	9999	9999

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

DB period: for subjects moved into OL period (OLP), from 1st DB dose up to day before 1st OL dose (till Week[W] 24) & for subjects did not begin OLP, from 1st DB dose up to W24+10 weeks (till W34); OLP: from 1st dose up to last dose+10 weeks (till W112)

Adverse event reporting additional description

Reported AEs were AEs which developed, worsened/became serious in each of the study periods, i.e. DB and OL, respectively.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

DB Period: Placebo Q2W

Reporting group description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q2W for 24 weeks in DB treatment period along with LMT.

Reporting group title

DB Period: Alirocumab Q2W

Reporting group description

Subjects received SC injection of alirocumab 40 mg (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W for 24 weeks in DB treatment period along with LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level >=110 mg/dL (2.85 mmol/L) at Week 8.

Reporting group title

DB Period: Placebo Q4W

Reporting group description

Subjects received SC injection of placebo (matched to alirocumab) based on their BW (<50 kg or >=50 kg) Q4W for 24 weeks in DB treatment period along with LMT.

Reporting group title

DB Period: Alirocumab Q4W

Reporting group description

Subjects received SC injection of alirocumab 150 mg (for BW <50 kg) or 300 mg (for BW >=50 kg) Q4W for 24 weeks in DB treatment period along with LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level >=110 mg/dL (2.85 mmol/L) at Week 8.

Reporting group title

OL Period: Placebo/Alirocumab Q2W

Reporting group description

Reporting group title

OL Period: Alirocumab Q2W

Reporting group description

Reporting group title

OL Period: Placebo/Alirocumab Q4W

Reporting group description

Reporting group title

OL Period: Alirocumab Q4W

Reporting group description

Serious adverse events	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W	OL Period: Placebo/Alirocumab Q2W	OL Period: Alirocumab Q2W	OL Period: Placebo/Alirocumab Q4W	OL Period: Alirocumab Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 25 (4.00%)	4 / 49 (8.16%)	1 / 27 (3.70%)	2 / 52 (3.85%)	0 / 25 (0.00%)	4 / 46 (8.70%)	2 / 25 (8.00%)	3 / 49 (6.12%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Injury, poisoning and procedural complications
Ligament Rupture
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	1 / 46 (2.17%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina Pectoris
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	2 / 52 (3.85%)	0 / 25 (0.00%)	0 / 46 (0.00%)	1 / 25 (4.00%)	1 / 49 (2.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	1 / 27 (3.70%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Hernia
subjects affected / exposed	0 / 25 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal Pain
subjects affected / exposed	0 / 25 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus Urinary
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	1 / 46 (2.17%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Major Depression
subjects affected / exposed	0 / 25 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Sympathetic Posterior Cervical Syndrome
subjects affected / exposed	0 / 25 (0.00%)	1 / 49 (2.04%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 25 (4.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	1 / 25 (4.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngitis Streptococcal
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	1 / 46 (2.17%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	1 / 46 (2.17%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	DB Period: Placebo Q2W	DB Period: Alirocumab Q2W	DB Period: Placebo Q4W	DB Period: Alirocumab Q4W	OL Period: Placebo/Alirocumab Q2W	OL Period: Alirocumab Q2W	OL Period: Placebo/Alirocumab Q4W	OL Period: Alirocumab Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 25 (36.00%)	15 / 49 (30.61%)	8 / 27 (29.63%)	10 / 52 (19.23%)	9 / 25 (36.00%)	12 / 46 (26.09%)	6 / 25 (24.00%)	15 / 49 (30.61%)
Investigations
Low Density Lipoprotein Decreased
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	2 / 25 (8.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	2 / 49 (4.08%)
occurrences all number	0	0	0	0	2	0	0	2
Nervous system disorders
Headache
subjects affected / exposed	2 / 25 (8.00%)	3 / 49 (6.12%)	1 / 27 (3.70%)	4 / 52 (7.69%)	1 / 25 (4.00%)	5 / 46 (10.87%)	4 / 25 (16.00%)	7 / 49 (14.29%)
occurrences all number	2	3	1	5	6	5	5	15
Migraine
subjects affected / exposed	2 / 25 (8.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	1 / 52 (1.92%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences all number	3	0	0	1	0	0	0	0
General disorders and administration site conditions
Injection Site Reaction
subjects affected / exposed	0 / 25 (0.00%)	3 / 49 (6.12%)	0 / 27 (0.00%)	2 / 52 (3.85%)	1 / 25 (4.00%)	3 / 46 (6.52%)	1 / 25 (4.00%)	1 / 49 (2.04%)
occurrences all number	0	12	0	3	2	17	2	1
Gastrointestinal disorders
Abdominal Pain Upper
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	2 / 27 (7.41%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0
Nausea
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	2 / 25 (8.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	1 / 49 (2.04%)
occurrences all number	0	0	0	0	2	0	0	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal Pain
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	4 / 46 (8.70%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences all number	0	0	0	0	0	4	0	0
Infections and infestations
Covid-19
subjects affected / exposed	0 / 25 (0.00%)	0 / 49 (0.00%)	0 / 27 (0.00%)	0 / 52 (0.00%)	0 / 25 (0.00%)	1 / 46 (2.17%)	1 / 25 (4.00%)	4 / 49 (8.16%)
occurrences all number	0	0	0	0	0	1	1	5
Nasopharyngitis
subjects affected / exposed	2 / 25 (8.00%)	7 / 49 (14.29%)	2 / 27 (7.41%)	1 / 52 (1.92%)	2 / 25 (8.00%)	3 / 46 (6.52%)	1 / 25 (4.00%)	3 / 49 (6.12%)
occurrences all number	2	7	2	4	2	5	2	5
Tonsillitis
subjects affected / exposed	1 / 25 (4.00%)	3 / 49 (6.12%)	1 / 27 (3.70%)	0 / 52 (0.00%)	0 / 25 (0.00%)	0 / 46 (0.00%)	0 / 25 (0.00%)	0 / 49 (0.00%)
occurrences all number	1	3	1	0	0	0	0	0
Upper Respiratory Tract Infection
subjects affected / exposed	3 / 25 (12.00%)	3 / 49 (6.12%)	3 / 27 (11.11%)	3 / 52 (5.77%)	2 / 25 (8.00%)	2 / 46 (4.35%)	0 / 25 (0.00%)	2 / 49 (4.08%)
occurrences all number	3	3	3	3	2	4	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

02 Jan 2019

The following changes were done: - Added Q4W efficacy evaluation in primary objectives. - Updated DB treatment period with dosing regimen of Q4W (alirocumab 150 mg and 300 mg; n~75 subjects) and number of enrolled subjects in Q2W dosing regimen would be administered study treatment (alirocumab 40 mg and 75 mg was changed to approximately half; n~75). - Description of Q4W dosing regimen and information on maintaining the blind was added for subjects in Q4W dosing regimen to indicate administration of alirocumab every 4 weeks during first 12 weeks and then after Week 12 administration of alirocumab Q4W alternating with placebo Q4W in order to maintain blind at time of possible dose-adjustment. - Dose-adjustment information at Week 24 and from Week 32 was added for subjects enrolled Q4W dosing regimen. - Added 1 mL of alirocumab 150 mg/mL solution for 150 mg dose. - Information of Q4W dose used added: alirocumab 150 mg Q4W for BW <50 kg and 300 mg Q4W for BW >=50 kg. - Revised statistical analysis: sample size determination and addition of alirocumab Q4W and placebo Q4W to treatment groups to be analysed. - Described sample size calculations and considerations for Q2W and Q4W dosing regimens. - Added duration of exposure description for Q4W dosing regimen. - Revised and described handling of multiplicity. - Graphical study design for Q4W dosing regimen was added as Flow chart. - Added clinical information of the additional cohort (Cohort 4) conducted with Q4W dosing regimen in the DFI14223 that support the evaluation of the Q4W dosing regimen in EFC14643 study. - Corrected Q2W dose-adjustment according to BW as per Investigator’s judgment. - Added information on fact that from total number of 150 subjects, half of those would enrolled in each dosing regimen. - Minor editorial revisions were done. - Clarified that all countries were allowed to perform monthly urine pregnancy tests, in keeping with clinical trial facilitation guidelines.

06 Jan 2021

The following changes were done: - Updated to clarify that Investigator was able to adjust dose of alirocumab, for increasing the efficacy or purpose of subject safety. - Revised in order to specify analysing each of two randomised dosing regimen cohorts separately (use of the contemporaneously randomised placebo group for each dosing regimen cohort (Q2W, Q4W) instead of combined placebo group). - Revised the comparisons and of statistical models (a separate model would be run for each dosing regimen cohort). - To be consistent with two-sided test with significance level of 2.5%, 97.5% CI would be computed instead of 95% CI for primary and secondary efficacy endpoints. - Revised treatment groups to be displayed in safety result summaries: by treatment groups within each dosing regimen cohort; and by treatment group regardless of dosing regimen cohorts (pooled across cohorts). - Added details to clarify two-step analysis process at the completion of double-blind treatment period and whole study, respectively. - Updated IRT listings. - Changed the description of process for the management of complementary source documents. - Update added for clarity of multiplicity. - Added the definition of the treatment period for the Q4W dosing regimen cohort. - Revised the treatment groups to be displayed in accordance with safety summaries. - Defined & clarified two-step analysis. - Included the possibility to perform remote monitoring in the context of regional or national emergency such as the current coronavirus disease (COVID-19) pandemic. - Added the dosing regimen cohort and treatment-by-dosing regimen cohort effects in the statistical model. - The use of the multiple imputations process was removed. - Added contingency measures for a regional or national emergency that can be declared by a governmental agency such as the current COVID-19 pandemic. - Minor grammatical & editorial revisions. - Added word “cohort” at relevant places.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Randomized, Double-Blind, Placebo-Controlled Study Followed by an Open Label Treatment Period to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous Familial Hypercholesterolemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Estimand

Primary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Estimand

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand

Secondary: DB Period: Percentage of Subjects Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Weeks 12, and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Weeks 12, and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein B at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Total Cholesterol at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 130 mg/dL (3.37 mmol/L) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 130 mg/dL (3.37 mmol/L) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 110 mg/dL (2.84 mmol/L) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved Low Density Lipoprotein Cholesterol < 110 mg/dL (2.84 mmol/L) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Lipoprotein (a) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Apolipoprotein A1 at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percent Change From Baseline in Fasting Triglycerides at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: ITT Estimand

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: ITT Estimand

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 30 Percent (%) Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 30 Percent (%) Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Achieved at Least 30% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Achieved at Least 30% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

Secondary: DB Period: Percentage of Subjects Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand

Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled Study Followed by an Open Label Treatment Period to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous Familial Hypercholesterolemia