An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03510715
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 18
• Locations: 10
• Arm: 1
• Actual Duration (Months): 17.6
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Primary Objective:

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

Secondary Objectives:

• To evaluate the efficacy of alirocumab after 24 and 48 weeks of treatment on LDL-C levels.

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

• To evaluate the safety and tolerability of alirocumab up to 48 weeks of treatment.

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia	Drug: Alirocumab SAR236553 (REGN727); Drug: Atorvastatin; Drug: Simvastatin; Drug: Fluvastatin; Drug: Pravastatin; Drug: Lovastatin; Drug: Rosuvastatin; Drug: Ezetimibe; Drug: Cholestyramine; Drug: Nicotinic acid; Drug: Fenofibrate; Drug: Omega-3 fatty acids	Phase 3

Detailed Description

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia
• Actual Study Start Date: Aug 31, 2018
• Actual Primary Completion Date: Feb 17, 2020
• Actual Study Completion Date: Feb 17, 2020

Arms and Interventions

Arm

Intervention/Treatment

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

Drug: Alirocumab SAR236553 (REGN727); Pharmaceutical form: solution for injection in pre-filled syringe, Route of administration: subcutaneous (SC); Drug: Atorvastatin; Pharmaceutical form: tablet, Route of administration: oral; Drug: Simvastatin; Pharmaceutical form: tablet, Route of administration: oral; Drug: Fluvastatin; Pharmaceutical form: capsule, Route of administration: oral; Drug: Pravastatin; Pharmaceutical form: tablet, Route of administration: oral; Drug: Lovastatin; Pharmaceutical form: tablet, Route of administration: oral; Drug: Rosuvastatin; Pharmaceutical form: tablet, Route of administration: oral; Drug: Ezetimibe; Pharmaceutical form: tablet, Route of administration: oral; Drug: Cholestyramine; Pharmaceutical form: oral suspension, Route of administration: oral; Drug: Nicotinic acid; Pharmaceutical form: tablet, Route of administration: oral; Drug: Fenofibrate; Pharmaceutical form: tablet, Route of administration: oral; Drug: Omega-3 fatty acids; Pharmaceutical form: capsule, Route of administration: oral

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis [Baseline to Week 12]

   Adjusted least square (LS) means and standard errors were obtained from the mixed model analysis with repeated measures (MMRM) to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis).

Secondary Outcome Measures

1. Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12: On-treatment Analysis [Baseline to Week 12]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline on-treatment data from Week 4 to Week 48 (on-treatment Analysis).

2. Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Weeks 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

3. Percent Change From Baseline in Apolipoprotein (Apo) B at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

4. Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 12, 24 and 48 - ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

5. Percent Change From Baseline in Total Cholesterol (Total-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

6. Percent Change From Baseline in Lipoprotein a (Lp) (a) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on-or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

7. Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

8. Percent Change From Baseline in Fasting Triglycerides (TG) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

9. Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

   Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

10. Percentage of Participants Reporting >=15 Percent (%) Reduction in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

    Adjusted Percentage were obtained from a multiple imputation approach for handling of missing data including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

11. Absolute Change From Baseline in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis [Baseline to Weeks 12, 24 and 48]

    Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.

12. Number of Participants With Tanner Staging at Baseline, Weeks 12, 24 and 48 [Baseline, Weeks 12, 24 and 48]

    Tanner stage defines physical measurements of development in children and adolescent based on external primary and secondary sex characteristics. Participants 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria :

• Participants genetically diagnosed with hoFH.

• Participants treated with optimal dose of statin +/- other lipid modifying therapies (LMTs), or non-statin LMTs if statin-intolerant at stable dose(s) for at least 4 weeks.

• A signed informed consent indicating parental permission with or without participants assent.

• For participants on apheresis, currently undergoing stable LDL apheresis therapy prior to the screening visit (Week -2) and had initiated apheresis treatment for at least 6 months.

Exclusion criteria:

• Participants with LDL-C <130 milligram per deciliter [mg/dL] (3.37 millimoles per liter [mmol/L]) obtained during the screening period after the participant had been on stable apheresis procedure or LMT (i.e., stable optimal dose of statin ± other stable LMTs, or stable non statin LMTs in statin-intolerant participants) treatment for at least 4 weeks.

• Participants with BW <25 kg.

• Participants aged 8 to 9 years not at Tanner Stage 1 and participants aged of 10 to 17 years not at least at Tanner Stage 2 in their development.

• Participants with uncontrolled Type 1 or 2 diabetes mellitus.

• Participants with known uncontrolled thyroid disease.

• Participants with uncontrolled hypertension.

• Participants who will receive statin de novo during the run-in period.

• Fasting triglycerides greater than (>) 350 mg/dL (3.95 mmol/L) at the screening visit.

• Severe renal impairment (i.e., estimated glomerular filtration rate <30 milliliter per minute/1.73 meter square) at the screening visit.

• Alanine aminotransferase or aspartate aminotransferase >2 * upper limit of normal (ULN) at the screening visit.

• Creatine phosphokinase >3 * ULN at the screening visit.

The above information was not intended to contain all considerations relevant to a participants potential participation in a clinical trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 0760001	Sao Paulo		Brazil	05403-000
2	Investigational Site Number 1240001	Quebec		Canada	G1V 4W2
3	Investigational Site Number 2080001	Viborg		Denmark	8800
4	Investigational Site Number 4840006	Oaxaca		Mexico	68000
5	Investigational Site Number 5280001	Amsterdam		Netherlands	1105AZ
6	Investigational Site Number 6430002	Kemerovo		Russian Federation	650002
7	Investigational Site Number 7050001	Ljubljana		Slovenia	1000
8	Investigational Site Number 7240001	A Coruna		Spain	15001
9	Investigational Site Number 1580001	Taipei		Taiwan	112
10	Investigational Site Number 7920001	Izmir		Turkey	35040

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

• Study Protocol - Sep 11, 2018
• Statistical Analysis Plan - Jan 27, 2020

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03510715
• Other Study ID Numbers: EFC14660; 2017-002297-39; U1111-1200-2046
• First Posted: Apr 27, 2018
• Last Update Posted: Dec 29, 2020
• Last Verified: Oct 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sanofi: Pediatrics, Homozygous Familial Hypercholesterolemia, Alirocumab, PCSK9 inhibitor, Low-density Lipoprotein Cholesterol (LDL-C)
• Additional relevant MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia; Nicotinic Acids; Niacin; Niacinamide; Atorvastatin; Rosuvastatin Calcium; Simvastatin; Ezetimibe; Pravastatin; Lovastatin; Cholestyramine Resin; Fenofibrate

Study Results

Participant Flow

Recruitment Details	The study was conducted at 10 active centers (which screened at least 1 participant) in 10 countries worldwide. Overall, 20 participants were screened between 31 August 2018 and 4 January 2019, of whom 2 were screen failures. Of the 10 centers which screened participants, 9 centers enrolled at least 1 participant.
Pre-assignment Detail	A total of 18 participants were enrolled and received treatment in this study.

Arm/Group Title	Alirocumab 75 mg Q2W/up to 150 mg Q2W	Alirocumab 150 mg Q2W
Arm/Group Description	Participants with body weight (BW) less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 75 milligrams (mg) every 2 weeks (Q2W) for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW greater than or equal to [>=] 50 kg.	Participants with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.
Period Title: Overall Study
STARTED	9	9
COMPLETED	8	9
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Alirocumab 75 mg Q2W/up to 150 mg Q2W	Alirocumab 150 mg Q2W	Total
Arm/Group Description	Participants with BW <50 kg received SC injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW >=50 kg.	Participants with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.	Total of all reporting groups
Overall Participants	9	9	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.4 (1.5)	14.3 (2.4)	12.4 (2.8)
Sex: Female, Male (Count of Participants)
Female	4 44.4%	5 55.6%	9 50%
Male	5 55.6%	4 44.4%	9 50%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 22.2%	1 11.1%	3 16.7%
Asian	1 11.1%	2 22.2%	3 16.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 11.1%	1 5.6%
White	6 66.7%	5 55.6%	11 61.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Low-Density Lipoprotein Cholesterol (LDL-C) (milligrams per deciliter (mg/dL)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter (mg/dL)]	437.7 (192.8)	308.3 (181.6)	373.0 (193.5)

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12: Intent-to-Treat (ITT) Analysis
Description	Adjusted least square (LS) means and standard errors were obtained from the mixed model analysis with repeated measures (MMRM) to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population which included all enrolled participants who had received at least one dose or partial dose of alirocumab. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e. for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Least Squares Mean (Standard Error) [percent change]	-4.1 (9.0)

2. Secondary Outcome

Title	Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Week 12: On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline on-treatment data from Week 4 to Week 48 (on-treatment Analysis).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e. for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Least Squares Mean (Standard Error) [percent change]	-4.1 (9.0)

3. Secondary Outcome

Title	Percent Change From Baseline in Low-Density Lipoprotein Cholesterol at Weeks 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 24	-10.1 (7.6)
Week 48	4.2 (12.8)

4. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein (Apo) B at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	-4.2 (6.8)
Week 24	-11.8 (6.1)
Week 48	0.9 (10.4)

5. Secondary Outcome

Title	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Weeks 12, 24 and 48 - ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	-3.9 (8.3)
Week 24	-9.2 (7.3)
Week 48	5.7 (13.1)

6. Secondary Outcome

Title	Percent Change From Baseline in Total Cholesterol (Total-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	-1.9 (7.2)
Week 24	-6.3 (6.5)
Week 48	5.5 (10.7)

7. Secondary Outcome

Title	Percent Change From Baseline in Lipoprotein a (Lp) (a) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
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 from Week 4 to Week 48 regardless of status on-or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	7.4 (7.6)
Week 24	-5.2 (8.1)
Week 48	-6.4 (12.2)

8. Secondary Outcome

Title	Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Weeks 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	13.0 (5.9)
Week 24	8.9 (4.4)
Week 48	10.1 (5.5)

9. Secondary Outcome

Title	Percent Change From Baseline in Fasting Triglycerides (TG) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
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 from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	2.8 (8.0)
Week 24	5.2 (16.2)
Week 48	10.0 (8.2)

10. Secondary Outcome

Title	Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data was planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	11.3 (6.9)
Week 24	14.6 (6.0)
Week 48	11.3 (5.8)

11. Secondary Outcome

Title	Percentage of Participants Reporting >=15 Percent (%) Reduction in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted Percentage were obtained from a multiple imputation approach for handling of missing data including all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	50.0 555.6%
Week 24	50.0 555.6%
Week 48	39.0 433.3%

12. Secondary Outcome

Title	Absolute Change From Baseline in LDL-C Level at Weeks 12, 24 and 48: ITT Analysis/On-treatment Analysis
Description	Adjusted LS means and standard errors were obtained from the MMRM model to account for missing data using all available post-baseline data from Week 4 to Week 48 regardless of status on- or off-treatment used in the model (ITT analysis). Although separate analyses of all available data (ITT analysis) and only data collected within a defined time window (On-treatment analysis) were planned, if all values used in the ITT approach were within the on-treatment time window, the on-treatment analysis would be identical to the ITT analysis, thus the results would be identical and a single outcome measure presenting the results for both types of analysis would be provided.
Time Frame	Baseline to Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. As pre-specified, efficacy analysis data were planned to be collected and analyzed for all doses combined (i.e., for combined population).

Arm/Group Title	Alirocumab
Arm/Group Description	All participants who received either 75 mg (BW <50 kg) or 150 mg (BW >=50 kg) alirocumab subcutaneously Q2W for 48 weeks.
Measure Participants	18
Week 12	-33.4 (19.1)
Week 24	-43.0 (19.0)
Week 48	-15.0 (25.7)

13. Secondary Outcome

Title	Number of Participants With Tanner Staging at Baseline, Weeks 12, 24 and 48
Description	Tanner stage defines physical measurements of development in children and adolescent based on external primary and secondary sex characteristics. Participants 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).
Time Frame	Baseline, Weeks 12, 24 and 48

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety population which included participants who had received at least one dose or partial dose of alirocumab. Here, 'number analyzed' = participants with available data for each specified category.

Arm/Group Title	Alirocumab 75 mg Q2W/up to 150 mg Q2W	Alirocumab 150 mg Q2W
Arm/Group Description	Participants with BW <50 kg received SC injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW >=50 kg.	Participants with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.
Measure Participants	9	9
Baseline: Prepubescent	3 33.3%	0 0%
Baseline: Pubescent	6 66.7%	9 100%
Baseline: Post-pubescent	0 0%	0 0%
Week 12: Prepubescent	3 33.3%	0 0%
Week 12: Pubescent	6 66.7%	8 88.9%
Week 12: Post-pubescent	0 0%	1 11.1%
Week 24: Prepubescent	2 22.2%	0 0%
Week 24: Pubescent	6 66.7%	8 88.9%
Week 24: Post-pubescent	0 0%	1 11.1%
Week 48: Prepubescent	1 11.1%	0 0%
Week 48: Pubescent	7 77.8%	7 77.8%
Week 48: Post-pubescent	0 0%	2 22.2%

Adverse Events

Time Frame	All Adverse Events (AEs) were collected from signature of the informed consent form up to 56 weeks of the study regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description	Reported AEs and death were treatment-emergent AEs (TEAE) that developed/worsened, and death that occurred during TEAE period (the time from the first dose of alirocumab up to the last dose of alirocumab + 70 days [10 weeks]). Analysis was performed on safety population.
Arm/Group Title	Alirocumab 75 mg Q2W/up to 150 mg Q2W		Alirocumab 150 mg Q2W
Arm/Group Description	Participants with BW <50 kg received SC injection of alirocumab 75 mg Q2W for 48 weeks. Alirocumab dose was up-titrated to 150 mg Q2W from Week 12 in case of increase in BW with BW >=50 kg.		Participants with BW >=50 kg received SC injection of alirocumab 150 mg Q2W for 48 weeks.
All Cause Mortality
	Alirocumab 75 mg Q2W/up to 150 mg Q2W		Alirocumab 150 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		0/9 (0%)
Serious Adverse Events
	Alirocumab 75 mg Q2W/up to 150 mg Q2W		Alirocumab 150 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		0/9 (0%)
Cardiac disorders
Cardiac Failure	1/9 (11.1%)	1	0/9 (0%)	0
Other (Not Including Serious) Adverse Events
	Alirocumab 75 mg Q2W/up to 150 mg Q2W		Alirocumab 150 mg Q2W
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/9 (88.9%)		9/9 (100%)
Blood and lymphatic system disorders
Splenomegaly	1/9 (11.1%)	1	0/9 (0%)	0
Cardiac disorders
Aortic Valve Incompetence	2/9 (22.2%)	2	1/9 (11.1%)	1
Congenital, familial and genetic disorders
Bicuspid Aortic Valve	0/9 (0%)	0	1/9 (11.1%)	1
Gastrointestinal disorders
Diarrhoea	0/9 (0%)	0	1/9 (11.1%)	1
Nausea	1/9 (11.1%)	1	0/9 (0%)	0
Vomiting	1/9 (11.1%)	1	0/9 (0%)	0
General disorders
Fatigue	1/9 (11.1%)	1	0/9 (0%)	0
Influenza Like Illness	1/9 (11.1%)	1	0/9 (0%)	0
Injection Site Pain	1/9 (11.1%)	1	0/9 (0%)	0
Injection Site Reaction	0/9 (0%)	0	1/9 (11.1%)	1
Pyrexia	0/9 (0%)	0	1/9 (11.1%)	1
Hepatobiliary disorders
Hepatomegaly	1/9 (11.1%)	1	0/9 (0%)	0
Infections and infestations
Gastroenteritis	1/9 (11.1%)	1	0/9 (0%)	0
Influenza	2/9 (22.2%)	2	0/9 (0%)	0
Nasopharyngitis	1/9 (11.1%)	1	2/9 (22.2%)	2
Parvovirus B19 Infection	1/9 (11.1%)	1	0/9 (0%)	0
Pharyngotonsillitis	1/9 (11.1%)	1	0/9 (0%)	0
Upper Respiratory Tract Infection	1/9 (11.1%)	1	0/9 (0%)	0
Urinary Tract Infection	1/9 (11.1%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Thermal Burn	0/9 (0%)	0	1/9 (11.1%)	1
Investigations
Alanine Aminotransferase Increased	0/9 (0%)	0	1/9 (11.1%)	1
Metabolism and nutrition disorders
Hypertriglyceridaemia	1/9 (11.1%)	1	0/9 (0%)	0
Musculoskeletal and connective tissue disorders
Pain In Extremity	0/9 (0%)	0	1/9 (11.1%)	1
Tendon Pain	0/9 (0%)	0	1/9 (11.1%)	1
Tendonitis	0/9 (0%)	0	1/9 (11.1%)	1
Nervous system disorders
Headache	2/9 (22.2%)	4	1/9 (11.1%)	2
Respiratory, thoracic and mediastinal disorders
Cough	1/9 (11.1%)	2	1/9 (11.1%)	1
Dyspnoea	0/9 (0%)	0	1/9 (11.1%)	1
Dyspnoea Paroxysmal Nocturnal	1/9 (11.1%)	1	0/9 (0%)	0
Epistaxis	0/9 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Dry Skin	0/9 (0%)	0	1/9 (11.1%)	1
Rash	0/9 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.