Back to results

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

Primary Purpose

Hypercholesterolaemia

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Alirocumab SAR236553 (REGN727)

Rosuvastatin

Atorvastatin

Simvastatin

Pravastatin

Lovastatin

Fluvastatin

Ezetimibe

Cholestyramine

Nicotinic acid

Fenofibrate

Omega-3 fatty acids

Placebo

About this trial

This is an interventional treatment trial for Hypercholesterolaemia

Eligibility Criteria

8 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Children and adolescent male and female Patients aged 8 to 17 years at the time of signed informed consent.
Patients with diagnosis of heterozygous familial hypercholesterolemia (heFH) through genotyping or clinical criteria.
Patients treated with optimal dose of statin +/- other LMT(s) or non-statin LMT(s) if statin intolerant at stable dose for at least 4 weeks prior to screening lipid sampling.
Patients with calculated LDL-C greater than or equal to 130 mg/dL (≥3.37 mmol/L) at the screening visit except for Patients who have previously participated in the DFI14223 study.
A signed informed consent indicating parental permission with or without patient assent.

Exclusion criteria:

Patient with body weight less than 25 kilograms.
Patients aged of 8 to 9 years not at Tanner stage 1 and patients aged of 10 to 17 years not at least at Tanner stage 2 in their development.
Patients with secondary hyperlipidemia.
Diagnosis of homozygous familial hypercholesterolemia.
Patient who has received lipid apheresis treatment within 2 months prior to the screening period, or has plans to receive it during the study.
Patients with uncontrolled type 1 or type 2 diabetes mellitus.
Patients with known uncontrolled thyroid disease.
Patients with uncontrolled hypertension.
Fasting triglycerides >350 mg/dL (3.95 mmol/L).
Severe renal impairment (ie, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m^2.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN).
Creatinine phosphokinase (CPK) >3 x ULN.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Sites / Locations

Excel Medical Clinical Trials, LLC-Site Number:8400001
Washington University School of Medicine-Site Number:8400006
Presbyterian Novant Heart & Wellness-Site Number:8400002
Cincinnati Children's Hospital Medical Center-Site Number:8400005
Vanderbilt University-Site Number:8400003
Investigational Site Number :0320001
Investigational Site Number :0400001
Investigational Site Number :0760004
Investigational Site Number :0760001
Investigational Site Number :1000002
Investigational Site Number :1240001
Investigational Site Number :2030002
Investigational Site Number :2030001
Investigational Site Number :2080001
Investigational Site Number :2460001
Investigational Site Number :2500001
Investigational Site Number :2500002
Investigational Site Number :3480001
Investigational Site Number :3800003
Investigational Site Number :3800001
Investigational Site Number :3800002
Investigational Site Number :4220001
Investigational Site Number :4220003
Investigational Site Number :4840008
Investigational Site Number :4840007
Investigational Site Number :5280001
Investigational Site Number :5780001
Investigational Site Number :6160002
Investigational Site Number :6160001
Investigational Site Number :6430006
Investigational Site Number :6430001
Investigational Site Number :6430004
Investigational Site Number :6430002
Investigational Site Number :7050001
Investigational Site Number :7100002
Investigational Site Number :7240003
Investigational Site Number :7240002
Investigational Site Number :7240004
Investigational Site Number :7240001
Investigational Site Number :7520001
Investigational Site Number :1580001
Investigational Site Number :7920002
Investigational Site Number :7920001

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

Placebo/Alirocumab Q2W

Alirocumab Q2W

Placebo/Alirocumab Q4W

Alirocumab Q4W

Arm Description

Participants received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their body weight (BW) (less than [<] 50 kilograms [kg] or greater than or equal to [>=] 50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 40 milligrams (mg) (for BW <50 kg) or 75 mg (for BW >=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from <50 kg to >=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW <50 kg) or 75 mg to 150 mg (for BW >=50 kg) or down titrated as 75 mg to 40 mg (for BW <50 kg) or 150 mg to 75 mg (for BW >=50 kg).

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

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

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

Outcomes

Primary Outcome Measures

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

Secondary Outcome Measures

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

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

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

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

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

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

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

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.

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

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.

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

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.

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

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 participants who discontinued treatment due to the coronavirus disease-2019 pandemic. Other post-treatment missing values were considered as failure.

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

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.

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

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.

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

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

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

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

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

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.

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

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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.

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

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

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.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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

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 participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

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

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

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

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

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

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.

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

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.

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

Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.

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

Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.

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

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 participant's age at Baseline and Weeks 24, 68 and 104. Composite score: calculated as 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 = an improvement in cognition, i.e., a better outcome; and negative change in z-score = worsening in cognition, i.e., a worse outcome.

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

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).

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

Anti-drug (alirocumab) antibodies samples were analyzed using a validated non-quantitative, titer-based bridging immunoassay. Number of participants with positive ADA during 24-week treatment period is reported. Treatment-emergent positive ADA response was defined as 1) participants with no ADA positive response at baseline but with any positive response in the post-baseline period or 2) participants with a positive ADA response at baseline and at least a 4- fold increase in titer in the post-baseline period. A persistent positive response was defined as a TE ADA positive response detected in at least 2 consecutive post-baseline samples separated by at least a 12-week period. Persistent positive response was only analyzed for participants with positive TE ADA response.

Full Information

NCT ID

NCT03510884

First Posted

April 18, 2018

Last Updated

April 12, 2023

Sponsor

Sanofi

Collaborators

Regeneron Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03510884

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Completed

Study Start Date

May 31, 2018 (Actual)

Primary Completion Date

January 14, 2021 (Actual)

Study Completion Date

August 5, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sanofi

Collaborators

Regeneron Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Primary Objective: To evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) and every 4 weeks (Q4W) versus placebo after 24 weeks of double-blind (DB) treatment on low-density lipoprotein cholesterol (LDL-C) levels in participants with heterozygous familial hypercholesterolemia (heFH) 8 to 17 years of age on optimal stable daily dose of statin therapy ± other lipid modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of intolerance to statins. Secondary Objectives: To evaluate the efficacy of alirocumab versus placebo on LDL-C levels. To evaluate the effects of alirocumab versus placebo on other lipid parameters. To evaluate the safety and tolerability of alirocumab in comparison with placebo. To evaluate the efficacy, safety, and tolerability of alirocumab after open label treatment. To evaluate the development of anti-alirocumab antibodies.

Detailed Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypercholesterolaemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

153 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo/Alirocumab Q2W

Arm Type

Experimental

Arm Description

Arm Title

Alirocumab Q2W

Arm Type

Experimental

Arm Description

Arm Title

Placebo/Alirocumab Q4W

Arm Type

Experimental

Arm Description

Arm Title

Alirocumab Q4W

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Alirocumab SAR236553 (REGN727)

Other Intervention Name(s)

Praluent

Intervention Description

Pharmaceutical form:solution Route of administration: subcutaneous injection

Intervention Type

Drug

Intervention Name(s)

Rosuvastatin

Intervention Description

Pharmaceutical form:tablet Route of administration: oral

Intervention Type

Drug

Intervention Name(s)

Atorvastatin

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Simvastatin

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Pravastatin

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Lovastatin

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Fluvastatin

Intervention Description

Pharmaceutical form:Capsule Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Ezetimibe

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Cholestyramine

Intervention Description

Pharmaceutical form:oral suspension Route of administration: oral

Intervention Type

Drug

Intervention Name(s)

Nicotinic acid

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Fenofibrate

Intervention Description

Pharmaceutical form:Tablet Route of administration: Oral

Intervention Type

Drug

Intervention Name(s)

Omega-3 fatty acids

Intervention Description

Pharmaceutical form:capsule Route of administration: oral

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Pharmaceutical form:solution Route of administration: subcutaneous injection

Primary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Week 24

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

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.

Time Frame

At Week 24

Title

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

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.

Time Frame

At Week 12

Title

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

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.

Time Frame

At Week 24

Title

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

Description

Time Frame

At Week 12

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

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.

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 24

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

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.

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Week 12

Title

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

Description

Time Frame

Baseline, Weeks 12, and 24

Title

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

Time Frame

Baseline, Weeks 12 and 24

Title

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

Time Frame

Baseline, Weeks 12 and 24

Title

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

Time Frame

Baseline, Weeks 12 and 24

Title

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

Description

Time Frame

Weeks 12 and 24

Title

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

Description

Time Frame

Weeks 12 and 24

Title

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

Description

Time Frame

Baseline, Weeks 12 and 24

Title

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

Description

Time Frame

Baseline, Weeks 12 and 24

Title

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

Time Frame

Baseline, Weeks 12, and 24

Title

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

Description

Time Frame

Baseline, Weeks 12, and 24

Title

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

Description

Time Frame

Baseline, Weeks 12, and 24

Title

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

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 participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.

Time Frame

Baseline, Weeks 12, and 24

Title

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

Description

Time Frame

At Weeks 12 and 24

Title

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

Description

Time Frame

At Weeks 12 and 24

Title

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

Description

Time Frame

At Weeks 12 and 24

Title

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

Description

Time Frame

At Weeks 12 and 24

Title

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

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.

Time Frame

Baseline to Weeks 8, 12 and 24

Title

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

Description

Time Frame

Baseline to Weeks 8, 12 and 24

Title

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

Description

Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.

Time Frame

Baseline, Week 104

Title

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

Description

Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.

Time Frame

Baseline, Week 104

Title

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

Description

Time Frame

Baseline, Weeks 24, 68 and 104

Title

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

Description

Time Frame

Baseline, Weeks 24, 68 and 104

Title

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

Description

Time Frame

Up to 24 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

8 Years

Maximum Age & Unit of Time

17 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: Children and adolescent male and female participants 8 to 17 years of age at the time of signed informed consent. Participants with diagnosis of heFH through genotyping or clinical criteria. Participants treated with optimal dose of statin +/- other LMT(s) or non-statin LMT(s) if statin intolerant at stable dose for at least 4 weeks prior to screening lipid sampling. Participants with calculated LDL-C greater than or equal to 130 mg/dL (>=3.37 mmol/L) at the screening visit except for participants who have previously participated in the DFI14223 (NCT02890992) study. A signed informed consent indicating parental permission with or without participant assent. Exclusion criteria: Participant with body weight < 25 kg. Participants aged of 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 secondary hyperlipidemia. Diagnosis of homozygous familial hypercholesterolemia. Participant who had received lipid apheresis treatment within 2 months prior to the screening period, or has plans to receive it during the study. Participants with uncontrolled type 1 or type 2 diabetes mellitus. Participants with known uncontrolled thyroid disease. Participants with uncontrolled hypertension. Fasting triglycerides greater than (>) 350 mg/dL (3.95 mmol/L). Severe renal impairment (ie, estimated glomerular filtration rate <30 mL/min/1.73 m^2). Alanine aminotransferase or aspartate aminotransferase >2*upper limit of normal (ULN). Creatinine phosphokinase (CPK) >3*ULN. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clinical Sciences & Operations

Organizational Affiliation

Sanofi

Official's Role

Study Director

Facility Information:

Facility Name

Excel Medical Clinical Trials, LLC-Site Number:8400001

City

Boca Raton

State/Province

Florida

ZIP/Postal Code

33434

Country

United States

Facility Name

Washington University School of Medicine-Site Number:8400006

City

Saint Louis

State/Province

Missouri

ZIP/Postal Code

63110

Country

United States

Facility Name

Presbyterian Novant Heart & Wellness-Site Number:8400002

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28204

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center-Site Number:8400005

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Vanderbilt University-Site Number:8400003

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Investigational Site Number :0320001

City

Buenos Aires

ZIP/Postal Code

C1245AAM

Country

Argentina

Facility Name

Investigational Site Number :0400001

City

Wien

ZIP/Postal Code

1090

Country

Austria

Facility Name

Investigational Site Number :0760004

City

Porto Alegre

State/Province

Rio Grande Do Sul

ZIP/Postal Code

91350-200

Country

Brazil

Facility Name

Investigational Site Number :0760001

City

Sao Paulo

ZIP/Postal Code

05403-900

Country

Brazil

Facility Name

Investigational Site Number :1000002

City

Plovdiv

ZIP/Postal Code

4002

Country

Bulgaria

Facility Name

Investigational Site Number :1240001

City

Quebec

ZIP/Postal Code

G1V 4W2

Country

Canada

Facility Name

Investigational Site Number :2030002

City

Brno

ZIP/Postal Code

62500

Country

Czechia

Facility Name

Investigational Site Number :2030001

City

Praha 5 - Motol

ZIP/Postal Code

15006

Country

Czechia

Facility Name

Investigational Site Number :2080001

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

Facility Name

Investigational Site Number :2460001

City

HUS

ZIP/Postal Code

00029

Country

Finland

Facility Name

Investigational Site Number :2500001

City

Bron

ZIP/Postal Code

69500

Country

France

Facility Name

Investigational Site Number :2500002

City

Nantes

ZIP/Postal Code

44093

Country

France

Facility Name

Investigational Site Number :3480001

City

Budapest

ZIP/Postal Code

1094

Country

Hungary

Facility Name

Investigational Site Number :3800003

City

Milano

ZIP/Postal Code

20142

Country

Italy

Facility Name

Investigational Site Number :3800001

City

Palermo

ZIP/Postal Code

90127

Country

Italy

Facility Name

Investigational Site Number :3800002

City

Roma

Country

Italy

Facility Name

Investigational Site Number :4220001

City

Beirut

Country

Lebanon

Facility Name

Investigational Site Number :4220003

City

Room Hospital Street, Achrafie

ZIP/Postal Code

00000

Country

Lebanon

Facility Name

Investigational Site Number :4840008

City

Guadalajara

State/Province

Jalisco

ZIP/Postal Code

44100

Country

Mexico

Facility Name

Investigational Site Number :4840007

City

Oaxaca

ZIP/Postal Code

68000

Country

Mexico

Facility Name

Investigational Site Number :5280001

City

Amsterdam

ZIP/Postal Code

1105AZ

Country

Netherlands

Facility Name

Investigational Site Number :5780001

City

Oslo

Country

Norway

Facility Name

Investigational Site Number :6160002

City

Gdansk

State/Province

Pomorskie

Country

Poland

Facility Name

Investigational Site Number :6160001

City

Lodz

ZIP/Postal Code

93-338

Country

Poland

Facility Name

Investigational Site Number :6430006

City

Kazan

ZIP/Postal Code

420138

Country

Russian Federation

Facility Name

Investigational Site Number :6430001

City

Kemerovo

ZIP/Postal Code

650002

Country

Russian Federation

Facility Name

Investigational Site Number :6430004

City

Moscow

ZIP/Postal Code

115446

Country

Russian Federation

Facility Name

Investigational Site Number :6430002

City

Ufa

ZIP/Postal Code

450083

Country

Russian Federation

Facility Name

Investigational Site Number :7050001

City

Ljubljana

ZIP/Postal Code

1000

Country

Slovenia

Facility Name

Investigational Site Number :7100002

City

Parow

ZIP/Postal Code

7500

Country

South Africa

Facility Name

Investigational Site Number :7240003

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

Facility Name

Investigational Site Number :7240002

City

A Coruña

ZIP/Postal Code

15001

Country

Spain

Facility Name

Investigational Site Number :7240004

City

Badalona

ZIP/Postal Code

08916

Country

Spain

Facility Name

Investigational Site Number :7240001

City

Barcelona

ZIP/Postal Code

08208

Country

Spain

Facility Name

Investigational Site Number :7520001

City

Stockholm

ZIP/Postal Code

171 76

Country

Sweden

Facility Name

Investigational Site Number :1580001

City

Taipei

ZIP/Postal Code

112

Country

Taiwan

Facility Name

Investigational Site Number :7920002

City

Ankara

ZIP/Postal Code

06500

Country

Turkey

Facility Name

Investigational Site Number :7920001

City

Izmir

ZIP/Postal Code

35040

Country

Turkey

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

We'll reach out to this number within 24 hrs