An 8-Week Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia

NCT02890992 | Completed Phase 2 Results DMC

• 3 other identifiers: DFI142232015-003766-85U1111-1178-4764
• Study Type: interventional
• Target: 42
• Locations: 10 countries
• Sites: 16

Brief Summary

Primary Objective: To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 8 weeks of treatment in heterozygous familial hypercholesterolemia (heFH) participants aged of 8 to 17 years, with LDL-C \>=130 milligrams per deciliter (mg/dL) (3.37 millimoles per litre \[mmol/L\]) 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 for at least 4 weeks prior to the screening period. Secondary Objective:

• To evaluate the safety and tolerability of alirocumab.
• To evaluate the pharmacokinetics profile of alirocumab.
• To evaluate the effects of alirocumab on other lipid parameters.

Conditions

Hypercholesterolaemia

Outcome Measures

Primary Outcomes (1)

• Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 8

  Percent change in calculated LDL-C was defined as 100\*(calculated LDL-C value at Week 8 - calculated LDL-C value at baseline)/calculated LDL-C value at baseline. All available baseline and post-baseline calculated LDL-C value during the OLDFI efficacy treatment period \& within one of the analysis windows up to Week 8 were used in the model. OLDFI efficacy treatment period was defined as the period from first investigational medicinal product (IMP) injection to last OLDFI IMP injection + 21 days(for Cohorts 1 \& 2) or +35 days (for Cohorts 3 \& 4). Adjusted Least-squares (LS) mean \& standard error (SE) at Week 8 were obtained from mixed-effect model with repeated measures (MMRM) analysis, with fixed categorical effects of alirocumab dose/dose regimen (30 mg Q2W \[\<50 kg\], 40 mg Q2W \[\<50 kg\], 50 mg Q2W \[\>=50 kg\], 75 mg Q2W \[\>=50 kg\], 75 mg Q4W \[\<50 kg\],150 mg Q4W \[\>=50 kg\], 150 mg Q4W \[\<50 kg\] and 300 mg Q4W (\[\>=50 kg\] dose), time point \& dose/dose regimen-by-time point interaction.

  Baseline, Week 8

Secondary Outcomes (19)

• Absolute Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at Week 8

  Baseline, Week 8

• Percentage of Participants Achieving Calculated Low Density Lipoprotein Cholesterol (LDL-C) <130 mg/dL (3.37 mmol/L) at Week 8

  At Week 8

• Percentage of Participants Achieving Calculated LDL-C <110 mg/dL (2.84 mmol/L) at Week 8

  At Week 8

• Percent Change From Baseline in Calculated LDL-C at Week 12: Cohort 4

  Baseline, Week 12

• Percent Change From Baseline in Apolipoprotein (Apo) B at Week 8

  Baseline, Week 8

Study Arms (8)

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg

EXPERIMENTAL

Period 1: Participants with body weight less than (\<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 30 milligram(mg) administered every 2 weeks (Q2W) up to 8 weeks added to lipid modifying therapy (LMT). Period 2: Participants with body weight \< 50 kg received SC injection of alirocumab 30 mg administered Q2W from Week 16 until they started receiving dose matching to Cohort 2 dosage including dose adjustment to body weight as required. Cohort 2 dosage was: if body weight was still \< 50 kg, participants received SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was \> = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg

EXPERIMENTAL

Period 1: Participants with body weight greater than or equal to (\>=) 50 kg received SC injection of alirocumab 50 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight \>= 50 kg received SC injection of alirocumab 50 mg administered Q2W from Week 16 until switch to Cohort 2 dosage then SC injection of alirocumab 75 mg administered Q2W until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 2 - Alirocumab 40 mg Q2W: <50 kg

EXPERIMENTAL

Period 1: Participants with body weight \< 50 kg received SC injection of alirocumab 40 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight \< 50 kg received SC injection of alirocumab 40 mg administered Q2W from Week 16 until switch of dosage in Cohorts 1 and 3. If body weight was still \< 50 kg, participants continued to receive SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was \> = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg

EXPERIMENTAL

Period 1: Participants with body weight \>= 50 kg received SC injection of alirocumab 75 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight \>= 50 kg received SC injection of alirocumab 75 mg administered Q2W from Week 16 until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 3 - Alirocumab 75 mg Q4W: <50 kg

EXPERIMENTAL

Period 1: Participants with body weight \< 50 kg received SC injection of alirocumab 75 mg administered every 4 weeks (Q4W) up to 8 weeks added to LMT. Period 2: Participants with body weight \< 50 kg received SC injection of alirocumab 75 mg administered Q4W from Week 14 until switch to Cohort 2 dosage including dose adjustment to body weight as required, then Cohort 2 dosage: if body weight was still \< 50 kg, participants received SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was \> = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg

EXPERIMENTAL

Period 1: Participants with body weight \>= 50 kg received SC injection of alirocumab 150 mg administered Q4W up to Week 8 added to LMT. Period 2: Participants with body weight \>= 50 kg received SC injection of alirocumab 150 mg administered Q4W from Week 14 until switch to Cohort 2 dosage then SC injection of alirocumab 75 mg administered Q2W until Week 130.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 4 - Alirocumab 150 mg Q4W: <50 kg

EXPERIMENTAL

Period 1: Participants with body weight \< 50 kg received SC injection of alirocumab 150 mg administered Q4W up to 12 weeks added to LMT. Period 2: Participants with body weight \< 50 kg received SC injection of Alirocumab 150 mg administered Q4W from Week 12 until Week 48.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

EXPERIMENTAL

Period 1: Participants with body weight \>= 50 kg received SC injection of alirocumab 300 mg administered Q4W up to 12 weeks added to LMT. Period 2: Participants with body weight \>= 50 kg received SC injection of alirocumab 300 mg administered Q4W from Week 12 until Week 48.

Drug: alirocumab SAR236553 (REGN727); Drug: statins; Drug: ezetimibe; Drug: cholestyramine; Drug: fenofibrate; Drug: omega-3 fatty acids; Drug: nicotinic acid

Interventions

alirocumab SAR236553 (REGN727) DRUG

Pharmaceutical form: solution Route of administration: subcutaneous injection

Also known as: Praluent

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

statins DRUG

Pharmaceutical form: tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

ezetimibe DRUG

Pharmaceutical form:tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

cholestyramine DRUG

Pharmaceutical form:tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

fenofibrate DRUG

Pharmaceutical form: tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

omega-3 fatty acids DRUG

Pharmaceutical form: tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

nicotinic acid DRUG

Pharmaceutical form: tablet Route of administration: oral

Cohort 1 - Alirocumab 30 mg Q2W: <50 kg; Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg; Cohort 2 - Alirocumab 40 mg Q2W: <50 kg; Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg; Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg; Cohort 3 - Alirocumab 75 mg Q4W: <50 kg; Cohort 4 - Alirocumab 150 mg Q4W: <50 kg; Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg

Eligibility Criteria

• Age: 8 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children and adolescent male and female participants aged of 8 to 17 years at the time of signed informed consent. For Russia only: Male and female participants aged \>=12 and \<=17 years at the time of signed informed consent.
• Participants with diagnosis of heterozygous familial hypercholesterolemia (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.
• Participants with body weight greater than or equal to 25 kg.
• Participants aged of 8 to 9 years to be at Tanner stage 1 and participants aged of 10 to 17 years to be at least at Tanner stage 2 in their development.
• A signed informed consent indicating parental permission with or without participant assent.

You may not qualify if:

• Participant 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.
• Known history of type 1 or type 2 diabetes mellitus.
• Known history of thyroid disease.
• Known history of hypertension.
• Fasting triglycerides \>350 mg/dL (3.95 mmol/L).
• Severe renal impairment (i.e., 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 participant's potential participation in a clinical trial.

Sponsors & Collaborators

• Sanofi: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (16)

Investigational Site Number 8400002

St Louis, Missouri, 63110, United States

Location

Investigational Site Number 8400005

Charlotte, North Carolina, 28204, United States

Location

Investigational Site Number 8400001

Cincinnati, Ohio, 45229, United States

Location

Investigational Site Number 1240001

Québec, G1V 4W2, Canada

Location

Investigational Site Number 2030001

Brno, 62500, Czechia

Location

Investigational Site Number 2030003

Praha 5 - Motol, 15006, Czechia

Location

Investigational Site Number 2030002

Zlín, 76275, Czechia

Location

Investigational Site Number 2500001

Bron, 69677, France

Location

Investigational Site Number 5280001

Amsterdam, 1105AZ, Netherlands

Location

Investigational Site Number 5780001

Oslo, Norway

Location

Investigational Site Number 6430001

Kemerovo, 650002, Russia

Location

Investigational Site Number 6430004

Saint Petersburg, 194100, Russia

Location

Investigational Site Number 7100001

Parow, 7500, South Africa

Location

Investigational Site Number 7240004

A Coruña, 15001, Spain

Location

Investigational Site Number 7240001

Madrid, 28009, Spain

Location

Investigational Site Number 7520001

Stockholm, 171 76, Sweden

Location

Related Publications (1)

• Daniels S, Caprio S, Chaudhari U, Manvelian G, Baccara-Dinet MT, Brunet A, Scemama M, Loizeau V, Bruckert E. PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study. J Clin Lipidol. 2020 May-Jun;14(3):322-330.e5. doi: 10.1016/j.jacl.2020.03.001. Epub 2020 Mar 28.

  PMID: 32331936 DERIVED

MeSH Terms

Conditions

Hypercholesterolemia

Interventions

alirocumab; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe; Cholestyramine Resin; Fenofibrate; Fatty Acids, Omega-3; Niacin

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Polystyrenes; Plastics; Polymers; Macromolecular Substances; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Fibric Acids; Isobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Phenyl Ethers; Ethers; Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Phenols; Ketones; Dietary Fats, Unsaturated; Dietary Fats; Fats; Lipids; Fatty Acids, Unsaturated; Fatty Acids; Fish Oils; Oils; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 31, 2016
• First Posted: September 7, 2016
• Study Start: September 15, 2016
• Primary Completion: September 13, 2018
• Study Completion: February 22, 2019
• Last Updated: September 6, 2019
• Results First Posted: September 6, 2019

Record last verified: 2019-08

Locations

CA (1); RU (2); FR (1); SE (1); NO (1); NL (1); ZA (1); US (3); CZ (3); ES (2)