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

• ClinicalTrials.gov Identifier: NCT03510715
• Recruitment Status: Completed
• First Posted: April 27, 2018
• Results First Posted: December 29, 2020
• Last Update Posted: December 29, 2020
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

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 (Clinical Trial)
• 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: August 31, 2018
• Actual Primary Completion Date: February 17, 2020
• Actual Study Completion Date: February 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

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

Criteria

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

Brazil

Investigational Site Number 0760001

Sao Paulo, Brazil, 05403-000

Canada

Investigational Site Number 1240001

Quebec, Canada, G1V 4W2

Denmark

Investigational Site Number 2080001

Viborg, Denmark, 8800

Mexico

Investigational Site Number 4840006

Oaxaca, Mexico, 68000

Netherlands

Investigational Site Number 5280001

Amsterdam, Netherlands, 1105AZ

Russian Federation

Investigational Site Number 6430002

Kemerovo, Russian Federation, 650002

Slovenia

Investigational Site Number 7050001

Ljubljana, Slovenia, 1000

Spain

Investigational Site Number 7240001

A Coruna, Spain, 15001

Taiwan

Investigational Site Number 1580001

Taipei, Taiwan, 112

Turkey

Investigational Site Number 7920001

Izmir, Turkey, 35040

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] September 11, 2018

Statistical Analysis Plan  [PDF] January 27, 2020

More Information

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03510715
• Other Study ID Numbers: EFC14660; 2017-002297-39 ( EudraCT Number ); U1111-1200-2046 ( Other Identifier: UTN )
• First Posted: April 27, 2018
• Results First Posted: December 29, 2020
• Last Update Posted: December 29, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• 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; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Hyperlipoproteinemias; Nicotinic Acids; Niacin; Niacinamide; Atorvastatin; Rosuvastatin Calcium; Simvastatin; Ezetimibe; Pravastatin; Lovastatin; Cholestyramine Resin; Fenofibrate; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Vitamin B Complex; Vitamins