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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

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.

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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

Resource links provided by the National Library of Medicine

Drug Information available for: Alirocumab

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





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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03510715


Locations
Layout table for location information
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
Layout table for investigator information
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

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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    Key Record Dates
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

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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:
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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