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

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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

Tracking Information
First Submitted Date  ICMJE April 18, 2018
First Posted Date  ICMJE April 27, 2018
Results First Submitted Date  ICMJE December 2, 2020
Results First Posted Date  ICMJE December 29, 2020
Last Update Posted Date December 29, 2020
Actual Study Start Date  ICMJE August 31, 2018
Actual Primary Completion Date February 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 2, 2020)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: April 18, 2018)
Percent change in LDL-C [ Time Frame: From baseline to Week 12 ]
Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Week 12, using all LDL-C values (pre-apheresis, if applicable) regardless of adherence to treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2020)
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: April 18, 2018)
  • Percent change in LDL-C [ Time Frame: From baseline to Week 12 ]
    Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Week 12, using all LDL-C values during the treatment period.
  • Percent change in LDL-C [ Time Frame: From baseline to Weeks 24 and 48 ]
    Percent change in LDL-C (pre-apheresis, if applicable) from baseline to Week 24 and to Week 48.
  • Percent change in Apo B [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in apolipoprotein B (Apo B) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in non-HDL-C [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in non-high density lipoprotein cholesterol (non-HDL-C) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in total-C [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in total cholesterol (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in Lp(a) [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in lipoprotein (a) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in HDL-C [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in high-density lipoprotein cholesterol (HDL-C) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in fasting Triglycerides (TG) [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in fasting triglycerides (TG) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Percent change in Apo A-1 [ Time Frame: From baseline to Week 12, to Week 24, and to Week 48 ]
    Percent change in apolipoprotein A1 (Apo A-1) (pre-apheresis, if applicable) from baseline to Week 12, to Week 24, and to Week 48.
  • Proportion of patients with ≥15% reduction in LDL-C [ Time Frame: From baseline to Weeks 12, 24 and 48 ]
    Proportion of patients with ≥15% reduction in LDL-C (pre-apheresis, if applicable) at Weeks 12, 24, and 48.
  • Absolute change in LDL-C [ Time Frame: From baseline to Weeks 12, 24 and 48 ]
    Absolute change in LDL-C from baseline to Weeks 12, 24, and 48
  • Number of patients with adverse events [ Time Frame: Up to Week 62 ]
    Number of patients with adverse events
  • Tanner stage [ Time Frame: At Weeks 24, 24, and 48 ]
    The Tanner stage will be measured to assess stages of pubertal development
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Efficacy and Safety Study of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia
Official Title  ICMJE An Open-Label Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hypercholesterolemia
Intervention  ICMJE
  • 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

Study Arms  ICMJE 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.

Interventions:
  • 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 18, 2018)
18
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 17, 2020
Actual Primary Completion Date February 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Canada,   Denmark,   Mexico,   Netherlands,   Russian Federation,   Slovenia,   Spain,   Taiwan,   Turkey
Removed Location Countries Austria,   France,   Italy,   Norway,   United States
 
Administrative Information
NCT Number  ICMJE NCT03510715
Other Study ID Numbers  ICMJE EFC14660
2017-002297-39 ( EudraCT Number )
U1111-1200-2046 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP