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Completed

NCT Number: NCT02890992

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

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.

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Key information

Conditions

Hypercholesterolaemia Dyslipidemias Hypercholesterolemia Hyperlipidemias Lipid Metabolism Disorders Metabolic Diseases Nutritional and Metabolic Diseases

Age range

8 year–17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Investigational Site Number 1240001, Québec, Canada

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About this study

For Cohorts 1 to 3, a study duration of approximately 16-23 weeks (screening period: up to 6 (+1) weeks, open-label dose finding treatment period: 8 weeks, follow up period: 6-8 weeks).

For Cohort 4, a study duration of approximately 14-19 weeks (screening period up to 6 [+1] weeks, open-label dose finding treatment period: 12 weeks).

Optional extension period: up to a maximum of 2 years for the first participants enrolled in Cohorts 1 to 3, but a maximum of approximately 5 months for the first participants enrolled in Cohort 4.

For all participants who declined participation in the phase 3 study, their last alirocumab injection was on December 2018.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.

Exclusion criteria

  • 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.

Treatment and study plan

alirocumab SAR236553 (REGN727)

Drug

Pharmaceutical form: solution Route of administration: subcutaneous injection

Other names: Praluent

Statins

Drug

Pharmaceutical form: tablet Route of administration: oral

ezetimibe

Drug

Pharmaceutical form:tablet Route of administration: oral

Cholestyramine

Drug

Pharmaceutical form:tablet Route of administration: oral

fenofibrate

Drug

Pharmaceutical form: tablet Route of administration: oral

Omega-3 Fatty acids

Drug

Pharmaceutical form: tablet Route of administration: oral

Nicotinic acid

Drug

Pharmaceutical form: tablet Route of administration: oral

Primary outcomes

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

    Time frame: Baseline, 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.

Secondary outcomes

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

    Time frame: Baseline, Week 8

    Absolute change in LDL-C was calculated by subtracting baseline value from Week 8 value. Adjusted LS means and SE were obtained using MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction.

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

    Time frame: At Week 8

    Combined estimate for percentage of participants was obtained by averaging out all the imputed percentage of participants reaching the level of interest. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively; with number of imputations = 1000. In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

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

    Time frame: At Week 8

    Combined estimate for percentage of participants was obtained by averaging out all the imputed percentage of participants reaching the level of interest. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively; with number of imputations = 1000. In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

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

    Time frame: Baseline, Week 12

    Adjusted LS means and standard error at Week 12 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction.

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

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline value and post-baseline values in at least one of the analysis windows used in the model.

  6. Percent Change From Baseline in Non-High Density Lipoprotein (HDL-C) at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baselines value and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  7. Percent Change From Baseline in Total Cholesterol (Total-C) at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  8. Percent Change From Baseline in Lipoprotein(a) at Week 8

    Time frame: Baseline, Week 8

    Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population in the two steps respectively (with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

  9. Percent Change From Baseline in Fasting Triglyceride at Week 8

    Time frame: Baseline, Week 8

    Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

  10. Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  11. Percent Change From Baseline in Apolipoprotein A-1 at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  12. Absolute Change From Baseline in Apolipoprotein B at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  13. Absolute Change From Baseline in Non-High-Density Lipoprotein (Non-HDL-C) at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  14. Absolute Change From Baseline in Total Cholesterol (Total-C) at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  15. Absolute Change From Baseline in Lipoprotein(a) at Week 8

    Time frame: Baseline, Week 8

    Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

  16. Absolute Change From Baseline in HDL-C at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  17. Absolute Change From Baseline in Fasting Triglyceride at Week 8

    Time frame: Baseline, Week 8

    Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets. The robust regression models included the fixed categorical effect of alirocumab dose/dose regimen. A two-step multiple imputation procedure was used to address missing values in the mITT population (in the two steps respectively; with number of imputations = 1000). In the first step, the monotone missing pattern was induced in the multiply-imputed data. In the second step, the missing data at subsequent visits were imputed using the regression method for continuous variables.

  18. Absolute Change From Baseline in Apolipoprotein A-1 at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

  19. Absolute Change From Baseline in Ratio Apolipoprotein B/Apolipoprotein A-1 at Week 8

    Time frame: Baseline, Week 8

    Adjusted LS means and SE at Week 8 were obtained from MMRM analysis, with fixed categorical effects of alirocumab dose/dose regimen, time point and dose/dose regimen-by-time point interaction. All available baseline values and post-baseline values in at least one of the analysis windows up to Week 8 were used in the model.

Sponsors and collaborators

Lead sponsor

Sanofi

Industry

Collaborators

  • Regeneron Pharmaceuticals

Registry information

Official study title

An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents With Heterozygous Familial Hypercholesterolemia Followed by an Extension Phase

Acronym: ODYSSEY KIDS

Important dates

Study start
2016
Primary completion
2018
Study completion
2019
First posted
Sep 7, 2016
Registry last updated
Sep 6, 2019

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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