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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
42
Pharmaceutical form: solution Route of administration: subcutaneous injection
Pharmaceutical form: tablet Route of administration: oral
Pharmaceutical form:tablet Route of administration: oral
Pharmaceutical form:tablet Route of administration: oral
Pharmaceutical form: tablet Route of administration: oral
Pharmaceutical form: tablet Route of administration: oral
Pharmaceutical form: tablet Route of administration: oral
Investigational Site Number 8400002
St Louis, Missouri, United States
Investigational Site Number 8400005
Charlotte, North Carolina, United States
Investigational Site Number 8400001
Cincinnati, Ohio, United States
Investigational Site Number 1240001
Québec, Canada
Investigational Site Number 2030001
Brno, Czechia
Investigational Site Number 2030003
Praha 5 - Motol, Czechia
Investigational Site Number 2030002
Zlín, Czechia
Investigational Site Number 2500001
Bron, France
Investigational Site Number 5280001
Amsterdam, Netherlands
Investigational Site Number 5780001
Oslo, Norway
...and 6 more locations
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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Calculated Low Density Lipoprotein Cholesterol (LDL-C) at 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.
Time frame: Baseline, Week 8
Percentage of Participants Achieving Calculated Low Density Lipoprotein Cholesterol (LDL-C) <130 mg/dL (3.37 mmol/L) 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.
Time frame: At Week 8
Percentage of Participants Achieving Calculated LDL-C <110 mg/dL (2.84 mmol/L) 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.
Time frame: At Week 8
Percent Change From Baseline in Calculated LDL-C at Week 12: Cohort 4
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.
Time frame: Baseline, Week 12
Percent Change From Baseline in Apolipoprotein (Apo) B at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Non-High Density Lipoprotein (HDL-C) at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Total Cholesterol (Total-C) at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Lipoprotein(a) at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Fasting Triglyceride at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at 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.
Time frame: Baseline, Week 8
Percent Change From Baseline in Apolipoprotein A-1 at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Apolipoprotein B at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Non-High-Density Lipoprotein (Non-HDL-C) at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Total Cholesterol (Total-C) at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Lipoprotein(a) at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in HDL-C at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Fasting Triglyceride at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Apolipoprotein A-1 at 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.
Time frame: Baseline, Week 8
Absolute Change From Baseline in Ratio Apolipoprotein B/Apolipoprotein A-1 at 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.
Time frame: Baseline, Week 8
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