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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Hypercholesterolaemia

Intervention / Treatment
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* Drug: alirocumab SAR236553 (REGN727)
* Drug: statins
* Drug: ezetimibe
* Drug: cholestyramine
* Drug: fenofibrate
* Drug: omega-3 fatty acids
* Drug: nicotinic acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Alirocumab 30 mg Q2W: <50 kg<br>Period 1: Participants with body weight less than (<) 50 kilograms (kg) received subcutaneous (SC) injection of alirocumab 30 milligram(mg) administered every 2 weeks (Q2W) up to 8 weeks added to lipid modifying therapy (LMT). Period 2: Participants with body weight < 50 kg received SC injection of alirocumab 30 mg administered Q2W from Week 16 until they started receiving dose matching to Cohort 2 dosage including dose adjustment to body weight as required. Cohort 2 dosage was: if body weight was still < 50 kg, participants received SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was > = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 1 - Alirocumab 50 mg Q2W: >=50 kg<br>Period 1: Participants with body weight greater than or equal to (>=) 50 kg received SC injection of alirocumab 50 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight >= 50 kg received SC injection of alirocumab 50 mg administered Q2W from Week 16 until switch to Cohort 2 dosage then SC injection of alirocumab 75 mg administered Q2W until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 2 - Alirocumab 40 mg Q2W: <50 kg<br>Period 1: Participants with body weight < 50 kg received SC injection of alirocumab 40 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight < 50 kg received SC injection of alirocumab 40 mg administered Q2W from Week 16 until switch of dosage in Cohorts 1 and 3. If body weight was still < 50 kg, participants continued to receive SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was > = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 2 - Alirocumab 75 mg Q2W: >=50 kg<br>Period 1: Participants with body weight >= 50 kg received SC injection of alirocumab 75 mg administered Q2W up to 8 weeks added to LMT. Period 2: Participants with body weight >= 50 kg received SC injection of alirocumab 75 mg administered Q2W from Week 16 until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 3 - Alirocumab 75 mg Q4W: <50 kg<br>Period 1: Participants with body weight < 50 kg received SC injection of alirocumab 75 mg administered every 4 weeks (Q4W) up to 8 weeks added to LMT. Period 2: Participants with body weight < 50 kg received SC injection of alirocumab 75 mg administered Q4W from Week 14 until switch to Cohort 2 dosage including dose adjustment to body weight as required, then Cohort 2 dosage: if body weight was still < 50 kg, participants received SC injection of alirocumab 40 mg administered Q2W until Week 130; if body weight was > = 50 kg participants received SC injection of alirocumab 75 mg administered Q2W until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 3 - Alirocumab 150 mg Q4W: >=50 kg<br>Period 1: Participants with body weight >= 50 kg received SC injection of alirocumab 150 mg administered Q4W up to Week 8 added to LMT. Period 2: Participants with body weight >= 50 kg received SC injection of alirocumab 150 mg administered Q4W from Week 14 until switch to Cohort 2 dosage then SC injection of alirocumab 75 mg administered Q2W until Week 130. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 4 - Alirocumab 150 mg Q4W: <50 kg<br>Period 1: Participants with body weight < 50 kg received SC injection of alirocumab 150 mg administered Q4W up to 12 weeks added to LMT. Period 2: Participants with body weight < 50 kg received SC injection of Alirocumab 150 mg administered Q4W from Week 12 until Week 48. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|
| Experimental: Cohort 4 - Alirocumab 300 mg Q4W: >=50 kg<br>Period 1: Participants with body weight >= 50 kg received SC injection of alirocumab 300 mg administered Q4W up to 12 weeks added to LMT. Period 2: Participants with body weight >= 50 kg received SC injection of alirocumab 300 mg administered Q4W from Week 12 until Week 48. | Drug: alirocumab SAR236553 (REGN727)<br>* Pharmaceutical form: solution Route of administration: subcutaneous injection<br>* Other names: Praluent;Drug: statins<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: ezetimibe<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: cholestyramine<br>* Pharmaceutical form:tablet Route of administration: oral<br>Drug: fenofibrate<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: omega-3 fatty acids<br>* Pharmaceutical form: tablet Route of administration: oral<br>Drug: nicotinic acid<br>* Pharmaceutical form: tablet Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Baseline, Week 8 |