A Phase 3 interventional study of Alirocumab SAR236553 (REGN727) and Rosuvastatin in Hypercholesterolaemia, sponsored by Sanofi. Completed at 43 sites in 24 countries. Open to participants aged 8 Years to 17 Years. Per ClinicalTrials.gov, last updated 2023-05-06.
Sponsored by Sanofi · Phase 3, Interventional, and Treatment
Primary Objective:
To evaluate the efficacy of alirocumab administered every 2 weeks (Q2W) and every 4 weeks (Q4W) versus placebo after 24 weeks of double-blind (DB) treatment on low-density lipoprotein cholesterol (LDL-C) levels in participants with heterozygous familial hypercholesterolemia (heFH) 8 to 17 years of age 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.
Secondary Objectives:
The study duration was approximately up to 110 weeks (run-in period [if needed]: up to 4 weeks [+2 days], screening period: up to 2 weeks [+5 days], double-blind treatment period: 24 weeks, open label (OL) treatment period: 80 weeks).
245 studies on the registry are indexed under Hyperlipoproteinemia Type II; 52 are open to participants now.
This study's enrollment of 153 is above the median of 86 across 170 interventional studies indexed under Hyperlipoproteinemia Type II.
Browse Hyperlipoproteinemia Type II studies →Sanofi is the lead sponsor of 1,508 studies on the registry; 90 are open to participants now.
Of its 198 completed or terminated interventional studies of FDA-regulated products, 118 (60%) have results posted.
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Exclusion criteria:
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Participants received subcutaneous (SC) injection of placebo (matched to alirocumab) based on their body weight (BW) (less than \[\<\] 50 kilograms \[kg\] or greater than or equal to \[\>=\] 50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 40 milligrams (mg) (for BW \<50 kg) or 75 mg (for BW \>=50 kg) Q2W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW \<50 kg) or 75 mg to 150 mg (for BW \>=50 kg) or down titrated as 75 mg to 40 mg (for BW \<50 kg) or 150 mg to 75 mg (for BW \>=50 kg).
Drug: Alirocumab SAR236553 (REGN727) · Drug: Rosuvastatin · Drug: Atorvastatin · Drug: Simvastatin · Drug: Pravastatin · Drug: Lovastatin · Drug: Fluvastatin · Drug: Ezetimibe · Drug: Cholestyramine · Drug: Nicotinic acid · Drug: Fenofibrate · Drug: Omega-3 fatty acids · Drug: Placebo
Participants received SC injection of alirocumab 40 mg (for BW \<50 kg) or 75 mg (for BW \>=50 kg) Q2W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level was \>=110 milligrams per deciliter (mg/dL) (2.85 millimoles per liter \[mmol/L\]) at Week 8. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 40 mg (for BW \<50 kg) or 75 mg (for BW \>=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 40 mg to 75 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 40 mg to 75 mg (for BW \<50 kg) or 75 mg to 150 mg (for BW \>=50 kg) or down titrated as 75 mg to 40 mg (for BW \<50 kg) or 150 mg to 75 mg (for BW \>=50 kg).
Drug: Alirocumab SAR236553 (REGN727) · Drug: Rosuvastatin · Drug: Atorvastatin · Drug: Simvastatin · Drug: Pravastatin · Drug: Lovastatin · Drug: Fluvastatin · Drug: Ezetimibe · Drug: Cholestyramine · Drug: Nicotinic acid · Drug: Fenofibrate · Drug: Omega-3 fatty acids
Participants received SC injection of placebo (matched to alirocumab) based on their BW (\<50 kg or \>=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) Q4W from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW \<50 kg) or 300 mg Q4W to 150 mg Q2W (for BW \>=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW \<50 kg) or 150 mg Q2W to 75 mg Q2W (for BW \>=50 kg).
Drug: Alirocumab SAR236553 (REGN727) · Drug: Rosuvastatin · Drug: Atorvastatin · Drug: Simvastatin · Drug: Pravastatin · Drug: Lovastatin · Drug: Fluvastatin · Drug: Ezetimibe · Drug: Cholestyramine · Drug: Nicotinic acid · Drug: Fenofibrate · Drug: Omega-3 fatty acids · Drug: Placebo
Participants received SC injection of alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) Q4W for 24 weeks in DB treatment period added to stable LMT. Alirocumab dose was up-titrated to 75 mg or 150 mg Q2W from Week 12, when LDL-C level \>=110 mg/dL (2.85 mmol/L) at Week 8. After completion of DB treatment period, eligible participants entered into OL treatment period and received alirocumab 150 mg (for BW \<50 kg) or 300 mg (for BW \>=50 kg) from Week 24 up to an additional 80 weeks (i.e., up to Week 104) added to stable LMT. After Week 24, dose up-titrated from 150 mg to 300 mg when BW increased from \<50 kg to \>=50 kg. From Week 32 up to Week 104, based on participant LDL-C value, alirocumab dose was either up-titrated as 150 mg Q4W to 75 mg Q2W (for BW \<50 kg) or 300 mg Q4W to 150 mg Q2W (for BW \>=50 kg) or down titrated as 75 mg Q2W to 40 mg Q2W (for BW \<50 kg) or 150 mg Q2W to 75 mg Q2W (for BW \>=50 kg).
Drug: Alirocumab SAR236553 (REGN727) · Drug: Rosuvastatin · Drug: Atorvastatin · Drug: Simvastatin · Drug: Pravastatin · Drug: Lovastatin · Drug: Fluvastatin · Drug: Ezetimibe · Drug: Cholestyramine · Drug: Nicotinic acid · Drug: Fenofibrate · Drug: Omega-3 fatty acids
Pharmaceutical form:solution Route of administration: subcutaneous injection
Also known as: Praluent
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:Capsule Route of administration: Oral
Pharmaceutical form:Tablet Route of administration: Oral
Pharmaceutical form:oral suspension Route of administration: oral
Pharmaceutical form:Tablet Route of administration: Oral
Pharmaceutical form:Tablet Route of administration: Oral
Pharmaceutical form:capsule Route of administration: oral
Pharmaceutical form:solution Route of administration: subcutaneous injection
DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 24: Intent-to-treat (ITT) Estimand
Adjusted least square (LS) means and standard errors (SE) were obtained from mixed-effect model with repeated measures (MMRM) model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand
Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 24 were included in the imputation model.
Time frame: At Week 24
DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand
Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 12 were included in the imputation model.
Time frame: At Week 12
DB Period: Percentage of Participants Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand
Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 24 were included in the imputation model.
Time frame: At Week 24
DB Period: Percentage of Participants Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand
Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data for Q4W. All available post-baseline data up to Week 12 were included in the imputation model. For Q2W, adjusted percentages at Week 12 were obtained from last observation carried forward approach (LOCF) to handle missing on-treatment LDL-C values as well as missing post-treatment LDL-C values in participants who discontinued treatment due to the coronavirus disease-2019 pandemic. Other post-treatment missing values were considered as failure.
Time frame: At Week 12
DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 24
DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Week 12
DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Weeks 12, and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st investigational medicinal product (IMP) injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12, and 24
DB Period: Percent Change From Baseline in Apolipoprotein B at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12 and 24
DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12 and 24
DB Period: Percent Change From Baseline in Total Cholesterol at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12 and 24
DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol < 130 mg/dL (3.37 mmol/L) at Weeks 12 and 24: On-treatment Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
Time frame: Weeks 12 and 24
DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol < 110 mg/dL (2.84 mmol/L) at Weeks 12 and 24: On-treatment Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
Time frame: Weeks 12 and 24
DB Period: Percent Change From Baseline in Lipoprotein (a) at Weeks 12 and 24: On-treatment Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline on-treatment data up to Week 12 and Week 24, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Weeks 12 and 24
DB Period: Percent Change From Baseline in Apolipoprotein A1 at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM mode, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12 and 24
DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 day otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12, and 24
DB Period: Percent Change From Baseline in Fasting Triglycerides at Weeks 12 and 24: On-treatment Estimand
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline on-treatment data up to Week 12 and Week 24, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
Time frame: Baseline, Weeks 12, and 24
DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 and Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
Time frame: Baseline, Weeks 12, and 24
DB Period: Absolute Change From Baseline in Apo B/Apo A-1 Ratio at Weeks 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
Time frame: Baseline, Weeks 12, and 24
DB Period: Percentage of Participants Who Achieved at Least 30 Percent (%) Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model.
Time frame: At Weeks 12 and 24
DB Period: Percentage of Participants Achieved at Least 30% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
Time frame: At Weeks 12 and 24
DB Period: Percentage of Participants Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: ITT Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model.
Time frame: At Weeks 12 and 24
DB Period: Percentage of Participants Who Achieved at Least 50% Reduction in Low Density Lipoprotein Cholesterol Level From Baseline at Weeks 12 and 24: On-treatment Estimand
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
Time frame: At Weeks 12 and 24
DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: ITT Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 8, Week 12 and Week 24 were used and missing data were accounted for by the MMRM model.
Time frame: Baseline to Weeks 8, 12 and 24
DB Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Weeks 8, 12 and 24: On-treatment Estimand
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 8, Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
Time frame: Baseline to Weeks 8, 12 and 24
OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: ITT Estimand
Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.
Time frame: Baseline, Week 104
OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: On-treatment Estimand
Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.
Time frame: Baseline, Week 104
Change From Baseline in Cogstate Battery Test - Overall Composite Score at Weeks 24, 68 and 104
Cogstate battery test (cognitive testing system) consisted of detection test (DET), identification test (IDN), one card learning test (OCL) and Groton maze learning test (GML) to assess processing speed, attention, visual learning and executive functioning, respectively. For each test, Z-scores were computed based on participant's age at Baseline and Weeks 24, 68 and 104. Composite score: calculated as mean of Z-scores equally weighted, provided that at least 3 of 4 tests were available and if all of these domains were covered as: attention, through either DET or IDN, visual learning, through OCL and executive function, through GML. There is not minimum/maximum since values were reported as z-score but z-score of 0 means result equals to mean with negative numbers indicating values lower than mean and positive values higher. Positive change in z-score = an improvement in cognition, i.e., a better outcome; and negative change in z-score = worsening in cognition, i.e., a worse outcome.
Time frame: Baseline, Weeks 24, 68 and 104
Number of Participants With Tanner Staging at Baseline and Weeks 24, 68 and 104
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).
Time frame: Baseline, Weeks 24, 68 and 104
DB Period: Number of Participants With Treatment-Emergent (TE) Positive Anti-Alirocumab Antibodies (ADA) Response
Anti-drug (alirocumab) antibodies samples were analyzed using a validated non-quantitative, titer-based bridging immunoassay. Number of participants with positive ADA during 24-week treatment period is reported. Treatment-emergent positive ADA response was defined as 1) participants with no ADA positive response at baseline but with any positive response in the post-baseline period or 2) participants with a positive ADA response at baseline and at least a 4- fold increase in titer in the post-baseline period. A persistent positive response was defined as a TE ADA positive response detected in at least 2 consecutive post-baseline samples separated by at least a 12-week period. Persistent positive response was only analyzed for participants with positive TE ADA response.
Time frame: Up to 24 weeks
Study was conducted at 43 active sites in 24 countries. A total of 203 participants were screened between 31-May-2018 and 31-Jul-2020, of whom 50 were screen failures. Screen failures were mainly due to exclusion criteria met. A total of 153 participants were randomized with a 2:1 ratio to receive study treatment (alirocumab: placebo).
| Milestone | Placebo/Alirocumab Q2W | Alirocumab Q2W | Placebo/Alirocumab Q4W | Alirocumab Q4W |
|---|---|---|---|---|
| Started | 25 | 49 | 27 | 52 |
| Completed | 25 | 45 | 26 | 49 |
| Not completed | 0 | 4 | 1 | 3 |
| Withdrew: Adverse event | 0 | 0 | 0 | 2 |
| Withdrew: Participant moved | 0 | 1 | 0 | 0 |
| Withdrew: Life events made continuing too difficult | 0 | 1 | 0 | 0 |
| Withdrew: Participant non-compliance to investigational medicinal product (imp) | 0 | 2 | 0 | 0 |
| Withdrew: Other than specified above | 0 | 0 | 1 | 1 |
| Milestone | Placebo/Alirocumab Q2W | Alirocumab Q2W | Placebo/Alirocumab Q4W | Alirocumab Q4W |
|---|---|---|---|---|
| Started | 25 | 46 | 25 | 49 |
| Completed | 22 | 43 | 24 | 49 |
| Not completed | 3 | 3 | 1 | 0 |
| Withdrew: Adverse event | 1 | 0 | 0 | 0 |
| Withdrew: Lack of efficacy | 0 | 1 | 0 | 0 |
| Withdrew: Participant moved | 1 | 0 | 1 | 0 |
| Withdrew: Life events made continuing too difficult | 0 | 1 | 0 | 0 |
| Withdrew: Other than specified above | 1 | 1 | 0 | 0 |
Adjusted least square (LS) means and standard errors (SE) were obtained from mixed-effect model with repeated measures (MMRM) model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) at Week 24: Intent-to-treat (ITT) Estimand | 9.7 ± 4.3 | -33.6 ± 3.4 | -4.4 ± 3.7 | -38.2 ± 4.0 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Low Density Lipoprotein Cholesterol at Week 12: ITT Estimand | 10.7 ± 3.6 | -34.8 ± 3.0 | 2.3 ± 3.6 | -39.2 ± 3.3 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Estimand | 10.4 ± 2.8 | -27.4 ± 3.2 | -3.6 ± 3.9 | -34.3 ± 2.9 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24: ITT Estimand | 9.7 ± 3.9 | -31.0 ± 3.2 | -3.7 ± 4.0 | -35.6 ± 3.5 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Estimand | 7.4 ± 3.0 | -23.4 ± 2.5 | -4.4 ± 3.3 | -27.7 ± 2.9 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Estimand | 8.9 ± 3.1 | -30.0 ± 2.5 | 1.1 ± 3.2 | -31.7 ± 2.9 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol at Week 12: ITT Estimand | 9.8 ± 3.8 | -33.0 ± 2.8 | 2.8 ± 3.5 | -34.7 ± 2.9 |
Adjusted LS means and SE were obtained from MMRM model including all available post-baseline data. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Total Cholesterol at Week 12: ITT Estimand | 7.5 ± 2.9 | -25.3 ± 2.2 | 0.9 ± 2.5 | -27.0 ± 2.3 |
Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 24 were included in the imputation model.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol Level Lower Than (<) 130 mg/dL (3.37 mmol/L) at Week 24: ITT Estimand | 8.0 | 73.3 | 22.2 | 76.3 |
Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 12 were included in the imputation model.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percentage of Participants Who Achieved Low Density Lipoprotein Cholesterol Level <130 mg/dL (3.37 mmol/L) at Week 12: ITT Estimand | 16.4 | 70.6 | 12.9 | 72.6 |
Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data up to Week 24 were included in the imputation model.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percentage of Participants Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 24: ITT Estimand | 4.0 | 57.2 | 9.0 | 67.2 |
Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data for Q4W. All available post-baseline data up to Week 12 were included in the imputation model. For Q2W, adjusted percentages at Week 12 were obtained from last observation carried forward approach (LOCF) to handle missing on-treatment LDL-C values as well as missing post-treatment LDL-C values in participants who discontinued treatment due to the coronavirus disease-2019 pandemic. Other post-treatment missing values were considered as failure.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percentage of Participants Achieving Low Density Lipoprotein Cholesterol <110 mg/dL (2.84 mmol/L) at Week 12: ITT Estimand | 0.0 | 61.2 | 4.3 | 57.0 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 24: ITT Estimand | 0.5 ± 5.3 | -14.7 ± 4.1 | 2.5 ± 7.1 | -22.4 ± 5.0 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Lipoprotein (a) at Week 12: ITT Estimand | -7.1 ± 5.9 | -12.7 ± 3.9 | -2.5 ± 6.9 | -16.0 ± 5.1 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 24: ITT Estimand | -0.8 ± 2.1 | 5.6 ± 1.4 | -1.1 ± 2.7 | 3.4 ± 2.1 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 24: ITT Estimand | 7.7 ± 8.4 | 11.9 ± 6.3 | 12.2 ± 8.2 | -6.8 ± 5.5 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Apolipoprotein A1 (Apo A1) at Week 24: ITT Estimand | -0.1 ± 2.6 | 1.0 ± 1.5 | -4.5 ± 2.6 | 4.4 ± 2.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at Week 12: ITT Estimand | -2.2 ± 3.2 | 3.5 ± 2.0 | -3.5 ± 3.2 | 4.0 ± 2.2 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 12. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | Db Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Fasting Triglycerides (TG) at Week 12: ITT Estimand | 6.5 ± 7.4 | -2.2 ± 5.0 | 7.8 ± 8.4 | -0.3 ± 6.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| DB Period: Percent Change From Baseline in Apolipoprotein A1 at Week 12: ITT Estimand | -0.1 ± 1.8 | -1.7 ± 1.7 | -0.7 ± 3.1 | 5.0 ± 1.7 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st investigational medicinal product (IMP) injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 10.7 ± 3.6 | -34.8 ± 3.0 | 2.3 ± 3.6 | -39.2 ± 3.3 |
| Week 24 | 9.7 ± 4.3 | -33.6 ± 3.4 | -4.4 ± 3.7 | -38.2 ± 4.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 8.9 ± 3.1 | -30.0 ± 2.5 | 1.1 ± 3.2 | -31.7 ± 2.9 |
| Week 24 | 10.4 ± 2.8 | -27.4 ± 3.2 | -3.6 ± 3.9 | -34.3 ± 2.9 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | Db Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 9.8 ± 3.8 | -33.0 ± 2.8 | 2.8 ± 3.5 | -34.7 ± 2.9 |
| Week 24 | 9.7 ± 3.9 | -31.0 ± 3.2 | -3.7 ± 4.0 | -35.6 ± 3.5 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 7.5 ± 2.9 | -25.3 ± 2.2 | 0.9 ± 2.5 | -27.0 ± 2.3 |
| Week 24 | 7.4 ± 3.0 | -23.4 ± 2.5 | -4.4 ± 3.3 | -27.7 ± 2.9 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | Db Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 16.4 | 70.6 | 12.9 | 72.6 |
| Week 24 | 8.0 | 73.3 | 22.2 | 76.3 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.1 | 61.7 | 4.3 | 57.0 |
| Week 24 | 4.0 | 57.2 | 9.0 | 67.2 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline on-treatment data up to Week 12 and Week 24, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | -7.099 ± 5.923 | -12.746 ± 3.889 | -2.545 ± 6.851 | -16.042 ± 5.139 |
| Week 24 | 0.492 ± 5.254 | -14.748 ± 4.083 | 2.468 ± 7.135 | -22.418 ± 5.030 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM mode, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | -0.1 ± 1.8 | -1.7 ± 1.7 | -0.7 ± 3.1 | 5.0 ± 1.7 |
| Week 24 | -0.1 ± 2.6 | 1.0 ± 1.5 | -4.5 ± 2.6 | 4.4 ± 2.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 day otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | -2.2 ± 3.2 | 3.5 ± 2.0 | -3.5 ± 3.2 | 4.0 ± 2.2 |
| Week 24 | -0.8 ± 2.1 | 5.6 ± 1.4 | -1.1 ± 2.7 | 3.4 ± 2.1 |
Adjusted means and standard errors were obtained from a multiple imputation approach followed by a robust regression model including all available post-baseline on-treatment data up to Week 12 and Week 24, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise. Combined estimates and SE were obtained by combining adjusted means and SE from robust regression model analyses of the different imputed data sets.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 6.5 ± 7.4 | -2.2 ± 5.0 | 7.8 ± 8.4 | -0.3 ± 6.0 |
| Week 24 | 7.7 ± 8.4 | 11.9 ± 6.3 | 12.2 ± 8.2 | -6.8 ± 5.5 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 12 and Week 24 were used and missing data were accounted for by the MMRM model. MMRM model was run on participants with a Baseline value and a post-baseline value for at least one timepoint used in the model.
| ratio (Apo B/Apo A-1) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.1 ± 0.0 | -0.2 ± 0.0 | 0.0 ± 0.0 | -0.3 ± 0.0 |
| Week 24 | 0.1 ± 0.0 | -0.2 ± 0.0 | 0.0 ± 0.0 | -0.3 ± 0.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise. MMRM model was run on participants with a Baseline value and at one on-treatment post-baseline value for a timepoint used in the model.
| ratio (Apo B/Apo A-1) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.1 ± 0.0 | -0.2 ± 0.0 | 0.0 ± 0.0 | -0.3 ± 0.0 |
| Week 24 | 0.1 ± 0.0 | -0.2 ± 0.0 | 0.0 ± 0.0 | -0.3 ± 0.0 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week12 | 0.8 | 65.8 | 4.2 | 70.8 |
| Week 24 | 4.0 | 66.7 | 18.5 | 72.5 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.8 | 65.8 | 4.2 | 70.8 |
| Week 24 | 4.0 | 66.7 | 18.5 | 72.5 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.0 | 25.2 | 0.1 | 31.9 |
| Week 24 | 0.0 | 21.6 | 9.1 | 32.4 |
Adjusted percentages at Weeks 12 and 24 were obtained from multiple imputation approach for handling of missing data followed by logistic regression model. All available post-baseline on-treatment data up to Week 12 and Week 24 were included in the imputation model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for those who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
| percentage of participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 12 | 0.0 | 25.2 | 0.1 | 31.9 |
| Week 24 | 0.0 | 21.6 | 9.1 | 32.4 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline data available up to Week 8, Week 12 and Week 24 were used and missing data were accounted for by the MMRM model.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 8 | 7.1 ± 4.2 | -35.4 ± 3.6 | -3.8 ± 3.5 | -42.0 ± 2.8 |
| Week 12 | 10.7 ± 3.6 | -34.8 ± 3.0 | 2.3 ± 3.6 | -39.2 ± 3.3 |
| Week 24 | 9.7 ± 4.3 | -33.6 ± 3.4 | -4.4 ± 3.7 | -38.2 ± 4.0 |
Adjusted LS means and SE were obtained from MMRM model. All post-baseline on-treatment data available up to Week 8, Week 12 and Week 24 were used for the MMRM model, i.e., for Q2W data: from 1st IMP injection up to last IMP injection + 21 days and for Q4W data: from 1st IMP injection up to last IMP injection + 35 days for who stopped IMP before switch to Q2W regimen, + 21 days otherwise.
| percent change | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| Week 8 | 7.1 ± 4.2 | -35.4 ± 3.6 | -3.8 ± 3.5 | -42.0 ± 2.8 |
| Week 12 | 10.7 ± 3.6 | -34.8 ± 3.0 | 2.3 ± 3.6 | -39.2 ± 3.3 |
| Week 24 | 9.7 ± 4.3 | -33.6 ± 3.4 | -4.4 ± 3.7 | -38.2 ± 4.0 |
Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.
| percent change | OL Period: Placebo/Alirocumab Q2W | OL Period: Alirocumab Q2W | OL Period: Placebo/Alirocumab Q4W | OL Period: Alirocumab Q4W |
|---|---|---|---|---|
| OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: ITT Estimand | -23.3 ± 4.9 | -22.2 ± 5.6 | -27.1 ± 7.0 | -23.7 ± 4.2 |
Percent Change in LDL-C from Baseline to Week 104 was reported in this outcome measure.
| percent change | OL Period: Placebo/Alirocumab Q2W | OL Period: Alirocumab Q2W | OL Period: Placebo/Alirocumab Q4W | OL Period: Alirocumab Q4W |
|---|---|---|---|---|
| OL Period: Percent Change in Low Density Lipoprotein Cholesterol From Baseline to Week 104: On-treatment Estimand | -22.8 ± 5.1 | -25.8 ± 4.9 | -27.6 ± 7.6 | -23.4 ± 4.7 |
Cogstate battery test (cognitive testing system) consisted of detection test (DET), identification test (IDN), one card learning test (OCL) and Groton maze learning test (GML) to assess processing speed, attention, visual learning and executive functioning, respectively. For each test, Z-scores were computed based on participant's age at Baseline and Weeks 24, 68 and 104. Composite score: calculated as mean of Z-scores equally weighted, provided that at least 3 of 4 tests were available and if all of these domains were covered as: attention, through either DET or IDN, visual learning, through OCL and executive function, through GML. There is not minimum/maximum since values were reported as z-score but z-score of 0 means result equals to mean with negative numbers indicating values lower than mean and positive values higher. Positive change in z-score = an improvement in cognition, i.e., a better outcome; and negative change in z-score = worsening in cognition, i.e., a worse outcome.
| Z-score | Placebo/Alirocumab Q2W | Alirocumab Q2W | Placebo/Alirocumab Q4W | Alirocumab Q4W |
|---|---|---|---|---|
| Week 24 | -0.403 ± 1.008 | -0.313 ± 0.444 | -0.218 ± 0.501 | -0.136 ± 0.637 |
| Week 68 | -0.421 ± 1.752 | -0.334 ± 0.912 | -0.272 ± 0.814 | -0.263 ± 0.717 |
| Week 104 | -0.601 ± 1.612 | -0.439 ± 0.917 | -0.393 ± 0.764 | -0.638 ± 0.791 |
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).
| Participants | Placebo/Alirocumab Q2W | Alirocumab Q2W | Placebo/Alirocumab Q4W | Alirocumab Q4W |
|---|---|---|---|---|
| Baseline: Boys - Prepubescent | 1 | 4 | 5 | 0 |
| Baseline: Boys - Pubescent | 13 | 13 | 4 | 14 |
| Baseline: Boys - Postpubescent | 3 | 2 | 3 | 4 |
| Baseline: Girls - Prepubescent | 1 | 4 | 1 | 7 |
| Baseline: Girls - Pubescent | 6 | 16 | 8 | 13 |
| Baseline: Girls - Postpubescent | 1 | 10 | 6 | 14 |
| Week 24: Boys - Prepubescent | 0 | 3 | 1 | 0 |
| Week 24: Boys - Pubescent | 13 | 11 | 7 | 12 |
| Week 24: Boys - Postpubescent | 4 | 3 | 3 | 5 |
| Week 24: Girls - Prepubescent | 1 | 4 | 1 | 2 |
| Week 24: Girls - Pubescent | 5 | 15 | 6 | 16 |
| Week 24: Girls - Postpubescent | 2 | 9 | 5 | 9 |
| Week 68: Boys - Prepubescent | 0 | 1 | 1 | 0 |
| Week 68: Boys - Pubescent | 7 | 9 | 5 | 9 |
| Week 68: Boys - Postpubescent | 4 | 6 | 3 | 6 |
| Week 68: Girls - Prepubescent | 0 | 3 | 1 | 1 |
| Week 68: Girls - Pubescent | 6 | 14 | 5 | 16 |
| Week 68: Girls - Postpubescent | 1 | 9 | 5 | 9 |
| Week 104: Boys - Prepubescent | 0 | 1 | 1 | 0 |
| Week 104: Boys - Pubescent | 6 | 8 | 5 | 8 |
| Week 104: Boys - Postpubescent | 7 | 6 | 2 | 7 |
| Week 104: Girls - Prepubescent | 0 | 0 | 1 | 1 |
| Week 104: Girls - Pubescent | 4 | 10 | 5 | 17 |
| Week 104: Girls - Postpubescent | 2 | 11 | 5 | 11 |
Anti-drug (alirocumab) antibodies samples were analyzed using a validated non-quantitative, titer-based bridging immunoassay. Number of participants with positive ADA during 24-week treatment period is reported. Treatment-emergent positive ADA response was defined as 1) participants with no ADA positive response at baseline but with any positive response in the post-baseline period or 2) participants with a positive ADA response at baseline and at least a 4- fold increase in titer in the post-baseline period. A persistent positive response was defined as a TE ADA positive response detected in at least 2 consecutive post-baseline samples separated by at least a 12-week period. Persistent positive response was only analyzed for participants with positive TE ADA response.
| Participants | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W |
|---|---|---|---|---|
| TE ADA positive response | 0 | 3 | 0 | 0 |
| Persistent positive response | — | 0 | — | — |
Collected over For the DB period: for participants proceeding into the OL treatment period, from first DB IMP dose up to the day before first OL IMP dose ( i.e., up to Week 24); and for participants not proceeding into the OL treatment period, from first DB IMP dose up to Week 24 + 10 weeks (i.e., up to Week 34); for the OL period: from first OL IMP dose up to 10 weeks after the last OL IMP dose (i.e., up to Week 112). Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| DB Period: Placebo Q2W | 0/25 (0%) | 1/25 (4%) | 9/25 (36%) |
| DB Period: Alirocumab Q2W | 0/49 (0%) | 4/49 (8.2%) | 15/49 (30.6%) |
| DB Period: Placebo Q4W | 0/27 (0%) | 1/27 (3.7%) | 8/27 (29.6%) |
| DB Period: Alirocumab Q4W | 0/52 (0%) | 2/52 (3.8%) | 10/52 (19.2%) |
| OL Period: Placebo/Alirocumab Q2W | 0/25 (0%) | 0/25 (0%) | 9/25 (36%) |
| OL Period: Alirocumab Q2W | 0/46 (0%) | 4/46 (8.7%) | 12/46 (26.1%) |
| OL Period: Placebo/Alirocumab Q4W | 0/25 (0%) | 2/25 (8%) | 6/25 (24%) |
| OL Period: Alirocumab Q4W | 0/49 (0%) | 3/49 (6.1%) | 15/49 (30.6%) |
| Event | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | OL Period: Placebo/Alirocumab Q2W | OL Period: Alirocumab Q2W | OL Period: Placebo/Alirocumab Q4W | OL Period: Alirocumab Q4W |
|---|---|---|---|---|---|---|---|---|
| AppendicitisInfections and infestations | 1/25 | 0/49 | 0/27 | 0/52 | 0/25 | 0/46 | 1/25 | 0/49 |
| SyncopeNervous system disorders | 0/25 | 0/49 | 0/27 | 2/52 | 0/25 | 0/46 | 1/25 | 1/49 |
| Non-Cardiac Chest PainGeneral disorders | 0/25 | 0/49 | 1/27 | 0/52 | 0/25 | 0/46 | 0/25 | 0/49 |
| Pharyngitis StreptococcalInfections and infestations | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 1/46 | 0/25 | 0/49 |
| PneumoniaInfections and infestations | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 1/46 | 0/25 | 0/49 |
| HypertensionVascular disorders | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 1/46 | 0/25 | 0/49 |
| Calculus UrinaryRenal and urinary disorders | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 1/46 | 0/25 | 0/49 |
| Major DepressionPsychiatric disorders | 0/25 | 1/49 | 0/27 | 0/52 | 0/25 | 0/46 | 0/25 | 0/49 |
| Angina PectorisCardiac disorders | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 0/46 | 0/25 | 1/49 |
| MyocarditisCardiac disorders | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 0/46 | 0/25 | 1/49 |
| Event | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | OL Period: Placebo/Alirocumab Q2W | OL Period: Alirocumab Q2W | OL Period: Placebo/Alirocumab Q4W | OL Period: Alirocumab Q4W |
|---|---|---|---|---|---|---|---|---|
| HeadacheNervous system disorders | 2/25 | 3/49 | 1/27 | 4/52 | 1/25 | 5/46 | 4/25 | 7/49 |
| NasopharyngitisInfections and infestations | 2/25 | 7/49 | 2/27 | 1/52 | 2/25 | 3/46 | 1/25 | 3/49 |
| Upper Respiratory Tract InfectionInfections and infestations | 3/25 | 3/49 | 3/27 | 3/52 | 2/25 | 2/46 | 0/25 | 2/49 |
| Oropharyngeal PainRespiratory, thoracic and mediastinal disorders | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 4/46 | 0/25 | 0/49 |
| Covid-19Infections and infestations | 0/25 | 0/49 | 0/27 | 0/52 | 0/25 | 1/46 | 1/25 | 4/49 |
| MigraineNervous system disorders | 2/25 | 0/49 | 0/27 | 1/52 | 0/25 | 0/46 | 0/25 | 0/49 |
| NauseaGastrointestinal disorders | 0/25 | 0/49 | 0/27 | 0/52 | 2/25 | 0/46 | 0/25 | 1/49 |
| Low Density Lipoprotein DecreasedInvestigations | 0/25 | 0/49 | 0/27 | 0/52 | 2/25 | 0/46 | 0/25 | 2/49 |
| Abdominal Pain UpperGastrointestinal disorders | 0/25 | 0/49 | 2/27 | 0/52 | 0/25 | 0/46 | 0/25 | 0/49 |
| Injection Site ReactionGeneral disorders | 0/25 | 3/49 | 0/27 | 2/52 | 1/25 | 3/46 | 1/25 | 1/49 |
Analysis was performed on all randomized participants.
| Age, Continuous(years) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | Total Title |
|---|---|---|---|---|---|
| Mean | 13.2 ± 2.4 | 12.5 ± 2.7 | 12.8 ± 3.0 | 13.1 ± 3.0 | 12.9 ± 2.8 |
| Sex: Female, Male(Participants) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | Total Title |
|---|---|---|---|---|---|
| Female | 8 | 30 | 15 | 34 | 87 |
| Male | 17 | 19 | 12 | 18 | 66 |
| Race (NIH/OMB)(Participants) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | Total Title |
|---|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 4 | 12 | 16 |
| Asian | 1 | 1 | 0 | 0 | 2 |
| Native Hawaiian or Other Pacific Islander | 0 | 1 | 0 | 0 | 1 |
| Black or African American | 0 | 1 | 1 | 1 | 3 |
| White | 23 | 42 | 22 | 38 | 125 |
| More than one race | 1 | 4 | 0 | 0 | 5 |
| Unknown or Not Reported | 0 | 0 | 0 | 1 | 1 |
| Low-Density Lipoprotein Cholesterol (LDL-C)(milligrams/deciliter (mg/dL)) | DB Period: Placebo Q2W | DB Period: Alirocumab Q2W | DB Period: Placebo Q4W | DB Period: Alirocumab Q4W | Total Title |
|---|---|---|---|---|---|
| Mean | 175.29 ± 50.23 | 169.69 ± 46.74 | 176.57 ± 49.01 | 176.79 ± 53.93 | 174.23 ± 49.85 |
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