Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy (ODYSSEY FH I)

• Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection) (on-treatment analysis).
• Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
• Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
• Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
• Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
• Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
• Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
• Percent Change From Baseline in Apo B at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
• Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
  Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to <60 ml/minute/1.73 m^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of >2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature CHD). Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model.
• Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On- Treatment Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
  Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
• Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
  Adjusted percentages at Week 24 from multiple imputation approach model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
  Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
• Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
• Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.

• Percent change in LDL-C [ Time Frame: From baseline up to week 78 ] [ Designated as safety issue: No ]
• Percent change in other lipid parameters [ Time Frame: From baseline up to Week 78 ] [ Designated as safety issue: No ]

• Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
• Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis [ Time Frame: From Baseline to Week 78 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 78 from MMRM including all available post-baseline data from Week 4 to Week 78 regardless of status on-or off-treatment.
• Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis [ Time Frame: From Baseline to Week 78 ] [ Designated as safety issue: No ]
  Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 (i.e. up to 21 days after last injection).

Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9).

Primary Objective of the study:

To evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 24 weeks of treatment in comparison with placebo.

Secondary Objectives:

• To evaluate the effect of alirocumab in comparison with placebo on LDL-C at other time points
• To evaluate the effects of alirocumab on other lipid parameters
• To evaluate the safety and tolerability of alirocumab

• Drug: Alirocumab
  Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre filled pen).
  Other Names:

  • SAR236553
  • REGN727
  • Praluent
• Drug: Placebo (for alirocumab)
  Solution for subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre filled pen).
• Drug: Lipid Modifying Therapy (LMT)
  Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.

• Placebo Comparator: Placebo
  Placebo for alirocumab every 2 weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks.
  Interventions:

  • Drug: Placebo (for alirocumab)
  • Drug: Lipid Modifying Therapy (LMT)
• Experimental: Alirocumab 75 mg/Up to 150 mg Q2W
  Alirocumab 75 mg Q2W on top of stable LMT for 78 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low-density lipoprotein cholesterol (LDL-C) levels ≥ 70 mg/dL (1.81 mmol/L) at Week 8.
  Interventions:

  • Drug: Alirocumab
  • Drug: Lipid Modifying Therapy (LMT)

• Kastelein JJ, Robinson JG, Farnier M, Krempf M, Langslet G, Lorenzato C, Gipe DA, Baccara-Dinet MT. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014 Jun;28(3):281-9. doi: 10.1007/s10557-014-6523-z.
• Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov 14;36(43):2996-3003. doi: 10.1093/eurheartj/ehv370. Epub 2015 Sep 1.

Inclusion criteria:

• Participants with heterozygous familial hypercholesterolemia who were not adequately controlled with their lipid-modifying therapy

Exclusion criteria:

• Age < 18 years or legal age of adulthood, whichever is greater
• LDL-C < 70 mg/dL (1.81 mmol/L) and with cardiovascular disease
• LDL-C < 100 mg/dL (2.59 mmol/L) and without cardiovascular disease
• Fasting serum triglycerides > 400 mg/dL (4.52 mmol/L)
• Known history of homozygous familial hypercholesterolemia

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.