Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II)

• Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis [ Time Frame: From Baseline to Week 52 ]
  Adjusted LS means and standard errors at Week 24 were obtained 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 or 3 days after the last capsule, whichever came first).
• Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ]
  Adjusted LS means and standard errors at Week 12 from a 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 ]
  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 or 3 days after the last capsule, whichever came first).
• Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ]
  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 ]
  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 or 3 days after the last capsule, whichever came first).
• 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 ]
  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 up to Week 52 ]
  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 or 3 days after the last capsule, whichever came first).
• Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ]
  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 ]
  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 ]
  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 ]
  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 ]
  Adjusted LS means and standard errors at Week 52 from a MMRM 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 - ITT Analysis [ Time Frame: Up to Week 52 ]
  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 Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 52 ]
  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 or 3 days after the last capsule, whichever came first).
• Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [ Time Frame: From baseline to Week 52 ]
  Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model 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.
• Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 ]
  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 12 ]
• Percent change in other lipid parameters [ Time Frame: At weeks 12 and 24 ]

• Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ]
  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 or 3 days after the last capsule, whichever came first).
• Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis [ Time Frame: From Baseline to Week 104 ]
  Adjusted LS means and standard errors at Week 104 from MMRM including all available post-baseline data from Week 4 to Week 104 regardless of status on-or off-treatment.
• Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis [ Time Frame: From Baseline to Week 104 ]
  Adjusted LS means and standard errors at Week 104 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 104 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).

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

Primary Objective of the study:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable maximally tolerated daily statin therapy in comparison with ezetimibe after 24 weeks of treatment in participants with hypercholesterolemia at high cardiovascular (CV) risk.

Secondary Objectives:

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

• Drug: Alirocumab
  1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
  Other Names:

  • REGN727/SAR236553
  • Praluent
• Drug: Placebo (for alirocumab)
  1 mL subcutaneous injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using the autoinjector.
• Drug: Ezetimibe
  One over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.
• Drug: Placebo (for ezetimibe)
  One capsule once daily orally at approximately the same time of the day with or without food.
• Drug: Lipid Modifying Therapy (LMT)
  Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.

• Experimental: Alirocumab 75 /up to 150 mg Q2W
  Alirocumab 75 mg every 2 weeks (Q2W) and oral placebo capsule for ezetimibe daily added to stable Lipid Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.
  Interventions:

  • Drug: Alirocumab
  • Drug: Placebo (for ezetimibe)
  • Drug: Lipid Modifying Therapy (LMT)
• Active Comparator: Ezetimibe 10 mg
  Ezetimibe 10 mg capsule daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.
  Interventions:

  • Drug: Placebo (for alirocumab)
  • Drug: Ezetimibe
  • Drug: Lipid Modifying Therapy (LMT)

• Colhoun HM, Robinson JG, Farnier M, Cariou B, Blom D, Kereiakes DJ, Lorenzato C, Pordy R, Chaudhari U. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc Disord. 2014 Sep 20;14:121. doi: 10.1186/1471-2261-14-121.
• Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM; ODYSSEY COMBO II Investigators. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015 May 14;36(19):1186-94. doi: 10.1093/eurheartj/ehv028. Epub 2015 Feb 16.
• Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, Eckel RH, Cannon CP. Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab With Control. Circulation. 2016 Dec 13;134(24):1931-1943. Epub 2016 Oct 24.

Inclusion criteria:

Participants with hypercholesterolemia and established coronary heart disease (CHD) or CHD risk equivalents who were not adequately controlled with a maximally tolerated daily dose of statin at stable dose for at least 4 weeks prior to the screening visit (Week -2).

Exclusion criteria:

• Age < 18 or legal age of adulthood, whichever was greater
• Participants without established CHD or CHD risk equivalents
• LDL-C <70 mg/dL (<1.81 mmol/L) and participants with a history of documented cardiovascular disease
• LDL-C <100 mg/dL (<2.59 mmol/L) and participants without a history of documented CV disease
• Fasting serum triglycerides >400 mg/dL (>4.52 mmol/L)

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