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

• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Alirocumab; Drug: Placebo (for alirocumab); Drug: Ezetimibe; Drug: Placebo (for ezetimibe); Drug: Lipid Modifying Therapy (LMT)	Phase 3

Detailed Description:

The maximum study duration was 115 weeks per participant, including a 3-week screening period, 104-week randomized treatment period and 8-week follow-up period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 720 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy
• Study Start Date: August 2012
• Actual Primary Completion Date: May 2014
• Actual Study Completion Date: July 2015

Arms and Interventions

Arm	Intervention/treatment
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.	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 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.
Active Comparator: Ezetimibe 10 mg; Ezetimibe 10 mg capsule daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.	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: Lipid Modifying Therapy (LMT); Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis [ Time Frame: From Baseline to Week 52 ]
   Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment were used in the model (ITT analysis).

Secondary Outcome Measures :

1. 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).
2. 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.
3. 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).
4. 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.
5. 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).
6. 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.
7. 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).
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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).
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.

Other Outcome Measures:

1. 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).
2. 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.
3. 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

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Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications of Results:

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.

Other Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Leiter LA, Tinahones FJ, Karalis DG, Bujas-Bobanovic M, Letierce A, Mandel J, Samuel R, Jones PH. Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials. Diabet Med. 2018 Dec;35(12):1742-1751. doi: 10.1111/dme.13817. Epub 2018 Oct 9.

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT01644188 History of Changes
• Other Study ID Numbers: EFC11569; U1111-1121-4315 ( Other Identifier: UTN ); 2011-004130-34 ( EudraCT Number )
• First Posted: July 18, 2012
• Results First Posted: November 6, 2015
• Last Update Posted: August 4, 2016
• Last Verified: June 2016

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Ezetimibe; Antibodies, Monoclonal; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Immunologic Factors; Physiological Effects of Drugs