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

Tracking Information
First Submitted Date ICMJE	July 16, 2012
First Posted Date ICMJE	July 18, 2012
Results First Submitted Date	August 20, 2015
Results First Posted Date	November 6, 2015
Last Update Posted Date	August 4, 2016
Study Start Date ICMJE	August 2012
Actual Primary Completion Date	May 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 7, 2015)	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).
Original Primary Outcome Measures ICMJE; (submitted: July 16, 2012)	Percent change in LDL-C [ Time Frame: From baseline to week 24 ]
Change History	Complete list of historical versions of study NCT01644188 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: June 23, 2016)	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.
Original Secondary Outcome Measures ICMJE; (submitted: July 16, 2012)	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 ]
Current Other Outcome Measures ICMJE; (submitted: June 23, 2016)	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).
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II)
Official Title ICMJE	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
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
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 Type ICMJE	Interventional
Study Phase	Phase 3
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition ICMJE	Hypercholesterolemia
Intervention ICMJE	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.
Study Arms	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)
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.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: February 9, 2015)	720
Original Estimated Enrollment ICMJE; (submitted: July 16, 2012)	660
Actual Study Completion Date	July 2015
Actual Primary Completion Date	May 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Senior)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Canada, Denmark, France, Hungary, Israel, Korea, Republic of, Russian Federation, South Africa, Ukraine, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT01644188
Other Study ID Numbers ICMJE	EFC11569; U1111-1121-4315 ( Other Identifier: UTN ); 2011-004130-34 ( EudraCT Number )
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	Sanofi
Study Sponsor ICMJE	Sanofi
Collaborators ICMJE	Regeneron Pharmaceuticals
Investigators ICMJE	Study Director: Clinical Sciences & Operations Sanofi
PRS Account	Sanofi
Verification Date	June 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP