Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia (ODYSSEY COMBO I)

Hypercholesterolemia Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01644175
• Other study ID #: EFC11568
• Secondary ID: U1111-1121-4356
• Status: Completed
• Phase: Phase 3
• First received: July 16, 2012
• Last updated: October 7, 2015
• Start date: July 2012
• Est. completion date: April 2014

Study information

• Verified date: October 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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

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 with or without other lipid-modifying therapy (LMT) in comparison with placebo after 24 weeks of treatment in high cardiovascular (CV) risk participants with hypercholesterolemia

Secondary Objectives:

• To evaluate the effect of alirocumab in comparison with placebo 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

Description:

The maximum study duration was 62 weeks per participant, including a 2-week screening period, 52-week randomized treatment period, and 8-week follow-up period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 316
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 with or without other LMT, both at stable dose for at least 4 weeks to 6 weeks prior to screening (Week -2)

Exclusion criteria:

• Age <18 or legal age of adulthood, whichever was greater

• Participants without established CHD or CHD risk equivalent

• 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 cardiovascular disease

• Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (Week -2) and from screening to randomization

• Fasting serum triglycerides > 400 mg/dL (>4.52 mmol/L)

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypercholesterolemia

Intervention

Drug:
• Placebo (for alirocumab)
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).
• Alirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).
• Lipid-Modifying Therapy (LMT)
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.

Locations

Country	Name	City	State
United States	Investigational Site Number 840872	Anderson	South Carolina
United States	Investigational Site Number 840890	Battle Creek	Michigan
United States	Investigational Site Number 840857	Birmingham	Alabama
United States	Investigational Site Number 840867	Boca Raton	Florida
United States	Investigational Site Number 840878	Bountiful	Utah
United States	Investigational Site Number 840884	Boynton Beach	Florida
United States	Investigational Site Number 840870	Burbank	California
United States	Investigational Site Number 840824	Cary	North Carolina
United States	Investigational Site Number 840885	Charleston	South Carolina
United States	Investigational Site Number 840842	Chicago	Illinois
United States	Investigational Site Number 840846	Cincinnati	Ohio
United States	Investigational Site Number 840899	Cincinnati	Ohio
United States	Investigational Site Number 840836	Clearwater	Florida
United States	Investigational Site Number 840831	Columbus	Ohio
United States	Investigational Site Number 840850	Columbus	Georgia
United States	Investigational Site Number 840866	Coral Gables	Florida
United States	Investigational Site Number 840868	Corpus Christi	Texas
United States	Investigational Site Number 840803	Downington	Pennsylvania
United States	Investigational Site Number 840840	Eagle	Idaho
United States	Investigational Site Number 840839	Edina	Minnesota
United States	Investigational Site Number 840812	Eugene	Oregon
United States	Investigational Site Number 840858	Eunice	Louisiana
United States	Investigational Site Number 840898	Evanston	Illinois
United States	Investigational Site Number 840895	Ft. Lauderdale	Florida
United States	Investigational Site Number 840865	Glendale	Arizona
United States	Investigational Site Number 840813	Greer	South Carolina
United States	Investigational Site Number 840820	Hialeah	Florida
United States	Investigational Site Number 840841	Houston	Texas
United States	Investigational Site Number 840877	Houston	Texas
United States	Investigational Site Number 840896	Indianapolis	Indiana
United States	Investigational Site Number 840814	Jefferson City	Missouri
United States	Investigational Site Number 840826	Jonesboro	Arkansas
United States	Investigational Site Number 840860	Kettering	Ohio
United States	Investigational Site Number 840851	Los Angeles	California
United States	Investigational Site Number 840845	Los Gatos	California
United States	Investigational Site Number 840804	Manassas	Virginia
United States	Investigational Site Number 840805	Miami	Florida
United States	Investigational Site Number 840894	Michigan City	Indiana
United States	Investigational Site Number 840888	Minneapolis	Minnesota
United States	Investigational Site Number 840838	Mishawaka	Indiana
United States	Investigational Site Number 840891	Mobile	Alabama
United States	Investigational Site Number 840876	Montgomery	Alabama
United States	Investigational Site Number 840847	Morton	Illinois
United States	Investigational Site Number 840827	Mt. Pleasant	South Carolina
United States	Investigational Site Number 840802	New Orleans	Louisiana
United States	Investigational Site Number 840853	New Windsor	New York
United States	Investigational Site Number 840817	Newington	New Hampshire
United States	Investigational Site Number 840882	Norfolk	Virginia
United States	Investigational Site Number 840818	Norman	Oklahoma
United States	Investigational Site Number 840819	Orem	Utah
United States	Investigational Site Number 840811	Oviedo	Florida
United States	Investigational Site Number 840823	Paducah	Kentucky
United States	Investigational Site Number 840869	Philadelphia	Pennsylvania
United States	Investigational Site Number 840825	Pittsburgh	Pennsylvania
United States	Investigational Site Number 840837	Port Gibson	Mississippi
United States	Investigational Site Number 840881	Port Orange	Florida
United States	Investigational Site Number 840822	Rochester	New York
United States	Investigational Site Number 840844	Sacramento	California
United States	Investigational Site Number 840855	Salisbury	Massachusetts
United States	Investigational Site Number 840863	Salt Lake City	Utah
United States	Investigational Site Number 840830	San Antonio	Texas
United States	Investigational Site Number 840854	San Antonio	Texas
United States	Investigational Site Number 840883	San Antonio	Texas
United States	Investigational Site Number 840801	San Jose	California
United States	Investigational Site Number 840880	Smithfield	North Carolina
United States	Investigational Site Number 840832	Southfield	Michigan
United States	Investigational Site Number 840833	Sparks	Nevada
United States	Investigational Site Number 840886	Tarzana	California
United States	Investigational Site Number 840889	Tomball	Texas
United States	Investigational Site Number 840862	Torrance	California
United States	Investigational Site Number 840893	Vista	California
United States	Investigational Site Number 840810	Weber City	Virginia
United States	Investigational Site Number 840816	West Palm Beach	Florida
United States	Investigational Site Number 840809	Willoughby Hills	Ohio
United States	Investigational Site Number 840502	Winston-Salem	North Carolina
United States	Investigational Site Number 840852	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View Citation

Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therap — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	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).	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis	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) (on-treatment analysis).	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis	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).	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis	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.	From baseline to Week 52	No
Secondary	Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis	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).	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis	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).	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Apo B at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Total-C at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis	Adjusted percentages at Week 24 were obtained from multiple imputation approach 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.	Up to Week 52	No
Secondary	Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment Analysis	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.	Up to Week 52	No
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis	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.	From baseline to Week 52	No
Secondary	Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis	Adjusted means and standard errors at Week 24 from multiple imputation approach followed be robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Apolipoprotein A-1 at Week 24 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Lipoprotein(a) at Week 12- ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis	Adjusted means and standard errors at Week 12 from multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.	From Baseline to Week 52	No
Secondary	Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis	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.	From Baseline to Week 52	No