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

NCT01644188 | Completed Phase 3 Results DMC

• 3 other identifiers: EFC11569U1111-1121-43152011-004130-34
• Study Type: interventional
• Target: 720
• Locations: 10 countries
• Sites: 126

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

Conditions

Hypercholesterolemia

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (22)

• Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis

  From Baseline to Week 52

• Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis

  From Baseline to Week 52

• Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis

  From Baseline to Week 52

• Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis

  From Baseline to Week 52

• Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis

  From Baseline to Week 52

Other Outcomes (3)

• Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis

  From Baseline to Week 52

• Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis

  From Baseline to Week 104

• Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis

  From Baseline to Week 104

Study Arms (2)

Alirocumab 75 /up to 150 mg Q2W

EXPERIMENTAL

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; Drug: Placebo (for ezetimibe); Drug: Lipid Modifying Therapy (LMT)

Ezetimibe 10 mg

ACTIVE COMPARATOR

Ezetimibe 10 mg capsule daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.

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

Interventions

Alirocumab DRUG

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.

Also known as: REGN727/SAR236553, Praluent

Alirocumab 75 /up to 150 mg Q2W

Placebo (for alirocumab) DRUG

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.

Ezetimibe 10 mg

Ezetimibe DRUG

One over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.

Ezetimibe 10 mg

Placebo (for ezetimibe) DRUG

One capsule once daily orally at approximately the same time of the day with or without food.

Alirocumab 75 /up to 150 mg Q2W

Lipid Modifying Therapy (LMT) DRUG

Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.

Alirocumab 75 /up to 150 mg Q2W; Ezetimibe 10 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Sanofi: lead
• Regeneron Pharmaceuticals: collaborator

Study Sites (126)

Investigational Site Number 840980

Birmingham, Alabama, 35209, United States

Location

Investigational Site Number 840918

Phoenix, Arizona, 85032, United States

Location

Investigational Site Number 840925

Tucson, Arizona, United States

Location

Investigational Site Number 840959

Anaheim, California, 92801, United States

Location

Investigational Site Number 840301

Beverly Hills, California, 90211, United States

Location

Investigational Site Number 840933

Chino, California, 91710, United States

Location

Investigational Site Number 840991

Lincoln, California, 95648, United States

Location

Investigational Site Number 840979

Los Angeles, California, 90057, United States

Location

Investigational Site Number 840952

Palm Springs, California, 92262, United States

Location

Investigational Site Number 840930

Thousand Oaks, California, 91360, United States

Location

Investigational Site Number 840921

Vista, California, 92083, United States

Location

Investigational Site Number 840962

Boynton Beach, Florida, 33472, United States

Location

Investigational Site Number 840987

Bradenton, Florida, 34203, United States

Location

Investigational Site Number 840302

Clearwater, Florida, 33756, United States

Location

Investigational Site Number 840935

Jacksonville, Florida, 32223, United States

Location

Investigational Site Number 840903

Miami, Florida, 33126, United States

Location

Investigational Site Number 840920

Miami, Florida, United States

Location

Investigational Site Number 840943

Ocala, Florida, 34471, United States

Location

Investigational Site Number 840981

Oveido, Florida, 32765, United States

Location

Investigational Site Number 840961

Port Orange, Florida, 32127, United States

Location

Investigational Site Number 840303

Sarasota, Florida, 34239, United States

Location

Investigational Site Number 840986

St. Petersburg, Florida, United States

Location

Investigational Site Number 840988

St. Petersburg, Florida, United States

Location

Investigational Site Number 840995

Meridian, Idaho, 83646, United States

Location

Investigational Site Number 840902

Evansville, Indiana, 47714, United States

Location

Investigational Site Number 840960

Topeka, Kansas, 66606, United States

Location

Investigational Site Number 840940

Oxon Hill, Maryland, 20745, United States

Location

Investigational Site Number 840966

Fall River, Massachusetts, 02720, United States

Location

Investigational Site Number 840917

Kansas City, Missouri, 64114, United States

Location

Investigational Site Number 840998

St Louis, Missouri, 63131, United States

Location

Investigational Site Number 840946

Butte, Montana, 59701, United States

Location

Investigational Site Number 840914

Lincoln, Nebraska, 68510, United States

Location

Investigational Site Number 840949

Albuquerque, New Mexico, 87106, United States

Location

Investigational Site Number 840974

New Windsor, New York, 12553, United States

Location

Investigational Site Number 840955

Greenville, North Carolina, 27834, United States

Location

Investigational Site Number 840938

Lexington, North Carolina, 27292, United States

Location

Investigational Site Number 840976

Smithfield, North Carolina, 27577, United States

Location

Investigational Site Number 840985

Winston-Salem, North Carolina, 27103, United States

Location

Investigational Site Number 840963

Cincinnati, Ohio, 45219, United States

Location

Investigational Site Number 840970

Lyndhust, Ohio, 44124, United States

Location

Investigational Site Number 840906

Marion, Ohio, 43302, United States

Location

Investigational Site Number 840997

Marion, Ohio, 43302, United States

Location

Investigational Site Number 840964

Perrysburg, Ohio, 43551, United States

Location

Investigational Site Number 840913

Charleston, South Carolina, 29412, United States

Location

Investigational Site Number 840912

Greer, South Carolina, 29651, United States

Location

Investigational Site Number 840992

Summerville, South Carolina, 29485, United States

Location

Investigational Site Number 840932

Bristol, Tennessee, 37620, United States

Location

Investigational Site Number 840944

Nashville, Tennessee, 37205, United States

Location

Investigational Site Number 840994

Fort Worth, Texas, 76104, United States

Location

Investigational Site Number 840973

Houston, Texas, 77070, United States

Location

Investigational Site Number 840939

Houston, Texas, 77074, United States

Location

Investigational Site Number 840945

Sugar Land, Texas, 77479, United States

Location

Investigational Site Number 840971

Tomball, Texas, 77375, United States

Location

Investigational Site Number 840982

Orem, Utah, 84058, United States

Location

Investigational Site Number 840931

Norfolk, Virginia, 23502, United States

Location

Investigational Site Number 840984

Richmond, Virginia, 23227, United States

Location

Investigational Site Number 840928

Renton, Washington, 98055, United States

Location

Investigational Site Number 840990

Spokane, Washington, 99204, United States

Location

Investigational Site Number 124902

Brampton, L6T 3J1, Canada

Location

Investigational Site Number 124914

Mirabel, J7J 2K8, Canada

Location

Investigational Site Number 124903

Montreal, H1T 3Y7, Canada

Location

Investigational Site Number 124918

Toronto, M9V 4B4, Canada

Location

Investigational Site Number 208913

Esbjerg, 6700, Denmark

Location

Investigational Site Number 208914

Glostrup Municipality, 2600, Denmark

Location

Investigational Site Number 208905

Hellerup, 2900, Denmark

Location

Investigational Site Number 208911

Herlev, 2730, Denmark

Location

Investigational Site Number 208907

Hvidovre, 2650, Denmark

Location

Investigational Site Number 208901

København S, 2300, Denmark

Location

Investigational Site Number 208906

Køge, 4600, Denmark

Location

Investigational Site Number 208908

Roskilde, 4000, Denmark

Location

Investigational Site Number 208903

Silkeborg, 8600, Denmark

Location

Investigational Site Number 250906

Dijon, 21079, France

Location

Investigational Site Number 250907

Montpellier, 34295, France

Location

Investigational Site Number 250903

Nantes, 44093, France

Location

Investigational Site Number 250905

Nîmes, 30900, France

Location

Investigational Site Number 348908

Budapest, 1036, Hungary

Location

Investigational Site Number 348901

Budapest, 1134, Hungary

Location

Investigational Site Number 348903

Budapest, 1134, Hungary

Location

Investigational Site Number 348905

Debrecen, 4032, Hungary

Location

Investigational Site Number 348906

Székesfehérvár, 8000, Hungary

Location

Investigational Site Number 376908

Holon, 58100, Israel

Location

Investigational Site Number 376903

Kfar Saba, 44281, Israel

Location

Investigational Site Number 376906

Ofakim, 80300, Israel

Location

Investigational Site Number 376902

Petah Tikva, Israel

Location

Investigational Site Number 376904

Rehovot, 76100, Israel

Location

Investigational Site Number 376907

Safed, 13100, Israel

Location

Investigational Site Number 376901

Tel Aviv, 64239, Israel

Location

Investigational Site Number 643906

Barnaul, 656055, Russia

Location

Investigational Site Number 643903

Kemerovo, 650002, Russia

Location

Investigational Site Number 643927

Moscow, 111539, Russia

Location

Investigational Site Number 643928

Moscow, 111539, Russia

Location

Investigational Site Number 643931

Moscow, 115404, Russia

Location

Investigational Site Number 643924

Moscow, 119048, Russia

Location

Investigational Site Number 643932

Moscow, 121374, Russia

Location

Investigational Site Number 643908

Moscow, 121552, Russia

Location

Investigational Site Number 643904

Moscow, 129090, Russia

Location

Investigational Site Number 643911

Orenburg, 450000, Russia

Location

Investigational Site Number 643921

Ryazan, 390026, Russia

Location

Investigational Site Number 643925

Saint Petersburg, 197110, Russia

Location

Investigational Site Number 643922

Saint Petersburg, 198205, Russia

Location

Investigational Site Number 643914

Saint Petersburg, 199106, Russia

Location

Investigational Site Number 643929

Saratov, 410028, Russia

Location

Investigational Site Number 710917

Alberton, 1450, South Africa

Location

Investigational Site Number 710909

Bloemfontein, 9301, South Africa

Location

Investigational Site Number 710914

Bloemfontein, 9301, South Africa

Location

Investigational Site Number 710905

Cape Town, 7500, South Africa

Location

Investigational Site Number 710904

Cape Town, 7925, South Africa

Location

Investigational Site Number 710918

Middelburg, 1055, South Africa

Location

Investigational Site Number 710913

Pretoria, 0002, South Africa

Location

Investigational Site Number 710915

Somerset West, 7130, South Africa

Location

Investigational Site Number 410908

Anyang-si, 431-070, South Korea

Location

Investigational Site Number 410920

Busan, 602-715, South Korea

Location

Investigational Site Number 410926

Daegu, 700-712, South Korea

Location

Investigational Site Number 410923

Gwangju, 501-757, South Korea

Location

Investigational Site Number 410909

Seoul, 110-744, South Korea

Location

Investigational Site Number 410922

Seoul, 120-752, South Korea

Location

Investigational Site Number 410921

Seoul, 135-710, South Korea

Location

Investigational Site Number 410905

Seoul, 135-720, South Korea

Location

Investigational Site Number 410901

Seoul, 137-701, South Korea

Location

Investigational Site Number 410914

Seoul, 138-736, South Korea

Location

Investigational Site Number 410924

Seoul, 156-707, South Korea

Location

Investigational Site Number 410915

Suwon, 443-721, South Korea

Location

Investigational Site Number 410913

Uijeongbu-si, 480-717, South Korea

Location

Investigational Site Number 410927

Wŏnju, 220-701, South Korea

Location

Investigational Site Number 804905

Kiev, 02091, Ukraine

Location

Investigational Site Number 804902

Uzhhorod, 88009, Ukraine

Location

Related Publications (5)

• 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.

  PMID: 25240705 BACKGROUND

• 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.

  PMID: 25687353 RESULT

• Mahmood T, Minnier J, Ito MK, Li QH, Koren A, Kam IW, Fazio S, Shapiro MD. Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: A pooled analysis from 10 ODYSSEY Phase 3 studies. Eur J Prev Cardiol. 2021 Jul 23;28(8):816-822. doi: 10.1177/2047487320915803. Epub 2020 Apr 10.

  PMID: 34298554 DERIVED

• 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.

  PMID: 30183102 DERIVED

• 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. doi: 10.1161/CIRCULATIONAHA.116.024604. Epub 2016 Oct 24.

  PMID: 27777279 DERIVED

MeSH Terms

Conditions

Hypercholesterolemia

Interventions

alirocumab; Ezetimibe

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Manual reclassification was done by the Sponsor for the "other reasons" of non-completion of study as specified in the electronic case report form (eCRF).

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-US@sanofi.com

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2012
• First Posted: July 18, 2012
• Study Start: August 1, 2012
• Primary Completion: May 1, 2014
• Study Completion: July 1, 2015
• Last Updated: August 4, 2016
• Results First Posted: November 6, 2015

Record last verified: 2016-06

Locations

KR (14); CA (4); HU (5); ZA (8); UA (2); IL (7); US (58); RU (15); DK (9); FR (4)