Study of Alirocumab (REGN727/SAR236553) added-on to Rosuvastatin Versus Other Lipid Modifying Treatments (LMT) (ODYSSEY OPTIONS II)

A Randomized, Double-Blind Study of the Efficacy and Safety of REGN727 Added-on to Rosuvastatin Versus Ezetimibe Added-on to Rosuvastatin Versus Rosuvastatin Dose Increase in Patients Who Are Not Controlled on Rosuvastatin

To evaluate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab (REGN727/SAR236553) as an add-on therapy to other LMT in patients with hypercholesterolemia at high cardiovascular (CV) risk.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Rosuvastatin; Drug: Placebo; Drug: Ezetimibe; Drug: Alirocumab

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Herston, Australia
  • New Lambton Heights, Australia
  • Perth, Australia
  • Sherwood, Australia
  • Woolloongabba, Australia
• Canada
  • Ontario
    • Brampton, Ontario, Canada
    • Burlington, Ontario, Canada
    • Etobicoke, Ontario, Canada
    • London, Ontario, Canada
    • Newmarket, Ontario, Canada
    • Thornhill, Ontario, Canada
    • Toronto, Ontario, Canada
  • Quebec
    • Chicoutimi, Quebec, Canada
• France
  • Dijon, France
  • Lille, France
• Germany
  • Bad Oeynhausen, Germany
  • Berlin, Germany
  • Koeln, Germany
  • Regensburg, Germany
  • Ulm, Germany
• Italy
  • Chieti, Italy
  • Genova, Italy
  • Napoli, Italy
  • Palermo, Italy
  • Roma, Italy
    • (2 Locations)
• Mexico
  • Baja California, Mexico
  • Distrito Federal, Mexico
  • Guadalajara, Mexico
    • (3 Locations)
  • Monterrey, Mexico
  • Zapopan Jalisco, Mexico
• Spain
  • Barcelona, Spain
    • (2 Locations)
  • Madrid, Spain
  • Santiago, Spain
  • Sevilla, Spain
• United Kingdom
  • Chester, United Kingdom
  • Peterborough, United Kingdom
  • Salford, United Kingdom
  • Stevenage, United Kingdom
  • West Midlands
    • West Bromwich, West Midlands, United Kingdom
• United States
  • Arizona
    • Chandler, Arizona, United States
    • Tucson, Arizona, United States
  • California
    • Anaheim, California, United States
    • Beverly Hills, California, United States
    • Fair Oaks, California, United States
    • Newport Beach, California, United States
    • Northridge, California, United States
    • Sacramento, California, United States
    • Walnut Creek, California, United States
  • Connecticut
    • Milford, Connecticut, United States
  • Florida
    • Atlantis, Florida, United States
    • Bradenton, Florida, United States
    • Clearwater, Florida, United States
    • Fort Lauderdale, Florida, United States
    • Jacksonville, Florida, United States
    • Lakeland, Florida, United States
    • Miami, Florida, United States
      • (2 Locations)
    • Oviedo, Florida, United States
    • Pinellas Park, Florida, United States
    • Port Orange, Florida, United States
    • Sarasota, Florida, United States
    • Tampa, Florida, United States
    • West Palm Beach, Florida, United States
    • Winter Park, Florida, United States
  • Idaho
    • Boise, Idaho, United States
  • Illinois
    • Morton, Illinois, United States
  • Indiana
    • Evansville, Indiana, United States
    • Indianapolis, Indiana, United States
  • Kansas
    • Newton, Kansas, United States
    • Overland Park, Kansas, United States
    • Wichita, Kansas, United States
  • Kentucky
    • Lexington, Kentucky, United States
    • Louisville, Kentucky, United States
  • Maine
    • Auburn, Maine, United States
  • Maryland
    • Bethesda, Maryland, United States
  • Minnesota
    • Edina, Minnesota, United States
    • Rochester, Minnesota, United States
  • Mississippi
    • Olive Branch, Mississippi, United States
    • Port Gibson, Mississippi, United States
  • Missouri
    • Saint Louis, Missouri, United States
  • Montana
    • Butte, Montana, United States
  • New York
    • Williamsville, New York, United States
  • Ohio
    • Cincinnati, Ohio, United States
    • Marion, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Rhode Island
    • Warwick, Rhode Island, United States
  • South Carolina
    • Greer, South Carolina, United States
    • Summerville, South Carolina, United States
  • Tennessee
    • Kingsport, Tennessee, United States
  • Texas
    • Dallas, Texas, United States
    • Fort Worth, Texas, United States
    • Houston, Texas, United States
  • Utah
    • Bountiful, Utah, United States
    • Salt Lake City, Utah, United States

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients with LDL-C greater than or equal to 70 mg/dL at the screening visit and who are not adequately controlled with a stable daily dose of rosuvastatin, with or without other LMT.

   OR

2. Patients with screening LDL-C greater than or equal to 100 mg/dL who are not adequately controlled with a stable daily dose of rosuvastatin before the screening visit, with or without other LMT.

Exclusion Criteria:

1. LDL-C less than 70 mg/dL at the screening visit in patients with history of documented cardiovascular disease (CVD)
2. LDL-C less than 100 mg/dL at the screening visit in patients without history of documented coronary heart disease (CHD) or non-CHD CVD, but with other risk factors
3. Homozygous familial hypercholesterolemia (FH) (clinically or previous genotyping)
4. Recent (within 3 months prior to the screening visit) myocardial infarction (MI), unstable angina leading to hospitalization, percutaneous coronary intervention (PCI), coronary bypass graft surgery (CABG), uncontrolled cardiac arrhythmia, stroke, transient ischemic attack, carotid revascularization, endovascular procedure or surgical intervention for peripheral vascular disease
5. Newly diagnosed (within 3 months prior to randomization visit) or poorly controlled diabetes
6. Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins

(The inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a patient's potential participation in this clinical trial).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Rosuvastatin 20 mg; Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received rosuvastatin 20 mg over-encapsulated tablet orally once daily (QD), placebo for alirocumab SC injection every two weeks (Q2W), and placebo for ezetimibe over-encapsulated tablet orally QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.
Active Comparator: Ezetimibe 10 mg + Rosuvastatin 10 mg; Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received ezetimibe 10 mg over-encapsulated tablet orally QD, rosuvastatin 10 mg over-encapsulated tablet orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.; Drug: Ezetimibe; Ezetimibe over-encapsulated tablets orally.; Other Names: Ezetrol
Experimental: Alirocumab 75 mg/up to 150 mg + Rosuvastatin 10 mg; Participants, who were receiving rosuvastatin 10 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg SC injection Q2W, rosuvastatin 10 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.; Drug: Alirocumab; Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.; Other Names: REGN727/SAR236553
Active Comparator: Rosuvastatin 40 mg; Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received rosuvastatin 40 mg over-encapsulated tablet orally QD, placebo for alirocumab Q2W SC injection, and placebo for ezetimibe QD over-encapsulated tablet orally added to stable LMT for 24 weeks.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.
Active Comparator: Ezetimibe 10 mg + Rosuvastatin 20 mg; Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received ezetimibe 10 mg over-encapsulated tablet orally QD, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for alirocumab Q2W SC injection added to stable LMT for 24 weeks.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.; Drug: Ezetimibe; Ezetimibe over-encapsulated tablets orally.; Other Names: Ezetrol
Experimental: Alirocumab 75 mg/ up to 150 mg + Rosuvastatin 20 mg; Participants, who were receiving rosuvastatin 20 mg over-encapsulated tablet orally at baseline, received alirocumab 75 mg Q2W SC injection, rosuvastatin 20 mg over-encapsulated tablet orally QD, and placebo for ezetimibe over-encapsulated tablet orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.	Drug: Rosuvastatin; Rosuvastatin over-encapsulated tablets orally.; Other Names: Crestor; Drug: Placebo; Placebo for alirocumab and ezetimibe.; Drug: Alirocumab; Alirocumab administered as a SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.; Other Names: REGN727/SAR236553

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis	Calculated LDL-C values were obtained from Friedewald formula. 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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).	From Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis	Calculated LDL-C values were obtained from Friedewald formula. 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 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).	From Baseline to Week 24
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment (ITT analysis).	From Baseline to Week 12
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first) (on-treatment analysis).	From Baseline to Week 12
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apo B 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 24 (ie. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Non-HDL-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 24 (i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first).	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 12
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 24 regardless of status on- or off-treatment.	From Baseline to Week 12
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 24 regardless of status on- or off-treatment.	From Baseline to Week 12
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).	Up to Week 24
Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).	Up to Week 24
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model for handling of missing data. All available post-baseline data from Week 4 to week 24 regardless of status on- or off-treatment were included in the imputation model (ITT analysis).	Up to Week 24
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis	Calculated LDL-C values were obtained from Friedewald formula. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 24 i.e. up to 21 days after last injection or 3 days after the last capsule [whatever rosuvastatin or ezetimibe], whichever came first (on-treatment analysis).	Up to Week 24
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis	Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis	Adjusted means and standard errors at Week 24 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apo 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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis	Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 12
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 24 regardless of status on- or off-treatment.	From Baseline to Week 12
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis	Adjusted means and standard errors at Week 12 from a multiple imputation approach model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 12
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 24 regardless of status on- or off-treatment.	From Baseline to Week 12

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Collaborators: Sanofi

Publications and helpful links

General Publications

• 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.
• 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. doi: 10.1161/CIRCULATIONAHA.116.024604. Epub 2016 Oct 24.
• Farnier M, Jones P, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, Du Y, Hanotin C, Donahue S. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016 Jan;244:138-46. doi: 10.1016/j.atherosclerosis.2015.11.010. Epub 2015 Nov 14.
• Robinson JG, Colhoun HM, Bays HE, Jones PH, Du Y, Hanotin C, Donahue S. Efficacy and safety of alirocumab as add-on therapy in high-cardiovascular-risk patients with hypercholesterolemia not adequately controlled with atorvastatin (20 or 40 mg) or rosuvastatin (10 or 20 mg): design and rationale of the ODYSSEY OPTIONS Studies. Clin Cardiol. 2014 Oct;37(10):597-604. doi: 10.1002/clc.22327. Epub 2014 Sep 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2012
• Primary Completion (Actual): April 30, 2014
• Study Completion (Actual): May 31, 2014

Study Registration Dates

• First Submitted: November 9, 2012
• First Submitted That Met QC Criteria: November 14, 2012
• First Posted (Estimate): November 21, 2012

Study Record Updates

• Last Update Posted (Actual): April 7, 2020
• Last Update Submitted That Met QC Criteria: March 26, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Rosuvastatin Calcium; Ezetimibe
• Other Study ID Numbers: R727-CL-1118