Study of Alirocumab (REGN727/SAR236553) in Patients With Primary Hypercholesterolemia and Moderate, High, or Very High Cardiovascular (CV) Risk, Who Are Intolerant to Statins (ODYSSEY ALTERNATIVE)

• ClinicalTrials.gov Identifier: NCT01709513
• Recruitment Status: Completed
• First Posted: October 18, 2012
• Results First Posted: August 28, 2015
• Last Update Posted: June 23, 2020
• Sponsor: Regeneron Pharmaceuticals
• Collaborator: Sanofi
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Study Description

Brief Summary:

This is a randomized, double-blind, double-dummy, active-controlled, parallel-group, multi-national, multi-center study to compare alirocumab (REGN727/SAR236553) versus ezetimibe in participants with primary hypercholesterolemia and moderate, high, or very high CV risk, who are intolerant to statins. An atorvastatin arm is added to determine that the population selected in the study is a truly statin intolerant population by assessing skeletal muscle-related adverse events.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Atorvastatin; Drug: Ezetimibe; Drug: Alirocumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 314 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Double-Dummy, Active-Controlled Study to Evaluate the Efficacy and Safety of REGN727/SAR236553 in Patients With Primary Hypercholesterolemia Who Are Intolerant to Statins
• Actual Study Start Date: September 30, 2012
• Actual Primary Completion Date: May 31, 2014
• Actual Study Completion Date: May 31, 2017

Arms and Interventions

Arm	Intervention/treatment
Atorvastatin (statin rechallenge arm); Atorvastatin 20 mg over-encapsulated tablets orally once daily (QD) for 24 weeks and placebo (for alirocumab) subcutaneous (SC) injection every two weeks (Q2W) for 24 weeks added to stable lipid-modifying therapy (LMT).	Drug: Atorvastatin; Atorvastatin over-encapsulated tablets.; Drug: Placebo; Placebo for alirocumab, ezitimibe and atorvastatin.
Active Comparator: Ezetimibe; Ezetimibe 10 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable LMT.	Drug: Ezetimibe; Ezetimibe over-encapsulated tablet.; Other Name: Zetia; Drug: Placebo; Placebo for alirocumab, ezitimibe and atorvastatin.
Experimental: Alirocumab 75 mg/ up to 150 mg; Alirocumab 75 mg SC injection Q2W for 24 weeks and placebo (for atorvastatin/ezetimibe) over-encapsulated tablets orally QD for 24 weeks added to stable LMT. 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 cardiovascular risk.	Drug: Alirocumab; Alirocumab SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.; Other Name: REGN727/SAR236553; Drug: Placebo; Placebo for alirocumab, ezitimibe and atorvastatin.

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 24 ]
   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).

Secondary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 24 - On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
2. Percent Change From Baseline in Calculated LDL--C at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
3. Percent Change From Baseline in Calculated LDL-C at Week 12 - On--Treatment Analysis [ Time Frame: From Baseline to Week 12 ]
   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, whichever came first) (on-treatment analysis).
4. Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 -- ITT Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
5. Percent Change From Baseline in Apo B at Week 24 -- On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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, 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 24 ]
   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.
7. Percent Change From Baseline in Non--HDL-C at Week 24 -- On--Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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, whichever came first).
8. Percent Change From Baseline in Total Cholesterol (Total--C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
9. Percent Change From Baseline in Apo B at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
10. Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    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.
11. Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    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.
12. Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 24 ]
    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).
13. Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or Moderate or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    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, whichever came first (on-treatment analysis).
14. Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 24 ]
    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).
15. Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis [ Time Frame: Up to Week 24 ]
    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, whichever came first (on-treatment analysis).
16. Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
17. Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
18. Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
19. Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
20. Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
21. Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis
22. Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Combined Estimate for Adjusted Mean (Standard Error) at Week 24 from multiple imputation followed by robust regression including all available post-baseline data from Week 4 to Week 24 regardless of status on or off-treatment.
23. Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis.

Other Outcome Measures:

1. Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE) [ Time Frame: From Baseline up to Week 24 ]
   Skeletal muscle-related adverse events were a predefined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness and muscle fatigue. Events that developed during treatment emergent adverse events period (the time from the first double-blindstudy treatment [injection or capsules, whichever came first] up to the day of the last double-blind injection + 70 days ) are reported.
2. Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis [ Time Frame: From Baseline up to Week 24 ]

Eligibility Criteria

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

Criteria

Inclusion:

1. Patients with primary hypercholesterolemia [Heterozygous Familial Hypercholesterolemia (heFH) or non-FH] with moderate, high or very high CV risk and a history of statin intolerance
2. Provide signed informed consent

Exclusion:

1. Calculated serum LDL-C <70 mg/dL (1.81 mmol/L) and very high CV risk at the screening visit
2. Calculated serum LDL-C <100 mg/dL (2.59 mmol/L) and high or moderate CV risk at the screening visit
3. A 10-year fatal cardiovascular disease risk score <1% at the screening visit

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

Contacts and Locations

Locations

United States, California

Anaheim, California, United States

Beverly Hills, California, United States

Mission Viejo, California, United States

Newport Beach, California, United States

Northridge, California, United States

Thousand Oaks, California, United States

United States, Connecticut

Hartford, Connecticut, United States

United States, Florida

Boynton Beach, Florida, United States

Jacksonville, Florida, United States

Lakeland, Florida, United States

Pembroke Pines, Florida, United States

Sarasota, Florida, United States

Tampa, Florida, United States

Trinity, Florida, United States

United States, Illinois

Addison, Illinois, United States

Chicago, Illinois, United States

United States, Indiana

Indianapolis, Indiana, United States

United States, Kansas

Kansas City, Kansas, United States

United States, Maine

Auburn, Maine, United States

United States, Massachusetts

Boston, Massachusetts, United States

United States, Minnesota

Minneapolis, Minnesota, United States

Rochester, Minnesota, United States

United States, Missouri

Saint Louis, Missouri, United States

United States, New Jersey

Clifton, New Jersey, United States

United States, New York

New York, New York, United States

Poughkeepsie, New York, United States

United States, North Carolina

Durham, North Carolina, United States

United States, Ohio

Cincinnati, Ohio, United States

Marion, Ohio, United States

United States, Pennsylvania

Danville, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

Port Matilda, Pennsylvania, United States

Scranton, Pennsylvania, United States

Wilkes-Barre, Pennsylvania, United States

United States, South Carolina

Summerville, South Carolina, United States

United States, Tennessee

Kingsport, Tennessee, United States

Nashville, Tennessee, United States

United States, Texas

Dallas, Texas, United States

Fort Worth, Texas, United States

United States, Utah

Salt Lake City, Utah, United States

United States, Virginia

Richmond, Virginia, United States

Austria

Feldkirch, Austria

Graz, Austria

Innsbruck, Austria

Canada, Quebec

Chicoutimi, Quebec, Canada

Montreal (2 locations), Quebec, Canada

Sainte-Foy, Quebec, Canada

France

Bron, France

Dijon, France

Lille, France

Paris, France

Saint-Herblain, France

Venissieux, France

Israel

Holon, Israel

Jerusalem, Israel

Ofakim, Israel

Safed, Israel

Tel-Hashomer, Israel

Italy

Cinisello Balsamo, Italy

Napoli, Italy

Palermo, Italy

Roma, Italy

Norway

Oslo (2 Locations), Norway

United Kingdom

Burton-on-Trent, United Kingdom

Chesterfield, United Kingdom

Isle Of White, United Kingdom

Londonderry/N. Ireland, United Kingdom

Peterborough, United Kingdom

Salford, United Kingdom

Stevenage, United Kingdom

Sponsors and Collaborators

Regeneron Pharmaceuticals

Sanofi

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

More Information

Publications of Results:

Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA; ODYSSEY ALTERNATIVE Investigators. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015 Nov-Dec;9(6):758-769. doi: 10.1016/j.jacl.2015.08.006. Epub 2015 Aug 29.

Other Publications:

Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, Gipe D. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. 2014 Nov-Dec;8(6):554-561. doi: 10.1016/j.jacl.2014.09.007. Epub 2014 Sep 19.

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

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.

Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Baccara-Dinet MT, Zhao J, Donahue S, Ali S, Manvelian G, Pordy R. Efficacy and safety of alirocumab in statin-intolerant patients over 3 years: open-label treatment period of the ODYSSEY ALTERNATIVE trial. J Clin Lipidol. 2020 Jan-Feb;14(1):88-97.e2. doi: 10.1016/j.jacl.2020.01.001. Epub 2020 Jan 13.

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.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP. Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia. J Clin Lipidol. 2017 Nov-Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum In: J Clin Lipidol. 2020 Sep - Oct;14(5):742.

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.

• Responsible Party: Regeneron Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01709513
• Other Study ID Numbers: R727-CL-1119
• First Posted: October 18, 2012
• Results First Posted: August 28, 2015
• Last Update Posted: June 23, 2020
• Last Verified: June 2020

Additional relevant MeSH terms:

Alirocumab; Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Ezetimibe; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; PCSK9 Inhibitors; Serine Proteinase Inhibitors; Protease Inhibitors