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)

NCT01709513 | Completed Phase 3 Results DMC

• 1 other identifier: R727-CL-1119
• Study Type: interventional
• Target: 314
• Locations: 8 countries
• Sites: 70

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.

Conditions

Hypercholesterolemia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (23)

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

  From Baseline to Week 24

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

  From Baseline to Week 12

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

  From Baseline to Week 12

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

  From Baseline to Week 24

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

  From Baseline to Week 24

Other Outcomes (2)

• Percentage of Participants Who Experienced Skeletal Muscle-related Adverse Event (AE)

  From Baseline up to Week 24

• Percent Change From Baseline in Calculated LDL-C at Week 24 Versus Atorvastatin - Raw Data Description - Intent-To-Treat (ITT) Analysis

  From Baseline up to Week 24

Study Arms (3)

Atorvastatin (statin rechallenge arm)

OTHER

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; Drug: Placebo

Ezetimibe

ACTIVE COMPARATOR

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; Drug: Placebo

Alirocumab 75 mg/ up to 150 mg

EXPERIMENTAL

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; Drug: Placebo

Interventions

Atorvastatin DRUG

Atorvastatin over-encapsulated tablets.

Atorvastatin (statin rechallenge arm)

Ezetimibe DRUG

Ezetimibe over-encapsulated tablet.

Also known as: Zetia

Ezetimibe

Alirocumab DRUG

Alirocumab SC injection of 1 mL into the abdomen, thigh, or outer area of the upper arm.

Also known as: REGN727/SAR236553

Alirocumab 75 mg/ up to 150 mg

Placebo DRUG

Placebo for alirocumab, ezitimibe and atorvastatin.

Alirocumab 75 mg/ up to 150 mg; Atorvastatin (statin rechallenge arm); Ezetimibe

Eligibility Criteria

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

You may qualify if:

• 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
• Provide signed informed consent

You may not qualify if:

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

Sponsors & Collaborators

• Regeneron Pharmaceuticals: lead
• Sanofi: collaborator

Study Sites (70)

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Anaheim, California, United States

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Beverly Hills, California, United States

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Mission Viejo, California, United States

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Newport Beach, California, United States

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Northridge, California, United States

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Thousand Oaks, California, United States

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Hartford, Connecticut, United States

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Boynton Beach, Florida, United States

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Jacksonville, Florida, United States

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Lakeland, Florida, United States

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Pembroke Pines, Florida, United States

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Sarasota, Florida, United States

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Tampa, Florida, United States

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Trinity, Florida, United States

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Addison, Illinois, United States

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Chicago, Illinois, United States

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Indianapolis, Indiana, United States

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Kansas City, Kansas, United States

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Auburn, Maine, United States

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Boston, Massachusetts, United States

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Minneapolis, Minnesota, United States

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Rochester, Minnesota, United States

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St Louis, Missouri, United States

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Clifton, New Jersey, United States

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New York, New York, United States

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Poughkeepsie, New York, United States

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Durham, North Carolina, United States

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Cincinnati, Ohio, United States

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Marion, Ohio, United States

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Danville, Pennsylvania, United States

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Philadelphia, Pennsylvania, United States

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Port Matilda, Pennsylvania, United States

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Scranton, Pennsylvania, United States

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Wilkes-Barre, Pennsylvania, United States

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Summerville, South Carolina, United States

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Kingsport, Tennessee, United States

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Nashville, Tennessee, United States

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Dallas, Texas, United States

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Fort Worth, Texas, United States

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Salt Lake City, Utah, United States

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Richmond, Virginia, United States

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Feldkirch, Austria

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Graz, Austria

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Innsbruck, Austria

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Chicoutimi, Quebec, Canada

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Montreal (2 Locations), Quebec, Canada

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Sainte-Foy, Quebec, Canada

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Bron, France

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Dijon, France

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Lille, France

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Paris, France

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Saint-Herblain, France

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Vénissieux, France

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Holon, Israel

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Jerusalem, Israel

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Ofakim, Israel

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Safed, Israel

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Tel Litwinsky, Israel

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Cinisello Balsamo, Italy

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Napoli, Italy

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Palermo, Italy

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Roma, Italy

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Oslo (2 Locations), Norway

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Burton-on-Trent, United Kingdom

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Chesterfield, United Kingdom

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Isle of White, United Kingdom

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Londonderry/N. Ireland, United Kingdom

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Peterborough, United Kingdom

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Salford, United Kingdom

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Stevenage, United Kingdom

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Related Publications (7)

• 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.

  PMID: 25499937 BACKGROUND

• 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.

  PMID: 26687696 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

• 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.

  PMID: 32192644 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

• 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.

  PMID: 28964736 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

Atorvastatin; Ezetimibe; alirocumab

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Azetidines; Azetines

Results Point of Contact

• Title: Clinical Trial Administrator
• Organization: Regeneron Pharmaceuticals, Inc

clinicaltrials@regeneron.com

Study Officials

• Clinical Trial Management

  Regeneron Pharmaceuticals

  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: October 8, 2012
• First Posted: October 18, 2012
• Study Start: September 30, 2012
• Primary Completion: May 31, 2014
• Study Completion: May 31, 2017
• Last Updated: June 23, 2020
• Results First Posted: August 28, 2015

Record last verified: 2020-06

Locations

IT (4); GB (7); AU (3); FR (6); NO (1); CA (3); IL (5); US (41)