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HypercholesterolemiaPhase 3NCT01709513

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)

A Phase 3 study testing Atorvastatin, Ezetimibe and Alirocumab in people with Hypercholesterolemia, run by Regeneron Pharmaceuticals at 70 sites in 8 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hypercholesterolemia
What is being tested?
Atorvastatin, Ezetimibe and Alirocumab
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
314 participants
Where
70 sitesin 8 countries
Study dates
30 Sep 2012to 31 May 2017
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

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

Trial locations and contacts

70 sites in 8 countries.

70 sites in 8 countries

United States41 sites

  • Study site

    Addison, Illinois

  • Study site

    Anaheim, California

  • Study site

    Auburn, Maine

  • Study site

    Beverly Hills, California

  • Study site

    Boston, Massachusetts

  • Study site

    Boynton Beach, Florida

  • Study site

    Chicago, Illinois

  • Study site

    Cincinnati, Ohio

  • Study site

    Clifton, New Jersey

  • Study site

    Dallas, Texas

  • Study site

    Danville, Pennsylvania

  • Study site

    Durham, North Carolina

  • Study site

    Fort Worth, Texas

  • Study site

    Hartford, Connecticut

  • Study site

    Indianapolis, Indiana

  • Study site

    Jacksonville, Florida

  • Study site

    Kansas City, Kansas

  • Study site

    Kingsport, Tennessee

  • Study site

    Lakeland, Florida

  • Study site

    Marion, Ohio

  • Study site

    Minneapolis, Minnesota

  • Study site

    Mission Viejo, California

  • Study site

    Nashville, Tennessee

  • Study site

    New York, New York

  • Study site

    Newport Beach, California

  • Study site

    Northridge, California

  • Study site

    Pembroke Pines, Florida

  • Study site

    Philadelphia, Pennsylvania

  • Study site

    Port Matilda, Pennsylvania

  • Study site

    Poughkeepsie, New York

  • Study site

    Richmond, Virginia

  • Study site

    Rochester, Minnesota

  • Study site

    Salt Lake City, Utah

  • Study site

    Sarasota, Florida

  • Study site

    Scranton, Pennsylvania

  • Study site

    St Louis, Missouri

  • Study site

    Summerville, South Carolina

  • Study site

    Tampa, Florida

  • Study site

    Thousand Oaks, California

  • Study site

    Trinity, Florida

  • Study site

    Wilkes-Barre, Pennsylvania

Other trials in United States

United Kingdom7 sites

  • Study site

    Burton-on-Trent

  • Study site

    Chesterfield

  • Study site

    Isle of White

  • Study site

    Londonderry/N. Ireland

  • Study site

    Peterborough

  • Study site

    Salford

  • Study site

    Stevenage

Other trials in United Kingdom

France6 sites

  • Study site

    Bron

  • Study site

    Dijon

  • Study site

    Lille

  • Study site

    Paris

  • Study site

    Saint-Herblain

  • Study site

    Vénissieux

Other trials in France

Israel5 sites

  • Study site

    Holon

  • Study site

    Jerusalem

  • Study site

    Ofakim

  • Study site

    Safed

  • Study site

    Tel HaShomer

Other trials in Israel

Italy4 sites

  • Study site

    Cinisello Balsamo

  • Study site

    Naples

  • Study site

    Palermo

  • Study site

    Roma

Other trials in Italy

Austria3 sites

  • Study site

    Feldkirch

  • Study site

    Graz

  • Study site

    Innsbruck

Other trials in Austria

Canada3 sites

  • Study site

    Chicoutimi, Quebec

  • Study site

    Montreal (2 Locations), Quebec

  • Study site

    Sainte-Foy, Quebec

Other trials in Canada

Norway1 site

  • Study site

    Oslo (2 Locations)

Other trials in Norway

About this study

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

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.

Being tested
Atorvastatin, Ezetimibe, Alirocumab, Placebo
Medical subject headings
Hypercholesterolemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AtorvastatinDrug

    Atorvastatin over-encapsulated tablets.

  • EzetimibeDrug

    Also called Zetia

    Ezetimibe over-encapsulated tablet.

  • AlirocumabDrug

    Also called REGN727/SAR236553

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

  • PlaceboDrug

    Placebo for alirocumab, ezitimibe and atorvastatin.

Study groups in NCT01709513
Study groupRoleWhat they receive
Atorvastatin (statin rechallenge arm)OtherAtorvastatin 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).
Receives: Drug: Atorvastatin; Drug: Placebo
EzetimibeActive comparatorEzetimibe 10 mg over-encapsulated tablets orally QD for 24 weeks and placebo (for alirocumab) SC injection Q2W for 24 weeks added to stable LMT.
Receives: Drug: Ezetimibe; Drug: Placebo
Alirocumab 75 mg/ up to 150 mgExperimentalAlirocumab 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.
Receives: Drug: Alirocumab; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: From Baseline to Week 24

Secondary outcomes (23)

  1. 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 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).

    Measured: From Baseline to Week 24

  2. 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.

    Measured: From Baseline to Week 12

  3. 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, whichever came first) (on-treatment analysis).

    Measured: From Baseline to Week 12

  4. 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.

    Measured: From Baseline to Week 24

  5. 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 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).

    Measured: From Baseline to Week 24

  6. 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.

    Measured: From Baseline to Week 24

  7. 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, whichever came first).

    Measured: From Baseline to Week 24

  8. 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.

    Measured: From Baseline to Week 24

  9. 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.

    Measured: From Baseline to Week 12

  10. 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.

    Measured: From Baseline to Week 12

  11. 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.

    Measured: From Baseline to Week 12

  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

    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).

    Measured: Up to Week 24

  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

    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).

    Measured: Up to Week 24

  14. 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 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).

    Measured: Up to Week 24

  15. 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 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).

    Measured: Up to Week 24

  16. Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis

    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.

    Measured: From Baseline to Week 24

  17. 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.

    Measured: From Baseline to Week 24

  18. Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis

    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.

    Measured: From Baseline to Week 24

  19. 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.

    Measured: From Baseline to Week 24

  20. Percent Change From Baseline in Lipoprotein(a) at Week 12 -- ITT Analysis

    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.

    Measured: From Baseline to Week 12

  21. Percent Change in HDL-C From Baseline to Week 12 -- ITT Analysis

    Least-squares (LS) means and standard errors (SE) taken from MMRM (mixed-effect model with repeated measures) analysis

    Measured: From Baseline to Week 12

  22. Percent Change in Fasting Triglycerides From Baseline to Week 12 -- ITT Analysis

    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.

    Measured: From Baseline to Week 12

  23. Percent Change From Baseline in Apo A--1 at Week 12 -- ITT Analysis

    Least squares (LS) means and standard errors (SE) taken from MMRM (mixed effect model with repeated measures) analysis.

    Measured: From Baseline to Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Oct 2012 (estimated)
  2. Study start30 Sep 2012
  3. Primary completion31 May 2014
  4. Study completion31 May 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
314 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01709513
Sponsor's protocol ID
R727-CL-1119
Status last verified
Jun 2020
First submitted
8 Oct 2012
Last updated
23 Jun 2020
Data monitoring committee
Yes

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.

    PubMed 25499937

  • 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.

    PubMed 26687696

  • 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.

    PubMed 34298554

  • 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.

    PubMed 32192644

  • 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.

    PubMed 30183102

  • 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.

    PubMed 28964736

  • 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.

    PubMed 27777279

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Atorvastatin, Ezetimibe and Alirocumab in people with Hypercholesterolemia, run by Regeneron Pharmaceuticals at 70 sites in 8 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 70 sites in United States, United Kingdom, France, Israel, Italy and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Aug 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent--To-Treat (ITT) Analysis (time frame: From Baseline to Week 24). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01709513, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2020.

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