HypercholesterolemiaPhase 3NCT01644188

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

A Phase 3 study testing Alirocumab, Ezetimibe and Lipid Modifying Therapy (LMT) in people with Hypercholesterolemia, run by Sanofi at 126 sites in 10 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

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… Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Hypercholesterolemia
What is being tested?: Alirocumab, Ezetimibe and Lipid Modifying Therapy (LMT)
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 720 participants
Where: 126 sitesin 10 countries
Study dates: Aug 2012to Jul 2015
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

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).

Who cannot join

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.

Trial locations and contacts

126 sites in 10 countries.

Country

City, postcode or hospital

126 sites in 10 countries

United States58 sites

Investigational Site Number 840949
Albuquerque, New Mexico, 87106
Investigational Site Number 840959
Anaheim, California, 92801
Investigational Site Number 840301
Beverly Hills, California, 90211
Investigational Site Number 840980
Birmingham, Alabama, 35209
Investigational Site Number 840962
Boynton Beach, Florida, 33472
Investigational Site Number 840987
Bradenton, Florida, 34203
Investigational Site Number 840932
Bristol, Tennessee, 37620
Investigational Site Number 840946
Butte, Montana, 59701
Investigational Site Number 840913
Charleston, South Carolina, 29412
Investigational Site Number 840933
Chino, California, 91710
Investigational Site Number 840963
Cincinnati, Ohio, 45219
Investigational Site Number 840302
Clearwater, Florida, 33756
Investigational Site Number 840902
Evansville, Indiana, 47714
Investigational Site Number 840966
Fall River, Massachusetts, 02720
Investigational Site Number 840994
Fort Worth, Texas, 76104
Investigational Site Number 840955
Greenville, North Carolina, 27834
Investigational Site Number 840912
Greer, South Carolina, 29651
Investigational Site Number 840973
Houston, Texas, 77070
Investigational Site Number 840939
Houston, Texas, 77074
Investigational Site Number 840935
Jacksonville, Florida, 32223
Investigational Site Number 840917
Kansas City, Missouri, 64114
Investigational Site Number 840938
Lexington, North Carolina, 27292
Investigational Site Number 840991
Lincoln, California, 95648
Investigational Site Number 840914
Lincoln, Nebraska, 68510
Investigational Site Number 840979
Los Angeles, California, 90057
Investigational Site Number 840970
Lyndhust, Ohio, 44124
Investigational Site Number 840906
Marion, Ohio, 43302
Investigational Site Number 840997
Marion, Ohio, 43302
Investigational Site Number 840995
Meridian, Idaho, 83646
Investigational Site Number 840903
Miami, Florida, 33126
Investigational Site Number 840920
Miami, Florida
Investigational Site Number 840944
Nashville, Tennessee, 37205
Investigational Site Number 840974
New Windsor, New York, 12553
Investigational Site Number 840931
Norfolk, Virginia, 23502
Investigational Site Number 840943
Ocala, Florida, 34471
Investigational Site Number 840982
Orem, Utah, 84058
Investigational Site Number 840981
Oveido, Florida, 32765
Investigational Site Number 840940
Oxon Hill, Maryland, 20745
Investigational Site Number 840952
Palm Springs, California, 92262
Investigational Site Number 840964
Perrysburg, Ohio, 43551
Investigational Site Number 840918
Phoenix, Arizona, 85032
Investigational Site Number 840961
Port Orange, Florida, 32127
Investigational Site Number 840928
Renton, Washington, 98055
Investigational Site Number 840984
Richmond, Virginia, 23227
Investigational Site Number 840303
Sarasota, Florida, 34239
Investigational Site Number 840976
Smithfield, North Carolina, 27577
Investigational Site Number 840990
Spokane, Washington, 99204
Investigational Site Number 840998
St Louis, Missouri, 63131
Investigational Site Number 840986
St. Petersburg, Florida
Investigational Site Number 840988
St. Petersburg, Florida
Investigational Site Number 840945
Sugar Land, Texas, 77479
Investigational Site Number 840992
Summerville, South Carolina, 29485
Investigational Site Number 840930
Thousand Oaks, California, 91360
Investigational Site Number 840971
Tomball, Texas, 77375
Investigational Site Number 840960
Topeka, Kansas, 66606
Investigational Site Number 840925
Tucson, Arizona
Investigational Site Number 840921
Vista, California, 92083
Investigational Site Number 840985
Winston-Salem, North Carolina, 27103

Other trials in United States

Russia15 sites

Investigational Site Number 643906
Barnaul, 656055
Investigational Site Number 643903
Kemerovo, 650002
Investigational Site Number 643927
Moscow, 111539
Investigational Site Number 643928
Moscow, 111539
Investigational Site Number 643931
Moscow, 115404
Investigational Site Number 643924
Moscow, 119048
Investigational Site Number 643932
Moscow, 121374
Investigational Site Number 643908
Moscow, 121552
Investigational Site Number 643904
Moscow, 129090
Investigational Site Number 643911
Orenburg, 450000
Investigational Site Number 643921
Ryazan, 390026
Investigational Site Number 643925
Saint Petersburg, 197110
Investigational Site Number 643922
Saint Petersburg, 198205
Investigational Site Number 643914
Saint Petersburg, 199106
Investigational Site Number 643929
Saratov, 410028

Other trials in Russia

South Korea14 sites

Investigational Site Number 410908
Anyang-si, 431-070
Investigational Site Number 410920
Busan, 602-715
Investigational Site Number 410926
Daegu, 700-712
Investigational Site Number 410923
Gwangju, 501-757
Investigational Site Number 410909
Seoul, 110-744
Investigational Site Number 410922
Seoul, 120-752
Investigational Site Number 410921
Seoul, 135-710
Investigational Site Number 410905
Seoul, 135-720
Investigational Site Number 410901
Seoul, 137-701
Investigational Site Number 410914
Seoul, 138-736
Investigational Site Number 410924
Seoul, 156-707
Investigational Site Number 410915
Suwon, 443-721
Investigational Site Number 410913
Uijeongbu-si, 480-717
Investigational Site Number 410927
Wŏnju, 220-701

Other trials in South Korea

Denmark9 sites

Investigational Site Number 208913
Esbjerg, 6700
Investigational Site Number 208914
Glostrup Municipality, 2600
Investigational Site Number 208905
Hellerup, 2900
Investigational Site Number 208911
Herlev, 2730
Investigational Site Number 208907
Hvidovre, 2650
Investigational Site Number 208901
København S, 2300
Investigational Site Number 208906
Køge, 4600
Investigational Site Number 208908
Roskilde, 4000
Investigational Site Number 208903
Silkeborg, 8600

Other trials in Denmark

South Africa8 sites

Investigational Site Number 710917
Alberton, 1450
Investigational Site Number 710909
Bloemfontein, 9301
Investigational Site Number 710914
Bloemfontein, 9301
Investigational Site Number 710905
Cape Town, 7500
Investigational Site Number 710904
Cape Town, 7925
Investigational Site Number 710918
Middelburg, 1055
Investigational Site Number 710913
Pretoria, 0002
Investigational Site Number 710915
Somerset West, 7130

Other trials in South Africa

Israel7 sites

Investigational Site Number 376908
Holon, 58100
Investigational Site Number 376903
Kfar Saba, 44281
Investigational Site Number 376906
Ofakim, 80300
Investigational Site Number 376902
Petah Tikva
Investigational Site Number 376904
Rehovot, 76100
Investigational Site Number 376907
Safed, 13100
Investigational Site Number 376901
Tel Aviv, 64239

Other trials in Israel

Hungary5 sites

Investigational Site Number 348908
Budapest, 1036
Investigational Site Number 348901
Budapest, 1134
Investigational Site Number 348903
Budapest, 1134
Investigational Site Number 348905
Debrecen, 4032
Investigational Site Number 348906
Székesfehérvár, 8000

Other trials in Hungary

Canada4 sites

Investigational Site Number 124902
Brampton, L6T 3J1
Investigational Site Number 124914
Mirabel, J7J 2K8
Investigational Site Number 124903
Montreal, H1T 3Y7
Investigational Site Number 124918
Toronto, M9V 4B4

Other trials in Canada

France4 sites

Investigational Site Number 250906
Dijon, 21079
Investigational Site Number 250907
Montpellier, 34295
Investigational Site Number 250903
Nantes, 44093
Investigational Site Number 250905
Nîmes, 30900

Other trials in France

Ukraine2 sites

Investigational Site Number 804905
Kiev, 02091
Investigational Site Number 804902
Uzhhorod, 88009

Other trials in Ukraine

About this study

Official title: A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

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

Read the detailed description

The maximum study duration was 115 weeks per participant, including a 3-week screening period, 104-week randomized treatment period and 8-week follow-up period.

Conditions: Hypercholesterolemia
Being tested: Alirocumab, Placebo (for alirocumab), Ezetimibe, Placebo (for ezetimibe), Lipid Modifying Therapy (LMT)
Medical subject headings: Hypercholesterolemia

What participants receive

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

AlirocumabDrug
Also called REGN727/SAR236553, Praluent
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.
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.
EzetimibeDrug
One over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.
Placebo (for ezetimibe)Drug
One capsule once daily orally at approximately the same time of the day with or without food.
Lipid Modifying Therapy (LMT)Drug
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.

Study groups in NCT01644188
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: Placebo (for alirocumab); Drug: Ezetimibe; Drug: Lipid Modifying Therapy (LMT)

What is being measured

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

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).
Measured: From Baseline to Week 52

Secondary outcomes (22)

Percent Change From Baseline in Calculated LDL--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 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Measured: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Adjusted LS means and standard errors at Week 12 from a MMRM including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Measured: From Baseline to Week 52
Percent Change From Baseline in Apolipoprotein B (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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Measured: From Baseline up to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Adjusted LS means and standard errors at Week 52 from a MMRM model including all available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Adjusted percentages at Week 24 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from week 4 to week 52 regardless of status on- or off-treatment were included in the imputation model.
Measured: Up to Week 52
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from week 4 to week 52 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first).
Measured: Up to Week 52
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were included in the imputation model.
Measured: From baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Apolipoprotein A-1 (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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Adjusted means and standard errors at Week 12 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52
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 52 regardless of status on- or off-treatment.
Measured: From Baseline to Week 52

Timeline

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

Aug 2012Jul 2015

First posted18 Jul 2012 (estimated)
Study startAug 2012
Primary completionMay 2014
Study completionJul 2015

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (5)Papers the sponsor has linked to this study.
Other trials for HypercholesterolemiaStudies of the same condition, open and under way.
More trials run by SanofiThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

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: 720 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01644188
Sponsor's protocol ID: EFC11569
Other IDs: U1111-1121-4315, 2011-004130-34
Status last verified: Jun 2016
First submitted: 16 Jul 2012
Last updated: 4 Aug 2016
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 25240705
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.
PubMed 25687353
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
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
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

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Not yet recruiting
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All Hypercholesterolemia trials

Study at a glance

From the registry record, last updated by the sponsor on 4 Aug 2016. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Randomized, Double-Blind, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 Versus Ezetimibe in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy
ClinicalTrials.gov ID: NCT01644188
Acronym / sponsor ID: EFC11569
Conditions: Hypercholesterolemia
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 720 participants (actual)
Lead sponsor: SanofiIndustry (pharma, biotech, devices)
Collaborators: Regeneron Pharmaceuticals
Study start: Aug 2012
Primary completion: May 2014 (actual)
Study completion: Jul 2015 (actual)
First posted: 18 Jul 2012 (estimated)
Results: Posted 6 Nov 2015

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Alirocumab (SAR236553/REGN727) is a fully human monoclonal antibody that binds PCSK9 (proprotein convertase subtilisin/kexin type 9).

Primary Objective of the study:

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

Detailed description

The maximum study duration was 115 weeks per participant, including a 3-week screening period, 104-week randomized treatment period and 8-week follow-up period.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Alirocumab 75 /up to 150 mg Q2W	Experimental	Drug: Alirocumab, Drug: Placebo (for ezetimibe), Drug: Lipid Modifying Therapy (LMT)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.
Ezetimibe 10 mg	Active comparator	Drug: Placebo (for alirocumab), Drug: Ezetimibe, Drug: Lipid Modifying Therapy (LMT)Ezetimibe 10 mg capsule daily and subcutaneous placebo for alirocumab Q2W added to stable LMT for 104 weeks.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (1 listed)

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).

Key exclusion criteria (6 listed)

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)

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
AlirocumabAlso: REGN727/SAR236553, Praluent1 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.	Drug	Alirocumab 75 /up to 150 mg Q2W
Placebo (for alirocumab)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.	Drug	Ezetimibe 10 mg
EzetimibeOne over-encapsulated tablet orally once daily at approximately the same time of the day with or without food.	Drug	Ezetimibe 10 mg
Placebo (for ezetimibe)One capsule once daily orally at approximately the same time of the day with or without food.	Drug	Alirocumab 75 /up to 150 mg Q2W
Lipid Modifying Therapy (LMT)Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose.	Drug	Alirocumab 75 /up to 150 mg Q2W, Ezetimibe 10 mg

Primary outcome

Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis
Time frame: From Baseline to Week 52
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).

22 secondary outcomes

Percent Change From Baseline in Calculated LDL--C at Week 24 - On--Treatment Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
Time frame: From Baseline up to Week 52
Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Apo-B at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Time frame: From Baseline to Week 52
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Time frame: Up to Week 52
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Time frame: Up to Week 52
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
Time frame: From baseline to Week 52
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
Time frame: From Baseline to Week 52

Results and safety

Results posted to the registry on 6 Nov 2015, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Alirocumab 75 /up to 150 mg Q2W	479	357
Ezetimibe 10 mg	241	166

Primary outcome: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis

Time frame: From Baseline to Week 52. Least squares mean (Standard Error). Unit: percent change

Measure	Alirocumab 75 /up to 150 mg Q2W n = 467	Ezetimibe 10 mg n = 240
Value	-50.6 (1.4)	-20.7 (1.9)

Alirocumab 75 /up to 150 mg Q2W vs Ezetimibe 10 mg: LS Mean Difference: -29.8 (95% CI -34.4 to -25.3), p <0.0001, Mixed Models Analysis

Population analysed: ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off-treatment.

22 secondary outcomes are reported in the full results.

Adverse events

Time frame: All Adverse Events (AE) were collected from signature of the informed consent form up to final visit (Week 112) in the study regardless of seriousness or relationship to study drugs.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Alirocumab 75/Up to 150 mg Q2W	124 of 479 (25.9%)	185 of 479 (38.6%)	Not reported
Ezetimibe 10 mg	60 of 241 (24.9%)	90 of 241 (37.3%)	Not reported

Limitations and caveats (from the sponsor): 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).

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 4 Aug 2016.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 25240705Colhoun 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.
Results publication: PubMed 25687353Cannon 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.
Derived from this study: PubMed 34298554Mahmood 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.
Derived from this study: PubMed 30183102Leiter 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.
Derived from this study: PubMed 27777279Ray 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.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Clinical Sciences & Operations study director

Sanofi

126 sites in 10 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Alirocumab, Ezetimibe and Lipid Modifying Therapy (LMT) in people with Hypercholesterolemia, run by Sanofi at 126 sites in 10 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 1 inclusion and 6 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 4 Aug 2016. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 126 sites in United States, Russia, South Korea, Denmark, South Africa and 5 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 6 Nov 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 52). 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 NCT01644188, which also lists 5 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 4 Aug 2016.