Clinical trial NCT01644175: Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia (ODYSSEY COMBO I)
Official title: A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of SAR236553/REGN727 in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Regeneron Pharmaceuticals
First posted: 2012-07-18
Enrollment: 316
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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 with or without other lipid-modifying therapy (LMT) in comparison with placebo after 24 weeks of treatment in high cardiovascular (CV) risk participants with hypercholesterolemia

Secondary Objectives:

* To evaluate the effect of alirocumab in comparison with placebo 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 62 weeks per participant, including a 2-week screening period, 52-week randomized treatment period, and 8-week follow-up period.

Eligibility criteria: Inclusion criteria:

* 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 with or without other LMT, both at stable dose for at least 4 weeks to 6 weeks prior to screening (Week -2)

Exclusion criteria:

* Age \<18 or legal age of adulthood, whichever was greater
* Participants without established CHD or CHD risk equivalent
* 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 cardiovascular disease
* Not on a stable dose of LMT (including statin) for at least 4 weeks and/or fenofibrate for at least 6 weeks, as applicable, prior to the screening visit (Week -2) and from screening to randomization
* Fasting serum triglycerides \> 400 mg/dL (\>4.52 mmol/L)

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Primary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis
timeFrame: From Baseline to Week 52
Secondary outcomes:
measure: Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis
timeFrame: From baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
timeFrame: Up to Week 52
measure: Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment Analysis
timeFrame: Up to Week 52
measure: Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis
timeFrame: From baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apolipoprotein A-1 at Week 24 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Lipoprotein(a) at Week 12- ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
timeFrame: From Baseline to Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number 840857
state: Alabama
city: Mobile
country: United States
facility: Investigational Site Number 840891
state: Alabama
city: Montgomery
country: United States
facility: Investigational Site Number 840876
state: Alabama
city: Glendale
country: United States
facility: Investigational Site Number 840865
state: Arizona
city: Jonesboro
country: United States
facility: Investigational Site Number 840826
state: Arkansas
city: Burbank
country: United States
facility: Investigational Site Number 840870
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 840851
state: California
city: Los Gatos
country: United States
facility: Investigational Site Number 840845
state: California
city: Sacramento
country: United States
facility: Investigational Site Number 840844
state: California
city: San Jose
country: United States
facility: Investigational Site Number 840801
state: California
city: Tarzana
country: United States
facility: Investigational Site Number 840886
state: California
city: Torrance
country: United States
facility: Investigational Site Number 840862
state: California
city: Vista
country: United States
facility: Investigational Site Number 840893
state: California
city: Boca Raton
country: United States
facility: Investigational Site Number 840867
state: Florida
city: Boynton Beach
country: United States
facility: Investigational Site Number 840884
state: Florida
city: Clearwater
country: United States
facility: Investigational Site Number 840836
state: Florida
city: Coral Gables
country: United States
facility: Investigational Site Number 840866
state: Florida
city: Ft. Lauderdale
country: United States
facility: Investigational Site Number 840895
state: Florida
city: Hialeah
country: United States
facility: Investigational Site Number 840820
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 840805
state: Florida
city: Oviedo
country: United States
facility: Investigational Site Number 840811
state: Florida
city: Port Orange
country: United States
facility: Investigational Site Number 840881
state: Florida
city: West Palm Beach
country: United States
facility: Investigational Site Number 840816
state: Florida
city: Columbus
country: United States
facility: Investigational Site Number 840850
state: Georgia
city: Eagle
country: United States
facility: Investigational Site Number 840840
state: Idaho
city: Chicago
country: United States
facility: Investigational Site Number 840842
state: Illinois
city: Evanston
country: United States
facility: Investigational Site Number 840898
state: Illinois
city: Morton
country: United States
facility: Investigational Site Number 840847
state: Illinois
city: Indianapolis
country: United States
facility: Investigational Site Number 840896
state: Indiana
city: Michigan City
country: United States
facility: Investigational Site Number 840894
state: Indiana
city: Mishawaka
country: United States
facility: Investigational Site Number 840838
state: Indiana
city: Paducah
country: United States
facility: Investigational Site Number 840823
state: Kentucky
city: Eunice
country: United States
facility: Investigational Site Number 840858
state: Louisiana
city: New Orleans
country: United States
facility: Investigational Site Number 840802
state: Louisiana
city: Salisbury
country: United States
facility: Investigational Site Number 840855
state: Massachusetts
city: Battle Creek
country: United States
facility: Investigational Site Number 840890
state: Michigan
city: Southfield
country: United States
facility: Investigational Site Number 840832
state: Michigan
city: Edina
country: United States
facility: Investigational Site Number 840839
state: Minnesota
city: Minneapolis
country: United States
facility: Investigational Site Number 840888
state: Minnesota
city: Port Gibson
country: United States
facility: Investigational Site Number 840837
state: Mississippi
city: Jefferson City
country: United States
facility: Investigational Site Number 840814
state: Missouri
city: Sparks
country: United States
facility: Investigational Site Number 840833
state: Nevada
city: Newington
country: United States
facility: Investigational Site Number 840817
state: New Hampshire
city: New Windsor
country: United States
facility: Investigational Site Number 840853
state: New York
city: Rochester
country: United States
facility: Investigational Site Number 840822
state: New York
city: Cary
country: United States
facility: Investigational Site Number 840824
state: North Carolina
city: Smithfield
country: United States
facility: Investigational Site Number 840880
state: North Carolina
city: Winston-Salem
country: United States
facility: Investigational Site Number 840502
state: North Carolina
city: Winston-Salem
country: United States
facility: Investigational Site Number 840852
state: North Carolina
city: Cincinnati
country: United States
facility: Investigational Site Number 840846
state: Ohio
city: Cincinnati
country: United States
facility: Investigational Site Number 840899
state: Ohio
city: Columbus
country: United States
facility: Investigational Site Number 840831
state: Ohio
city: Kettering
country: United States
facility: Investigational Site Number 840860
state: Ohio
city: Willoughby Hills
country: United States
facility: Investigational Site Number 840809
state: Ohio
city: Norman
country: United States
facility: Investigational Site Number 840818
state: Oklahoma
city: Eugene
country: United States
facility: Investigational Site Number 840812
state: Oregon
city: Downington
country: United States
facility: Investigational Site Number 840803
state: Pennsylvania
city: Philadelphia
country: United States
facility: Investigational Site Number 840869
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Investigational Site Number 840825
state: Pennsylvania
city: Anderson
country: United States
facility: Investigational Site Number 840872
state: South Carolina
city: Charleston
country: United States
facility: Investigational Site Number 840885
state: South Carolina
city: Greer
country: United States
facility: Investigational Site Number 840813
state: South Carolina
city: Mt. Pleasant
country: United States
facility: Investigational Site Number 840827
state: South Carolina
city: Corpus Christi
country: United States
facility: Investigational Site Number 840868
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 840877
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 840841
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number 840830
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number 840854
state: Texas
city: San Antonio
country: United States
facility: Investigational Site Number 840883
state: Texas
city: Tomball
country: United States
facility: Investigational Site Number 840889
state: Texas
city: Bountiful
country: United States
facility: Investigational Site Number 840878
state: Utah
city: Orem
country: United States
facility: Investigational Site Number 840819
state: Utah
city: Salt Lake City
country: United States
facility: Investigational Site Number 840863
state: Utah
city: Manassas
country: United States
facility: Investigational Site Number 840804
state: Virginia
city: Norfolk
country: United States
facility: Investigational Site Number 840882
state: Virginia
city: Weber City
country: United States
facility: Investigational Site Number 840810
state: Virginia
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J. 2015 Jun;169(6):906-915.e13. doi: 10.1016/j.ahj.2015.03.004. Epub 2015 Mar 13.
citation: 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.
citation: 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.
citation: 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.