Clinical trial NCT01644188: Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II)
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
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: 720
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 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

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.

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 at stable dose for at least 4 weeks prior to the screening visit (Week -2).

Exclusion criteria:

* 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.

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 B (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 up 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 Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
timeFrame: Up to Week 52
measure: Percentage of Participants Achieving 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 (Apo 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:
measure: Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
timeFrame: From Baseline to Week 52
measure: Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis
timeFrame: From Baseline to Week 104
measure: Percent Change From Baseline in Calculated LDL-C at Week 104 - On-Treatment Analysis
timeFrame: From Baseline to Week 104
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number 840980
state: Alabama
city: Phoenix
country: United States
facility: Investigational Site Number 840918
state: Arizona
city: Tucson
country: United States
facility: Investigational Site Number 840925
state: Arizona
city: Anaheim
country: United States
facility: Investigational Site Number 840959
state: California
city: Beverly Hills
country: United States
facility: Investigational Site Number 840301
state: California
city: Chino
country: United States
facility: Investigational Site Number 840933
state: California
city: Lincoln
country: United States
facility: Investigational Site Number 840991
state: California
city: Los Angeles
country: United States
facility: Investigational Site Number 840979
state: California
city: Palm Springs
country: United States
facility: Investigational Site Number 840952
state: California
city: Thousand Oaks
country: United States
facility: Investigational Site Number 840930
state: California
city: Vista
country: United States
facility: Investigational Site Number 840921
state: California
city: Boynton Beach
country: United States
facility: Investigational Site Number 840962
state: Florida
city: Bradenton
country: United States
facility: Investigational Site Number 840987
state: Florida
city: Clearwater
country: United States
facility: Investigational Site Number 840302
state: Florida
city: Jacksonville
country: United States
facility: Investigational Site Number 840935
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 840903
state: Florida
city: Miami
country: United States
facility: Investigational Site Number 840920
state: Florida
city: Ocala
country: United States
facility: Investigational Site Number 840943
state: Florida
city: Oveido
country: United States
facility: Investigational Site Number 840981
state: Florida
city: Port Orange
country: United States
facility: Investigational Site Number 840961
state: Florida
city: Sarasota
country: United States
facility: Investigational Site Number 840303
state: Florida
city: St. Petersburg
country: United States
facility: Investigational Site Number 840986
state: Florida
city: St. Petersburg
country: United States
facility: Investigational Site Number 840988
state: Florida
city: Meridian
country: United States
facility: Investigational Site Number 840995
state: Idaho
city: Evansville
country: United States
facility: Investigational Site Number 840902
state: Indiana
city: Topeka
country: United States
facility: Investigational Site Number 840960
state: Kansas
city: Oxon Hill
country: United States
facility: Investigational Site Number 840940
state: Maryland
city: Fall River
country: United States
facility: Investigational Site Number 840966
state: Massachusetts
city: Kansas City
country: United States
facility: Investigational Site Number 840917
state: Missouri
city: St. Louis
country: United States
facility: Investigational Site Number 840998
state: Missouri
city: Butte
country: United States
facility: Investigational Site Number 840946
state: Montana
city: Lincoln
country: United States
facility: Investigational Site Number 840914
state: Nebraska
city: Albuquerque
country: United States
facility: Investigational Site Number 840949
state: New Mexico
city: New Windsor
country: United States
facility: Investigational Site Number 840974
state: New York
city: Greenville
country: United States
facility: Investigational Site Number 840955
state: North Carolina
city: Lexington
country: United States
facility: Investigational Site Number 840938
state: North Carolina
city: Smithfield
country: United States
facility: Investigational Site Number 840976
state: North Carolina
city: Winston-Salem
country: United States
facility: Investigational Site Number 840985
state: North Carolina
city: Cincinnati
country: United States
facility: Investigational Site Number 840963
state: Ohio
city: Lyndhust
country: United States
facility: Investigational Site Number 840970
state: Ohio
city: Marion
country: United States
facility: Investigational Site Number 840906
state: Ohio
city: Marion
country: United States
facility: Investigational Site Number 840997
state: Ohio
city: Perrysburg
country: United States
facility: Investigational Site Number 840964
state: Ohio
city: Charleston
country: United States
facility: Investigational Site Number 840913
state: South Carolina
city: Greer
country: United States
facility: Investigational Site Number 840912
state: South Carolina
city: Summerville
country: United States
facility: Investigational Site Number 840992
state: South Carolina
city: Bristol
country: United States
facility: Investigational Site Number 840932
state: Tennessee
city: Nashville
country: United States
facility: Investigational Site Number 840944
state: Tennessee
city: Fort Worth
country: United States
facility: Investigational Site Number 840994
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 840973
state: Texas
city: Houston
country: United States
facility: Investigational Site Number 840939
state: Texas
city: Sugar Land
country: United States
facility: Investigational Site Number 840945
state: Texas
city: Tomball
country: United States
facility: Investigational Site Number 840971
state: Texas
city: Orem
country: United States
facility: Investigational Site Number 840982
state: Utah
city: Norfolk
country: United States
facility: Investigational Site Number 840931
state: Virginia
city: Richmond
country: United States
facility: Investigational Site Number 840984
state: Virginia
city: Renton
country: United States
facility: Investigational Site Number 840928
state: Washington
city: Spokane
country: United States
facility: Investigational Site Number 840990
state: Washington
city: Brampton
country: Canada
facility: Investigational Site Number 124902
city: Mirabel
country: Canada
facility: Investigational Site Number 124914
city: Montreal
country: Canada
facility: Investigational Site Number 124903
city: Toronto
country: Canada
facility: Investigational Site Number 124918
city: Esbjerg
country: Denmark
facility: Investigational Site Number 208913
city: Glostrup
country: Denmark
facility: Investigational Site Number 208914
city: Hellerup
country: Denmark
facility: Investigational Site Number 208905
city: Herlev
country: Denmark
facility: Investigational Site Number 208911
city: Hvidovre
country: Denmark
facility: Investigational Site Number 208907
city: København S
country: Denmark
facility: Investigational Site Number 208901
city: Køge
country: Denmark
facility: Investigational Site Number 208906
city: Roskilde
country: Denmark
facility: Investigational Site Number 208908
city: Silkeborg
country: Denmark
facility: Investigational Site Number 208903
city: Dijon
country: France
facility: Investigational Site Number 250906
city: Montpellier Cedex 5
country: France
facility: Investigational Site Number 250907
city: Nantes
country: France
facility: Investigational Site Number 250903
city: Nimes
country: France
facility: Investigational Site Number 250905
city: Budapest
country: Hungary
facility: Investigational Site Number 348908
city: Budapest
country: Hungary
facility: Investigational Site Number 348901
city: Budapest
country: Hungary
facility: Investigational Site Number 348903
city: Debrecen
country: Hungary
facility: Investigational Site Number 348905
city: Szekesfehervar
country: Hungary
facility: Investigational Site Number 348906
city: Holon
country: Israel
facility: Investigational Site Number 376908
city: Kfar Saba
country: Israel
facility: Investigational Site Number 376903
city: Ofakim
country: Israel
facility: Investigational Site Number 376906
city: Petach Tikva
country: Israel
facility: Investigational Site Number 376902
city: Rehovot
country: Israel
facility: Investigational Site Number 376904
city: Safed
country: Israel
facility: Investigational Site Number 376907
city: Tel Aviv
country: Israel
facility: Investigational Site Number 376901
city: Anyang-Si
country: Korea, Republic of
facility: Investigational Site Number 410908
city: Busan
country: Korea, Republic of
facility: Investigational Site Number 410920
city: Daegu
country: Korea, Republic of
facility: Investigational Site Number 410926
city: Gwangju
country: Korea, Republic of
facility: Investigational Site Number 410923
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410909
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410922
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410921
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410905
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410901
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410914
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 410924
city: Suwon
country: Korea, Republic of
facility: Investigational Site Number 410915
city: Uijeongbu
country: Korea, Republic of
facility: Investigational Site Number 410913
city: Wonju
country: Korea, Republic of
facility: Investigational Site Number 410927
city: Barnaul
country: Russian Federation
facility: Investigational Site Number 643906
city: Kemerovo
country: Russian Federation
facility: Investigational Site Number 643903
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643927
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643928
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643931
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643924
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643932
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643908
city: Moscow
country: Russian Federation
facility: Investigational Site Number 643904
city: Orenburg
country: Russian Federation
facility: Investigational Site Number 643911
city: Ryazan
country: Russian Federation
facility: Investigational Site Number 643921
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number 643925
city: Saint-Petersburg
country: Russian Federation
facility: Investigational Site Number 643922
city: Saratov
country: Russian Federation
facility: Investigational Site Number 643929
city: St-Petersburg
country: Russian Federation
facility: Investigational Site Number 643914
city: Alberton
country: South Africa
facility: Investigational Site Number 710917
city: Bloemfontein
country: South Africa
facility: Investigational Site Number 710909
city: Bloemfontein
country: South Africa
facility: Investigational Site Number 710914
city: Cape Town
country: South Africa
facility: Investigational Site Number 710905
city: Cape Town
country: South Africa
facility: Investigational Site Number 710904
city: Middelburg
country: South Africa
facility: Investigational Site Number 710918
city: Pretoria
country: South Africa
facility: Investigational Site Number 710913
city: Somerset West
country: South Africa
facility: Investigational Site Number 710915
city: Kiev
country: Ukraine
facility: Investigational Site Number 804905
city: Uzhhorod
country: Ukraine
facility: Investigational Site Number 804902
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: 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.
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.