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)

This study has been completed.
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT01644175
First received: July 16, 2012
Last updated: October 7, 2015
Last verified: October 2015
  Purpose

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

Condition Intervention Phase
Hypercholesterolemia
Drug: Placebo (for alirocumab)
Drug: Alirocumab
Drug: Lipid-Modifying Therapy (LMT)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT) Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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) (on-treatment analysis).

  • Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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).

  • Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis [ Time Frame: From baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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).

  • Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Apo B at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.

  • Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
    Adjusted percentages at Week 24 were obtained from multiple imputation approach 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.

  • Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment Analysis [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
    Adjusted percentages at Week 24 from multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.

  • Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis [ Time Frame: From baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    Adjusted means and standard errors at Week 24 from multiple imputation approach followed be robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.

  • Percent Change From Baseline in Apolipoprotein A-1 at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Lipoprotein(a) at Week 12- ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    Adjusted means and standard errors at Week 12 from multiple imputation approach followed by a robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.

  • Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 52 ] [ Designated as safety issue: No ]
    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.


Enrollment: 316
Study Start Date: July 2012
Study Completion Date: April 2014
Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Q2W
Placebo (for alirocumab) every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 52 weeks.
Drug: Placebo (for alirocumab)
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).
Drug: Lipid-Modifying Therapy (LMT)
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.
Experimental: Alirocumab
Alirocumab 75 mg Q2W added to stable LMT for 52 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.
Drug: Alirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector (also known as pre-filled pen).
Other Names:
  • SAR236553
  • REGN727
Drug: Lipid-Modifying Therapy (LMT)
Statin (rosuvastatin, simvastatin or atorvastatin) at stable dose with or without other LMT as clinically indicated.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01644175

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Locations
United States, Alabama
Investigational Site Number 840857
Birmingham, Alabama, United States, 35209
Investigational Site Number 840891
Mobile, Alabama, United States, 36693
Investigational Site Number 840876
Montgomery, Alabama, United States, 36109
United States, Arizona
Investigational Site Number 840865
Glendale, Arizona, United States, 85306
United States, Arkansas
Investigational Site Number 840826
Jonesboro, Arkansas, United States, 72401
United States, California
Investigational Site Number 840870
Burbank, California, United States, 91505
Investigational Site Number 840851
Los Angeles, California, United States, 90057
Investigational Site Number 840845
Los Gatos, California, United States, 95032
Investigational Site Number 840844
Sacramento, California, United States, 95823
Investigational Site Number 840801
San Jose, California, United States, 95116
Investigational Site Number 840886
Tarzana, California, United States, 91356
Investigational Site Number 840862
Torrance, California, United States, 90505
Investigational Site Number 840893
Vista, California, United States, 92083
United States, Florida
Investigational Site Number 840867
Boca Raton, Florida, United States, 33432
Investigational Site Number 840884
Boynton Beach, Florida, United States, 33472
Investigational Site Number 840836
Clearwater, Florida, United States, 33761
Investigational Site Number 840866
Coral Gables, Florida, United States, 33134
Investigational Site Number 840895
Ft. Lauderdale, Florida, United States, 33308-4311
Investigational Site Number 840820
Hialeah, Florida, United States
Investigational Site Number 840805
Miami, Florida, United States, 33143
Investigational Site Number 840811
Oviedo, Florida, United States, 32765
Investigational Site Number 840881
Port Orange, Florida, United States, 32127
Investigational Site Number 840816
West Palm Beach, Florida, United States
United States, Georgia
Investigational Site Number 840850
Columbus, Georgia, United States, 31904
United States, Idaho
Investigational Site Number 840840
Eagle, Idaho, United States
United States, Illinois
Investigational Site Number 840842
Chicago, Illinois, United States, 60611
Investigational Site Number 840898
Evanston, Illinois, United States, 60201
Investigational Site Number 840847
Morton, Illinois, United States, 61550
United States, Indiana
Investigational Site Number 840896
Indianapolis, Indiana, United States, 46260
Investigational Site Number 840894
Michigan City, Indiana, United States, 46360
Investigational Site Number 840838
Mishawaka, Indiana, United States, 46545
United States, Kentucky
Investigational Site Number 840823
Paducah, Kentucky, United States, 42003
United States, Louisiana
Investigational Site Number 840858
Eunice, Louisiana, United States, 70535
Investigational Site Number 840802
New Orleans, Louisiana, United States, 70119
United States, Massachusetts
Investigational Site Number 840855
Salisbury, Massachusetts, United States, 01952
United States, Michigan
Investigational Site Number 840890
Battle Creek, Michigan, United States, 49015
Investigational Site Number 840832
Southfield, Michigan, United States, 48034
United States, Minnesota
Investigational Site Number 840839
Edina, Minnesota, United States, 55435
Investigational Site Number 840888
Minneapolis, Minnesota, United States, 55455
United States, Mississippi
Investigational Site Number 840837
Port Gibson, Mississippi, United States, 39150
United States, Missouri
Investigational Site Number 840814
Jefferson City, Missouri, United States, 65109
United States, Nevada
Investigational Site Number 840833
Sparks, Nevada, United States
United States, New Hampshire
Investigational Site Number 840817
Newington, New Hampshire, United States, 3801
United States, New York
Investigational Site Number 840853
New Windsor, New York, United States, 12553
Investigational Site Number 840822
Rochester, New York, United States, 14609
United States, North Carolina
Investigational Site Number 840824
Cary, North Carolina, United States
Investigational Site Number 840880
Smithfield, North Carolina, United States
Investigational Site Number 840502
Winston-Salem, North Carolina, United States, 27103
Investigational Site Number 840852
Winston-Salem, North Carolina, United States, 27103
United States, Ohio
Investigational Site Number 840899
Cincinnati, Ohio, United States, 45245
Investigational Site Number 840846
Cincinnati, Ohio, United States, 45219
Investigational Site Number 840831
Columbus, Ohio, United States, 43231
Investigational Site Number 840860
Kettering, Ohio, United States, 45429
Investigational Site Number 840809
Willoughby Hills, Ohio, United States, 44094
United States, Oklahoma
Investigational Site Number 840818
Norman, Oklahoma, United States, 73069
United States, Oregon
Investigational Site Number 840812
Eugene, Oregon, United States, 97404
United States, Pennsylvania
Investigational Site Number 840803
Downington, Pennsylvania, United States, 19335
Investigational Site Number 840869
Philadelphia, Pennsylvania, United States, 19146
Investigational Site Number 840825
Pittsburgh, Pennsylvania, United States, 15206
United States, South Carolina
Investigational Site Number 840872
Anderson, South Carolina, United States, 29621
Investigational Site Number 840885
Charleston, South Carolina, United States, 29407
Investigational Site Number 840813
Greer, South Carolina, United States, 29651
Investigational Site Number 840827
Mt. Pleasant, South Carolina, United States, 29464
United States, Texas
Investigational Site Number 840868
Corpus Christi, Texas, United States, 78404
Investigational Site Number 840877
Houston, Texas, United States, 77070
Investigational Site Number 840841
Houston, Texas, United States, 77072
Investigational Site Number 840830
San Antonio, Texas, United States, 78224
Investigational Site Number 840854
San Antonio, Texas, United States, 78229
Investigational Site Number 840883
San Antonio, Texas, United States, 78258
Investigational Site Number 840889
Tomball, Texas, United States, 77375
United States, Utah
Investigational Site Number 840878
Bountiful, Utah, United States, 84010
Investigational Site Number 840819
Orem, Utah, United States, 84058
Investigational Site Number 840863
Salt Lake City, Utah, United States, 84102
United States, Virginia
Investigational Site Number 840804
Manassas, Virginia, United States, 20110
Investigational Site Number 840882
Norfolk, Virginia, United States, 23507
Investigational Site Number 840810
Weber City, Virginia, United States, 24290
Sponsors and Collaborators
Sanofi
Regeneron Pharmaceuticals
Investigators
Study Director: Clinical Sciences & Operations Sanofi