Efficacy and Safety Evaluation of Alirocumab in Patients With Heterozygous Familial Hypercholesterolemia or High Cardiovascular Risk Patients With Hypercholesterolemia on Lipid Modifying Therapy (ODYSSEY JAPAN)

This study has been completed.
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT02107898
First received: April 4, 2014
Last updated: December 23, 2015
Last verified: December 2015
  Purpose

Primary Objective:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab as add-on therapy to stable daily statin therapy with or without other lipid modifying therapy in comparison with placebo after 24 weeks of treatment in heterozygous familial hypercholesterolemia (HeFH) or high cardiovascular risk participants with hypercholesterolemia.

Secondary Objectives:

  • To evaluate the effect of alirocumab in comparison with placebo on LDL-C after 12 weeks of treatment.
  • To evaluate the effect of alirocumab on other lipid parameters.
  • To evaluate the long-term effect of alirocumab in comparison with placebo on LDL-C after 52 weeks of treatment.
  • To evaluate the safety and tolerability of alirocumab.
  • To evaluate the development of anti-alirocumab antibodies.
  • To evaluate the pharmacokinetics 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, Multicenter Study to Evaluate the Efficacy and Safety of Alirocumab in Heterozygous Familial Hypercholesterolemia or 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 24 ] [ 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 24 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 24 ] [ 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 24 (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 24 ] [ Designated as safety issue: No ]
    Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline data from Week 4 to Week 24 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 24 ] [ 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 24 (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 24 ] [ 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 24 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 24 ] [ 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 24 (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 24 ] [ 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 24 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 24 ] [ 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 24 (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 24 ] [ 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 24 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 24 ] [ 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 24 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 24 ] [ 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 24 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 24 ] [ 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 24 regardless of status on- or off-treatment.

  • Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis [ Time Frame: Up to Week 24 ] [ Designated as safety issue: No ]

    Calculated LDL-C goal was defined as:

    • <100 mg/dL (2.59 mmol/L) for heFH or non-FH participants who had a history of documented congestive heart disease (CHD), or
    • <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases (ischemic stroke, peripheral artery disease, chronic kidney disease or diabetes) or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.

    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 24 regardless of status on- or off-treatment were included in imputation model.


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

  • Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    Adjusted means and standard errors at Week 24 from a multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment were included in the imputation model.

  • Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    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 24 regardless of status on-or off-treatment.

  • Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ] [ 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 24 regardless of status on- or off-treatment.

  • Percent Change From Baseline in Apo A1 at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ] [ 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 24 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 24 ] [ 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 24 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 24 ] [ 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 24 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 24 ] [ 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 24 regardless of status on- or off-treatment.

  • Percent Change From Baseline in Apo A1 at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ] [ 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 24 regardless of status on- or off-treatment.


Enrollment: 216
Study Start Date: March 2014
Study Completion Date: September 2015
Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo Q2W
Placebo (for alirocumab) every two weeks (Q2W) added to stable lipid-modifying therapy (LMT).
Drug: Placebo (for alirocumab)
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.
Drug: Lipid-Modifying Therapy (LMT)
Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) at stable dose with or without other LMT as clinically indicated.
Experimental: Alirocumab 75 mg/Up to 150 mg Q2W

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 above pre-specified threshold at Week 8 as defined in Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012 ie.

  • ≥100 mg/dL (2.59 mmol/L) in heFH participants or in non-familial hypercholesterolemia (non-FH) participants who had a history of documented coronary heart disease (CHD)
  • ≥120 mg/dL (3.10 mmol/L) in non-FH participants who had a history of documented diseases or other risk factors as categorized in primary prevention category III
Drug: Alirocumab
Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with an auto-injector.
Other Names:
  • SAR236553
  • REGN727
  • Praluent
Drug: Lipid-Modifying Therapy (LMT)
Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) at stable dose with or without other LMT as clinically indicated.

Detailed Description:
Total duration per participant of approximately 63 weeks (14 months) (screening: 3 weeks, double-blind treatment period: 52 weeks, and follow-up period: 8 weeks).
  Eligibility

Ages Eligible for Study:   20 Years to 80 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Participants with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia who were not adequately controlled with a stable daily dose of statin with or without other lipid modifying therapy, at stable dose prior to the screening visit (Week -3).

Exclusion criteria:

  1. LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit in participants with heterozygous familial hypercholesterolemia or in participants with non-familial hypercholesterolemia who had a history of documented coronary heart disease as described in Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
  2. LDL-C <120 mg/dL (<3.10 mmol/L) at the screening visit in participants with non-familial hypercholesterolemia who had a history of documented diseases or other risk factors as categorized in primary prevention category III as described in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
  3. Not on a stable daily dose of lipid modifying therapy (including statin) within 4 weeks prior to the screening visit or between screening and randomization visits.
  4. Age <20 years at the screening visit.

The above information is not intended to contain all considerations relevant to a participants'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: NCT02107898

Locations
Japan
Investigational Site Number 392016
Adachi-Ku, Japan
Investigational Site Number 392029
Adachi-Ku, Japan
Investigational Site Number 392024
Aki-Gun, Japan
Investigational Site Number 392012
Chuo-Ku, Japan
Investigational Site Number 392013
Chuo-Ku, Japan
Investigational Site Number 392032
Fukui-Shi, Japan
Investigational Site Number 392004
Hakusan-Shi, Japan
Investigational Site Number 392028
Kaga-Shi, Japan
Investigational Site Number 392002
Kanazawa-Shi, Japan
Investigational Site Number 392005
Kanazawa-Shi, Japan
Investigational Site Number 392023
Kawanishi-Shi, Japan
Investigational Site Number 392009
Kisarazu-Shi, Japan
Investigational Site Number 392026
Kitakyushu-Shi, Japan
Investigational Site Number 392003
Komatsu-Shi, Japan
Investigational Site Number 392011
Kuki-Shi, Japan
Investigational Site Number 392017
Matsumoto-Shi, Japan
Investigational Site Number 392007
Mito-Shi, Japan
Investigational Site Number 392006
Moriya-Shi, Japan
Investigational Site Number 392018
Nagoya-Shi, Japan
Investigational Site Number 392014
Oota-Ku, Japan
Investigational Site Number 392019
Osaka-Shi, Japan
Investigational Site Number 392020
Osaka-Shi, Japan
Investigational Site Number 392022
Osaka-Shi, Japan
Investigational Site Number 392030
Osaka-Shi, Japan
Investigational Site Number 392027
Oyabe-Shi, Japan
Investigational Site Number 392010
Saitama-Shi, Japan
Investigational Site Number 392015
Shinjuku-Ku, Japan
Investigational Site Number 392031
Shizuoka-Shi, Japan
Investigational Site Number 392021
Suita-Shi, Japan
Investigational Site Number 392025
Takamatsu-Shi, Japan
Investigational Site Number 392008
Tsuchiura-Shi, Japan
Investigational Site Number 392001
Yamagata-Shi, Japan
Sponsors and Collaborators
Sanofi
Regeneron Pharmaceuticals
Investigators
Study Director: Clinical Sciences & Operations Sanofi
  More Information

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT02107898     History of Changes
Other Study ID Numbers: EFC13672  U1111-1115-7486 
Study First Received: April 4, 2014
Results First Received: December 23, 2015
Last Updated: December 23, 2015
Health Authority: Japan: Ministry of Health, Labor and Welfare

Additional relevant MeSH terms:
Hypercholesterolemia
Hyperlipoproteinemia Type II
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 30, 2016