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)

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

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.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo (for alirocumab); Drug: Lipid-Modifying Therapy (LMT); Drug: Alirocumab

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).

• Study Type: Interventional
• Enrollment (Actual): 216
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Adachi-Ku, Japan
    • Investigational Site Number 392016
  • Adachi-Ku, Japan
    • Investigational Site Number 392029
  • Aki-Gun, Japan
    • Investigational Site Number 392024
  • Chuo-Ku, Japan
    • Investigational Site Number 392012
  • Chuo-Ku, Japan
    • Investigational Site Number 392013
  • Fukui-Shi, Japan
    • Investigational Site Number 392032
  • Hakusan-Shi, Japan
    • Investigational Site Number 392004
  • Kaga-Shi, Japan
    • Investigational Site Number 392028
  • Kanazawa-Shi, Japan
    • Investigational Site Number 392002
  • Kanazawa-Shi, Japan
    • Investigational Site Number 392005
  • Kawanishi-Shi, Japan
    • Investigational Site Number 392023
  • Kisarazu-Shi, Japan
    • Investigational Site Number 392009
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392026
  • Komatsu-Shi, Japan
    • Investigational Site Number 392003
  • Kuki-Shi, Japan
    • Investigational Site Number 392011
  • Matsumoto-Shi, Japan
    • Investigational Site Number 392017
  • Mito-Shi, Japan
    • Investigational Site Number 392007
  • Moriya-Shi, Japan
    • Investigational Site Number 392006
  • Nagoya-Shi, Japan
    • Investigational Site Number 392018
  • Oota-Ku, Japan
    • Investigational Site Number 392014
  • Osaka-Shi, 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
  • Oyabe-Shi, Japan
    • Investigational Site Number 392027
  • Saitama-Shi, Japan
    • Investigational Site Number 392010
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392015
  • Shizuoka-Shi, Japan
    • Investigational Site Number 392031
  • Suita-Shi, Japan
    • Investigational Site Number 392021
  • Takamatsu-Shi, Japan
    • Investigational Site Number 392025
  • Tsuchiura-Shi, Japan
    • Investigational Site Number 392008
  • Yamagata-Shi, Japan
    • Investigational Site Number 392001

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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' potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 i.e.; ≥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: Lipid-Modifying Therapy (LMT); Statin (pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin) at stable dose with or without other LMT as clinically indicated.; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 24 regardless of status on- or off-treatment were used in the model (ITT analysis).	From Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 24 (i.e. up to 21 days after last injection) (on-treatment analysis).	From Baseline to Week 24
Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis	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.	From Baseline to Week 24
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 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percent Change From Baseline in Apolipoprotein (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 24 regardless of status on- or off-treatment.	From baseline to Week 24
Percent Change From Baseline in Apo B 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 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - ITT Analysis	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.	Up to Week 24
Percentage of Participants Reaching Calculated LDL-C Goal at Week 24 - On-Treatment Analysis	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).	Up to Week 24
Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis	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.	From Baseline to Week 24
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 24 regardless of status on-or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apo A1 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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
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 24 regardless of status on-or off-treatment.	From Baseline to Week 24
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 24 regardless of status on-or off-treatment.	From Baseline to Week 24
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 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apo A1 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 24 regardless of status on- or off-treatment.	From Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis	Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.	From Baseline to Week 52
Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis	Adjusted LS means and standard errors at Week 52 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).	From Baseline to Week 52

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Teramoto T, Kobayashi M, Tasaki H, Yagyu H, Higashikata T, Takagi Y, Uno K, Baccara-Dinet MT, Nohara A. Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins - ODYSSEY JAPAN Randomized Controlled Trial. Circ J. 2016 Aug 25;80(9):1980-7. doi: 10.1253/circj.CJ-16-0387. Epub 2016 Jul 22. Erratum In: Circ J. 2016;80(11):2414.
• Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Oct 20;10(10):CD011748. doi: 10.1002/14651858.CD011748.pub3.

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (ACTUAL): January 1, 2015
• Study Completion (ACTUAL): September 1, 2015

Study Registration Dates

• First Submitted: April 4, 2014
• First Submitted That Met QC Criteria: April 4, 2014
• First Posted (ESTIMATE): April 8, 2014

Study Record Updates

• Last Update Posted (ESTIMATE): October 4, 2016
• Last Update Submitted That Met QC Criteria: September 27, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: EFC13672; U1111-1115-7486 (OTHER: UTN)