Evaluation of Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients Hospitalized for Acute Coronary Syndrome With Hypercholesterolemia (ODYSSEY J-IVUS)

A Randomized, Open-label, Blinded Intravascular Ultrasound Analysis, Parallel Group, Multicenter Study to Evaluate the Effect of Praluent® (Alirocumab) on Coronary Atheroma Volume in Japanese Patients Hospitalized for Acute Coronary Syndrome With Hypercholesterolemia Not Adequately Controlled With Statin

Primary Objective:

To compare the efficacy of alirocumab (Praluent®) with standard of care (SoC) on coronary atheroma progression (percent change in normalized total atheroma volume [TAV]) after 9 months of treatment in participants who had acute coronary syndrome (ACS) within 4 weeks prior to randomization, with hypercholesterolemia treated with statin.

Secondary Objectives:

• To compare the efficacy of alirocumab (Praluent®) with SoC on secondary endpoints including absolute change in percent atheroma volume and normalized TAV after 9 months of treatment.
• To evaluate the efficacy of alirocumab (Praluent®) on low-density lipoprotein cholesterol (LDL-C), apolipoprotein B, triglycerides, non-high-density lipoprotein cholesterol and lipoprotein (a) after 9 months treatment.
• To evaluate the safety of alirocumab (Praluent®) including the occurrence of cardiovascular events (coronary heart disease death, non-fatal myocardial infarction, fatal and non-fatal ischemic stroke, unstable angina requiring hospitalization) throughout the study.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia; Acute Coronary Syndrome
• Intervention / Treatment: Drug: Atorvastatin; Drug: Rosuvastatin; Drug: Fenofibrate; Drug: Bezafibrate; Drug: Ezetimibe; Drug: Antiplatelets; Drug: Anticoagulants; Drug: Alirocumab SAR236553

Detailed Description

The duration of study per participant was 9 months.

• Study Type: Interventional
• Enrollment (Actual): 206
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Bunkyō-Ku, Japan
    • Investigational Site Number 392026
  • Chiyoda-ku, Japan
    • Investigational Site Number 392022
  • Fujisawa-shi, Japan
    • Investigational Site Number 392032
  • Fukui-shi, Japan
    • Investigational Site Number 392004
  • Fukuoka-shi, Japan
    • Investigational Site Number 392007
  • Fukuoka-shi, Japan
    • Investigational Site Number 392048
  • Gifu-shi, Japan
    • Investigational Site Number 392008
  • Hiroshima-shi, Japan
    • Investigational Site Number 392039
  • Isehara-shi, Japan
    • Investigational Site Number 392028
  • Itabashi-ku, Japan
    • Investigational Site Number 392036
  • Itabashi-ku, Japan
    • Investigational Site Number 392037
  • Izumisano-shi, Japan
    • Investigational Site Number 392024
  • Izunokuni-shi, Japan
    • Investigational Site Number 392013
  • Kawaguchi-shi, Japan
    • Investigational Site Number 392020
  • Kitakyushu-shi, Japan
    • Investigational Site Number 392009
  • Kitakyushu-shi, Japan
    • Investigational Site Number 392034
  • Kochi-shi, Japan
    • Investigational Site Number 392044
  • Kumamoto-shi, Japan
    • Investigational Site Number 392002
  • Kumamoto-shi, Japan
    • Investigational Site Number 392011
  • Kurashiki-shi, Japan
    • Investigational Site Number 392003
  • Matsuyama-shi, Japan
    • Investigational Site Number 392018
  • Morioka-shi, Japan
    • Investigational Site Number 392021
  • Nagakute-shi, Japan
    • Investigational Site Number 392017
  • Nagaoka-shi, Japan
    • Investigational Site Number 392047
  • Okayama-shi, Japan
    • Investigational Site Number 392033
  • Osaka-shi, Japan
    • Investigational Site Number 392006
  • Osaka-shi, Japan
    • Investigational Site Number 392010
  • Osaka-shi, Japan
    • Investigational Site Number 392045
  • Osaka-shi, Japan
    • Investigational Site Number 392046
  • Sagamihara-shi, Japan
    • Investigational Site Number 392015
  • Sakai-shi, Japan
    • Investigational Site Number 392019
  • Sapporo-shi, Japan
    • Investigational Site Number 392035
  • Tenri-shi, Japan
    • Investigational Site Number 392001
  • Toyoake-shi, Japan
    • Investigational Site Number 392016
  • Tsukuba-shi, Japan
    • Investigational Site Number 392025
  • Tsukuba-shi, Japan
    • Investigational Site Number 392040
  • Wakayama-shi, Japan
    • Investigational Site Number 392005
  • Yokohama-shi, Japan
    • Investigational Site Number 392027
  • Yokohama-shi, Japan
    • Investigational Site Number 392043

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

• Participants hospitalized for ACS (Acute ST-segment elevation myocardial infarction [STEMI], Acute non-ST-segment elevation myocardial infarction [NSTEMI], and unstable angina.
• LDL-C >=100 mg/dL at ACS diagnosis.
• Participants who has stenosis with at least >50% stenosis angiographically within 1 week after the ACS onset, and has analyzable coronary intravascular Ultrasound image.
• Participants aged >=20 years old at ACS diagnosis.
• Negative Hepatitis B surface antigen, negative Hepatitis B core antibody, and negative Hepatitis C antibody. Or, negative Hepatitis B surface antigen, positive Hepatitis B core antibody, negative Hepatitis B deoxyribonucleic acid, and negative Hepatitis C antibody.
• Written informed consent.

Exclusion criteria:

• Participants who had previously treated with at least one dose of any anti-proprotein convertase subtilisin/kexin type 9 monoclonal antibody.
• Uncontrolled hypertension (multiple reading with systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg) between ACS diagnosis and randomization visit.
• Known history of hemorrhagic stroke.
• Currently under treatment for cancer.
• Participants on LDL apheresis.
• Any clinically significant abnormality identified that in the judgment of the Investigator or any sub-Investigator would preclude safe completion of the study or constrain endpoints assessment such as major systemic diseases, participants with short life expectancy.

• Considered by the Investigator or any sub-Investigator as inappropriate for this study for any reason, including:

  • Unable to meet specific protocol requirements, such as scheduled visits;
  • Investigator or any sub-Investigator, pharmacist, study coordinator, other study staff or relative thereof directly involved in the conduct of the protocol, etc;
  • Presence of any other conditions (eg, geographic, social, etc.) actual or anticipated, that the Investigator feels would restrict or limit the participant's participation for the duration of the study.
• Laboratory findings measured within 4 weeks after the ACS diagnosis (positive serum or urine pregnancy test in females of childbearing potential).

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; Statin therapy (atorvastatin or rosuvastatin) will be administered with or without non-statin lipid modifying therapies (LMTs). Non-statin LMTs will be adjusted by physicians to achieve the LDL-C target level <100 milligrams per deciliter (mg/dL).	Drug: Atorvastatin; Pharmaceutical form: tablet Route of administration: oral; Drug: Rosuvastatin; Pharmaceutical form: tablet Route of administration: oral; Drug: Fenofibrate; Pharmaceutical form: tablet Route of administration: oral; Drug: Bezafibrate; Pharmaceutical form: tablet Route of administration: oral; Drug: Ezetimibe; Pharmaceutical form: tablet Route of administration: oral; Drug: Antiplatelets; Pharmaceutical form: tablet or capsule Route of administration: oral; Drug: Anticoagulants; Pharmaceutical form: tablet or capsule Route of administration: oral
Experimental: Alirocumab; Alirocumab will be given subcutaneously every 2 weeks on top of stable dose statin therapy (atorvastatin or rosuvastatin) with or without stable dose non-statin LMTs.	Drug: Atorvastatin; Pharmaceutical form: tablet Route of administration: oral; Drug: Rosuvastatin; Pharmaceutical form: tablet Route of administration: oral; Drug: Fenofibrate; Pharmaceutical form: tablet Route of administration: oral; Drug: Bezafibrate; Pharmaceutical form: tablet Route of administration: oral; Drug: Ezetimibe; Pharmaceutical form: tablet Route of administration: oral; Drug: Antiplatelets; Pharmaceutical form: tablet or capsule Route of administration: oral; Drug: Anticoagulants; Pharmaceutical form: tablet or capsule Route of administration: oral; Drug: Alirocumab SAR236553; Pharmaceutical form: Solution for injection Route of administration: Subcutaneous; Other Names: Praluent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Normalized Total Atheroma Volume (TAV) at Week 36	Least-squares (LS) means and standard errors (SE) at Week 36 were obtained from analysis of covariance (ANCOVA) model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and the baseline normalized TAV as continuous fixed covariate.	Baseline, Week 36

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Percent Atheroma Volume (PAV) at Week 36	LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and the baseline PAV as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in Normalized Total Atheroma Volume at Week 36	LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and the baseline normalized TAV as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in External Elastic Membrane (EEM) Volume at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model with treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]), as fixed categorical effects, and the baseline EEM volume value as continuous fixed covariate.	Baseline, Week 36
Percent Change From Baseline in External Elastic Membrane Volume at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and the baseline EEM volume value as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in Lumen Volume at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and the baseline lumen volume value as continuous fixed covariate.	Baseline, Week 36
Percent Change From Baseline in Lumen Volume at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effect, and the baseline lumen volume value as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in Calculated Low-density Lipoprotein Cholesterol at Week 12 and Week 36	Adjusted LS mean and SE at Week 12 and Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline calculated LDL-C value and baseline calculated LDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 12, Week 36
Percent Change From Baseline in Calculated Low-density Lipoprotein Cholesterol at Week 12 and Week 36	Adjusted LS mean and SE at Week 12 and Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline calculated LDL-C value and baseline calculated LDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 12, Week 36
Absolute Change From Baseline in Apolipoprotein B (Apo B) at Week 36	Adjusted LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and baseline Apo B value as continuous fixed covariate.	Baseline, Week 36
Percent Change From Baseline in Apolipoprotein B at Week 36	Adjusted LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and baseline Apo B value as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 36	Adjusted LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline calculated non-HDL-C value and baseline calculated non-HDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol at Week 36	Adjusted LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline calculated non-HDL-C value and baseline calculated non-HDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Absolute Change From Baseline in Total Cholesterol (TC) at Week 36	LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline calculated TC value and baseline calculated TC value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Percent Change From Baseline in Total Cholesterol at Week 36	Adjusted LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline TC value and baseline TC value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Absolute Change From Baseline in Lipoprotein (a) (Lp[a]) at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effect, and baseline Lp(a) value as continuous fixed covariate.	Baseline, Week 36
Percent Change From Baseline in Lipoprotein (a) at Week 36	Adjusted mean and SE at Week 36 were obtained from robust regression model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effect, and baseline Lp(a) value as continuous fixed covariate.	Baseline, Week 36
Absolute Change From Baseline in High-density Lipoprotein Cholesterol at Week 36	Adjusted LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline HDL-C value and baseline HDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Percent Change From Baseline in High-density Lipoprotein Cholesterol at Week 36	Adjusted LS mean and SE at Week 36 were obtained from mixed-effect model including all available post-baseline data from Week 4 to Week 36. Model included treatment arm (SoC arm, alirocumab arm), randomization strata (statin at ACS onset [Yes / No]), time point, treatment-by-time point and randomization strata-by-time point interaction as fixed categorical effects, and baseline HDL-C value and baseline HDL-C value-by-time point interaction as continuous fixed covariates.	Baseline, Week 36
Absolute Change From Baseline in Fasting Triglycerides (TGs) at Week 36	Adjusted mean and SE were obtained from multiple imputation approach followed by robust regression model including fixed categorical effect of treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) and the continuous fixed covariate of baseline fasting TGs value.	Baseline, Week 36
Percent Change From Baseline in Fasting Triglycerides at Week 36	Adjusted mean and SE were obtained by multiple imputation approach followed by robust regression model included fixed categorical effect of treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) and the continuous fixed covariate of baseline fasting TGs value.	Baseline, Week 36
Absolute Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 36	Adjusted LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and baseline Apo A-1 value as continuous fixed covariate.	Baseline, Week 36
Percent Change From Baseline in Apolipoprotein A-1 at Week 36	Adjusted LS mean and SE at Week 36 were obtained from ANCOVA model including treatment arm (SoC arm, alirocumab arm) and randomization strata (statin at ACS onset [Yes / No]) as fixed categorical effects, and baseline Apo A-1 value as continuous fixed covariate.	Baseline, Week 36
Number of Participants With Cardiovascular (CV) Adverse Events	The suspected or confirmed CV events that occurred from randomization until end of the study visit were collected and reported. The various CV events included CV death, myocardial infarction, ischemic stroke, unstable angina requiring hospitalization , congestive heart failure requiring hospitalization, congestive heart failure requiring hospitalization, ischemia-driven coronary revascularization procedure.	Up to 36 weeks

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Ako J, Hibi K, Tsujita K, Hiro T, Morino Y, Kozuma K, Shinke T, Otake H, Uno K, Louie MJ, Takagi Y, Miyauchi K. Effect of Alirocumab on Coronary Atheroma Volume in Japanese Patients With Acute Coronary Syndrome - The ODYSSEY J-IVUS Trial. Circ J. 2019 Sep 25;83(10):2025-2033. doi: 10.1253/circj.CJ-19-0412. Epub 2019 Aug 20.
• Ako J, Hibi K, Kozuma K, Miyauchi K, Morino Y, Shinke T, Tsujita K, Uno K, Kawabata Y, Hiro T. Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design. J Cardiol. 2018 Jun;71(6):583-589. doi: 10.1016/j.jjcc.2017.11.013. Epub 2018 Mar 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2016
• Primary Completion (Actual): July 27, 2018
• Study Completion (Actual): July 27, 2018

Study Registration Dates

• First Submitted: December 5, 2016
• First Submitted That Met QC Criteria: December 5, 2016
• First Posted (Estimate): December 7, 2016

Study Record Updates

• Last Update Posted (Actual): September 9, 2019
• Last Update Submitted That Met QC Criteria: July 26, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Disease; Pathological Conditions, Anatomical; Coronary Disease; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Coronary Artery Disease; Myocardial Ischemia; Syndrome; Hypercholesterolemia; Acute Coronary Syndrome; Plaque, Atherosclerotic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Rosuvastatin Calcium; Fenofibrate; Anticoagulants; Ezetimibe; Bezafibrate
• Other Study ID Numbers: ALIROL08069; U1111-1184-8764 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Not available for request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No