Evaluation of Alirocumab in Addition to Lipid-Modifying Therapy in Patients With High Cardiovascular Risk and Hypercholesterolemia in South Korea and Taiwan

A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy in South Korea and Taiwan

Primary Objective:

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 risk participants with hypercholesterolemia in South Korea and Taiwan.

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: apolipoprotein B (Apo B), non high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein (a) (Lp [a]), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs), and apolipoprotein A-1 (Apo A-1).
• To evaluate the safety and tolerability of alirocumab.
• To evaluate the development of anti-alirocumab antibodies (ADA).

Study Overview

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

Detailed Description

The maximum study duration was approximately 35 weeks per participant, including up to 3 weeks screening period, 24 weeks double-blind treatment period, and 8 weeks follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 199
• Phase: Phase 3

Contacts and Locations

Study Locations

• Korea, Republic of
  • Anyang, Korea, Republic of, 431-070
    • Investigational Site Number 410001
  • Anyang-Si, Korea, Republic of, 431-070
    • Investigational Site Number 410009
  • Busan, Korea, Republic of, 602-715
    • Investigational Site Number 410017
  • Busan, Korea, Republic of, 614-735
    • Investigational Site Number 410007
  • Daegu, Korea, Republic of, 700-712
    • Investigational Site Number 410002
  • Goyang-Si, Korea, Republic of, 410-773
    • Investigational Site Number 410011
  • Gwangju, Korea, Republic of, 501-757
    • Investigational Site Number 410003
  • Incheon, Korea, Republic of, 405-760
    • Investigational Site Number 410012
  • Jeonju-Si, Korea, Republic of, 561-712
    • Investigational Site Number 410018
  • Seoul, Korea, Republic of, 06591
    • Investigational Site Number 410006
  • Seoul, Korea, Republic of, 07061
    • Investigational Site Number 410004
  • Seoul, Korea, Republic of, 08308
    • Investigational Site Number 410015
  • Seoul, Korea, Republic of, 110-746
    • Investigational Site Number 410008
  • Seoul, Korea, Republic of, 134-727
    • Investigational Site Number 410005
  • Seoul, Korea, Republic of, 152-703
    • Investigational Site Number 410010
  • Ulsan, Korea, Republic of
    • Investigational Site Number 410013
• Taiwan
  • Changhua, Taiwan, 500
    • Investigational Site Number 158007
  • Hsinchu, Taiwan, 30071
    • Investigational Site Number 158005
  • Kaohsiung, Taiwan, 807
    • Investigational Site Number 158011
  • Kaohsiung, Taiwan, 833
    • Investigational Site Number 158010
  • Taichung, Taiwan
    • Investigational Site Number 158006
  • Tainan, Taiwan, 704
    • Investigational Site Number 158008
  • Tainan Hsien, Taiwan, 710
    • Investigational Site Number 158009
  • Taipei, Taiwan, 100
    • Investigational Site Number 158001
  • Taipei, Taiwan, 104
    • Investigational Site Number 158003
  • Taipei, Taiwan, 112
    • Investigational Site Number 158002
  • Taoyuan Hsien, Taiwan
    • Investigational Site Number 158004

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 with hypercholesterolemia and established coronary heart disease (CHD) or CHD risk equivalents who are 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 prior to screening visit (Week -3).

Exclusion criteria:

• Aged <18 years 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) in participants with a history of documented cardiovascular disease.
• LDL-C <100 mg/dL (<2.59 mmol/L) in participants without a history of documented cardiovascular disease.
• Not on a stable dose of LMT (including statin) for at least 4 weeks prior to the screening visit (Week -3) or between screening to randomization visits.
• Currently taking a statin other than atorvastatin, rosuvastatin or simvastatin.
• Atorvastatin, rosuvastatin or simvastatin was not taken daily or not taken at a registered dose.
• Daily doses above atorvastatin 80 mg, rosuvastatin 20 mg or simvastatin 40 mg.
• Fasting serum triglycerides >400 mg/dL (>4.52 mmol/L) at the screening period.

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Q2W; Placebo (for alirocumab) subcutaneous (SC) injection every 2 weeks (Q2W) added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.	Drug: Placebo (for Alirocumab); Solution for injection, one subcutaneous injection in the abdomen with a disposable auto-injector.; Drug: Lipid-Modifying Therapy (LMT); Statins (Rosuvastatin, Simvastatin or Atorvastatin) at stable dose with or without other LMT as clinically indicated.
Placebo Comparator: Alirocumab 75 mg Q2W/Up to 150 mg Q2W; Alirocumab 75 mg SC injection Q2W added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) at Week 8.	Drug: Lipid-Modifying Therapy (LMT); Statins (Rosuvastatin, Simvastatin or Atorvastatin) at stable dose with or without other LMT as clinically indicated.; Drug: Alirocumab; Solution for injection, one subcutaneous injection in the abdomen with a disposable 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 up 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 up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from MMRM model including available post-baseline on-treatment data up 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 were obtained from MMRM model including all available post-baseline data up 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 up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from MMRM model including available post-baseline on-treatment data up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from MMRM model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis	Adjusted percentages at Week 24 were obtained from multiple imputation approach model for handling of missing data. All available post-baseline data up to Week 24 regardless of status on- or off-treatment were included in the imputation model.	From Baseline to Week 24
Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-treatment Analysis	Adjusted percentages at Week 24 were obtained from multiple imputation approach model including available post-baseline on-treatment data up to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis	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 up 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 High Density Lipoprotein (HDL-C) at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment.	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 were obtained from multiple imputation approach followed by robust regression model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data up 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 were obtained from multiple imputation approach followed by robust regression model including all available post-baseline data up 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 were obtained from MMRM model including all available post-baseline data up 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 were obtained from multiple imputation approach followed by a robust regression model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis	Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all available post-baseline data up to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• Chao TH, Hsiao PJ, Liu ME, Wu CJ, Chiang FT, Chen ZC, Chen CP, Yeh HI, Lee TH, Chiang CE. A subanalysis of Taiwanese patients from ODYSSEY South Korea and Taiwan study evaluating the efficacy and safety of alirocumab. J Chin Med Assoc. 2019 Apr;82(4):265-271. doi: 10.1097/JCMA.0000000000000062.
• Koh KK, Nam CW, Chao TH, Liu ME, Wu CJ, Kim DS, Kim CJ, Li I, Li J, Baccara-Dinet MT, Hsiao PJ, Chiang CE. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol. 2018 Jan-Feb;12(1):162-172.e6. doi: 10.1016/j.jacl.2017.09.007. Epub 2017 Oct 19.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: November 10, 2014
• First Submitted That Met QC Criteria: November 10, 2014
• First Posted (Estimate): November 13, 2014

Study Record Updates

• Last Update Posted (Actual): June 26, 2017
• Last Update Submitted That Met QC Criteria: June 22, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Physiological Effects of Drugs; Immunologic Factors; Antibodies, Monoclonal
• Other Study ID Numbers: EFC14074; U1111-1157-3294 (Other Identifier: UTN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• product manufactured in and exported from the U.S.: Yes