Evaluation of Alirocumab Versus Ezetimibe on Top of Statin in Asia in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY EAST)

• ClinicalTrials.gov Identifier: NCT02715726
• Recruitment Status: Completed
• First Posted: March 22, 2016
• Results First Posted: September 30, 2019
• Last Update Posted: September 30, 2019
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: March 16, 2016
• First Posted Date: March 22, 2016
• Results First Submitted Date: August 5, 2019
• Results First Posted Date: September 30, 2019
• Last Update Posted Date: September 30, 2019
• Actual Study Start Date: July 27, 2016
• Actual Primary Completion Date: August 6, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2019)

Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: Intent-to-treat (ITT) Analysis [ Time Frame: From Baseline to Week 24 ]

Adjusted least square (LS) means and standard errors at Week 24 were obtained from mixed models analysis 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).

• Original Primary Outcome Measures (submitted: March 16, 2016): Percent change in calculated LDL-C in the intent-to-treat (ITT) population [ Time Frame: Baseline to Week 24 ]

Current Secondary Outcome Measures (submitted: September 9, 2019)

• Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
• Percent Change From Baseline in Calculated Low Density Lipoprotein Cholesterol at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained 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 Calculated Low Density Lipoprotein Cholesterol at Week 12: On-Treatment Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
• Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained 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 Apolipoprotein B at Week 24: On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
• 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 ]
  Adjusted LS means and standard errors at Week 24 were obtained 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-High Density Lipoprotein Cholesterol at Week 24: On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
• Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained from MMRM model including all available post-baseline data from Week 4 up to Week 24 regardless of status on- or off-treatment.
• Percent Change From Baseline in Apolipoprotein B at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained 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-High Density Lipoprotein Cholesterol at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained 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 Cholesterol at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained 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 Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: ITT Analysis [ Time Frame: Up to Week 24 ]
  Adjusted percentages at Week 24 were obtained from multiple imputation approach 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.
• Percentage of Participants Reaching Calculated Low Density Lipoprotein Cholesterol <70 mg/dL (1.81 mmol/L) at Week 24: On-Treatment Analysis [ Time Frame: Up to Week 24 ]
  Adjusted percentages at Week 24 were obtained from multiple imputation approach including all available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection or 3 days after the last capsule, whichever came first) (on-treatment analysis).
• Percent Change From Baseline in Lipoprotein (a) (Lp[a]) at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted means and standard errors at Week 24 were obtained from multiple imputation approach followed by robust regression model for handling 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 High Density Lipoprotein Cholesterol at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained 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 Fasting Triglycerides (TG) at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted means and standard errors at Week 24 were obtained by using 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 Apolipoprotein A-1 (Apo A-1) at Week 24: ITT Analysis [ Time Frame: From Baseline to Week 24 ]
  Adjusted LS means and standard errors at Week 24 were obtained 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 12 ]
  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 from Week 4 to Week 24 regardless of status on- or off-treatment.
• Percent Change From Baseline in High Density Lipoprotein Cholesterol at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained 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 Fasting Triglycerides at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted means and standard errors at Week 12 were obtained by using multiple imputation approach followed by a 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 Apolipoprotein A-1 at Week 12 : ITT Analysis [ Time Frame: From Baseline to Week 12 ]
  Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.

Original Secondary Outcome Measures (submitted: March 16, 2016)

• Percent change in calculated LDL-C in the modified ITT (mITT) population [ Time Frame: Baseline to Week 24 ]
• Percent change in calculated LDL-C [ Time Frame: Baseline to Week 12 ]
• Percent change in Apo B [ Time Frame: Baseline to Week 12 and Week 24 ]
• Percent change in non-HDL-C [ Time Frame: Baseline to Week 12 and Week 24 ]
• Percent change in TC [ Time Frame: Baseline to Week 12 and Week 24 ]
• Proportion of patients reaching calculated LDL-C <70 mg/dL (1.81 mmol/L) [ Time Frame: Week 24 ]
• Percent change in Lp(a) [ Time Frame: Baseline to Week 12 and Week 24 ]
• Percent change in HDL-C [ Time Frame: Baseline to Week 12 and Week 24 ]
• Percent change in fasting TG [ Time Frame: Baseline to Week 12 and Week 24 ]
• Percent change in Apo A-1 [ Time Frame: Baseline to Week 12 and Week 24 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Evaluation of Alirocumab Versus Ezetimibe on Top of Statin in Asia in High Cardiovascular Risk Patients With Hypercholesterolemia
• Official Title: A Randomized, Double-blind, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe in Asia in High Cardiovascular Risk Patients With Hypercholesterolemia Not Adequately Controlled With Their Statin Therapy

Brief Summary

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 in comparison to ezetimibe 10 mg daily after 24 weeks of treatment in Asia in participants with hypercholesterolemia at high cardiovascular (CV) risk.

Secondary Objectives:

• To evaluate the effect of alirocumab 75 mg in comparison with ezetimibe 10 mg on LDL-C after 12 weeks of treatment.
• To evaluate the effect of alirocumab on other lipid parameters: e.g., apolipoprotein B (Apo B), non-high density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), lipoprotein a (Lp[a]), HDL-C, triglycerides (TG), apolipoprotein A-1 (Apo A-1).
• To evaluate the safety and tolerability of alirocumab.
• To evaluate the development of anti-alirocumab antibodies.
• To evaluate the pharmacokinetics (PK) of alirocumab.

• Detailed Description: The maximum study duration was 35 weeks per participant, which included a screening period of up to 3 weeks, a 24-week randomized treatment period, and an 8-week post-treatment follow-up period.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hypercholesterolemia

Intervention

• Drug: Alirocumab
  Pharmaceutical form:solution Route of administration: subcutaneous
  Other Name: SAR236553 (REGN727)
• Drug: Placebo for alirocumab
  Pharmaceutical form:solution Route of administration: subcutaneous
• Drug: ezetimibe
  Pharmaceutical form:capsule Route of administration: oral
• Drug: placebo for ezetimibe
  Pharmaceutical form:capsule Route of administration: oral
• Drug: atorvastatin
  Pharmaceutical form:tablet Route of administration: oral
• Drug: rosuvastatin
  Pharmaceutical form:tablet Route of administration: oral
• Drug: simvastatin
  Pharmaceutical form:tablet Route of administration: oral

Study Arms

• Active Comparator: Ezetimibe 10 mg
  Oral ezetimibe 10 mg capsule once daily with or without food for 24 weeks and subcutaneous placebo injection for alirocumab every 2 weeks (Q2W) for 22 weeks added to lipid modifying therapy (LMT).
  Interventions:

  • Drug: Placebo for alirocumab
  • Drug: ezetimibe
  • Drug: atorvastatin
  • Drug: rosuvastatin
  • Drug: simvastatin
• Experimental: Alirocumab 75 mg Q2W/up to 150 mg Q2W
  Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe once daily with or without food added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C level was >=70 milligrams per deciliter (mg/dL) (1.81 millimoles per liter [mmol/L]) at Week 8.
  Interventions:

  • Drug: Alirocumab
  • Drug: placebo for ezetimibe
  • Drug: atorvastatin
  • Drug: rosuvastatin
  • Drug: simvastatin

• Publications *: Han Y, Chen J, Chopra VK, Zhang S, Su G, Ma C, Huang Z, Ma Y, Yao Z, Yuan Z, Zhao Q, Kuanprasert S, Baccara-Dinet MT, Manvelian G, Li J, Chen R. ODYSSEY EAST: Alirocumab efficacy and safety vs ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand. J Clin Lipidol. 2020 Jan - Feb;14(1):98-108.e8. doi: 10.1016/j.jacl.2019.10.015. Epub 2019 Nov 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 13, 2018): 615
• Original Estimated Enrollment (submitted: March 16, 2016): 600
• Actual Study Completion Date: August 6, 2018
• Actual Primary Completion Date: August 6, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 at a stable dose for at least 4 weeks prior to the screening visit (Week -3).

Exclusion criteria:

• Participants without established CHD or CHD risk equivalents.
• LDL-C <70 mg/dL (<1.81 mmol/L) at the screening visit (Week -3) in participants with history of documented CV disease.
• LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) in participants without history of documented CV disease.
• Change in statin dose or dose regimen from screening to randomization.
• 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 40 mg, or simvastatin 40 mg.
• Use of cholesterol absorption inhibitor (ie, ezetimibe), omega-3 fatty acid (at doses ≥1000 mg daily), nicotinic acid, fibrates, bile acid-binding sequestrant, or red yeast rice products in the past 4 weeks prior to screening visit (Week -3).
• 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 participant's potential participation in a clinical trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, India, Thailand

Administrative Information

• NCT Number: NCT02715726
• Other Study ID Numbers: EFC13889; U1111-1150-8859 ( Other Identifier: UTN )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi
• Original Responsible Party: Same as current
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

• PRS Account: Sanofi
• Verification Date: September 2019