Efficacy and Safety of Alirocumab in Patients With Hypercholesterolemia Not Adequately Controlled With Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin (ODYSSEY-NIPPON)

A Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Alirocumab in Patients With Hypercholesterolemia Not Adequately Controlled With Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin

Primary Objective:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by alirocumab administration as add-on therapy to non-statin lipid modifying therapy (LMT) including diet therapy alone or the lowest strength of statin in comparison with placebo after 12 weeks of treatment in participants with hypercholesterolemia.

Secondary Objective:

• To evaluate the effect of two treatment regimens 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), triglyceride (TG), and apolipoprotein A-1 (Apo A-1).
• To evaluate the safety and tolerability of alirocumab administration.
• To evaluate the development of anti-alirocumab antibodies.
• To evaluate the pharmacokinetic and pharmacodynamic profiles of alirocumab administration.
• To evaluate the long-term safety in participants receiving open-label alirocumab administration.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Other: Diet Alone; Drug: Alirocumab; Drug: Placebo; Drug: Atorvastatin; Drug: Non-statin Lipid-Modifying Therapy

Detailed Description

The duration of study per participant was approximately 71 weeks consisting of a run-in period (4 weeks), a screening period (3 weeks), a double-blind treatment period (12 weeks), and an open-label treatment period (52 weeks).

• Study Type: Interventional
• Enrollment (Actual): 163
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Ageo-Shi, Japan
    • Investigational Site Number 392028
  • Chuo-Ku, Japan
    • Investigational Site Number 392007
  • Chuo-Ku, Japan
    • Investigational Site Number 392029
  • Fukui-Shi, Japan
    • Investigational Site Number 392014
  • Hachioji-Shi, Japan
    • Investigational Site Number 392023
  • Itoshima-Shi, Japan
    • Investigational Site Number 392013
  • Kanazawa-Shi, Japan
    • Investigational Site Number 392010
  • Kasuga-Shi, Japan
    • Investigational Site Number 392024
  • Kawanishi-Shi, Japan
    • Investigational Site Number 392004
  • Kitakyushu-Shi, Japan
    • Investigational Site Number 392015
  • Komatsu-Shi, Japan
    • Investigational Site Number 392005
  • Matsudo-Shi, Japan
    • Investigational Site Number 392032
  • Matsumoto-Shi, Japan
    • Investigational Site Number 392017
  • Mito-Shi, Japan
    • Investigational Site Number 392003
  • Morioka-Shi, Japan
    • Investigational Site Number 392018
  • Moriya-Shi, Japan
    • Investigational Site Number 392009
  • Nagoya-Shi, Japan
    • Investigational Site Number 392025
  • Nagoya-Shi, Japan
    • Investigational Site Number 392006
  • Nagoya-Shi, Japan
    • Investigational Site Number 392011
  • Nagoya-Shi, Japan
    • Investigational Site Number 392019
  • Osaka-Shi, Japan
    • Investigational Site Number 392027
  • Sakura-Shi, Japan
    • Investigational Site Number 392030
  • Shinagawa-Ku, Japan
    • Investigational Site Number 392016
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392001
  • Shinjuku-Ku, Japan
    • Investigational Site Number 392008
  • Shizuoka-Shi, Japan
    • Investigational Site Number 392012
  • Suita-Shi, Japan
    • Investigational Site Number 392002
  • Suita-Shi, Japan
    • Investigational Site Number 392031
  • Toyonaka-Shi, Japan
    • Investigational Site Number 392020
  • Yao-Shi, Japan
    • Investigational Site Number 392022

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

Participants with hypercholesterolemia (heFH or non-FH) receiving non statin LMTs or the lowest strength of statin.

Exclusion criteria:

• LDL-C <100 mg/dL (<2.59 mmol/L) at the screening visit (Week -3) in participants with heFH or in participants with non-FH who have a history of documented coronary heart disease.
• LDL-C <120 mg/dL (<3.10 mmol/L) at the screening visit (Week -3) in participants with non-FH participants who had a history of documented diseases or other risk factors classified as primary prevention category III as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
• Not on a stable dose of LMT (including diet therapy alone) in the run-in period or the screening period.
• Fasting serum TGs >400 mg/dL (>4.52 mmol/L) at the screening period.
• Systolic blood pressure (BP) >160 mmHg or diastolic BP >100 mmHg at the run-in visit (Week -7) or the screening visit (Week -3) or the randomization visit (Week 0).

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: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alirocumab 150 mg Q4W; Double-blind treatment period(DBTP):participants received Alirocumab 150 mg subcutaneous injection every 4 week(Q4W) alternating with placebo(for alirocumab)Q4W added to lowest-strength statin therapy(atorvastatin 5 mg daily),stable non-statin LMT/diet therapy alone for 12weeks. Participants completed DBTP,entered open-label treatment period(OLTP),received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg every 2 weeks(Q2W) at Week 24(OLTP:Week 12),when targeted LDL-C level at Week 20 not achieved as Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012:1) ≥100 mg/dL(2.59 mmol/L) in heterozygous familial hypercholesterolemia (heFH) participants/non-familial hypercholesterolemia (non-FH)participants with history of documented coronary heart disease;2) ≥120 mg/dL(3.10 mmol/L)in non-FH participants with history of documented diseases/other risk factors as categorized in primary prevention category III)	Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.; Drug: Alirocumab; Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.; Other Names: SAR236553; REGN727; Drug: Placebo; Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.; Drug: Atorvastatin; Atorvastatin 5 mg tablet orally.; Drug: Non-statin Lipid-Modifying Therapy; Ezetimibe, Bezafibrate or Fenofibrate at stable dose as background therapy.
Experimental: Alirocumab 150 mg Q2W; In DBTP, participants received Alirocumab 150 mg subcutaneous (SC) injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when targeted LDL-C levels at Week 20 were not achieved i.e. LDL-C ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) according to Japan Atherosclerosis Society(JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.; Drug: Alirocumab; Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.; Other Names: SAR236553; REGN727; Drug: Atorvastatin; Atorvastatin 5 mg tablet orally.; Drug: Non-statin Lipid-Modifying Therapy; Ezetimibe, Bezafibrate or Fenofibrate at stable dose as background therapy.
Placebo Comparator: Placebo Q2W; In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when targeted LDL-C levels at Week 20 were not achieved i.e. LDL-C ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.	Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.; Drug: Placebo; Solution for injection, one subcutaneous injection in the abdomen, thigh, or outer area of upper arm with a disposable auto-injector.; Drug: Atorvastatin; Atorvastatin 5 mg tablet orally.; Drug: Non-statin Lipid-Modifying Therapy; Ezetimibe, Bezafibrate or Fenofibrate at stable dose as background therapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis	Adjusted Least-squares (LS) means and standard errors at Week 12 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 12 regardless of status on- or off-treatment were used in the model (ITT analysis).	From Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).	From Baseline to Week 12
Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 12 regardless of status on- or off-treatment and assigning a weight of 0.5 for Week 10 and 12 time points.	From Baseline to Week 12
Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection) and assigning a weight of 0.5 for Week 10 and 12 time points.	From Baseline to Week 12
Percent Change From Baseline in Apolipoprotein B (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 12 regardless of status on- or off-treatment.	From Baseline to Week 12
Percent Change From Baseline in Apo-B 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 at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).	From Baseline to Week 12
Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.	From Baseline to Week 12
Percent Change From Baseline in Non-HDL-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 from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).	From Baseline to Week 12
Percent Change From Baseline in Total Cholesterol (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 12 regardless of status on- or off-treatment.	From Baseline to Week 12
Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis	Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heterozygous familiar hypercholesterolemia (heFH) participants or non-familial hypercholesterolemia (non-FH) participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.	Up to Week 12
Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis	Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heFH participants or non-FH participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).	Up to Week 12
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 for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.	From Baseline to Week 12
Percent Change From Baseline in High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.	From Baseline to Week 12
Percent Change From Baseline in Fasting Triglycerides (TGs) 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 12 regardless of status on- or off-treatment.	From Baseline to Week 12
Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) 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 12 regardless of status on- or off-treatment.	From Baseline to Week 12

Other Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis	Baseline, Weeks 20, 24, 36, 48 and 64

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Teramoto T, Kondo A, Kiyosue A, Harada-Shiba M, Ishigaki Y, Tobita K, Kawabata Y, Ozaki A, Baccara-Dinet MT, Sata M. Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale. Lipids Health Dis. 2017 Jun 17;16(1):121. doi: 10.1186/s12944-017-0513-7.
• Teramoto T, Kiyosue A, Ishigaki Y, Harada-Shiba M, Kawabata Y, Ozaki A, Baccara-Dinet MT, Sata M. Efficacy and safety of alirocumab 150mg every 4 weeks in hypercholesterolemic patients on non-statin lipid-lowering therapy or lowest strength dose of statin: ODYSSEY NIPPON. J Cardiol. 2019 Mar;73(3):218-227. doi: 10.1016/j.jjcc.2018.10.004. Epub 2018 Nov 30.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2015
• Primary Completion (Actual): April 5, 2017
• Study Completion (Actual): January 9, 2018

Study Registration Dates

• First Submitted: October 21, 2015
• First Submitted That Met QC Criteria: October 21, 2015
• First Posted (Estimate): October 22, 2015

Study Record Updates

• Last Update Posted (Actual): January 23, 2019
• Last Update Submitted That Met QC Criteria: January 3, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Non-statin LMT; Low dose statin
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin
• Other Study ID Numbers: EFC14305; U1111-1170-7697 (Other Identifier: UTN)

Drug and device information, study documents

• 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