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)

• ClinicalTrials.gov Identifier: NCT02584504
• Recruitment Status: Completed
• First Posted: October 22, 2015
• Results First Posted: May 7, 2018
• Last Update Posted: January 23, 2019
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Alirocumab; Drug: Placebo; Drug: Atorvastatin; Drug: Non-statin Lipid-Modifying Therapy; Other: Diet Alone	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 163 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 30, 2015
• Actual Primary Completion Date: April 5, 2017
• Actual Study Completion Date: January 9, 2018

Arms and Interventions

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)	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.; Other: Diet Alone; Stable cholesterol-lowering diet 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.	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.; Other: Diet Alone; Stable cholesterol-lowering diet 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.	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.; Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis [ Time Frame: From Baseline to Week 12 ]
   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).

Secondary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C 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 available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
2. Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
3. Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 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.
4. Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
5. Percent Change From Baseline in Apo-B 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 available post-baseline on-treatment data at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
6. Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
7. Percent Change From Baseline in Non-HDL-C 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 available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
8. Percent Change From Baseline in Total Cholesterol (Total-C) at Week 12- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
   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.
9. Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis [ Time Frame: Up to Week 12 ]
   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.
10. Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis [ Time Frame: Up to Week 12 ]
    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).
11. 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 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.
12. Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Week 12- ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    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.
13. Percent Change From Baseline in Fasting Triglycerides (TGs) at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    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.
14. Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 12: ITT Analysis [ Time Frame: From Baseline to Week 12 ]
    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.

Other Outcome Measures:

1. Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis [ Time Frame: Baseline, Weeks 20, 24, 36, 48 and 64 ]

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

Japan

Investigational Site Number 392028

Ageo-Shi, Japan

Investigational Site Number 392007

Chuo-Ku, Japan

Investigational Site Number 392029

Chuo-Ku, Japan

Investigational Site Number 392014

Fukui-Shi, Japan

Investigational Site Number 392023

Hachioji-Shi, Japan

Investigational Site Number 392013

Itoshima-Shi, Japan

Investigational Site Number 392010

Kanazawa-Shi, Japan

Investigational Site Number 392024

Kasuga-Shi, Japan

Investigational Site Number 392004

Kawanishi-Shi, Japan

Investigational Site Number 392015

Kitakyushu-Shi, Japan

Investigational Site Number 392005

Komatsu-Shi, Japan

Investigational Site Number 392032

Matsudo-Shi, Japan

Investigational Site Number 392017

Matsumoto-Shi, Japan

Investigational Site Number 392003

Mito-Shi, Japan

Investigational Site Number 392018

Morioka-Shi, Japan

Investigational Site Number 392009

Moriya-Shi, Japan

Investigational Site Number 392006

Nagoya-Shi, Japan

Investigational Site Number 392011

Nagoya-Shi, Japan

Investigational Site Number 392019

Nagoya-Shi, Japan

Investigational Site Number 392025

Nagoya-Shi, Japan

Investigational Site Number 392027

Osaka-Shi, Japan

Investigational Site Number 392030

Sakura-Shi, Japan

Investigational Site Number 392016

Shinagawa-Ku, Japan

Investigational Site Number 392001

Shinjuku-Ku, Japan

Investigational Site Number 392008

Shinjuku-Ku, Japan

Investigational Site Number 392012

Shizuoka-Shi, Japan

Investigational Site Number 392002

Suita-Shi, Japan

Investigational Site Number 392031

Suita-Shi, Japan

Investigational Site Number 392020

Toyonaka-Shi, Japan

Investigational Site Number 392022

Yao-Shi, Japan

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi:

Study Protocol  [PDF] April 26, 2017

Statistical Analysis Plan  [PDF] June 17, 2016

More Information

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT02584504 History of Changes
• Other Study ID Numbers: EFC14305; U1111-1170-7697 ( Other Identifier: UTN )
• First Posted: October 22, 2015
• Results First Posted: May 7, 2018
• Last Update Posted: January 23, 2019
• Last Verified: January 2019

• 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

Keywords provided by Sanofi:

Non-statin LMT; Low dose statin

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antibodies, Monoclonal; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Enzyme Inhibitors; Immunologic Factors; Physiological Effects of Drugs