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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)

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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:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE October 21, 2015
First Posted Date  ICMJE October 22, 2015
Results First Submitted Date  ICMJE April 3, 2018
Results First Posted Date  ICMJE May 7, 2018
Last Update Posted Date January 23, 2019
Actual Study Start Date  ICMJE November 30, 2015
Actual Primary Completion Date April 5, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 3, 2018)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: October 21, 2015)
Percent change in calculated LDL-C using all LDL-C values regardless of adherence to treatment [ Time Frame: Baseline to Week 12 ]
Change History Complete list of historical versions of study NCT02584504 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 3, 2018)
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 21, 2015)
  • Percent change in calculated LDL-C using all LDL-C values during the efficacy treatment period [ Time Frame: Baseline to Week 12 ]
  • Percent change in calculated LDL-C [ Time Frame: Baseline to average Week 10-12 ]
  • Percent change in Apo-B [ Time Frame: Baseline to Week 12 ]
  • Percent change non-HDL-C [ Time Frame: Baseline to Week 12 ]
  • Percent change in TC [ Time Frame: Baseline to Week 12 ]
  • Proportion of patients reaching LDL-C goal [ Time Frame: Week 12 ]
  • Percent change in Lp(a) [ Time Frame: Baseline to Week 12 ]
  • Percent change in HDL-C [ Time Frame: Baseline to Week 12 ]
  • Percent change in fasting TG [ Time Frame: Baseline to Week 12 ]
  • Percent change in Apo A-1 [ Time Frame: Baseline to Week 12 ]
Current Other Pre-specified Outcome Measures
 (submitted: January 3, 2019)
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 ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Efficacy and Safety of Alirocumab in Patients With Hypercholesterolemia Not Adequately Controlled With Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin
Official Title  ICMJE 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
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Hypercholesterolemia
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Alirocumab
    • Drug: Placebo
    • Drug: Atorvastatin
    • Drug: Non-statin Lipid-Modifying Therapy
    • Other: Diet Alone
  • 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.
    Interventions:
    • Drug: Alirocumab
    • Drug: Atorvastatin
    • Drug: Non-statin Lipid-Modifying Therapy
    • Other: Diet Alone
  • 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.
    Interventions:
    • Drug: Placebo
    • Drug: Atorvastatin
    • Drug: Non-statin Lipid-Modifying Therapy
    • Other: Diet Alone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 17, 2018)
163
Original Estimated Enrollment  ICMJE
 (submitted: October 21, 2015)
159
Actual Study Completion Date  ICMJE January 9, 2018
Actual Primary Completion Date April 5, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02584504
Other Study ID Numbers  ICMJE EFC14305
U1111-1170-7697 ( 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  ICMJE Not Provided
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP