Phase III Study To Evaluate Alirocumab in Patients With Hypercholesterolemia Not Treated With a Statin (ODYSSEY CHOICE II)

A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating the Efficacy and Safety of Alirocumab in Patients With Primary Hypercholesterolemia Not Treated With a Statin

Primary Objective:

To demonstrate the reduction of low-density lipoprotein cholesterol (LDL-C) by a regimen of Alirocumab including a starting dose of 150 mg every 4 weeks (Q4W) as add-on to non-statin lipid modifying background therapy or as monotherapy in comparison with placebo in participants with primary hypercholesterolemia not treated with a statin.

Secondary Objective:

• To evaluate the effects on other lipid parameters of Alirocumab 150 mg Q4W versus placebo.
• To evaluate the safety and tolerability of Alirocumab 150 mg Q4W.

Alirocumab 75 mg Q2W was added as a calibrator arm.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Alirocumab; Drug: Placebo (for Alirocumab); Drug: Non-statin LMT; Other: Diet Alone

Detailed Description

The core study duration was approximately 35 weeks per participant (screening: 3 weeks, double-blind treatment period: 24 weeks; follow-up: 8 weeks). Participants who successfully completed the treatment period had the possibility to participate in an optional open-label treatment period with Alirocumab 150 mg Q4W until second quarter 2017 or until the drug is commercially available in the country, whatever occurred first.

• Study Type: Interventional
• Enrollment (Actual): 233
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Ashford, Australia, 5035
    • Investigational Site Number 036703
  • Perth, Australia, 6000
    • Investigational Site Number 036702
  • Woolloongabba, Australia, 4102
    • Investigational Site Number 036701
• Belgium
  • Antwerpen, Belgium, 2060
    • Investigational Site Number 056702
  • Haine-Saint-Paul, Belgium, 7100
    • Investigational Site Number 056703
  • Leuven, Belgium, 3000
    • Investigational Site Number 056701
• Canada
  • Chicoutimi, Canada, G7H 7P2
    • Investigational Site Number 124703
  • Quebec, Canada, G1V 4M6
    • Investigational Site Number 124701
  • Sherbrooke, Canada, J1H 1Z1
    • Investigational Site Number 124704
  • Toronto, Canada, M9V 4B4
    • Investigational Site Number 124706
  • Vancouver, Canada, V5Z 1M9
    • Investigational Site Number 124702
  • Victoria, Canada, V8T 5G4
    • Investigational Site Number 124705
• Denmark
  • Aarhus, Denmark, 8200
    • Investigational Site Number 208703
  • Esbjerg, Denmark, 6700
    • Investigational Site Number 208702
  • Glostrup, Denmark, 2600
    • Investigational Site Number 208701
  • Hvidovre, Denmark, 2650
    • Investigational Site Number 208704
  • Køge, Denmark, 4600
    • Investigational Site Number 208705
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Investigational Site Number 528701
  • Den Helder, Netherlands, 1782 GZ
    • Investigational Site Number 528708
  • Hoogeveen, Netherlands, 7909 AA
    • Investigational Site Number 528702
  • Hoorn, Netherlands, 1625 HV
    • Investigational Site Number 528703
  • Rotterdam, Netherlands, 3045 PM
    • Investigational Site Number 528706
  • Sneek, Netherlands, 8601 ZK
    • Investigational Site Number 528709
  • Utrecht, Netherlands, 3584 CX
    • Investigational Site Number 528704
  • Venlo, Netherlands, 5912 BL
    • Investigational Site Number 528707
• New Zealand
  • Auckland, New Zealand, 1023
    • Investigational Site Number 554702
  • Christchurch, New Zealand, 8011
    • Investigational Site Number 554701
• Spain
  • A Coruna, Spain, 15006
    • Investigational Site Number 724703
  • Barcelona, Spain, 08025
    • Investigational Site Number 724707
  • Barcelona, Spain, 08035
    • Investigational Site Number 724710
  • Córdoba, Spain, 14004
    • Investigational Site Number 724702
  • Granada, Spain, 18012
    • Investigational Site Number 724705
  • Sant Joan Despí, Spain, 08970
    • Investigational Site Number 724709
  • Santiago De Compostela, Spain, 15706
    • Investigational Site Number 724706
  • Zaragoza, Spain, 50009
    • Investigational Site Number 724701
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Investigational Site Number 840703
  • Florida
    • Atlantis, Florida, United States, 33462
      • Investigational Site Number 840704
    • Jacksonville, Florida, United States, 32216
      • Investigational Site Number 840708
    • Sarasota, Florida, United States, 34239
      • Investigational Site Number 840701
  • Massachusetts
    • Fall River, Massachusetts, United States, 02720
      • Investigational Site Number 840706
  • Missouri
    • Saint Louis, Missouri, United States, 63131
      • Investigational Site Number 840705
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Investigational Site Number 840707
  • South Carolina
    • Summerville, South Carolina, United States, 29485
      • Investigational Site Number 840702

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 primary hypercholesterolemia (heterozygous familial hypercholesterolemia [heFH] or non-FH) not adequately controlled with their non-statin LMT (either ezetimibe or fenofibrate) or diet alone.

Exclusion criteria:

• LDL-C <70 mg/dL (1.81 mmol/L) at screening for statin intolerant participants at very high cardiovascular (CV) risk;
• LDL-C <100 mg/dL (<2.59 mmol/L) at screening for statin intolerant participants at high or moderate CV risk or, participants not fulfilling the statin intolerant definition at moderate CV risk;
• LDL-C ≥160 mg/dL (≥4.1 mmol/L) at screening for participants receiving diet only or, participants not fulfilling the statin intolerant definition at moderate CV risk and receiving a non-statin LMT.

The above information is 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: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Q2W; Period 1: Placebo (for Alirocumab) subcutaneous (SC) injection every 2 weeks (Q2W) added to stable non-statin lipid modifying therapy (LMT) or diet alone for 24 weeks. Period 2: Alirocumab 150 mg SC injection every 4 weeks (Q4W) from Week 24 until second quarter 2017 or until the drug is commercially available in the country, whatever occurred first. Alirocumab dose could be either up-titrated to 150 mg Q2W from Week 36 or maintained according to the investigator judgement and low-density lipoprotein cholesterol (LDL-C) values. Subsequent down titration to 150 mg Q4W was allowed.	Drug: Alirocumab; Solution for injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre-filled pen).; Other Names: SAR236553; REGN727; Praluent®; Drug: Placebo (for Alirocumab); Solution for injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre-filled pen).; Drug: Non-statin LMT; Ezetimibe or Fenofibrate at stable dose as background therapy.; Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.
Other: Alirocumab 75 mg Q2W/Up to 150 mg Q2W (Calibrator); Period 1: Alirocumab 75 mg SC injection Q2W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted LDL-C levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline. Period 2: Alirocumab 150 mg SC injection Q4W from Week 24 until second quarter 2017 or until the drug is commercially available in the country, whatever occurred first. Alirocumab dose could be either up-titrated to 150 mg Q2W from Week 36 or maintained according to the investigator judgement and LDL-C values. Subsequent down titration to 150 mg Q4W was allowed.	Drug: Alirocumab; Solution for injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre-filled pen).; Other Names: SAR236553; REGN727; Praluent®; Drug: Non-statin LMT; Ezetimibe or Fenofibrate at stable dose as background therapy.; Other: Diet Alone; Stable cholesterol-lowering diet as background therapy.
Experimental: Alirocumab 150 mg Q4W/Up to 150 mg Q2W; Period 1: Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to stable non-statin LMT or diet alone for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when targeted LDL-C levels at Week 8 were not achieved i.e. LDL-C ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) depending on cardiovascular risk or <30% LDL-C reduction from baseline. Period 2: Alirocumab 150 mg SC injection Q4W from Week 24 until second quarter 2017 or until the drug is commercially available in the country, whatever occurred first. Alirocumab dose could be either up-titrated to 150 mg Q2W from Week 36 or maintained according to the investigator judgement and LDL-C values. Subsequent down titration to 150 mg Q4W was allowed.	Drug: Alirocumab; Solution for injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre-filled pen).; Other Names: SAR236553; REGN727; Praluent®; Drug: Placebo (for Alirocumab); Solution for injection in the abdomen, thigh, or outer area of the upper arm by self-injection or by another designated person using auto-injector (also known as pre-filled pen).; Drug: Non-statin LMT; Ezetimibe or Fenofibrate at stable dose as background therapy.; Other: Diet Alone; Stable cholesterol-lowering diet 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 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 from Week 4 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 from MMRM model including available post-baseline on-treatment data from Week 4 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 from MMRM including all available post-baseline data from Week 4 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 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percent Change From Baseline in Calculated LDL-C to Averaged Weeks 9 to 12 - ITT- Analysis	Adjusted LS means and standard errors at Week 12 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment and assigning a weight of 0.25 for Week 9, 10, 11 and 12 time points.	From Baseline to Week 24
Percent Change From Baseline in Calculated LDL-C at Averaged Week 9 to 12 - On-Treatment Analysis	Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection) and assigning a weight of 0.25 for Week 9, 10, 11 and 12 time points.	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 from MMRM including all available post-baseline data from Week 4 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 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percent Change From Baseline in Non-HDL-C at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 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 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percent Change From Baseline in Total-C at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 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 from MMRM including all available post-baseline data from Week 4 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 from MMRM including all available post-baseline data from Week 4 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 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment.	From Baseline to Week 24
Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C <70 mg/dL (<1.81 mmol/L) or Moderate or High CV Risk Participants Achieving Calculated LDL-C <100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis	Moderate CV risk: 10-year fatal cardiovascular disease (CVD) risk Systemic Coronary Risk Evaluation (SCORE) ≥1 and <5%. High CV risk: 10-year fatal CVD risk SCORE ≥5% or moderate chronic kidney disease or type 1 or type 2 diabetes mellitus without target organ damage or familial hypercholesterolemia. Very high CV risk: history of documented coronary heart disease, ischemic stroke, peripheral artery disease, transient ischemic attack, abdominal aortic aneurysm, or carotid artery occlusion >50% without symptoms; carotid endarterectomy or carotid artery stent procedure; renal artery stenosis, or renal artery stent procedure; or type 1 or type 2 diabetes mellitus with target organ damage. Adjusted percentages at Week 24 were obtained from a multiple imputation approach model 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.	From Baseline to Week 24
Percentage of Very High CV Risk Participants Achieving Calculated LDL-C< 70 mg/dL (<1.81 mmol/L) or Moderate or High CV Risk Participants Achieving Calculated LDL-C< 100 mg/dL (<2.59 mmol/L) at Week 24 - On-treatment Analysis	Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 24 (i.e. up to 21 days after last injection).	From Baseline to Week 24
Percentage of Participants Achieving Calculated LDL-C< 70 mg/dL (<1.81 mmol/L) at Week 24 - ITT Analysis	Adjusted percentages at Week 24 from last observation carried forward (LOCF) approach including all available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment.	From Baseline to Week 24
Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (<1.81 mmol/L) at Week 24 - On-treatment Analysis	Adjusted percentages at Week 24 from LOCF approach including available post-baseline on-treatment data from Week 4 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 from a 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.	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 from a 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.	From Baseline to Week 24
Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 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 from MMRM including all available post-baseline data from Week 4 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 from a 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.	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 from a 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.	From Baseline to Week 24
Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis	Adjusted LS means and standard errors at Week 24 from MMRM including all available post-baseline data from Week 4 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 from MMRM including all available post-baseline data from Week 4 to Week 24 regardless of status on-or off-treatment.	From Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Calculated LDL-C at Week 32, 36, 48, 72, 96, 120, 144, 168 On-Treatment Analysis in Open Label Extension Treatment Phase	Mean percent changes (and standard deviations) observed during the open-label extension period are provided.	Baseline, Week 32, 36, 48, 72, 96, 120, 144 and Week 168

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, Baccara-Dinet MT, Lecorps G, Manvelian G, Farnier M; ODYSSEY CHOICE II Investigators. Efficacy and Safety of Alirocumab 150 mg Every 4 Weeks in Patients With Hypercholesterolemia Not on Statin Therapy: The ODYSSEY CHOICE II Study. J Am Heart Assoc. 2016 Sep 13;5(9):e003421. doi: 10.1161/JAHA.116.003421.

Study record dates

Study Major Dates

• Study Start: December 16, 2013
• Primary Completion (Actual): October 27, 2014
• Study Completion (Actual): June 30, 2017

Study Registration Dates

• First Submitted: December 6, 2013
• First Submitted That Met QC Criteria: December 24, 2013
• First Posted (Estimate): December 30, 2013

Study Record Updates

• Last Update Posted (Actual): July 27, 2018
• Last Update Submitted That Met QC Criteria: June 29, 2018
• Last Verified: June 1, 2018

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: EFC13786; 2013-002659-14 (EudraCT Number); U1111-1146-3517 (Other Identifier: UTN)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No