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

• ClinicalTrials.gov Identifier: NCT02023879
• Recruitment Status: Completed
• First Posted: December 30, 2013
• Results First Posted: March 15, 2017
• Last Update Posted: July 27, 2018
• 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 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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia	Drug: Alirocumab; Drug: Placebo (for Alirocumab); Drug: Non-statin LMT; Other: Diet Alone	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 233 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A double-blind treatment period of 24 weeks (3 parallel arms) followed by an open-label extension period (single arm)
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Masking during the double-blind treatment period
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: December 16, 2013
• Actual Primary Completion Date: October 27, 2014
• Actual Study Completion Date: June 30, 2017

Arms and Interventions

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.
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.

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-Treat (ITT Analysis) [ Time Frame: From Baseline to Week 24 ]
   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).

Secondary Outcome Measures :

1. Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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).
2. Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
3. Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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).
4. Percent Change From Baseline in Calculated LDL-C to Averaged Weeks 9 to 12 - ITT- Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
5. Percent Change From Baseline in Calculated LDL-C at Averaged Week 9 to 12 - On-Treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
6. Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
7. Percent Change From Baseline in Apo B at Week 24 - On-treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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).
8. Percent Change From Baseline in Non-HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
   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.
9. Percent Change From Baseline in Non-HDL-C at Week 24 - On-treatment Analysis [ Time Frame: From Baseline to Week 24 ]
   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).
10. Percent Change From Baseline in Total-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
11. Percent Change From Baseline in Apo B at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
12. Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
13. Percent Change From Baseline in Total-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
14. 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 [ Time Frame: From Baseline to Week 24 ]

    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.

15. 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 [ Time Frame: From Baseline to Week 24 ]
    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).
16. Percentage of Participants Achieving Calculated LDL-C< 70 mg/dL (<1.81 mmol/L) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
17. Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (<1.81 mmol/L) at Week 24 - On-treatment Analysis [ Time Frame: From Baseline to Week 24 ]
    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).
18. Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
19. Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
20. Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
21. Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
22. Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
23. Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
24. Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.
25. Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis [ Time Frame: From Baseline to Week 24 ]
    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.

Other Outcome Measures:

1. 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 [ Time Frame: Baseline, Week 32, 36, 48, 72, 96, 120, 144 and Week 168 ]
   Mean percent changes (and standard deviations) observed during the open-label extension period are provided.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

  Show 43 Study Locations

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications of Results:

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). pii: e003421. doi: 10.1161/JAHA.116.003421.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT02023879 History of Changes
• Other Study ID Numbers: EFC13786; 2013-002659-14 ( EudraCT Number ); U1111-1146-3517 ( Other Identifier: UTN )
• First Posted: December 30, 2013
• Results First Posted: March 15, 2017
• Last Update Posted: July 27, 2018
• Last Verified: June 2018

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs