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Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Ezetimibe on Top of Statin in High Cardiovascular Risk Patients With Hypercholesterolemia (ODYSSEY COMBO II)

This study has been completed.
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi
ClinicalTrials.gov Identifier:
NCT01644188
First received: July 16, 2012
Last updated: June 23, 2016
Last verified: June 2016
Results First Received: August 20, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Hypercholesterolemia
Interventions: Drug: Alirocumab
Drug: Placebo (for alirocumab)
Drug: Ezetimibe
Drug: Placebo (for ezetimibe)
Drug: Lipid Modifying Therapy (LMT)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The study was conducted at 126 centers in 10 countries. Overall, 1112 participants were screened between August 2012 and May 2013, 392 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Randomization was stratified according to prior history of myocardial infarction or ischemic stroke, intensity of statin treatment and geographical region. Assignment to arms was done centrally using Interactive Voice/Web Response System in 2:1 ratio (alirocumab: ezetimibe) after confirmation of selection criteria. 720 participants were randomized.

Reporting Groups
  Description
Alirocumab 75 /up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg every 2 weeks (Q2W) and oral placebo capsule for ezetimibe daily added to stable Lipid­ Modifying Therapy (LMT) for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when low density lipoprotein cholesterol (LDL-C) level ≥70 mg/dL (1.81 mmol/L) at Week 8.
Ezetimibe 10 mg Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.

Participant Flow:   Overall Study
    Alirocumab 75 /up to 150 mg Q2W   Ezetimibe 10 mg
STARTED   479 [1]   241 [1] 
Treated   479   241 
COMPLETED   357   166 
NOT COMPLETED   122   75 
Adverse Event                44                20 
Poor compliance to protocol                26                14 
Physician Decision                1                3 
Participant moved                7                2 
Related to auto-injector administration                2                2 
Consent withdrawn by participant                14                7 
Selection criteria finally not met                2                0 
Lost to Follow-up                1                0 
Death                4                3 
Last visit outside protocol visit window                14                16 
Site closure                1                1 
Other than specified above                6                7 
[1] Randomized



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Alirocumab 75 /up to 150 mg Q2W Subcutaneous injection of alirocumab 75 mg Q2W and oral placebo capsule for ezetimibe daily added to stable LMT for 104 weeks. Alirocumab dose up-titrated to 150 mg from Week 12 when LDL-C level ≥70 mg/dL (1.81 mmol/L) at Week 8.
Ezetimibe 10 mg Oral ezetimibe 10 mg capsule daily and subcutaneous placebo injection for alirocumab Q2W added to stable LMT for 104 weeks.
Total Total of all reporting groups

Baseline Measures
    Alirocumab 75 /up to 150 mg Q2W   Ezetimibe 10 mg   Total
Overall Participants Analyzed 
[Units: Participants]
 479   241   720 
Age 
[Units: Years]
Mean (Standard Deviation)
 61.7  (9.4)   61.3  (9.2)   61.6  (9.3) 
Gender 
[Units: Participants]
     
Female   119   71   190 
Male   360   170   530 
Calculated LDL-C in mg/dL [1] 
[Units: mg/dL]
Mean (Standard Deviation)
 108.6  (36.5)   104.6  (34.1)   107.3  (35.7) 
[1] Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]).
Calculated LDL-C in mmol/L 
[Units: mmol/L]
Mean (Standard Deviation)
 2.812  (0.945)   2.710  (0.884)   2.778  (0.926) 


  Outcome Measures
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1.  Primary:   Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis   [ Time Frame: From Baseline to Week 52 ]

2.  Secondary:   Percent Change From Baseline in Calculated LDL­-C at Week 24 - On­-Treatment Analysis   [ Time Frame: From Baseline to Week 52 ]

3.  Secondary:   Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

4.  Secondary:   Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis   [ Time Frame: From Baseline to Week 52 ]

5.  Secondary:   Percent Change From Baseline in Apolipoprotein B (Apo-B) at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

6.  Secondary:   Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis   [ Time Frame: From Baseline to Week 52 ]

7.  Secondary:   Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

8.  Secondary:   Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis   [ Time Frame: From Baseline up to Week 52 ]

9.  Secondary:   Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

10.  Secondary:   Percent Change From Baseline in Apo-B at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

11.  Secondary:   Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

12.  Secondary:   Percent Change From Baseline in Total-C at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

13.  Secondary:   Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

14.  Secondary:   Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis   [ Time Frame: Up to Week 52 ]

15.  Secondary:   Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis   [ Time Frame: Up to Week 52 ]

16.  Secondary:   Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis   [ Time Frame: From baseline to Week 52 ]

17.  Secondary:   Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

18.  Secondary:   Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

19.  Secondary:   Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

20.  Secondary:   Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

21.  Secondary:   Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

22.  Secondary:   Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

23.  Secondary:   Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis   [ Time Frame: From Baseline to Week 52 ]

24.  Other Pre-specified:   Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis   [ Time Frame: From Baseline to Week 52 ]

25.  Other Pre-specified:   Percent Change From Baseline in Calculated LDL-C at Week 104 - ITT Analysis   [ Time Frame: From Baseline to Week 104 ]

26.  Other Pre-specified:   Percent Change From Baseline in Calculated LDL-C at Week 104 – On-Treatment Analysis   [ Time Frame: From Baseline to Week 104 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Manual reclassification was done by the Sponsor for the "other reasons" of non-completion of study as specified in the electronic case report form (eCRF).


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Trial Transparency Team
Organization: Sanofi
e-mail: Contact-US@sanofi.com


Publications of Results:
Other Publications:

Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT01644188     History of Changes
Other Study ID Numbers: EFC11569
U1111-1121-4315 ( Other Identifier: UTN )
2011-004130-34 ( EudraCT Number )
Study First Received: July 16, 2012
Results First Received: August 20, 2015
Last Updated: June 23, 2016
Health Authority: United States: Food and Drug Administration