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Efficacy and Safety of Alirocumab (SAR236553/REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia (ODYSSEY HIGH FH)

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ClinicalTrials.gov Identifier: NCT01617655
Recruitment Status : Completed
First Posted : June 12, 2012
Results First Posted : November 6, 2015
Last Update Posted : October 4, 2016
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypercholesterolaemia
Interventions Drug: Alirocumab
Drug: Placebo (for alirocumab)
Drug: Lipid Modifying Therapy (LMT)
Enrollment 107
Recruitment Details The study was conducted at 33 centers in 5 countries. A total of 206 participants were screened between June 2012 and May 2013, 99 of whom were screen failures. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details Randomization was stratified according to prior history of myocardial infarction (MI) or ischemic stroke, and intensity of statin treatment. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:2 ratio (placebo:alirocumab) after confirmation of selection criteria. 107 participants were randomized.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description Placebo for alirocumab subcutaneous (SC) injection every two weeks (Q2W) on top of stable lipid-modifying therapy (LMT) for 78 weeks. Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Period Title: Overall Study
Started 35 [1] 72 [1]
Treated 35 72
Completed 26 43
Not Completed 9 29
Reason Not Completed
Adverse Event             2             3
Poor compliance to protocol             1             4
Participants moved             0             4
Consent withdrawn by participant             1             1
Last visit outside protocol visit window             1             10
Site closure             3             5
Other than specified above             1             2
[1]
Randomized
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W Total
Hide Arm/Group Description Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks. Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks. Total of all reporting groups
Overall Number of Baseline Participants 35 72 107
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 35 participants 72 participants 107 participants
52.1  (11.2) 49.8  (14.2) 50.6  (13.3)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 35 participants 72 participants 107 participants
Female
13
  37.1%
37
  51.4%
50
  46.7%
Male
22
  62.9%
35
  48.6%
57
  53.3%
Calculated LDL-C in mg/dL   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 35 participants 72 participants 107 participants
201  (43.4) 196.3  (57.9) 197.8  (53.4)
[1]
Measure Description: Calculated LDL-C from Friedewald formula (LDL cholesterol = Total cholesterol - HDL cholesterol - [Triglyceride/5]).
Calculated low density lipoprotein cholesterol (LDL-C) in mmol/L  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 35 participants 72 participants 107 participants
5.205  (1.125) 5.083  (1.499) 5.123  (1.382)
1.Primary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 24 - ITT Analysis
Hide Description 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 post­baseline data from Week 4 to Week 52 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population: all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on- or off- treatment.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.6  (4.9) -45.7  (3.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Alirocumab group was compared to placebo group using an appropriate contrast statement.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -39.1
Confidence Interval (2-Sided) 95%
-51.1 to -27.1
Estimation Comments Alirocumab vs Placebo
2.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection (on-treatment analysis).
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified ITT (mITT) population: all randomized and treated participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.6  (5) -45.5  (3.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments A hierarchical testing procedure was used to control type I error and handle multiple secondary endpoint analyses. Testing was then performed sequentially in the order the endpoints are reported. The hierarchical testing sequence continued only when previous endpoint was statistically significant at 0.05 level.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -38.9
Confidence Interval (2-Sided) 95%
-51 to -26.9
Estimation Comments Alirocumab vs Placebo
3.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.6  (4.6) -46.9  (3.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -40.3
Confidence Interval (2-Sided) 95%
-51.4 to -29.3
Estimation Comments Alirocumab vs Placebo
4.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.6  (4.6) -46.9  (3.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -40.3
Confidence Interval (2-Sided) 95%
-51.4 to -29.2
Estimation Comments Alirocumab vs Placebo
5.Secondary Outcome
Title Percent Change From Baseline in Apolipoprotein B (Apo B) at Week 24 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the ITT population with one baseline and at least one post-baseline Apo B value on- or off-treatment (Apo B ITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 34 69
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-8.7  (3.8) -39  (2.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -30.3
Confidence Interval (2-Sided) 95%
-39.7 to -20.9
Estimation Comments Alirocumab vs Placebo
6.Secondary Outcome
Title Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the mITT population with one baseline and at least one post-baseline Apo B value on-treatment (Apo B mITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 34 69
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-8.7  (3.9) -38.9  (2.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -30.2
Confidence Interval (2-Sided) 95%
-39.7 to -20.7
Estimation Comments Alirocumab vs Placebo
7.Secondary Outcome
Title Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the ITT population with one baseline and at least one post-baseline non-HDL-C value on- or off-treatment (non-HDL-C ITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.2  (4.3) -41.9  (3.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -35.8
Confidence Interval (2-Sided) 95%
-46.3 to -25.3
Estimation Comments Alirocumab vs Placebo
8.Secondary Outcome
Title Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 (i.e. up to 21 days after last injection).
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the mITT population with one baseline and at least one post-baseline non-HDL-C value on-treatment (non-HDL-C mITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.1  (4.3) -41.7  (3.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -35.5
Confidence Interval (2-Sided) 95%
-46.2 to -24.9
Estimation Comments Alirocumab vs Placebo
9.Secondary Outcome
Title Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the ITT population with one baseline and at least one post-baseline total-C value on- or off-treatment (total-C ITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-4.8  (3.6) -33.2  (2.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -28.4
Confidence Interval (2-Sided) 95%
-37.3 to -19.6
Estimation Comments Alirocumab vs Placebo
10.Secondary Outcome
Title Percent Change From Baseline in Apo B at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Apo B ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 34 69
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-9  (3.7) -39.2  (2.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -30.2
Confidence Interval (2-Sided) 95%
-39.2 to -21.1
Estimation Comments Alirocumab vs Placebo
11.Secondary Outcome
Title Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Non-HDL-C ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-6.9  (4.3) -41.4  (3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -34.5
Confidence Interval (2-Sided) 95%
-44.8 to -24.1
Estimation Comments Alirocumab vs Placebo
12.Secondary Outcome
Title Percent Change From Baseline in Total-C at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Total-C ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-5.2  (3.5) -33  (2.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -27.8
Confidence Interval (2-Sided) 95%
-36.2 to -19.4
Estimation Comments Alirocumab vs Placebo
13.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 52 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 52 from MMRM model including all available post-baseline data from week 4 to week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-3  (5.9) -42.1  (4.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -39.1
Confidence Interval (2-Sided) 95%
-53.6 to -24.6
Estimation Comments Alirocumab vs Placebo
14.Secondary Outcome
Title Percentage of Very High Cardiovascular (CV) Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - ITT Analysis
Hide Description Very high CV risk participants: Heterozygous Familial Hypercholesterolemia (heFH) participants with coronary heart disease (CHD) or CHD risk equivalents. High CV risk participants: heFH participants without CHD or CHD risk equivalents. CHD risk equivalent: peripheral arterial disease, ischemic stroke, moderate chronic kidney disease (estimated glomerular filtration rate, 30 to <60 ml/minute/1.73 m^2 of body-surface area), or diabetes mellitus plus 2 or more additional risk factors (hypertension; ankle-brachial index of ≤0.90; microalbuminuria, macroalbuminuria, or a urinary dipstick result of >2+ protein; preproliferative or proliferative retinopathy or laser treatment for retinopathy; or a family history of premature CHD). 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 52 regardless of status on- or off-treatment were included in the imputation model.
Time Frame Up to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Measure Type: Number
Unit of Measure: percentage of participants
5.7 41.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0016
Comments Threshold for significance ≤ 0.05.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 11.7
Confidence Interval (2-Sided) 95%
2.5 to 53.5
Estimation Comments Alirocumab vs Placebo
15.Secondary Outcome
Title Percentage of Very High CV Risk Participants Achieving Calculated LDL-C < 70 mg/dL (<1.81 mmol/L) or High CV Risk Participants Achieving Calculated LDL-C < 100 mg/dL (<2.59 mmol/L) at Week 24 - On-Treatment Analysis
Hide Description Adjusted percentages at Week 24 from a multiple imputation approach model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time Frame Up to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Measure Type: Number
Unit of Measure: percentage of participants
5.7 41.4
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0014
Comments Threshold for significance ≤ 0.05.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 11.9
Confidence Interval (2-Sided) 95%
2.6 to 54.9
Estimation Comments Alirocumab vs Placebo
16.Secondary Outcome
Title Percent Change From Baseline in Lipoprotein (a) at Week 24 - ITT Analysis
Hide Description 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 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Mean (Standard Error)
Unit of Measure: percent change
-8.7  (5) -23.5  (3.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0164
Comments Threshold for significance ≤ 0.05.
Method Regression, Robust
Comments Multiple imputation approach followed by robust regression model.
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value -14.8
Confidence Interval (2-Sided) 95%
-26.9 to -2.7
Estimation Comments Alirocumab vs Placebo
17.Secondary Outcome
Title Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the ITT population with one baseline and at least one post-baseline HDL-C value on-or off-treatment (HDL-C ITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
3.9  (2.7) 7.5  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Q2W, Alirocumab 150 mg Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2745
Comments Threshold for significance ≤ 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value 3.7
Confidence Interval (2-Sided) 95%
-2.9 to 10.2
Estimation Comments Alirocumab vs Placebo
18.Secondary Outcome
Title Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis
Hide Description Adjusted means and standard errors at Week 24 from multiple imputation approach followed by robust regression model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Mean (Standard Error)
Unit of Measure: percent change
-1.9  (4.8) -10.5  (3.3)
19.Secondary Outcome
Title Percent Change From Baseline in Apolipoprotein A-1 (Apo A-1) at Week 24 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 24 from MMRM model including all available post­baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Participants of the ITT population with one baseline and at least one post-baseline Apo A-1 value on-or off-treatment (Apo A-1 ITT population).
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 34 69
Least Squares Mean (Standard Error)
Unit of Measure: percent change
2  (2.1) 5.6  (1.5)
20.Secondary Outcome
Title Percent Change From Baseline in Lipoprotein (a) at Week 12 - ITT Analysis
Hide Description 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 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Mean (Standard Error)
Unit of Measure: percent change
-1.5  (5.1) -23.2  (3.6)
21.Secondary Outcome
Title Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
HDL-C ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
8.0  (3.4) 7.9  (2.4)
22.Secondary Outcome
Title Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis
Hide Description 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 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Mean (Standard Error)
Unit of Measure: percent change
-4.4  (5.1) -9.4  (3.7)
23.Secondary Outcome
Title Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 12 from MMRM model including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Apo A-1 ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 34 69
Least Squares Mean (Standard Error)
Unit of Measure: percent change
1.1  (2.2) 4.6  (1.5)
24.Secondary Outcome
Title Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis
Hide Description Adjusted percentages at Week 24 from multiple imputation approach including all available post-baseline data from Week 4 to Week 52 regardless of status on-or off-treatment.
Time Frame Up to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Measure Type: Number
Unit of Measure: percentage of participants
2.9 32.4
25.Secondary Outcome
Title Percentage of Participants Achieving Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis
Hide Description Adjusted percentages at Week 24 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time Frame Up to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Measure Type: Number
Unit of Measure: percentage of participants
2.9 32.6
26.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 52 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 52 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 52 i.e. up to 21 days after last injection.
Time Frame From Baseline to Week 52
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-2.9  (6.1) -42.0  (4.4)
27.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 78 - ITT Analysis
Hide Description Adjusted LS means and standard errors at Week 78 from MMRM model including all available post-baseline data from Week 4 to Week 78 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 78
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 Q2W
Hide Arm/Group Description:
Participants exposed to placebo Q2W on top of stable LMT (mean exposure of 78 weeks).
Participants exposed to Alirocumab 150 mg Q2W on top of stable LMT (mean exposure of 78 weeks).
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
1.2  (6.4) -37.9  (4.5)
28.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 78 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 78 from MMRM model including available post-baseline on-treatment data from Week 4 to Week 78 i.e. up to 21 days after last injection.
Time Frame From Baseline to Week 78
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo for alirocumab SC injection Q2W on top of stable LMT for 78 weeks.
Alirocumab 150 mg SC injection Q2W on top of stable LMT for 78 weeks.
Overall Number of Participants Analyzed 35 71
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-0.2  (6.2) -40.9  (4.5)
Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to the final visit in the study regardless of seriousness or relationship to study drug.
Adverse Event Reporting Description Reported adverse events are treatment-emergent that is AEs that developed/worsened during the 'treatment-emergent period' (from the first double-blind injection up to the day of the last injection + 70 days or up to first intake in the extension study, whichever came first).
 
Arm/Group Title Placebo Q2W Alirocumab 150 Q2W
Hide Arm/Group Description Participants exposed to placebo Q2W on top of stable LMT (mean exposure of 71 weeks). Participants exposed to Alirocumab 150 mg Q2W on top of stable LMT (mean exposure of 68 weeks).
All-Cause Mortality
Placebo Q2W Alirocumab 150 Q2W
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Q2W Alirocumab 150 Q2W
Affected / at Risk (%) Affected / at Risk (%)
Total   4/35 (11.43%)   10/72 (13.89%) 
Cardiac disorders     
Myocardial infarction  1  0/35 (0.00%)  2/72 (2.78%) 
Acute coronary syndrome  1  0/35 (0.00%)  1/72 (1.39%) 
Acute myocardial infarction  1  0/35 (0.00%)  1/72 (1.39%) 
Angina pectoris  1  1/35 (2.86%)  1/72 (1.39%) 
Cardiac failure  1  0/35 (0.00%)  1/72 (1.39%) 
Gastrointestinal disorders     
Gastrooesophageal reflux disease  1  0/35 (0.00%)  1/72 (1.39%) 
Hepatobiliary disorders     
Cholecystitis chronic  1  0/35 (0.00%)  1/72 (1.39%) 
Biliary colic  1  1/35 (2.86%)  0/72 (0.00%) 
Immune system disorders     
Anaphylactic reaction  1  1/35 (2.86%)  0/72 (0.00%) 
Infections and infestations     
Bronchitis  1  0/35 (0.00%)  1/72 (1.39%) 
Diverticulitis  1  0/35 (0.00%)  1/72 (1.39%) 
Musculoskeletal and connective tissue disorders     
Rheumatoid arthritis  1  1/35 (2.86%)  0/72 (0.00%) 
Nervous system disorders     
Carpal tunnel syndrome  1  0/35 (0.00%)  1/72 (1.39%) 
Renal and urinary disorders     
Renal failure  1  0/35 (0.00%)  1/72 (1.39%) 
Renal colic  1  1/35 (2.86%)  0/72 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Q2W Alirocumab 150 Q2W
Affected / at Risk (%) Affected / at Risk (%)
Total   20/35 (57.14%)   39/72 (54.17%) 
Ear and labyrinth disorders     
Vertigo  1  2/35 (5.71%)  1/72 (1.39%) 
Gastrointestinal disorders     
Diarrhoea  1  3/35 (8.57%)  4/72 (5.56%) 
Vomiting  1  0/35 (0.00%)  4/72 (5.56%) 
Nausea  1  2/35 (5.71%)  2/72 (2.78%) 
Dyspepsia  1  2/35 (5.71%)  0/72 (0.00%) 
General disorders     
Injection site reaction  1  2/35 (5.71%)  6/72 (8.33%) 
Fatigue  1  0/35 (0.00%)  5/72 (6.94%) 
Infections and infestations     
Nasopharyngitis  1  4/35 (11.43%)  10/72 (13.89%) 
Influenza  1  1/35 (2.86%)  9/72 (12.50%) 
Bronchitis  1  2/35 (5.71%)  4/72 (5.56%) 
Urinary tract infection  1  0/35 (0.00%)  5/72 (6.94%) 
Sinusitis  1  2/35 (5.71%)  4/72 (5.56%) 
Upper respiratory tract infection  1  0/35 (0.00%)  4/72 (5.56%) 
Investigations     
Blood uric acid increased  1  2/35 (5.71%)  0/72 (0.00%) 
Musculoskeletal and connective tissue disorders     
Myalgia  1  3/35 (8.57%)  4/72 (5.56%) 
Nervous system disorders     
Dizziness  1  0/35 (0.00%)  5/72 (6.94%) 
Headache  1  0/35 (0.00%)  5/72 (6.94%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.1
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).
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.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
Name/Title: Trial Transparency Team
Organization: Sanofi
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT01617655     History of Changes
Other Study ID Numbers: EFC12732
U1111-1128-5459 ( Other Identifier: UTN )
2012-001096-37 ( EudraCT Number )
First Submitted: June 8, 2012
First Posted: June 12, 2012
Results First Submitted: August 20, 2015
Results First Posted: November 6, 2015
Last Update Posted: October 4, 2016