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Efficacy and Safety of Alirocumab in Patients With Hypercholesterolemia Not Adequately Controlled With Non-statin Lipid Modifying Therapy or the Lowest Strength of Statin (ODYSSEY-NIPPON)

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ClinicalTrials.gov Identifier: NCT02584504
Recruitment Status : Completed
First Posted : October 22, 2015
Results First Posted : May 7, 2018
Last Update Posted : January 23, 2019
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Hypercholesterolemia
Interventions Drug: Alirocumab
Drug: Placebo
Drug: Atorvastatin
Drug: Non-statin Lipid-Modifying Therapy
Other: Diet Alone
Enrollment 163
Recruitment Details The study was conducted at 30 active centers in Japan. Overall 241 participants were screened between 30 November 2015 and 19 October 2016, of whom 78 were screen failures and 163 were randomized. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details Randomization stratified per background statin therapy (Yes/No). “No statin” also stratified per background fibrate/ezetimibe therapy (Yes/No), ‘Yes’ =fibrate/ezetimibe, ‘No’ =diet therapy alone. Randomization followed 1:1:1 ratio (Alirocumab 150 mg Q4W: Alirocumab 150 mg Q2W: Placebo Q2W).
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description In double-blind treatment period (DBTP), participants received Alirocumab 150 mg subcutaneous (SC) injection every 4 weeks (Q4W) alternating with placebo (for alirocumab) Q4W added to lowest-strength statin therapy (atorvastatin 5 mg daily), stable non-statin Lipid-Modifying Therapy (LMT) or diet therapy alone for 12 weeks. Participants who completed DBTP, entered in open-label treatment period (OLTP) and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg every 2 weeks (Q2W) at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. In DBTP, participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Period Title: Double-blind Treatment
Started 54 [1] 53 [1] 56 [1]
ITT Population 54 53 56
mITT Population 54 53 56
Safety Population 54 53 56
Completed 54 51 55
Not Completed 0 2 1
Reason Not Completed
Participant withdrew consent             0             0             1
Adverse Event             0             1             0
Family Matter             0             1             0
[1]
Randomized
Period Title: Open-label Treatment
Started 54 51 55
Treated 54 50 54
Completed 52 47 47
Not Completed 2 4 8
Reason Not Completed
Participant withdrew consent             0             0             4
Adverse Event             2             2             3
Physician Decision             0             1             0
Entered but not treated             0             1             1
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W Total
Hide Arm/Group Description In DBTP, participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. In DBTP, participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. In DBTP, participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants who completed DBTP were entered in OLTP and received alirocumab 150 mg Q4W up to additional 52 weeks (up to Week 64). Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Total of all reporting groups
Overall Number of Baseline Participants 54 53 56 163
Hide Baseline Analysis Population Description
Baseline population included all randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 54 participants 53 participants 56 participants 163 participants
62.6  (9.8) 63.6  (10.4) 64.6  (10.0) 63.6  (10.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 54 participants 53 participants 56 participants 163 participants
Female
21
  38.9%
20
  37.7%
19
  33.9%
60
  36.8%
Male
33
  61.1%
33
  62.3%
37
  66.1%
103
  63.2%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Asian Number Analyzed 54 participants 53 participants 56 participants 163 participants
54
 100.0%
53
 100.0%
56
 100.0%
163
 100.0%
Calculated LDL-C in mg/dL   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 54 participants 53 participants 56 participants 163 participants
154.2  (59.5) 149.2  (31.1) 149.4  (32.6) 150.9  (42.8)
[1]
Measure Description: Calculated LDL-C in mg/dL from Friedewald formula (LDL cholesterol = Total cholesterol - high density lipoprotein [HDL] cholesterol - [Triglyceride/5]).
Calculated LDL-C in mmol/L  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 54 participants 53 participants 56 participants 163 participants
3.993  (1.541) 3.865  (0.806) 3.870  (0.844) 3.909  (1.109)
1.Primary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 12- Intent to Treat (ITT) Analysis
Hide Description Adjusted Least-squares (LS) means and standard errors at Week 12 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were used in the model (ITT analysis).
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-43.8  (2.2) -70.1  (2.3) -4.3  (2.2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Alirocumab 150 mg Q4W group was compared to placebo group using an appropriate contrast statement.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments Threshold for significance at 0.025 level.
Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
Estimated Value -39.5
Confidence Interval (2-Sided) 97.5%
-46.5 to -32.4
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Alirocumab 150 mg Q2W group was compared to placebo group using an appropriate contrast statement.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -65.8
Confidence Interval (2-Sided) 97.5%
-72.9 to -58.7
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Alirocumab 150 mg Q2W
Comments Alirocumab 150 mg Q4W group was compared to Alirocumab 150 mg Q2W group using an appropriate contrast statement.
Type of Statistical Test Other
Comments Statistical test was not planned because this comparison was for a descriptive purpose.
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -26.3
Confidence Interval (2-Sided) 95%
-32.5 to -20.0
Estimation Comments Alirocumab 150 mg Q4W group vs Alirocumab 150 mg Q2W
2.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 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-43.4  (2.1) -70.1  (2.2) -2.8  (2.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo 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 0.025 level. Hierarchical procedure for comparisons of Alirocumab 150 mg Q4W versus Placebo Q2W and Alirocumab 150 mg Q2W versus Placebo Q2W were processed separately.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -40.6
Confidence Interval (2-Sided) 97.5%
-47.4 to -33.8
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -67.4
Confidence Interval (2-Sided) 97.5%
-74.2 to -60.5
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
3.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 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 12 regardless of status on- or off-treatment and assigning a weight of 0.5 for Week 10 and 12 time points.
Time Frame From Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-54.2  (1.9) -69.9  (1.9) -3.7  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -50.5
Confidence Interval (2-Sided) 97.5%
-56.6 to -44.5
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -66.2
Confidence Interval (2-Sided) 97.5%
-72.3 to -60.1
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
4.Secondary Outcome
Title Percent Change From Baseline in Calculated LDL-C to Averaged Week 10 to 12- On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection) and assigning a weight of 0.5 for Week 10 and 12 time points.
Time Frame From Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-54.0  (1.9) -69.9  (1.9) -2.6  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -51.4
Confidence Interval (2-Sided) 97.5%
-57.4 to -45.4
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -67.3
Confidence Interval (2-Sided) 97.5%
-73.3 to -61.3
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
5.Secondary Outcome
Title Percent Change From Baseline in Apolipoprotein B (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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-32.2  (2.0) -57.9  (2.0) -6.0  (2.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -26.2
Confidence Interval (2-Sided) 97.5%
-32.5 to -19.9
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -51.9
Confidence Interval (2-Sided) 97.5%
-58.3 to -45.5
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
6.Secondary Outcome
Title Percent Change From Baseline in Apo-B at Week 12- On-Treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data at from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 55
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-31.8  (2.0) -58.0  (2.0) -4.6  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -27.2
Confidence Interval (2-Sided) 97.5%
-33.5 to -20.9
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -53.4
Confidence Interval (2-Sided) 97.5%
-59.7 to -47.1
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
7.Secondary Outcome
Title Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-36.2  (2.0) -61.1  (2.0) -4.9  (2.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -31.3
Confidence Interval (2-Sided) 97.5%
-37.7 to -25.0
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -56.2
Confidence Interval (2-Sided) 97.5%
-62.5 to -49.8
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
8.Secondary Outcome
Title Percent Change From Baseline in Non-HDL-C at Week 12- On-treatment Analysis
Hide Description Adjusted LS means and standard errors at Week 12 were obtained from MMRM model including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-35.9  (1.9) -61.1  (2.0) -3.5  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -32.4
Confidence Interval (2-Sided) 97.5%
-38.6 to -26.3
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -57.6
Confidence Interval (2-Sided) 97.5%
-63.8 to -51.4
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
9.Secondary Outcome
Title Percent Change From Baseline in Total Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-25.8  (1.5) -44.7  (1.6) -3.3  (1.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -22.5
Confidence Interval (2-Sided) 97.5%
-27.4 to -17.6
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -41.4
Confidence Interval (2-Sided) 97.5%
-46.4 to -36.5
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
10.Secondary Outcome
Title Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- ITT Analysis
Hide Description Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heterozygous familiar hypercholesterolemia (heFH) participants or non-familial hypercholesterolemia (non-FH) participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 were obtained from multiple imputation approach for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time Frame Up to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Measure Type: Number
Unit of Measure: percentage of participants
85.2 96.2 14.3
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 61.2
Confidence Interval (2-Sided) 97.5%
13.9 to 268.9
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 281.4
Confidence Interval (2-Sided) 97.5%
33.3 to 2382.2
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
11.Secondary Outcome
Title Percentage of Participants Reaching Calculated LDL-C Goal at Week 12- On-Treatment Analysis
Hide Description Calculated LDL-C goal was defined as calculated LDL-C <100 mg/dL (2.59 mmol/L) for heFH participants or non-FH participants who had a history of documented CHD, or <120 mg/dL (3.10 mmol/L) for non-FH participants who had a history of documented diseases or other risk factors as defined in JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012. Adjusted percentages at Week 12 from multiple imputation approach including available post-baseline on-treatment data from Week 4 to Week 12 (i.e. up to 21 days after last double-blind injection).
Time Frame Up to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Measure Type: Number
Unit of Measure: percentage of participants
85.2 96.2 10.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 102.8
Confidence Interval (2-Sided) 97.5%
19.0 to 556.8
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Logistic
Comments Multiple imputation approach followed by logistic regression model.
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 500.8
Confidence Interval (2-Sided) 97.5%
47.9 to 5230.9
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
12.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 were obtained from multiple imputation approach followed by robust regression model for handling of missing data. All available post-baseline data from Week 4 to Week 12 regardless of status on- or off-treatment were included in the imputation model.
Time Frame From Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Mean (Standard Error)
Unit of Measure: percent change
-31.7  (3.3) -49.6  (3.3) 1.3  (3.3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Robust
Comments Multiple imputation approach followed by robust regression model.
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value -32.9
Confidence Interval (2-Sided) 97.5%
-43.4 to -22.5
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Robust
Comments Multiple imputation approach followed by robust regression model.
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value -50.9
Confidence Interval (2-Sided) 97.5%
-61.5 to -40.3
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
13.Secondary Outcome
Title Percent Change From Baseline in High Density Lipoprotein Cholesterol (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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
7.7  (1.8) 9.9  (1.8) 2.0  (1.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0241
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 5.7
Confidence Interval (2-Sided) 97.5%
0.0 to 11.3
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0022
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 7.8
Confidence Interval (2-Sided) 97.5%
2.1 to 13.5
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
14.Secondary Outcome
Title Percent Change From Baseline in Fasting Triglycerides (TGs) 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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
ITT population.
Arm/Group Title Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Mean (Standard Error)
Unit of Measure: percent change
-0.6  (3.7) -18.0  (3.8) -6.4  (3.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q4W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2645
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Robust
Comments Multiple imputation approach followed by robust regression model.
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value 5.9
Confidence Interval (2-Sided) 97.5%
-5.9 to 17.7
Estimation Comments Alirocumab 150 mg Q4W vs. Placebo
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Alirocumab 150 mg Q2W, Placebo Q2W
Comments Testing according to the hierarchical testing procedure (only performed if the previous endpoint was statistically significant for the relevant compared arms).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0299
Comments Threshold for significance at 0.025 level for Bonferroni adjustment.
Method Regression, Robust
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted Mean Difference
Estimated Value -11.6
Confidence Interval (2-Sided) 97.5%
-23.5 to 0.4
Estimation Comments Alirocumab 150 mg Q2W vs. Placebo
15.Secondary Outcome
Title Percent Change From Baseline in Apolipoprotein A-1 (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 12 regardless of status on- or off-treatment.
Time Frame From Baseline to Week 12
Hide 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 Alirocumab 150 mg Q4W Alirocumab 150 mg Q2W Placebo Q2W
Hide Arm/Group Description:
Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks in DBTP.
Overall Number of Participants Analyzed 54 53 56
Least Squares Mean (Standard Error)
Unit of Measure: percent change
6.8  (1.6) 9.1  (1.7) 2.9  (1.6)
16.Other Pre-specified Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 20, 24, 36, 48 and 64 -OLTP Analysis
Hide Description [Not Specified]
Time Frame Baseline, Weeks 20, 24, 36, 48 and 64
Hide Outcome Measure Data
Hide Analysis Population Description
Open-label treatment (OLT) population included all randomized participants who received at least one dose or part of dose of open-label investigational medicinal product. Here, “number analyzed” signifies participants with available data at each specified time-point.
Arm/Group Title Alirocumab 150mgQ4W/Up Q2W(After Alirocumab 150mgQ4W in DBTP) Alirocumab 150mgQ4W/Up Q2W(After Alirocumab 150mgQ2W in DBTP) Alirocumab 150mg Q4W/Up Q2W (After Placebo Q2W in DBTP)
Hide Arm/Group Description:
Participants who received alirocumab 150 mg Q4W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Participants who received alirocumab 150 mg Q2W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Participants who received Placebo Q2W during DBTP and completed DBTP, entered in OLTP and received alirocumab 150 mg Q4W from Week 12 up to Week 64. Alirocumab dose up-titrated to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥100 mg/dL (2.59 mmol/L) or ≥120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
Overall Number of Participants Analyzed 54 50 54
Mean (Standard Deviation)
Unit of Measure: Percent change
Week 20 Number Analyzed 53 participants 50 participants 53 participants
-42.1  (20.1) -47.8  (24.2) -45.5  (20.5)
Week 24 Number Analyzed 53 participants 49 participants 51 participants
-39.7  (20.4) -46.0  (20.0) -47.8  (21.7)
Week 36 Number Analyzed 52 participants 49 participants 51 participants
-49.2  (19.4) -51.5  (19.6) -56.2  (18.8)
Week 48 Number Analyzed 52 participants 48 participants 48 participants
-48.6  (21.6) -53.9  (17.6) -57.8  (17.4)
Week 64 Number Analyzed 51 participants 48 participants 47 participants
-44.3  (22.8) -55.2  (17.5) -58.1  (19.6)
Time Frame All Adverse Events (AEs) were collected from signature of the informed consent form up to the end of study (up to Week 64) regardless of seriousness or relationship to investigational product.
Adverse Event Reporting Description Reported AEs and deaths are TEAEs that is AEs that developed/ worsened and death that occurred during ‘treatment-emergent period’ (time from first dose of study drug up to last dose of study drug +70 days). Analysis performed on safety population which included randomized participants who actually received at least 1 dose or partial dose of double-blind IMP injection for double-blind treatment period and at least 1 dose or partial dose of open-label IMP injection for open-label treatment period.
 
Arm/Group Title Double-blind Treatment Period: Placebo Q2W Double-blind Treatment Period: Alirocumab 150 mg Q4W Double-blind Treatment Period: Alirocumab 150 mg Q2W Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
Hide Arm/Group Description Participants received Placebo (for alirocumab) SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. Participants received Alirocumab 150 mg SC injection Q4W alternating with placebo (for alirocumab) Q4W added to lowest-strength of statin therapy (atorvastatin 5 mg daily) stable non-statin LMT or diet therapy alone for 12 weeks. Participants received Alirocumab 150 mg SC injection Q2W added to lowest-strength statin therapy (atorvastatin 5 mg), stable non-statin LMT or diet therapy alone for 12 weeks. All participants received alirocumab 150 mg Q4W from the start of the open-label treatment period. Alirocumab dose up-titrated from 150 mg Q4W to 150 mg Q2W at Week 24 (Week 12 of OLTP), when LDL-C levels ≥ 100 mg/dL (2.59 mmol/L) or ≥ 120 mg/dL (3.10 mmol/L) at Week 20 according to JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2012.
All-Cause Mortality
Double-blind Treatment Period: Placebo Q2W Double-blind Treatment Period: Alirocumab 150 mg Q4W Double-blind Treatment Period: Alirocumab 150 mg Q2W Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/56 (0.00%)   0/54 (0.00%)   1/53 (1.89%)   0/158 (0.00%) 
Show Serious Adverse Events Hide Serious Adverse Events
Double-blind Treatment Period: Placebo Q2W Double-blind Treatment Period: Alirocumab 150 mg Q4W Double-blind Treatment Period: Alirocumab 150 mg Q2W Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/56 (1.79%)   1/54 (1.85%)   2/53 (3.77%)   12/158 (7.59%) 
Blood and lymphatic system disorders         
Anaemia  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  0/158 (0.00%) 
Cardiac disorders         
Acute myocardial infarction  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Angina unstable  1  1/56 (1.79%)  0/54 (0.00%)  0/53 (0.00%)  0/158 (0.00%) 
Coronary artery stenosis  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  2/158 (1.27%) 
Injury, poisoning and procedural complications         
Multiple fractures  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Subdural haematoma  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Metabolism and nutrition disorders         
Diabetes mellitus inadequate control  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Musculoskeletal and connective tissue disorders         
Osteoarthritis  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Basal cell carcinoma  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Metastases to stomach  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  0/158 (0.00%) 
Non-small cell lung cancer  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  0/158 (0.00%) 
Pituitary tumour benign  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Nervous system disorders         
Dizziness postural  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  0/158 (0.00%) 
Facial spasm  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Loss of consciousness  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  0/158 (0.00%) 
Psychiatric disorders         
Schizophrenia  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Respiratory, thoracic and mediastinal disorders         
Haemoptysis  1  0/56 (0.00%)  0/54 (0.00%)  0/53 (0.00%)  1/158 (0.63%) 
Interstitial lung disease  1  0/56 (0.00%)  1/54 (1.85%)  0/53 (0.00%)  0/158 (0.00%) 
1
Term from vocabulary, MedDra 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Double-blind Treatment Period: Placebo Q2W Double-blind Treatment Period: Alirocumab 150 mg Q4W Double-blind Treatment Period: Alirocumab 150 mg Q2W Open-label Treatment Period: Alirocumab 150 mg Q4W/Up Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   14/56 (25.00%)   11/54 (20.37%)   13/53 (24.53%)   72/158 (45.57%) 
General disorders         
Non-cardiac chest pain  1  1/56 (1.79%)  0/54 (0.00%)  4/53 (7.55%)  3/158 (1.90%) 
Infections and infestations         
Pharyngitis  1  0/56 (0.00%)  3/54 (5.56%)  0/53 (0.00%)  5/158 (3.16%) 
Viral upper respiratory tract infection  1  9/56 (16.07%)  8/54 (14.81%)  8/53 (15.09%)  54/158 (34.18%) 
Injury, poisoning and procedural complications         
Fall  1  3/56 (5.36%)  0/54 (0.00%)  1/53 (1.89%)  11/158 (6.96%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  0/56 (0.00%)  0/54 (0.00%)  1/53 (1.89%)  8/158 (5.06%) 
Nervous system disorders         
Dizziness  1  3/56 (5.36%)  0/54 (0.00%)  0/53 (0.00%)  2/158 (1.27%) 
1
Term from vocabulary, MedDra 20.0
Indicates events were collected by systematic assessment
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
Layout table for Results Point of Contact information
Name/Title: Trial Transparency Team
Organization: Sanofi
Phone: 800-633-1610 ext 1#
EMail: Contact-US@sanofi.com
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT02584504     History of Changes
Other Study ID Numbers: EFC14305
U1111-1170-7697 ( Other Identifier: UTN )
First Submitted: October 21, 2015
First Posted: October 22, 2015
Results First Submitted: April 3, 2018
Results First Posted: May 7, 2018
Last Update Posted: January 23, 2019