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Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia

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ClinicalTrials.gov Identifier: NCT01288469
Recruitment Status : Completed
First Posted : February 2, 2011
Results First Posted : September 24, 2015
Last Update Posted : September 24, 2015
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 (for alirocumab)
Drug: Atorvastatin
Drug: Placebo (for atorvastatin)
Enrollment 92

Recruitment Details The study was conducted at 20 centers in the United States of America. Overall, 214 participants were screened between January 2011 and April 2011. Screen failures were mainly due to exclusion criteria met.
Pre-assignment Details Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1 ratio after confirmation of selection criteria. 92 participants were randomized.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description Placebo (for alirocumab) subcutaneous (SC) injection every two weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Period Title: Overall Study
Started 31 [1] 31 [1] 30 [1]
Treated 31 31 30
Completed 24 28 28
Not Completed 7 3 2
Reason Not Completed
Adverse Event             4             1             1
Poor compliance to protocol             0             1             0
Participant Moved             1             0             0
Consent withdrawn by subject             1             1             1
Exclusion criteria finally met             1             0             0
[1]
Randomized
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg Total
Hide Arm/Group Description Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. Total of all reporting groups
Overall Number of Baseline Participants 31 31 30 92
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 31 participants 31 participants 30 participants 92 participants
55.3  (10.3) 57.9  (10.0) 57.6  (9.3) 56.9  (9.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 31 participants 31 participants 30 participants 92 participants
Female
18
  58.1%
17
  54.8%
20
  66.7%
55
  59.8%
Male
13
  41.9%
14
  45.2%
10
  33.3%
37
  40.2%
Low-Density Lipoprotein Cholesterol (LDL-C) in mmol/L  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 31 participants 31 participants 30 participants 92 participants
3.138  (0.469) 3.101  (0.402) 3.288  (0.564) 3.174  (0.484)
LDL-C in mg/dL  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 31 participants 31 participants 30 participants 92 participants
121.2  (18.1) 119.7  (15.5) 126.9  (21.8) 122.6  (18.7)
1.Primary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 8 - On-treatment Analysis
Hide Description Calculated LDL-C values were obtained using the Friedewald formula. Baseline adjusted least squares (LS) means and standard errors were estimated using an analysis of covariance (ANCOVA) model including available post-baseline data on treatment from first investigational product (IP) injection up to 21 days after last IP injection (on-treatment analysis). Missing Week 8 data were imputed by last observation carried forward [LOCF] method.
Time Frame From Baseline to Week 8 (LOCF)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Modified Intent-To-Treat (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 + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-17.3  (3.5) -66.2  (3.5) -73.2  (3.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo + Atorvastatin 80 mg, Alirocumab + Atorvastatin 80 mg
Comments Throughout the ANCOVA model, the Alirocumab + atorvastatin 80 mg group was compared to the placebo + atorvastatin 80 mg group using appropriate contrast and the 95% confidence interval (CI) of the difference was provided.
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 ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -55.82
Confidence Interval (2-Sided) 95%
-65.62 to -46.03
Estimation Comments Alirocumab vs. placebo
2.Secondary Outcome
Title Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame From baseline to Week 8 (LOCF)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-0.56  (0.11) -2.09  (0.11) -2.31  (0.11)
3.Secondary Outcome
Title Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame From baseline to Week 8 (LOCF)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
-21.5  (4.2) -80.7  (4.2) -89.3  (4.1)
4.Secondary Outcome
Title Percentage of Participants Achieving Calculated LDL-C <100 mg/dL (2.59 mmol/L) and < 70 mg/dL (1.81 mmol/L) at Week 8 - On-treatment Analysis
Hide Description [Not Specified]
Time Frame Week 8 (LOCF)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Measure Type: Number
Unit of Measure: percentage of participants
LDL-C < 100 mg/dL (2.59 mmol/L) 51.7 100.0 100.0
LDL-C < 70 mg/dL (1.81 mmol/L) 17.2 96.6 90.0
5.Secondary Outcome
Title Percent Change From Baseline in Total Cholesterol, Fasting Triglycerides, Non-high-Density Lipoprotein Cholesterol (Non-HDL-C), Apolipoprotein B (Apo-B) and Lipoprotein(a) at Week 8 - On-treatment Analysis
Hide Description Since the assumptions of normal distribution and equality of variances were not verified for the lipid parameters, percent changes were expressed as median (interquartile range).
Time Frame From baseline to Week 8 (LOCF)
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 on treatment value for lipid parameters analyzed. Here, n signifies number of participants analysed for each lipid parameter.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Median (Inter-Quartile Range)
Unit of Measure: percent change
Total Cholesterol (n=29, 29, 30)
-16.6
(-25.1 to -3.2)
-40.5
(-44.8 to -36.0)
-47.2
(-51.5 to -37.8)
Fasting Triglycerides (n=29, 29, 30)
-11.9
(-30.4 to 14.3)
-4.0
(-30.5 to 17.4)
-24.7
(-40.3 to -4.4)
Non-HDL-C (n= 29, 29, 30)
-22.3
(-31.4 to -3.7)
-58.3
(-63.9 to -50.2)
-63.9
(-73.9 to -56.1)
Apo-B (n = 29, 28, 29)
-12.0
(-23.6 to -3.5)
-54.4
(-60.2 to -48.3)
-58.0
(-67.1 to -46.1)
Lipoprotein(a) (n= 29, 28, 29)
-2.7
(-19.5 to 16.7)
-34.7
(-50.0 to -24.7)
-31.0
(-50.0 to -15.4)
6.Secondary Outcome
Title Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame From Baseline to Week 8 (LOCF)
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 on treatment HDL-C value.
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 29 30
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-3.6  (2.3) 2.6  (2.3) 5.8  (2.3)
7.Secondary Outcome
Title Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint.
Time Frame From Baseline to Week 8 (LOCF)
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 on treatment value for lipid parameter analyzed
Arm/Group Title Placebo + Atorvastatin 80 mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description:
Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Overall Number of Participants Analyzed 29 28 29
Median (Inter-Quartile Range)
Unit of Measure: ratio
-0.03
(-0.12 to 0.08)
-0.34
(-0.44 to -0.27)
-0.36
(-0.40 to -0.29)
Time Frame All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 16) regardless of seriousness or relationship to investigational medicianal product (IMP).
Adverse Event Reporting Description Reported adverse events are treatment-emergent adverse events that is AEs that developed/worsened during the ‘treatment emergent period’ (the time from the first dose to the last dose of IMP + 70 days). Safety population: participants received at least one dose or partial dose of IMP.
 
Arm/Group Title Placebo + Atorvastatin 80mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Hide Arm/Group Description Placebo (for alirocumab) SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks. Alirocumab 150 mg SC injection Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
All-Cause Mortality
Placebo + Atorvastatin 80mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo + Atorvastatin 80mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/31 (0.00%)   0/31 (0.00%)   1/30 (3.33%) 
Metabolism and nutrition disorders       
Dehydration  1  0/31 (0.00%)  0/31 (0.00%)  1/30 (3.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo + Atorvastatin 80mg Alirocumab + Atorvastatin 10 mg Alirocumab + Atorvastatin 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   13/31 (41.94%)   4/31 (12.90%)   10/30 (33.33%) 
Gastrointestinal disorders       
Diarrhoea  1  3/31 (9.68%)  1/31 (3.23%)  3/30 (10.00%) 
General disorders       
Injection site pruritus  1  2/31 (6.45%)  0/31 (0.00%)  1/30 (3.33%) 
Infections and infestations       
Upper respiratory tract infection  1  2/31 (6.45%)  2/31 (6.45%)  1/30 (3.33%) 
Injury, poisoning and procedural complications       
Accidental overdose  1  0/31 (0.00%)  2/31 (6.45%)  2/30 (6.67%) 
Musculoskeletal and connective tissue disorders       
Pain in extremity  1  5/31 (16.13%)  0/31 (0.00%)  1/30 (3.33%) 
Nervous system disorders       
Dizziness  1  0/31 (0.00%)  0/31 (0.00%)  3/30 (10.00%) 
Headache  1  2/31 (6.45%)  0/31 (0.00%)  3/30 (10.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
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: NCT01288469     History of Changes
Other Study ID Numbers: DFI11566
U1111-1117-9994 ( Other Identifier: UTN )
First Submitted: February 1, 2011
First Posted: February 2, 2011
Results First Submitted: August 21, 2015
Results First Posted: September 24, 2015
Last Update Posted: September 24, 2015