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Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy in Japan

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ClinicalTrials.gov Identifier: NCT01812707
Recruitment Status : Completed
First Posted : March 18, 2013
Results First Posted : September 24, 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: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Hypercholesterolemia
Interventions Drug: Alirocumab
Drug: Placebo (for alirocumab)
Drug: Atorvastatin
Enrollment 100
Recruitment Details The study was conducted at 4 centers in Japan. Overall, 162 participants were screened between March 2013 and August 2013, 62 of whom were run-in/screen failures, mainly due to exclusion criteria met.
Pre-assignment Details Randomization was stratified according to atorvastatin dose. Assignment to treatment arms was done centrally using an Interactive Voice/Web Response System in a 1:1:1:1 ratio after confirmation of selection criteria. 100 participants were randomized.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description Placebo (for alirocumab) every 2 weeks (Q2W) for 12-weeks in combination with atorvastatin stable dose. Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Period Title: Overall Study
Started 25 25 25 25
Treated 25 25 25 25
Completed 23 25 25 23
Not Completed 2 0 0 2
Reason Not Completed
Adverse Event             0             0             0             2
Poor compliance to protocol             1             0             0             0
Consent withdrawn by participant             1             0             0             0
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W Total
Hide Arm/Group Description Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Total of all reporting groups
Overall Number of Baseline Participants 25 25 25 25 100
Hide Baseline Analysis Population Description
Randomized population.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 25 participants 25 participants 25 participants 25 participants 100 participants
58.6  (9.2) 57.8  (12.3) 56.3  (12.0) 58.2  (8.8) 57.7  (10.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 25 participants 25 participants 25 participants 100 participants
Female
11
  44.0%
16
  64.0%
12
  48.0%
16
  64.0%
55
  55.0%
Male
14
  56.0%
9
  36.0%
13
  52.0%
9
  36.0%
45
  45.0%
Low-Density Lipoprotein Cholesterol (LDL-C) in mmol/L  
Mean (Standard Deviation)
Unit of measure:  mmol/L
Number Analyzed 25 participants 25 participants 25 participants 25 participants 100 participants
3.13  (0.55) 3.16  (0.43) 3.13  (0.43) 3.12  (0.42) 3.14  (0.45)
LDL-C in mg/dL  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 25 participants 25 participants 25 participants 25 participants 100 participants
121.0  (21.1) 122.2  (16.6) 120.9  (16.7) 120.5  (16.2) 121.2  (17.5)
1.Primary Outcome
Title Percent Change From Baseline in Calculated LDL-C at Week 12 - 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 12 data were imputed by last observation carried forward [LOCF] method.
Time Frame Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
Modified Intent-To-Treat (mITT) population included all randomized participants with one baseline and at least one post-baseline calculated LDL-C value on-treatment.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Least Squares Mean (Standard Error)
Unit of Measure: percent change
-2.7  (3.1) -54.8  (3.1) -62.3  (3.1) -71.7  (3.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 150 mg Q2W
Comments

Each treatment group was compared to placebo using ANCOVA-derived contrasts.

A hierarchical testing procedure was applied to ensure strong control of overall Type-I error rate at 0.05 level. Order was following:

  1. Alirocumab 150 mg Q2W versus placebo
  2. Alirocumab 75 mg Q2W versus placebo
  3. Alirocumab 50 mg Q2W versus placebo

Testing continued only when high-order test was statistically significant at 5% 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 ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 75 mg Q2W
Comments [Not Specified]
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]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Alirocumab 50 mg Q2W
Comments [Not Specified]
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]
2.Secondary Outcome
Title Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 12 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Least Squares Mean (Standard Error)
Unit of Measure: mmol/L
-0.1  (0.1) -1.7  (0.1) -1.9  (0.1) -2.2  (0.1)
3.Secondary Outcome
Title Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 12 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Least Squares Mean (Standard Error)
Unit of Measure: mg/dL
-5.0  (3.6) -67.1  (3.6) -74.6  (3.6) -85.8  (3.6)
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 12 - On-Treatment Analysis
Hide Description [Not Specified]
Time Frame Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
mITT population.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Measure Type: Number
Unit of Measure: percentage of participants
LDL-C <100 mg/dL (2.59 mmol/L) 8.0 100.0 100.0 100.0
LDL-C < 70 mg/dL (1.81 mmol/L) 0.0 84.0 84.0 88.0
5.Secondary Outcome
Title Percent Change From Baseline in Total Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C), Non-HDL-C, and Apolipoprotein B (Apo-B) at Week 12 - On-Treatment Analysis
Hide Description Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Time Frame Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants of the mITT population with one baseline and at least one post baseline on-treatment value of lipid parameters analyzed.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Least Squares Mean (Standard Error)
Unit of Measure: percent change
Total Cholesterol -1.2  (2.1) -31.9  (2.1) -36.3  (2.1) -41.4  (2.1)
HDL-C -0.2  (2.0) 5.1  (2.0) 5.0  (2.0) 3.2  (2.1)
Non-HDL-C -0.9  (2.9) -46.3  (2.9) -53.1  (2.9) -62.2  (2.9)
Apo-B -2.3  (3.3) -43.5  (3.3) -48.6  (3.3) -60.0  (3.3)
6.Secondary Outcome
Title Percent Change From Baseline in Fasting Triglycerides and Lipoprotein (a) at Week 12 - 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 (inter-quartile range).
Time Frame Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants of the mITT population with one baseline and at least one post baseline on-treatment value of Fasting Triglycerides and Lipoprotein (a) analyzed.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Median (Inter-Quartile Range)
Unit of Measure: percent change
Fasting Triglycerides
1.3
(-13.1 to 22.5)
-21.1
(-28.2 to 4.2)
-10.7
(-25.0 to 6.5)
-15.0
(-24.1 to 0.0)
Lipoprotein (a)
-3.7
(-26.2 to 8.4)
-35.6
(-52.5 to -7.5)
-40.2
(-62.9 to -27.4)
-43.3
(-69.4 to -14.2)
7.Secondary Outcome
Title Absolute Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) Ratio at Week 12 - On-Treatment Analysis
Hide Description Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint.
Time Frame From Baseline to Week 12 (LOCF)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants of the mITT population with one baseline and at least one post baseline on-treatment value of ApoB/ApoA-1 ratio analyzed.
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description:
Placebo (for alirocumab) Q2W for 12 weeks in combination with atorvastatin stable dose.
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Overall Number of Participants Analyzed 25 25 25 25
Least Squares Mean (Standard Error)
Unit of Measure: ratio
0.02  (0.02) -0.30  (0.02) -0.32  (0.02) -0.38  (0.02)
Time Frame All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (Week 20) regardless of seriousness or relationship to investigational medicinal 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 who received at least one dose or partial dose of IMP.
 
Arm/Group Title Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Hide Arm/Group Description Placebo Q2W for 12 weeks in combination with atorvastatin stable dose. Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 75 mg Q2W for 12-weeks in combination with atorvastatin stable dose. Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
All-Cause Mortality
Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/25 (4.00%)   0/25 (0.00%)   0/25 (0.00%)   1/25 (4.00%) 
Ear and labyrinth disorders         
Vertigo  1  1/25 (4.00%)  0/25 (0.00%)  0/25 (0.00%)  0/25 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
Breast cancer  1  0/25 (0.00%)  0/25 (0.00%)  0/25 (0.00%)  1/25 (4.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Alirocumab 50 mg Q2W Alirocumab 75 mg Q2W Alirocumab 150 mg Q2W
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/25 (20.00%)   11/25 (44.00%)   8/25 (32.00%)   9/25 (36.00%) 
General disorders         
Injection site reaction  1  1/25 (4.00%)  3/25 (12.00%)  2/25 (8.00%)  2/25 (8.00%) 
Infections and infestations         
Nasopharyngitis  1  2/25 (8.00%)  6/25 (24.00%)  6/25 (24.00%)  4/25 (16.00%) 
Cystitis  1  1/25 (4.00%)  0/25 (0.00%)  0/25 (0.00%)  2/25 (8.00%) 
Injury, poisoning and procedural complications         
Ligament sprain  1  1/25 (4.00%)  0/25 (0.00%)  0/25 (0.00%)  2/25 (8.00%) 
Musculoskeletal and connective tissue disorders         
Back pain  1  1/25 (4.00%)  2/25 (8.00%)  0/25 (0.00%)  1/25 (4.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.1
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: NCT01812707     History of Changes
Other Study ID Numbers: DFI12361
U1111-1134-4749 ( Other Identifier: UTN )
First Submitted: March 14, 2013
First Posted: March 18, 2013
Results First Submitted: August 21, 2015
Results First Posted: September 24, 2015
Last Update Posted: October 4, 2016