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

Primary Purpose

Hypercholesterolemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Alirocumab
Placebo (for alirocumab)
Atorvastatin
Sponsored by
Sanofi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hypercholesterolemia

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Participants with primary hypercholesterolemia receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period or drug naive participants if they are likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the end of the 6-week run-in treatment period on atorvastatin therapy

OR

  • Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period and likely to have LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit

Exclusion criteria:

  1. LDL-C < 100 mg/dL (< 2.59 mmol/L):

    • After the run-in period on atorvastatin (10 mg, 20 mg, or 40 mg) for participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to the screening, or drug naive participant

    OR

    • At the first visit for participants who were being treated with stable dose of atorvastatin (10 mg, 20 mg, or 40 mg) for at least 6 weeks prior to screening
  2. Participants not previously instructed on a cholesterol-lowering diet
  3. Participants with type 1 diabetes
  4. Participants with type 2 diabetes treated with insulin
  5. Participants with type 2 diabetes and with an glycated hemoglobin (HbA1c) ≥ 8.5% at screening visit (considered poorly controlled)

  6. Laboratory findings measured before randomization:

    • Triglycerides (TG) > 350 mg/dL (> 3.95 mmol/L) at screening visit
    • Positive serum or urine pregnancy test in females of childbearing potential
  7. Pregnant or breast-feeding women
  8. Women of childbearing potential with no effective contraceptive method

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Sites / Locations

  • Investigational Site Number 840525
  • Investigational Site Number 840516
  • Investigational Site Number 840528
  • Investigational Site Number 840509
  • Investigational Site Number 840523
  • Investigational Site Number 840534
  • Investigational Site Number 840530
  • Investigational Site Number 840504
  • Investigational Site Number 840519
  • Investigational Site Number 840514
  • Investigational Site Number 840539
  • Investigational Site Number 840502
  • Investigational Site Number 840520
  • Investigational Site Number 840524
  • Investigational Site Number 840536
  • Investigational Site Number 840507
  • Investigational Site Number 840527
  • Investigational Site Number 840506
  • Investigational Site Number 840529
  • Investigational Site Number 840515
  • Investigational Site Number 840532
  • Investigational Site Number 840535
  • Investigational Site Number 840503
  • Investigational Site Number 840512
  • Investigational Site Number 840505
  • Investigational Site Number 840538
  • Investigational Site Number 840508
  • Investigational Site Number 840522
  • Investigational Site Number 840511
  • Investigational Site Number 840526
  • Investigational Site Number 840510
  • Investigational Site Number 840533
  • Investigational Site Number 840537
  • Investigational Site Number 840521
  • Investigational Site Number 840531
  • Investigational Site Number 840517
  • Investigational Site Number 840518
  • Investigational Site Number 840513

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Placebo Q2W

Alirocumab 50 mg Q2W

Alirocumab 100 mg Q2W

Alirocumab 150 mg Q2W

Alirocumab 200 mg Q4W

Alirocumab 300 mg Q4W

Arm 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 100 mg Q2W for 12-weeks in combination with atorvastatin stable dose.

Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.

Alirocumab 200 mg every 4 weeks (Q4W) and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.

Alirocumab 300 mg Q4W and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.

Outcomes

Primary Outcome Measures

Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
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 study drug injection up to 21 days after last study drug injection (on-treatment analysis). Missing Week 12 data were imputed by last observation carried forward [LOCF] method.

Secondary Outcome Measures

Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 12 - On-Treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 12 - On-Treatment Analysis
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
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
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
Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.
Percent Change From Baseline in Fasting Triglycerides and Lipoprotein(a) at Week 12 - On-Treatment Analysis
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).
Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 12 - On-Treatment Analysis
Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint.

Full Information

First Posted
February 1, 2011
Last Updated
August 21, 2015
Sponsor
Sanofi
Collaborators
Regeneron Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01288443
Brief Title
Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) in Patients With Primary Hypercholesterolemia on Stable Atorvastatin Therapy
Official Title
A Randomized, Double-blind, Parallel-group, Placebo-controlled, Multicenter Study Evaluating the Efficacy and Safety of Five Doses and Two Dose Regimens of SAR236553 Over 12 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥ 100 mg/dL (≥ 2.59 mmol/L) on Ongoing Stable Atorvastatin Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
August 2015
Overall Recruitment Status
Completed
Study Start Date
January 2011 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
December 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi
Collaborators
Regeneron Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary Objective: To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels after 12 weeks of treatment in comparison with placebo in participants with LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) on ongoing stable atorvastatin therapy. Secondary Objectives: To evaluate the effects of alirocumab on other lipid levels after 12 weeks of treatment in comparison with placebo To evaluate the safety and tolerability of alirocumab To evaluate the development of anti-alirocumab antibodies To evaluate the pharmacokinetics of alirocumab
Detailed Description
The duration of study participation depended on the status of the participant at screening: For participants receiving atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 21 weeks including a screening period of 1 week, a double-blind treatment period of 12 weeks and a follow-up period of 8 weeks. For participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 27 weeks including a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg, 20 mg, or 40 mg at a stable dose of 6 weeks, a double-blind treatment period of 12 weeks, and a follow-up period of 8 weeks.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
183 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo Q2W
Arm Type
Placebo Comparator
Arm Description
Placebo (for alirocumab) every 2 weeks (Q2W) for 12-weeks in combination with atorvastatin stable dose.
Arm Title
Alirocumab 50 mg Q2W
Arm Type
Experimental
Arm Description
Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Arm Title
Alirocumab 100 mg Q2W
Arm Type
Experimental
Arm Description
Alirocumab 100 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Arm Title
Alirocumab 150 mg Q2W
Arm Type
Experimental
Arm Description
Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.
Arm Title
Alirocumab 200 mg Q4W
Arm Type
Experimental
Arm Description
Alirocumab 200 mg every 4 weeks (Q4W) and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.
Arm Title
Alirocumab 300 mg Q4W
Arm Type
Experimental
Arm Description
Alirocumab 300 mg Q4W and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.
Intervention Type
Drug
Intervention Name(s)
Alirocumab
Other Intervention Name(s)
SAR236553, REGN727
Intervention Description
Two SC injections in the abdomen only.
Intervention Type
Drug
Intervention Name(s)
Placebo (for alirocumab)
Intervention Description
Two subcutaneous (SC) injections in the abdomen only.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Intervention Description
Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis
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 study drug injection up to 21 days after last study drug injection (on-treatment analysis). Missing Week 12 data were imputed by last observation carried forward [LOCF] method.
Time Frame
Baseline to Week 12 (LOCF)
Secondary Outcome Measure Information:
Title
Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 12 - On-Treatment Analysis
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)
Title
Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 12 - On-Treatment Analysis
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)
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
Time Frame
Week 12 (LOCF)
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
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)
Title
Percent Change From Baseline in Fasting Triglycerides and Lipoprotein(a) at Week 12 - On-Treatment Analysis
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)
Title
Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 12 - On-Treatment Analysis
Description
Adjusted LS mean and standard errors were estimated using the same ANCOVA as for primary endpoint.
Time Frame
Baseline to Week 12 (LOCF)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Participants with primary hypercholesterolemia receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period or drug naive participants if they are likely to have low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥ 2.59 mmol/L) at the end of the 6-week run-in treatment period on atorvastatin therapy OR Participants with primary hypercholesterolemia treated with atorvastatin at stable dose of 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to screening period and likely to have LDL-C ≥ 100 mg/dL (≥ 2.59 mmol/L) at the screening visit Exclusion criteria: LDL-C < 100 mg/dL (< 2.59 mmol/L): After the run-in period on atorvastatin (10 mg, 20 mg, or 40 mg) for participants receiving a lipid-lowering treatment other than atorvastatin or not at stable dose of atorvastatin 10 mg, 20 mg, or 40 mg for at least 6 weeks prior to the screening, or drug naive participant OR At the first visit for participants who were being treated with stable dose of atorvastatin (10 mg, 20 mg, or 40 mg) for at least 6 weeks prior to screening Participants not previously instructed on a cholesterol-lowering diet Participants with type 1 diabetes Participants with type 2 diabetes treated with insulin Participants with type 2 diabetes and with an glycated hemoglobin (HbA1c) ≥ 8.5% at screening visit (considered poorly controlled) Laboratory findings measured before randomization: Triglycerides (TG) > 350 mg/dL (> 3.95 mmol/L) at screening visit Positive serum or urine pregnancy test in females of childbearing potential Pregnant or breast-feeding women Women of childbearing potential with no effective contraceptive method The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Investigational Site Number 840525
City
Tempe
State/Province
Arizona
ZIP/Postal Code
85282
Country
United States
Facility Name
Investigational Site Number 840516
City
Los Angeles
State/Province
California
ZIP/Postal Code
90057
Country
United States
Facility Name
Investigational Site Number 840528
City
Mission Viejo
State/Province
California
ZIP/Postal Code
92691
Country
United States
Facility Name
Investigational Site Number 840509
City
Newport Beach
State/Province
California
ZIP/Postal Code
92660
Country
United States
Facility Name
Investigational Site Number 840523
City
Palm Springs
State/Province
California
ZIP/Postal Code
92262
Country
United States
Facility Name
Investigational Site Number 840534
City
Westlake Village
State/Province
California
ZIP/Postal Code
91361
Country
United States
Facility Name
Investigational Site Number 840530
City
Colorado Springs
State/Province
Colorado
ZIP/Postal Code
80903
Country
United States
Facility Name
Investigational Site Number 840504
City
Aventura
State/Province
Florida
ZIP/Postal Code
33108
Country
United States
Facility Name
Investigational Site Number 840519
City
Aventura
State/Province
Florida
ZIP/Postal Code
33108
Country
United States
Facility Name
Investigational Site Number 840514
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32216
Country
United States
Facility Name
Investigational Site Number 840539
City
Jupiter
State/Province
Florida
ZIP/Postal Code
33458
Country
United States
Facility Name
Investigational Site Number 840502
City
Miami
State/Province
Florida
ZIP/Postal Code
33143
Country
United States
Facility Name
Investigational Site Number 840520
City
Pembroke Pines
State/Province
Florida
ZIP/Postal Code
33026
Country
United States
Facility Name
Investigational Site Number 840524
City
Ponte Vedra
State/Province
Florida
ZIP/Postal Code
32081
Country
United States
Facility Name
Investigational Site Number 840536
City
Port Orange
State/Province
Florida
ZIP/Postal Code
32127
Country
United States
Facility Name
Investigational Site Number 840507
City
St. Petersburg
State/Province
Florida
ZIP/Postal Code
33609
Country
United States
Facility Name
Investigational Site Number 840527
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Investigational Site Number 840506
City
Evansville
State/Province
Indiana
ZIP/Postal Code
47714
Country
United States
Facility Name
Investigational Site Number 840529
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Investigational Site Number 840515
City
Wichita
State/Province
Kansas
ZIP/Postal Code
67203
Country
United States
Facility Name
Investigational Site Number 840532
City
Madisonville
State/Province
Kentucky
ZIP/Postal Code
42431
Country
United States
Facility Name
Investigational Site Number 840535
City
Auburn
State/Province
Maine
ZIP/Postal Code
04210
Country
United States
Facility Name
Investigational Site Number 840503
City
Brockton
State/Province
Massachusetts
ZIP/Postal Code
02301
Country
United States
Facility Name
Investigational Site Number 840512
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89123
Country
United States
Facility Name
Investigational Site Number 840505
City
Edison
State/Province
New Jersey
ZIP/Postal Code
08817
Country
United States
Facility Name
Investigational Site Number 840538
City
Rochester
State/Province
New York
ZIP/Postal Code
14609
Country
United States
Facility Name
Investigational Site Number 840508
City
Raleigh
State/Province
North Carolina
ZIP/Postal Code
27612
Country
United States
Facility Name
Investigational Site Number 840522
City
Statesville
State/Province
North Carolina
ZIP/Postal Code
28677
Country
United States
Facility Name
Investigational Site Number 840511
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Investigational Site Number 840526
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
Facility Name
Investigational Site Number 840510
City
Lyndhurst
State/Province
Ohio
ZIP/Postal Code
44124
Country
United States
Facility Name
Investigational Site Number 840533
City
Tulsa
State/Province
Oklahoma
ZIP/Postal Code
74136
Country
United States
Facility Name
Investigational Site Number 840537
City
Eugene
State/Province
Oregon
ZIP/Postal Code
97404
Country
United States
Facility Name
Investigational Site Number 840521
City
Bristol
State/Province
Tennessee
ZIP/Postal Code
37620
Country
United States
Facility Name
Investigational Site Number 840531
City
Bountiful
State/Province
Utah
ZIP/Postal Code
84010
Country
United States
Facility Name
Investigational Site Number 840517
City
Norfolk
State/Province
Virginia
ZIP/Postal Code
23502
Country
United States
Facility Name
Investigational Site Number 840518
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23227
Country
United States
Facility Name
Investigational Site Number 840513
City
Olympia
State/Province
Washington
ZIP/Postal Code
98502
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22463922
Citation
McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012 Jun 19;59(25):2344-53. doi: 10.1016/j.jacc.2012.03.007. Epub 2012 Mar 28.
Results Reference
result
PubMed Identifier
25060413
Citation
Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014 Sep 1;114(5):711-5. doi: 10.1016/j.amjcard.2014.05.060. Epub 2014 Jun 18.
Results Reference
result
PubMed Identifier
30183102
Citation
Leiter LA, Tinahones FJ, Karalis DG, Bujas-Bobanovic M, Letierce A, Mandel J, Samuel R, Jones PH. Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials. Diabet Med. 2018 Dec;35(12):1742-1751. doi: 10.1111/dme.13817. Epub 2018 Oct 9.
Results Reference
derived
PubMed Identifier
26872608
Citation
Toth PP, Hamon SC, Jones SR, Martin SS, Joshi PH, Kulkarni KR, Banerjee P, Hanotin C, Roth EM, McKenney JM. Effect of alirocumab on specific lipoprotein non-high-density lipoprotein cholesterol and subfractions as measured by the vertical auto profile method: analysis of 3 randomized trials versus placebo. Lipids Health Dis. 2016 Feb 13;15:28. doi: 10.1186/s12944-016-0197-4.
Results Reference
derived
PubMed Identifier
26586732
Citation
Koren MJ, Kereiakes D, Pourfarzib R, Winegar D, Banerjee P, Hamon S, Hanotin C, McKenney JM. Effect of PCSK9 Inhibition by Alirocumab on Lipoprotein Particle Concentrations Determined by Nuclear Magnetic Resonance Spectroscopy. J Am Heart Assoc. 2015 Nov 19;4(11):e002224. doi: 10.1161/JAHA.115.002224.
Results Reference
derived

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

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