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

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

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

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: Placebo (for alirocumab); Drug: Atorvastatin; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 183
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tempe, Arizona, United States, 85282
      • Investigational Site Number 840525
  • California
    • Los Angeles, California, United States, 90057
      • Investigational Site Number 840516
    • Mission Viejo, California, United States, 92691
      • Investigational Site Number 840528
    • Newport Beach, California, United States, 92660
      • Investigational Site Number 840509
    • Palm Springs, California, United States, 92262
      • Investigational Site Number 840523
    • Westlake Village, California, United States, 91361
      • Investigational Site Number 840534
  • Colorado
    • Colorado Springs, Colorado, United States, 80903
      • Investigational Site Number 840530
  • Florida
    • Aventura, Florida, United States, 33108
      • Investigational Site Number 840504
    • Aventura, Florida, United States, 33108
      • Investigational Site Number 840519
    • Jacksonville, Florida, United States, 32216
      • Investigational Site Number 840514
    • Jupiter, Florida, United States, 33458
      • Investigational Site Number 840539
    • Miami, Florida, United States, 33143
      • Investigational Site Number 840502
    • Pembroke Pines, Florida, United States, 33026
      • Investigational Site Number 840520
    • Ponte Vedra, Florida, United States, 32081
      • Investigational Site Number 840524
    • Port Orange, Florida, United States, 32127
      • Investigational Site Number 840536
    • St. Petersburg, Florida, United States, 33609
      • Investigational Site Number 840507
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Investigational Site Number 840527
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Investigational Site Number 840506
    • Indianapolis, Indiana, United States, 46260
      • Investigational Site Number 840529
  • Kansas
    • Wichita, Kansas, United States, 67203
      • Investigational Site Number 840515
  • Kentucky
    • Madisonville, Kentucky, United States, 42431
      • Investigational Site Number 840532
  • Maine
    • Auburn, Maine, United States, 04210
      • Investigational Site Number 840535
  • Massachusetts
    • Brockton, Massachusetts, United States, 02301
      • Investigational Site Number 840503
  • Nevada
    • Las Vegas, Nevada, United States, 89123
      • Investigational Site Number 840512
  • New Jersey
    • Edison, New Jersey, United States, 08817
      • Investigational Site Number 840505
  • New York
    • Rochester, New York, United States, 14609
      • Investigational Site Number 840538
  • North Carolina
    • Raleigh, North Carolina, United States, 27612
      • Investigational Site Number 840508
    • Statesville, North Carolina, United States, 28677
      • Investigational Site Number 840522
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Investigational Site Number 840511
    • Cincinnati, Ohio, United States, 45219
      • Investigational Site Number 840526
    • Lyndhurst, Ohio, United States, 44124
      • Investigational Site Number 840510
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Investigational Site Number 840533
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Investigational Site Number 840537
  • Tennessee
    • Bristol, Tennessee, United States, 37620
      • Investigational Site Number 840521
  • Utah
    • Bountiful, Utah, United States, 84010
      • Investigational Site Number 840531
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Investigational Site Number 840517
    • Richmond, Virginia, United States, 23227
      • Investigational Site Number 840518
  • Washington
    • Olympia, Washington, United States, 98502
      • Investigational Site Number 840513

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo Q2W; Placebo (for alirocumab) every 2 weeks (Q2W) for 12-weeks in combination with atorvastatin stable dose.	Drug: Placebo (for alirocumab); Two subcutaneous (SC) injections in the abdomen only.; Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.
EXPERIMENTAL: Alirocumab 50 mg Q2W; Alirocumab 50 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.; Drug: Alirocumab; Two SC injections in the abdomen only.; Other Names: SAR236553; REGN727
EXPERIMENTAL: Alirocumab 100 mg Q2W; Alirocumab 100 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.; Drug: Alirocumab; Two SC injections in the abdomen only.; Other Names: SAR236553; REGN727
EXPERIMENTAL: Alirocumab 150 mg Q2W; Alirocumab 150 mg Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.; Drug: Alirocumab; Two SC injections in the abdomen only.; Other Names: SAR236553; REGN727
EXPERIMENTAL: Alirocumab 200 mg Q4W; Alirocumab 200 mg every 4 weeks (Q4W) and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Placebo (for alirocumab); Two subcutaneous (SC) injections in the abdomen only.; Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.; Drug: Alirocumab; Two SC injections in the abdomen only.; Other Names: SAR236553; REGN727
EXPERIMENTAL: Alirocumab 300 mg Q4W; Alirocumab 300 mg Q4W and alternating placebo Q2W for 12-weeks in combination with atorvastatin stable dose.	Drug: Placebo (for alirocumab); Two subcutaneous (SC) injections in the abdomen only.; Drug: Atorvastatin; Orally once daily at a stable dose of 10 mg, 20 mg, or 40 mg as background therapy.; Drug: Alirocumab; Two SC injections in the abdomen only.; Other Names: SAR236553; REGN727

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to Week 12 (LOCF)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to Week 12 (LOCF)
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.	Baseline to Week 12 (LOCF)
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		Week 12 (LOCF)
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.	Baseline to Week 12 (LOCF)
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).	Baseline to Week 12 (LOCF)
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.	Baseline to Week 12 (LOCF)

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): December 1, 2011
• Study Completion (ACTUAL): December 1, 2011

Study Registration Dates

• First Submitted: February 1, 2011
• First Submitted That Met QC Criteria: February 1, 2011
• First Posted (ESTIMATE): February 2, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): September 24, 2015
• Last Update Submitted That Met QC Criteria: August 21, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Immunologic Factors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Antibodies, Monoclonal
• Other Study ID Numbers: DFI11565; U1111-1116-5252 (OTHER: UTN)