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

A Randomized, Double-blind, Parallel-group, Placebo-controlled, Fixed Dose/Dose Regimen, Multicenter Study Evaluating the Efficacy and Safety of SAR236553 When Co-administered With 80 mg of Atorvastatin Over 8 Weeks in Patients With Primary Hypercholesterolemia and LDL-cholesterol ≥ 100 mg/dL (≥2.59 mmol/L) on Atorvastatin 10 mg

Primary Objective:

To evaluate the effect of alirocumab (SAR236553/REGN727) on low-density lipoprotein cholesterol (LDL-C) levels compared with placebo when co-administered with 80 mg of atorvastatin after 8 weeks of treatment in participants with LDL-C ≥ 100mg/dL (≥ 2.59 mmol/L) on atorvastatin 10 mg.

Secondary Objectives:

• To evaluate the effects of alirocumab on other lipid levels in comparison with placebo, when co-administered with 80 mg of atorvastatin after 8 weeks of treatment.
• To evaluate the efficacy of alirocumab when co-administered with a high dose of atorvastatin (80 mg) versus atorvastatin 10 mg.
• To evaluate the safety and tolerability of alirocumab when co-administered with 2 different doses of atorvastatin.
• 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; Drug: Placebo (for atorvastatin)

Detailed Description

The duration of study participation depended on the status of the patient at screening:

• For participants receiving atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening, the study participation was to be approximately 17 weeks including a screening period of 1 week, a double-blind treatment period of 8 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 for at least 6 weeks prior to screening, or drug naive participants, the study participation was to be approximately 23 weeks with a screening period of 1 week, a run-in treatment period with atorvastatin 10 mg of 6 weeks, a double-blind treatment period of 8 weeks and a follow-up period of 8 weeks.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Mesa, Arizona, United States, 85206
      • Investigational Site Number 840616
    • Tucson, Arizona, United States, 85710
      • Investigational Site Number 840601
  • California
    • Los Angeles, California, United States, 90057
      • Investigational Site Number 840610
    • Newport Beach, California, United States, 92660
      • Investigational Site Number 840608
  • Florida
    • Doral, Florida, United States, 33166
      • Investigational Site Number 840603
    • Jacksonville, Florida, United States, 32223
      • Investigational Site Number 840611
    • Jupiter, Florida, United States, 33458
      • Investigational Site Number 840618
    • Miami, Florida, United States, 33138
      • Investigational Site Number 840612
    • Miami, Florida, United States, 33138
      • Investigational Site Number 840614
    • St. Petersburg, Florida, United States, 33609
      • Investigational Site Number 840607
  • Illinois
    • Chicago, Illinois, United States, 60610
      • Investigational Site Number 840605
    • Chicago, Illinois, United States, 60610
      • Investigational Site Number 840619
  • New Jersey
    • Edison, New Jersey, United States, 08817
      • Investigational Site Number 840604
  • New York
    • Rochester, New York, United States, 14609
      • Investigational Site Number 840606
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Investigational Site Number 840615
    • Cincinnati, Ohio, United States, 45219
      • Investigational Site Number 840617
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Investigational Site Number 840602
  • Virginia
    • Richmond, Virginia, United States, 23227
      • Investigational Site Number 840621
  • Washington
    • Olympia, Washington, United States, 98502
      • Investigational Site Number 840609
  • Wisconsin
    • Oregon, Wisconsin, United States, 53575
      • Investigational Site Number 840613

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 receiving a lipid-lowering treatment other than atorvastatin/ or not at stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening, or drug naive participants with primary hypercholesterolemia 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 stable dose of atorvastatin 10 mg for at least 6 weeks prior to screening and likely to have low-density lipoprotein cholesterol (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) at Week -1 (V1):

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

   OR

   • At the first visit for participants who are being treated with atorvastatin 10 mg at stable dose for at least 6 weeks prior to screening visit.
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 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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo + Atorvastatin 80 mg; Placebo (for alirocumab) subcutaneous (SC) administration every 2 weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Drug: Placebo (for alirocumab); One SC injection in the abdomen only.; Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.
EXPERIMENTAL: Alirocumab + Atorvastatin 10 mg; Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.	Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.; Drug: Alirocumab; One subcutaneous (SC) injection in the abdomen only.; Other Names: SAR236553; REGN727; Drug: Placebo (for atorvastatin); One over-encapsulated tablet of placebo for atorvastatin orally once daily in the evening with dinner.
EXPERIMENTAL: Alirocumab + Atorvastatin 80 mg; Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.	Drug: Atorvastatin; Over-encapsulated tablet orally once daily in the evening with dinner.; Drug: Alirocumab; One subcutaneous (SC) injection 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 8 - 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 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.	From Baseline to Week 8 (LOCF)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.	From baseline to Week 8 (LOCF)
Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.	From baseline to Week 8 (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 8 - On-treatment Analysis		Week 8 (LOCF)
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	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).	From baseline to Week 8 (LOCF)
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis	Adjusted LS means and standard errors were estimated using the same ANCOVA model as for primary endpoint.	From Baseline to Week 8 (LOCF)
Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis	Adjusted LS means and standard errors were estimated using the same ANCOVA as for primary endpoint.	From Baseline to Week 8 (LOCF)

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012 Nov 15;367(20):1891-900. doi: 10.1056/NEJMoa1201832. Epub 2012 Oct 31.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2011
• Primary Completion (ACTUAL): September 1, 2011
• Study Completion (ACTUAL): September 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: January 1, 2015

More Information

Terms related to this study

• Keywords: 10020603
• 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: DFI11566; U1111-1117-9994 (OTHER: UTN)