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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

Primary Purpose

Hypercholesterolemia

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

About this trial

This is an interventional treatment trial for Hypercholesterolemia focused on measuring 10020603

Eligibility Criteria

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

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.

Sites / Locations

  • Investigational Site Number 840616
  • Investigational Site Number 840601
  • Investigational Site Number 840610
  • Investigational Site Number 840608
  • Investigational Site Number 840603
  • Investigational Site Number 840611
  • Investigational Site Number 840618
  • Investigational Site Number 840612
  • Investigational Site Number 840614
  • Investigational Site Number 840607
  • Investigational Site Number 840605
  • Investigational Site Number 840619
  • Investigational Site Number 840604
  • Investigational Site Number 840606
  • Investigational Site Number 840615
  • Investigational Site Number 840617
  • Investigational Site Number 840602
  • Investigational Site Number 840621
  • Investigational Site Number 840609
  • Investigational Site Number 840613

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Experimental

Experimental

Arm Label

Placebo + Atorvastatin 80 mg

Alirocumab + Atorvastatin 10 mg

Alirocumab + Atorvastatin 80 mg

Arm Description

Placebo (for alirocumab) subcutaneous (SC) administration every 2 weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks.

Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.

Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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
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).
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.
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.

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
NCT01288469
Brief Title
Efficacy and Safety Evaluation of Alirocumab (SAR236553/REGN727) When Co-administered With High Dose of Atorvastatin in Patients With Primary Hypercholesterolemia
Official Title
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
Study Type
Interventional

2. Study Status

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypercholesterolemia
Keywords
10020603

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Placebo + Atorvastatin 80 mg
Arm Type
Placebo Comparator
Arm Description
Placebo (for alirocumab) subcutaneous (SC) administration every 2 weeks (Q2W) in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Arm Title
Alirocumab + Atorvastatin 10 mg
Arm Type
Experimental
Arm Description
Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 10 mg orally once daily for 8 weeks.
Arm Title
Alirocumab + Atorvastatin 80 mg
Arm Type
Experimental
Arm Description
Alirocumab 150 mg SC administration Q2W in combination with atorvastatin 80 mg orally once daily for 8 weeks.
Intervention Type
Drug
Intervention Name(s)
Alirocumab
Other Intervention Name(s)
SAR236553, REGN727
Intervention Description
One subcutaneous (SC) injection in the abdomen only.
Intervention Type
Drug
Intervention Name(s)
Placebo (for alirocumab)
Intervention Description
One SC injection in the abdomen only.
Intervention Type
Drug
Intervention Name(s)
Atorvastatin
Intervention Description
Over-encapsulated tablet orally once daily in the evening with dinner.
Intervention Type
Drug
Intervention Name(s)
Placebo (for atorvastatin)
Intervention Description
One over-encapsulated tablet of placebo for atorvastatin orally once daily in the evening with dinner.
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Calculated LDL-C at Week 8 - 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 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)
Secondary Outcome Measure Information:
Title
Absolute Change From Baseline in Calculated LDL-C (mmol/L) at Week 8 - On-treatment Analysis
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)
Title
Absolute Change From Baseline in Calculated LDL-C (mg/dL) at Week 8 - On-treatment Analysis
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)
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
Time Frame
Week 8 (LOCF)
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
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)
Title
Percent Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Week 8 - On-treatment Analysis
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)
Title
Absolute Change in the Ratio Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) From Baseline to Week 8 - On-treatment Analysis
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)

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

12. IPD Sharing Statement

Citations:
PubMed Identifier
23113833
Citation
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.
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

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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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