A Randomized, Double-Blind Study of the Efficacy and Safety of Alirocumab Added on to Atorvastatin Versus Ezetimibe Added on to Atorvastatin Versus Atorvastatin Dose Increase Versus Switch to Rosuvastatin in Patients Who Are Not Controlled on Atorvastatin
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Regeneron Pharmaceuticals
- Enrollment
- 355
- Primary Endpoint
- Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis
Study Overview
Brief Summary
This is a randomized, double-blind, active-comparator, parallel-group study in patients at high cardiovascular risk with nonfamilial hypercholesterolemia or heterozygous familial hypercholesterolemia (heFH).
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients with screening (visit 1) LDL-C greater than or equal to 70 mg/dL with documented CVD, not adequately controlled with a daily dose of atorvastatin. OR
- •Patients with screening (visit 1) LDL-C greater than or equal to 100 mg/dL at high risk for CVD who are not adequately controlled with a daily dose of atorvastatin.
Exclusion Criteria
- •LDL-C greater than 250 mg/dL
- •LDL-C less than 70 mg/dL at the screening visit in patients with history of documented CVD
- •LDL-C less than 100 mg/dL at the screening visit in patients without history of documented CHD or non-CHD CVD, but with other risk factors
- •TG greater than 400 mg/dL
- •Homozygous FH (clinically or previous genotyping)
- •Currently taking a statin that is not atorvastatin
- •Currently taking Ezetimibe (EZE)
- •Not on a stable dose of allowable lipid modifying treatments (LMT)
- •(The inclusion/ exclusion criteria provided above is not intended to contain all considerations relevant to a patient's potential participation in this clinical trial).
Arms & Interventions
Atorvastatin 40 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received atorvastatin 40 mg over-encapsulated tablets orally once daily (QD), placebo for alirocumab SC injection every two weeks (Q2W), and placebo for ezetimibe over-encapsulated tablets orally QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.
Intervention: Atorvastatin (Drug)
Atorvastatin 40 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received atorvastatin 40 mg over-encapsulated tablets orally once daily (QD), placebo for alirocumab SC injection every two weeks (Q2W), and placebo for ezetimibe over-encapsulated tablets orally QD added to stable Lipid-Modifying Therapy (LMT) for 24 weeks.
Intervention: Placebo (Drug)
Ezetimibe 10 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Atorvastatin (Drug)
Ezetimibe 10 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Ezetimibe (Drug)
Ezetimibe 10 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Placebo (Drug)
Alirocumab 75 mg/up to 150 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received Alirocumab 75 mg SC injection Q2W, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Alirocumab (Drug)
Ezetimibe 10 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Atorvastatin (Drug)
Alirocumab 75 mg/up to 150 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received Alirocumab 75 mg SC injection Q2W, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Atorvastatin (Drug)
Alirocumab 75 mg/up to 150 mg + Atorvastatin 20 mg
Participants, who were receiving atorvastatin 20 mg over-encapsulated tablets orally at baseline, received Alirocumab 75 mg SC injection Q2W, atorvastatin 20 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Placebo (Drug)
Atorvastatin 80 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received Atorvastatin 80 mg over-encapsulated tablets orally QD, placebo for alirocumab SC injection Q2W, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks.
Intervention: Atorvastatin (Drug)
Atorvastatin 80 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received Atorvastatin 80 mg over-encapsulated tablets orally QD, placebo for alirocumab SC injection Q2W, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks.
Intervention: Placebo (Drug)
Rosuvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received rosuvastatin 40 mg over-encapsulated tablets orally QD, placebo for alirocumab SC injection Q2W, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks.
Intervention: Rosuvastatin (Drug)
Rosuvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received rosuvastatin 40 mg over-encapsulated tablets orally QD, placebo for alirocumab SC injection Q2W, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks.
Intervention: Placebo (Drug)
Ezetimibe 10 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Ezetimibe (Drug)
Ezetimibe 10 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received ezetimibe 10 mg over-encapsulated tablets orally QD, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for alirocumab SC injection Q2W added to stable LMT for 24 weeks.
Intervention: Placebo (Drug)
Alirocumab 75 mg/ up to 150 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received alirocumab 75 mg SC injection Q2W, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Alirocumab (Drug)
Alirocumab 75 mg/ up to 150 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received alirocumab 75 mg SC injection Q2W, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Atorvastatin (Drug)
Alirocumab 75 mg/ up to 150 mg + Atorvastatin 40 mg
Participants, who were receiving atorvastatin 40 mg over-encapsulated tablets orally at baseline, received alirocumab 75 mg SC injection Q2W, atorvastatin 40 mg over-encapsulated tablets orally QD, and placebo for ezetimibe over-encapsulated tablets orally QD added to stable LMT for 24 weeks. Alirocumab dose up-titrated to 150 mg Q2W from Week 12 when LDL-C levels ≥70 mg/dL (1.81 mmol/L) or ≥100 mg/dL (2.59 mmol/L) at Week 8, based on baseline disease characteristic and medical history.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Percent Change From Baseline in Calculated LDL-C at Week 24 - Intent-to-treat (ITT) Analysis
Time Frame: From Baseline to Week 24
Calculated LDL-C values were obtained from Friedewald formula. Adjusted Least-squares (LS) means and standard errors at Week 24 were obtained from a mixed-effect model with repeated measures (MMRM) to account for missing data. All available post-baseline data from Week 4 to Week 24 regardless of status on- or off-treatment were used in the model (ITT analysis).
Secondary Outcomes
- Percent Change From Baseline in Apo A-1 at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Calculated LDL-C at Week 24 - On-Treatment Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Fasting Triglycerides at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Apo A-1 at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Calculated LDL-C at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Calculated LDL-C at Week 12 - On-Treatment Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Apolipoprotein (Apo) B at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Apo B at Week 24 - On-Treatment Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Non-High-density Lipoprotein Cholesterol (Non-HDL-C) at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Non-HDL-C at Week 24 - On-Treatment Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Total Cholesterol (Total-C) at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Apo B at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Non-HDL-C at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Total-C at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - ITT Analysis(Up to Week 24)
- Percentage of Very High CV Risk Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) or High CV Risk Participants Reaching Calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 - On-Treatment Analysis(Up to Week 24)
- Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - ITT Analysis(Up to Week 24)
- Percentage of Participants Reaching Calculated LDL-C <70 mg/dL (1.81 mmol/L) at Week 24 - On-Treatment Analysis(Up to Week 24)
- Percent Change From Baseline in Lipoprotein(a) at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in HDL-C at Week 24 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Lipoprotein(a) at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in HDL-C at Week 12 - ITT Analysis(From Baseline to Week 24)
- Percent Change From Baseline in Fasting Triglycerides at Week 12 - ITT Analysis(From Baseline to Week 24)