A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in Hypercholesterolemic Japanese Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Amgen
- Enrollment
- 61
- Locations
- 1
- Primary Endpoint
- Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
Study Overview
Brief Summary
The primary objective of the study was to evaluate the effect of 12 weeks of subcutaneous (SC) evolocumab compared with ezetimibe, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic adults unable to tolerate an effective dose of a statin.
Detailed Description
After screening participants who met all inclusion/exclusion criteria were randomized with an allocation ratio of 2:2:1:1 into 4 groups: evolocumab (AMG 145) 420 mg administered by subcutaneous injection monthly and placebo pill daily; evolocumab 140 mg administered by subcutaneous injection every two weeks and placebo pill by mouth daily; placebo 420 mg administered by subcutaneous injection monthly and ezetimibe 10 mg pill daily; placebo 140 mg administered subcutaneous injection every two weeks and ezetimibe 10 mg pill daily. Randomization was stratified by screening LDL-C level and baseline statin use. Participants on low or atypical statin dose therapy must have been on a stable dose for at least 4 weeks prior to screening and throughout the blinded portion of the study; the dose could not be adjusted during screening and for the duration of the study. After Week 12, ezetimibe was discontinued and participants moved to an open-label dose of evolocumab administered by subcutaneous injection either every two weeks or monthly and their standard of care.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 20 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female ≥ 20 to ≤ 80 years of age
- •Japanese by self-identification
- •Not on a statin or on a low dose statin with stable dose for at least 4 weeks.
- •Subject not at LDL-C goal
- •History of statin intolerance to at least 2 statins
- •Lipid lowering therapy has been stable prior to screening for at least 4 weeks
- •Fasting triglycerides ≤ 400 mg/dL
Exclusion Criteria
- •New York Heart Association (NYHA) III or IV heart failure
- •Uncontrolled cardiac arrhythmia
- •Uncontrolled hypertension
- •Type 1 diabetes
- •Poorly controlled type 2 diabetes
- •Uncontrolled hypothyroidism or hyperthyroidism
Arms & Interventions
Ezetimibe (QM)
Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Intervention: Evolocumab (Biological)
Ezetimibe (Q2W)
Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48.
Intervention: Evolocumab (Biological)
Ezetimibe (Q2W)
Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48.
Intervention: Ezetimibe (Drug)
Ezetimibe (Q2W)
Participants received placebo subcutaneous injection once every 2 weeks and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48.
Intervention: Placebo to Evolocumab (Drug)
Ezetimibe (QM)
Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Intervention: Ezetimibe (Drug)
Ezetimibe (QM)
Participants received placebo subcutaneous injection once a month and 10 mg ezetimibe orally once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Intervention: Placebo to Evolocumab (Drug)
Evolocumab Q2W
Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48.
Intervention: Evolocumab (Biological)
Evolocumab Q2W
Participants received 140 mg evolocumab by subcutaneous injection once every 2 weeks and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 140 mg subcutaneously once every 2 weeks until week 48.
Intervention: Placebo Ezetimibe (Drug)
Evolocumab QM
Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Intervention: Evolocumab (Biological)
Evolocumab QM
Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo tablets once a day for 12 weeks. From week 12 participants received open-label evolocumab 420 mg subcutaneously once a month until week 48.
Intervention: Placebo Ezetimibe (Drug)
Outcomes
Primary Outcomes
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12
Time Frame: Baseline and week 12
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at the Mean of Weeks 10 and 12
Time Frame: Baseline and Weeks 10 and 12
For all efficacy endpoints the two dosing regimens (every 2 weeks and every month) for each treatment were pooled for analysis.
Secondary Outcomes
- Percent Change From Baseline in HDL-C at Week 12(Baseline and week 12)
- Percent Change From Baseline in VLDL-C at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in Total Cholesterol at Week 12(Baseline and week 12)
- Percent Change From Baseline in Triglycerides at Week 12(Baseline and week 12)
- Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at Week 12(Baseline and week 12)
- Change From Baseline in LDL-C at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in the Total Cholesterol/HDL-C Ratio at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Change From Baseline in LDL-C at Week 12(Baseline and week 12)
- Percentage of Participants Who Achieved a Mean LDL-C at Weeks 10 and 12 of Less Than 70 mg/dL(Weeks 10 and 12)
- Percentage of Participants Who Achieved a LDL-C of Less Than 70 mg/dL at Week 12(Week 12)
- Percent Change From Baseline in Non-HDL-C at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in Non-HDL-C at Week 12(Baseline and week 12)
- Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12(Baseline and Weeks 10 and 12)
- Percent Change From Baseline in Apolipoprotein B at Week 12(Baseline and week 12)
- Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in Lipoprotein(a) at Week 12(Baseline and week 12)
- Percent Change From Baseline in HDL-C at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at Week 12(Baseline and week 12)
- Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)
- Percent Change From Baseline in VLDL-C at Week 12(Baseline and week 12)
- Percent Change From Baseline in Triglycerides at the Mean of Weeks 10 and 12(Baseline and weeks 10 and 12)