Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-4 (GAUSS-4)

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

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.

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.

Japanese, High cholesterol, Treatment of high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia, Statin intolerant

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.

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.

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.

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.

Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at the Mean of 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.

Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A-1 Ratio at the Mean of Weeks 10 and 12

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

Koba S, Inoue I, Cyrille M, Lu C, Inomata H, Shimauchi J, Kajinami K. Evolocumab vs. Ezetimibe in Statin-Intolerant Hyperlipidemic Japanese Patients: Phase 3 GAUSS-4 Trial. J Atheroscler Thromb. 2020 May 1;27(5):471-484. doi: 10.5551/jat.50963. Epub 2019 Nov 21.