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.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Biological: Evolocumab; Drug: Ezetimibe; Drug: Placebo to Evolocumab; Drug: Placebo Ezetimibe

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 Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Aichi
    • Nagoya-shi, Aichi, Japan, 466-8560
      • Research Site
    • Nagoya-shi, Aichi, Japan, 466-8650
      • Research Site
  • Chiba
    • Chiba-shi, Chiba, Japan, 260-8677
      • Research Site
    • Kisarazu-shi, Chiba, Japan, 292-8535
      • Research Site
    • Matsudo-shi, Chiba, Japan, 271-0077
      • Research Site
  • Fukuoka
    • Chikushino-shi, Fukuoka, Japan, 818-8516
      • Research Site
    • Koga-shi, Fukuoka, Japan, 811-3195
      • Research Site
  • Fukushima
    • Sukagawa-shi, Fukushima, Japan, 962-0001
      • Research Site
    • Sukagawa-shi, Fukushima, Japan, 962-8503
      • Research Site
  • Hiroshima
    • Hiroshima-shi, Hiroshima, Japan, 734-8551
      • Research Site
  • Hyogo
    • Kobe-shi, Hyogo, Japan, 650-0017
      • Research Site
  • Ibaraki
    • Koga-shi, Ibaraki, Japan, 306-0041
      • Research Site
  • Ishikawa
    • Kahoku-gun, Ishikawa, Japan, 920-0293
      • Research Site
    • Kanazawa-shi, Ishikawa, Japan, 920-8650
      • Research Site
    • Komatsu-shi, Ishikawa, Japan, 923-8560
      • Research Site
  • Iwate
    • Morioka-shi, Iwate, Japan, 020-8505
      • Research Site
    • Morioka-shi, Iwate, Japan, 020-0866
      • Research Site
  • Kagoshima
    • Kagoshima-shi, Kagoshima, Japan, 890-8520
      • Research Site
  • Kanagawa
    • Yokohama-shi, Kanagawa, Japan, 245-8575
      • Research Site
  • Kumamoto
    • Kumamoto-shi, Kumamoto, Japan, 860-8556
      • Research Site
    • Kumamoto-shi, Kumamoto, Japan, 862-0976
      • Research Site
  • Kyoto
    • Kyoto-shi, Kyoto, Japan, 606-8507
      • Research Site
  • Miyagi
    • Ohsaki-shi, Miyagi, Japan, 989-6143
      • Research Site
  • Okinawa
    • Nakagami-gun, Okinawa, Japan, 901-2393
      • Research Site
  • Osaka
    • Osaka-Shi, Osaka, Japan, 553-0003
      • Research Site
    • Osaka-shi, Osaka, Japan, 530-0001
      • Research Site
  • Saitama
    • Fujimi-shi, Saitama, Japan, 354-0031
      • Research Site
    • Iruma-gun, Saitama, Japan, 350-0495
      • Research Site
    • Kawaguchi-shi, Saitama, Japan, 332-0012
      • Research Site
  • Shizuoka
    • Hamamatsu-shi, Shizuoka, Japan, 430-0929
      • Research Site
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8655
      • Research Site
    • Chuo-ku, Tokyo, Japan, 103-0027
      • Research Site
    • Higashiyamato-shi, Tokyo, Japan, 207-0014
      • Research Site
    • Musashino-shi, Tokyo, Japan, 180-0022
      • Research Site
    • Shinagawa-ku, Tokyo, Japan, 142-8666
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145; Drug: Ezetimibe; Tablet for oral administration; Other Names: Zetia; Drug: Placebo to Evolocumab; Administered by subcutaneous injection
Active Comparator: 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.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145; Drug: Ezetimibe; Tablet for oral administration; Other Names: Zetia; Drug: Placebo to Evolocumab; Administered by subcutaneous injection
Experimental: 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.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145; Drug: Placebo Ezetimibe; Tablet for oral administration
Experimental: 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.	Biological: Evolocumab; Administered by subcutaneous injection; Other Names: Repatha; AMG 145; Drug: Placebo Ezetimibe; Tablet for oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline and Weeks 10 and 12
Percent Change From Baseline in Low-Density Lipoprotein Cholesterol (LDL-C) at Week 12		Baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 10 and 12		Baseline and Weeks 10 and 12
Change From Baseline in LDL-C 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
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 Week 12		Baseline and week 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 Lipoprotein(a) 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 Triglycerides at the Mean of Weeks 10 and 12		Baseline and weeks 10 and 12
Percent Change From Baseline in Triglycerides 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 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 VLDL-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	Mean low density lipoprotein-cholesterol response was defined as LDL-C < 70 mg/dL [1.8 mol/L].	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 the Total Cholesterol/HDL-C Ratio 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 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 Apolipoprotein B/Apolipoprotein A-1 Ratio at Week 12		Baseline and week 12

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• 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.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2016
• Primary Completion (Actual): August 10, 2017
• Study Completion (Actual): May 26, 2018

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: December 16, 2015
• First Posted (Estimate): December 18, 2015

Study Record Updates

• Last Update Posted (Actual): November 10, 2020
• Last Update Submitted That Met QC Criteria: October 20, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Japanese; Hypercholesterolemia; High cholesterol; Statin intolerant; Lowering cholesterol; Lowering high cholesterol; Treatment of high cholesterol
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Immunologic Factors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Antibodies, Monoclonal; Evolocumab; Ezetimibe
• Other Study ID Numbers: 20140234

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No