Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)

A Double-blind, Randomized, Multicenter Study to Evaluate the Safety and Efficacy of Evolocumab, Compared With Ezetimibe, in Hypercholesterolemic Subjects Unable to Tolerate an Effective Dose of a HMG-CoA Reductase Inhibitor Due to Muscle Related Side Effects

The primary objective of this study was to evaluate the effect of 24 weeks of evolocumab administered subcutaneously (SC) every month, compared with ezetimibe, on low-density lipoprotein cholesterol (LDL-C) levels in adults with high cholesterol who are unable to tolerate an effective dose of a statin due to muscle-related side effects (MRSE).

Study Overview

• Status: Completed
• Conditions: Hyperlipidemia
• Intervention / Treatment: Drug: Atorvastatin; Drug: Placebo to Atorvastatin; Drug: Ezetimibe; Other: Placebo to Evolocumab; Other: Placebo to Ezetimibe; Drug: Evolocumab

Detailed Description

The study is divided into 3 parts (A, B, C). After an initial 4-week washout period in which any statins, ezetimibe, or other lipid-lowering agents were discontinued, participants were enrolled in phase A, a double-blind, placebo-controlled crossover procedure to rechallenge patients with atorvastatin. Patients were randomly assigned in a 1:1 ratio to receive either atorvastatin (20 mg daily) or matching placebo for the first 10 weeks (period 1), then underwent a 2-week washout period, followed by crossover to the alternate therapy for a second 10-week period (period 2). Patients who experienced intolerable muscle symptoms during the first period did not complete the full 10 weeks of exposure but entered a 2-week washout period before proceeding to period 2.

Participants who did not develop muscle-related side effects were removed from the study, as were patients who reported muscle-related side effects during a placebo period.

After completion of phase A, patients who experienced muscle-related adverse effects while taking atorvastatin but not placebo were eligible for phase B, a 24-week, double-blind randomization to ezetimibe or evolocumab using a double-dummy design in which patients received either injectable placebo and oral ezetimibe or injectable evolocumab and oral placebo. A patient could proceed directly to phase B if they had a documented history of creatine kinase (CK) elevation more than 10 times the upper limit of normal accompanied by muscle symptoms while taking statin therapy, with documented resolution of both CK elevation and symptoms upon discontinuation of statin therapy.

These study procedures were designed to ensure that only patients with reproducible statin-associated muscle symptoms entered phase B of the study. For phase B, participants were randomized 2:1 to receive subcutaneously administered evolocumab (420 mg monthly) or oral ezetimibe (10 mg daily). Randomization in part B was stratified by screening LDL-C level (< 180 mg/dL [4.66 mmol/L] vs. ≥ 180 mg/dL) at study baseline.

Participants who completed phase B and did not discontinue SC investigational product for any reason, including an adverse event, were eligible to proceed to the 2-year open-label extension phase C to evaluate the long-term safety and efficacy of evolocumab in statin-intolerant patients. Participants in phase C were allowed to choose quarterly between evolocumab 420 mg SC QM or evolocumab 140 mg SC every 2 weeks (Q2W).

• Study Type: Interventional
• Enrollment (Actual): 511
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2015
      • Research Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Research Site
  • South Australia
    • Ashford, South Australia, Australia, 5035
      • Research Site
• Canada
  • Quebec, Canada, G1V 4M6
    • Research Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Research Site
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Research Site
    • London, Ontario, Canada, N6A 4V2
      • Research Site
    • Peterborough, Ontario, Canada, K9J 0B2
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2W 1R7
      • Research Site
    • St-Charles-Borromee, Quebec, Canada, J6E 6J2
      • Research Site
• Czechia
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Praha 2, Czechia, 128 08
    • Research Site
  • Praha 4, Czechia, 140 21
    • Research Site
• Denmark
  • Aarhus N, Denmark, 8200
    • Research Site
  • Glostrup, Denmark, 2600
    • Research Site
• France
  • Nantes Cedex 1, France, 44093
    • Research Site
  • Paris Cedex 13, France, 75651
    • Research Site
  • Vénissieux, France, 69200
    • Research Site
• Germany
  • Berlin, Germany, 13353
    • Research Site
  • Köln, Germany, 50937
    • Research Site
  • München, Germany, 80638
    • Research Site
• Italy
  • Bologna, Italy, 40138
    • Research Site
  • Cagliari, Italy, 09134
    • Research Site
  • Cinisello Balsamo (MI), Italy, 20092
    • Research Site
  • Ferrara, Italy, 44100
    • Research Site
  • Perugia, Italy, 06129
    • Research Site
  • Pisa, Italy, 56124
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Research Site
  • Rotterdam, Netherlands, 3045 PM
    • Research Site
  • Zwijndrecht, Netherlands, 3331 LZ
    • Research Site
• New Zealand
  • Christchurch, New Zealand, 8011
    • Research Site
• Norway
  • Oslo, Norway, 0373
    • Research Site
  • Ålesund, Norway, 6003
    • Research Site
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2157
      • Research Site
    • Midrand, Gauteng, South Africa, 1685
      • Research Site
  • Western Cape
    • Observatory, Western Cape, South Africa, 7925
      • Research Site
    • Parow, Western Cape, South Africa, 7505
      • Research Site
• United Kingdom
  • Birmingham, United Kingdom, B15 2TH
    • Research Site
  • Glasgow, United Kingdom, G12 8TA
    • Research Site
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Research Site
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Research Site
    • Huntington Beach, California, United States, 92648
      • Research Site
    • Los Angeles, California, United States, 90048
      • Research Site
    • San Pedro, California, United States, 90732
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Research Site
  • Illinois
    • Sterling, Illinois, United States, 61081
      • Research Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
    • Towson, Maryland, United States, 21204
      • Research Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • New York
    • New York, New York, United States, 10029
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Research Site
  • Pennsylvania
    • York, Pennsylvania, United States, 17405
      • Research Site
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Research Site
  • Texas
    • Houston, Texas, United States, 77030
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female ≥ 18 to ≤ 80 years of age
• Subject not at LDL-C goal
• History of statin intolerance
• Lipid lowering therapy has been stable prior to enrolment 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

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Part A: Atorvastatin 20 mg => Placebo; Participants received atorvastatin 20 mg orally for 10 weeks (period 1) followed by placebo orally for 10 weeks (period 2), separated by a 2-week washout period.	Drug: Atorvastatin; Atorvastatin was supplied as over-encapsulated 20 mg tablets; Other Names: Lipitor; Drug: Placebo to Atorvastatin; Placebo matching to atorvastatin supplied as over-encapsulated tablets
Other: Part A: Placebo => Atorvastatin 20 mg; Participants received placebo orally for 10 weeks (period 1) followed by atorvastatin 20 mg orally for 10 weeks (period 2), separated by a 2-week washout period.	Drug: Atorvastatin; Atorvastatin was supplied as over-encapsulated 20 mg tablets; Other Names: Lipitor; Drug: Placebo to Atorvastatin; Placebo matching to atorvastatin supplied as over-encapsulated tablets
Active Comparator: Part B: Ezetimibe; Participants received 10 mg ezetimibe orally only a day and placebo to evolocumab by subcutaneous injection once a month for 24 weeks.	Drug: Ezetimibe; Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.; Other Names: Zetia; Other: Placebo to Evolocumab; Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)
Experimental: Part B: Evolocumab; Participants received 420 mg evolocumab by subcutaneous injection once a month and placebo to ezetimibe orally once a day for 24 weeks.	Other: Placebo to Ezetimibe; Placebo matching to Ezetimibe supplied as over-encapsulated tablets.; Drug: Evolocumab; Evolocumab supplied as single-use prefilled autoinjector/pen(s); Other Names: Repatha
Experimental: Part C: Open-label Evolocumab; Participants who completed part B and were eligible to proceed to open-label extension part C and could choose quarterly between evolocumab 420 mg once a month or evolocumab 140 mg every 2 weeks for up to 2 years.	Drug: Evolocumab; Evolocumab supplied as single-use prefilled autoinjector/pen(s); Other Names: Repatha

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in LDL-C at Week 24	Baseline and week 24

Secondary Outcome Measures

Outcome Measure	Time Frame
Change From Baseline in LDL-C at the Mean of Weeks 22 and 24	Baselie and weeks 22 and 24
Change From Baseline in LDL-C at Week 24	Baseline and week 24
Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL	Weeks 22 and 24
Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL	Week 24
Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in Total Cholesterol at Week 24	Baseline and week 24
Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in Non-HDL-C at Week 24	Baseline and week 24
Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in Apolipoprotein B at Week 24	Baseline and week 24
Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24	Baseline and week 24
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24	Baseline and Weeks 22 and 24
Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24	Baseline and week 24
Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24	Baseline and Weeks 22 and 24
Percent Change From Baseline in Lipoprotein(a) at Week 24	Baseline and week 24
Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in Triglycerides at Week 24	Baseline and week 24
Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24	Baseline and weeks 22 and 24
Percent Change From Baseline in HDL-C at Week 24	Baseline and week 24
Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24	Baseline and weeks 22 and 24
Percent Change From Baseline in VLDL-C at Week 24	Baseline and week 24

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Cho L, Dent R, Stroes ESG, Stein EA, Sullivan D, Ruzza A, Flower A, Somaratne R, Rosenson RS. Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies. Cardiovasc Drugs Ther. 2018 Aug;32(4):365-372. doi: 10.1007/s10557-018-6817-7.
• Schmidt AF, Carter JL, Pearce LS, Wilkins JT, Overington JP, Hingorani AD, Casas JP. PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2020 Oct 20;10(10):CD011748. doi: 10.1002/14651858.CD011748.pub3.
• Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, Preiss D, Bruckert E, Ceska R, Lepor N, Ballantyne CM, Gouni-Berthold I, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA; GAUSS-3 Investigators. Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial. JAMA. 2016 Apr 19;315(15):1580-90. doi: 10.1001/jama.2016.3608.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2013
• Primary Completion (Actual): November 10, 2015
• Study Completion (Actual): November 21, 2017

Study Registration Dates

• First Submitted: November 8, 2013
• First Submitted That Met QC Criteria: November 8, 2013
• First Posted (Estimate): November 14, 2013

Study Record Updates

• Last Update Posted (Actual): November 29, 2018
• Last Update Submitted That Met QC Criteria: November 1, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Keywords: High Cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hyperlipidemias; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Immunologic Factors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atorvastatin; Antibodies, Monoclonal; Evolocumab; Ezetimibe
• Other Study ID Numbers: 20120332; 2013-000935-29 (EudraCT Number)