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

NCT ID: NCT01984424

Last Updated: 2018-11-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 511 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-12-10
• Study Completion Date: 2017-11-21

Brief Summary

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).

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).

Conditions

Hyperlipidemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: OTHER

Atorvastatin

Intervention Type: DRUG

Atorvastatin was supplied as over-encapsulated 20 mg tablets

Placebo to Atorvastatin

Intervention Type: DRUG

Placebo matching to atorvastatin supplied as over-encapsulated tablets

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.

Group Type: OTHER

Atorvastatin

Intervention Type: DRUG

Atorvastatin was supplied as over-encapsulated 20 mg tablets

Placebo to Atorvastatin

Intervention Type: DRUG

Placebo matching to atorvastatin supplied as over-encapsulated tablets

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.

Group Type: ACTIVE_COMPARATOR

Ezetimibe

Intervention Type: DRUG

Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.

Placebo to Evolocumab

Intervention Type: OTHER

Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)

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.

Group Type: EXPERIMENTAL

Placebo to Ezetimibe

Intervention Type: OTHER

Placebo matching to Ezetimibe supplied as over-encapsulated tablets.

Evolocumab

Intervention Type: DRUG

Evolocumab supplied as single-use prefilled autoinjector/pen(s)

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.

Group Type: EXPERIMENTAL

Evolocumab

Intervention Type: DRUG

Evolocumab supplied as single-use prefilled autoinjector/pen(s)

Interventions

Atorvastatin

Atorvastatin was supplied as over-encapsulated 20 mg tablets

Intervention Type: DRUG

Placebo to Atorvastatin

Placebo matching to atorvastatin supplied as over-encapsulated tablets

Intervention Type: DRUG

Placebo to Ezetimibe

Placebo matching to Ezetimibe supplied as over-encapsulated tablets.

Intervention Type: OTHER

Ezetimibe

Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.

Intervention Type: DRUG

Placebo to Evolocumab

Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)

Intervention Type: OTHER

Evolocumab

Evolocumab supplied as single-use prefilled autoinjector/pen(s)

Intervention Type: DRUG

Other Intervention Names

Lipitor; Zetia; Repatha

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Amgen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Amgen

Locations

Research Site

Beverly Hills, California, United States

Research Site

Huntington Beach, California, United States

Research Site

Los Angeles, California, United States

Research Site

San Pedro, California, United States

Research Site

Atlanta, Georgia, United States

Research Site

Sterling, Illinois, United States

Research Site

Kansas City, Kansas, United States

Research Site

Baltimore, Maryland, United States

Research Site

Towson, Maryland, United States

Research Site

Ann Arbor, Michigan, United States

Research Site

Rochester, Minnesota, United States

Research Site

St Louis, Missouri, United States

Research Site

New York, New York, United States

Research Site

Durham, North Carolina, United States

Research Site

Cleveland, Ohio, United States

Research Site

York, Pennsylvania, United States

Research Site

Charleston, South Carolina, United States

Research Site

Houston, Texas, United States

Research Site

Camperdown, New South Wales, Australia

Research Site

Woolloongabba, Queensland, Australia

Research Site

Ashford, South Australia, Australia

Research Site

Vancouver, British Columbia, Canada

Research Site

Hamilton, Ontario, Canada

Research Site

London, Ontario, Canada

Research Site

Peterborough, Ontario, Canada

Research Site

Montreal, Quebec, Canada

Research Site

Québec, Quebec, Canada

Research Site

Saint-Charles-Borromée, Quebec, Canada

Research Site

Hradec Králové, , Czechia

Research Site

Prague, , Czechia

Research Site

Prague, , Czechia

Research Site

Aarhus N, , Denmark

Research Site

Glostrup Municipality, , Denmark

Research Site

Nantes, , France

Research Site

Paris, , France

Research Site

Vénissieux, , France

Research Site

Berlin, , Germany

Research Site

Cologne, , Germany

Research Site

München, , Germany

Research Site

Bologna, , Italy

Research Site

Cagliari, , Italy

Research Site

Cinisello Balsamo (MI), , Italy

Research Site

Ferrara, , Italy

Research Site

Perugia, , Italy

Research Site

Pisa, , Italy

Research Site

Amsterdam, , Netherlands

Research Site

Rotterdam, , Netherlands

Research Site

Zwijndrecht, , Netherlands

Research Site

Christchurch, , New Zealand

Research Site

Ålesund, , Norway

Research Site

Oslo, , Norway

Research Site

Johannesburg, Gauteng, South Africa

Research Site

Midrand, Gauteng, South Africa

Research Site

Observatory, Western Cape, South Africa

Research Site

Parow, Western Cape, South Africa

Research Site

Birmingham, , United Kingdom

Research Site

Glasgow, , United Kingdom

Research Site

Newcastle upon Tyne, , United Kingdom

Countries

United States; Australia; Canada; Czechia; Denmark; France; Germany; Italy; Netherlands; New Zealand; Norway; South Africa; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 30073585 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33078867 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 27039291 (View on PubMed)

Related Links

http://www.amgentrials.com

AmgenTrials clinical trials website

Other Identifiers

2013-000935-29

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

20120332

Identifier Type: -

Identifier Source: org_study_id