Clinical trial NCT01984424: Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hyperlipidemia
Keywords: High Cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2013-11-14
Enrollment: 511
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in LDL-C at Week 24
timeFrame: Baseline and week 24
Secondary outcomes:
measure: Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
timeFrame: Baselie and weeks 22 and 24
measure: Change From Baseline in LDL-C at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL
timeFrame: Weeks 22 and 24
measure: Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL
timeFrame: Week 24
measure: Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in Total Cholesterol at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in Non-HDL-C at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in Apolipoprotein B at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24
timeFrame: Baseline and Weeks 22 and 24
measure: Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24
timeFrame: Baseline and Weeks 22 and 24
measure: Percent Change From Baseline in Lipoprotein(a) at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in Triglycerides at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in HDL-C at Week 24
timeFrame: Baseline and week 24
measure: Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24
timeFrame: Baseline and weeks 22 and 24
measure: Percent Change From Baseline in VLDL-C at Week 24
timeFrame: Baseline and week 24
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Research Site
state: California
city: Huntington Beach
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: San Pedro
country: United States
facility: Research Site
state: California
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Sterling
country: United States
facility: Research Site
state: Illinois
city: Kansas City
country: United States
facility: Research Site
state: Kansas
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Towson
country: United States
facility: Research Site
state: Maryland
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Rochester
country: United States
facility: Research Site
state: Minnesota
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: New York
country: United States
facility: Research Site
state: New York
city: Durham
country: United States
facility: Research Site
state: North Carolina
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: York
country: United States
facility: Research Site
state: Pennsylvania
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Houston
country: United States
facility: Research Site
state: Texas
city: Camperdown
country: Australia
facility: Research Site
state: New South Wales
city: Woolloongabba
country: Australia
facility: Research Site
state: Queensland
city: Ashford
country: Australia
facility: Research Site
state: South Australia
city: Vancouver
country: Canada
facility: Research Site
state: British Columbia
city: Hamilton
country: Canada
facility: Research Site
state: Ontario
city: London
country: Canada
facility: Research Site
state: Ontario
city: Peterborough
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: St-Charles-Borromee
country: Canada
facility: Research Site
state: Quebec
city: Quebec
country: Canada
facility: Research Site
city: Hradec Kralove
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 4
country: Czechia
facility: Research Site
city: Aarhus N
country: Denmark
facility: Research Site
city: Glostrup
country: Denmark
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Paris Cedex 13
country: France
facility: Research Site
city: Vénissieux
country: France
facility: Research Site
city: Berlin
country: Germany
facility: Research Site
city: Köln
country: Germany
facility: Research Site
city: München
country: Germany
facility: Research Site
city: Bologna
country: Italy
facility: Research Site
city: Cagliari
country: Italy
facility: Research Site
city: Cinisello Balsamo (MI)
country: Italy
facility: Research Site
city: Ferrara
country: Italy
facility: Research Site
city: Perugia
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Amsterdam
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Zwijndrecht
country: Netherlands
facility: Research Site
city: Christchurch
country: New Zealand
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Ålesund
country: Norway
facility: Research Site
city: Johannesburg
country: South Africa
facility: Research Site
state: Gauteng
city: Midrand
country: South Africa
facility: Research Site
state: Gauteng
city: Observatory
country: South Africa
facility: Research Site
state: Western Cape
city: Parow
country: South Africa
facility: Research Site
state: Western Cape
city: Birmingham
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.