Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)
1 de novembro de 2018 atualizado por: Amgen
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).
Visão geral do estudo
Status
Concluído
Condições
Descrição detalhada
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).
Tipo de estudo
Intervencional
Inscrição (Real)
511
Estágio
- Fase 3
Contactos e Locais
Esta seção fornece os detalhes de contato para aqueles que conduzem o estudo e informações sobre onde este estudo está sendo realizado.
Locais de estudo
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Berlin, Alemanha, 13353
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Köln, Alemanha, 50937
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München, Alemanha, 80638
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New South Wales
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Camperdown, New South Wales, Austrália, 2015
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Queensland
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Woolloongabba, Queensland, Austrália, 4102
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South Australia
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Ashford, South Australia, Austrália, 5035
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Quebec, Canadá, G1V 4M6
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British Columbia
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Vancouver, British Columbia, Canadá, V5Z 1M9
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Ontario
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Hamilton, Ontario, Canadá, L8L 2X2
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London, Ontario, Canadá, N6A 4V2
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Peterborough, Ontario, Canadá, K9J 0B2
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Quebec
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Montreal, Quebec, Canadá, H2W 1R7
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St-Charles-Borromee, Quebec, Canadá, J6E 6J2
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Aarhus N, Dinamarca, 8200
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Glostrup, Dinamarca, 2600
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California
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Beverly Hills, California, Estados Unidos, 90211
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Huntington Beach, California, Estados Unidos, 92648
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Los Angeles, California, Estados Unidos, 90048
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San Pedro, California, Estados Unidos, 90732
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Georgia
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Atlanta, Georgia, Estados Unidos, 30322
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Illinois
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Sterling, Illinois, Estados Unidos, 61081
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Kansas
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Kansas City, Kansas, Estados Unidos, 66160
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Maryland
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Baltimore, Maryland, Estados Unidos, 21201
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Towson, Maryland, Estados Unidos, 21204
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Michigan
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Ann Arbor, Michigan, Estados Unidos, 48106
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Minnesota
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Rochester, Minnesota, Estados Unidos, 55905
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Missouri
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Saint Louis, Missouri, Estados Unidos, 63110
- Research Site
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New York
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New York, New York, Estados Unidos, 10029
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North Carolina
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Durham, North Carolina, Estados Unidos, 27710
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Ohio
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Cleveland, Ohio, Estados Unidos, 44195
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Pennsylvania
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York, Pennsylvania, Estados Unidos, 17405
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South Carolina
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Charleston, South Carolina, Estados Unidos, 29425
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Texas
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Houston, Texas, Estados Unidos, 77030
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Nantes Cedex 1, França, 44093
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Paris Cedex 13, França, 75651
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Vénissieux, França, 69200
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Amsterdam, Holanda, 1105 AZ
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Rotterdam, Holanda, 3045 PM
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Zwijndrecht, Holanda, 3331 LZ
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Bologna, Itália, 40138
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Cagliari, Itália, 09134
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Cinisello Balsamo (MI), Itália, 20092
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Ferrara, Itália, 44100
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Perugia, Itália, 06129
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Pisa, Itália, 56124
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Oslo, Noruega, 0373
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Ålesund, Noruega, 6003
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Christchurch, Nova Zelândia, 8011
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Birmingham, Reino Unido, B15 2TH
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Glasgow, Reino Unido, G12 8TA
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Newcastle upon Tyne, Reino Unido, NE1 4LP
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Hradec Kralove, Tcheca, 500 05
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Praha 2, Tcheca, 128 08
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Praha 4, Tcheca, 140 21
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Gauteng
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Johannesburg, Gauteng, África do Sul, 2157
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Midrand, Gauteng, África do Sul, 1685
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Western Cape
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Observatory, Western Cape, África do Sul, 7925
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Parow, Western Cape, África do Sul, 7505
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Critérios de participação
Os pesquisadores procuram pessoas que se encaixem em uma determinada descrição, chamada de critérios de elegibilidade. Alguns exemplos desses critérios são a condição geral de saúde de uma pessoa ou tratamentos anteriores.
Critérios de elegibilidade
Idades elegíveis para estudo
18 anos a 80 anos (Adulto, Adulto mais velho)
Aceita Voluntários Saudáveis
Não
Gêneros Elegíveis para o Estudo
Tudo
Descrição
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
Plano de estudo
Esta seção fornece detalhes do plano de estudo, incluindo como o estudo é projetado e o que o estudo está medindo.
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
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Outro: 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.
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Atorvastatin was supplied as over-encapsulated 20 mg tablets
Outros nomes:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Outro: 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.
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Atorvastatin was supplied as over-encapsulated 20 mg tablets
Outros nomes:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Comparador Ativo: 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.
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Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.
Outros nomes:
Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)
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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.
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Placebo matching to Ezetimibe supplied as over-encapsulated tablets.
Evolocumab supplied as single-use prefilled autoinjector/pen(s)
Outros nomes:
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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.
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Evolocumab supplied as single-use prefilled autoinjector/pen(s)
Outros nomes:
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Prazo |
|---|---|
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Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in LDL-C at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Medidas de resultados secundários
Medida de resultado |
Prazo |
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Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Prazo: Baselie and weeks 22 and 24
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Baselie and weeks 22 and 24
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Change From Baseline in LDL-C at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percentage of Participants Who Achieved a Mean LDL-C at Weeks 22 and 24 of Less Than 70 mg/dL
Prazo: Weeks 22 and 24
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Weeks 22 and 24
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Percentage of Participants Who Achieved LDL-C at Week 24 of Less Than 70 mg/dL
Prazo: Week 24
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Week 24
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Percent Change From Baseline in Total Cholesterol at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in Total Cholesterol at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Non-high-density Lipoprotein Cholesterol (Non-HDL-C) at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in Non-HDL-C at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Apolipoprotein B at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in Apolipoprotein B at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in Total Cholesterol/HDL-C Ratio at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at the Mean of Weeks 22 and 24
Prazo: Baseline and Weeks 22 and 24
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Baseline and Weeks 22 and 24
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Percent Change From Baseline in Apolipoprotein B/Apolipoprotein A1 Ratio at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Lipoprotein(a) at the Mean of Weeks 22 and 24
Prazo: Baseline and Weeks 22 and 24
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Baseline and Weeks 22 and 24
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Percent Change From Baseline in Lipoprotein(a) at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Triglycerides at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in Triglycerides at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in High-density Lipoprotein Cholesterol (HDL-C) at Week 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in HDL-C at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Percent Change From Baseline in Very Low-density Lipoprotein Cholesterol (VLDL-C) at the Mean of Weeks 22 and 24
Prazo: Baseline and weeks 22 and 24
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Baseline and weeks 22 and 24
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Percent Change From Baseline in VLDL-C at Week 24
Prazo: Baseline and week 24
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Baseline and week 24
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Colaboradores e Investigadores
É aqui que você encontrará pessoas e organizações envolvidas com este estudo.
Patrocinador
Publicações e links úteis
A pessoa responsável por inserir informações sobre o estudo fornece voluntariamente essas publicações. Estes podem ser sobre qualquer coisa relacionada ao estudo.
Publicações Gerais
- 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.
Links úteis
Datas de registro do estudo
Essas datas acompanham o progresso do registro do estudo e os envios de resumo dos resultados para ClinicalTrials.gov. Os registros do estudo e os resultados relatados são revisados pela National Library of Medicine (NLM) para garantir que atendam aos padrões específicos de controle de qualidade antes de serem publicados no site público.
Datas Principais do Estudo
Início do estudo (Real)
10 de dezembro de 2013
Conclusão Primária (Real)
10 de novembro de 2015
Conclusão do estudo (Real)
21 de novembro de 2017
Datas de inscrição no estudo
Enviado pela primeira vez
8 de novembro de 2013
Enviado pela primeira vez que atendeu aos critérios de CQ
8 de novembro de 2013
Primeira postagem (Estimativa)
14 de novembro de 2013
Atualizações de registro de estudo
Última Atualização Postada (Real)
29 de novembro de 2018
Última atualização enviada que atendeu aos critérios de controle de qualidade
1 de novembro de 2018
Última verificação
1 de novembro de 2018
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças Metabólicas
- Distúrbios do metabolismo lipídico
- Dislipidemias
- Hiperlipidemias
- Efeitos Fisiológicos das Drogas
- Mecanismos Moleculares de Ação Farmacológica
- Inibidores Enzimáticos
- Antimetabólitos
- Fatores imunológicos
- Agentes Anticolesterêmicos
- Agentes Hipolipidêmicos
- Agentes Reguladores Lipídicos
- Inibidores da hidroximetilglutaril-CoA redutase
- Atorvastatina
- Anticorpos Monoclonais
- Evolocumabe
- Ezetimiba
Outros números de identificação do estudo
- 20120332
- 2013-000935-29 (Número EudraCT)
Essas informações foram obtidas diretamente do site clinicaltrials.gov sem nenhuma alteração. Se você tiver alguma solicitação para alterar, remover ou atualizar os detalhes do seu estudo, entre em contato com register@clinicaltrials.gov. Assim que uma alteração for implementada em clinicaltrials.gov, ela também será atualizada automaticamente em nosso site .