Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)
1 de noviembre de 2018 actualizado 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).
Descripción general del estudio
Estado
Terminado
Condiciones
Descripción detallada
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 estudio
Intervencionista
Inscripción (Actual)
511
Fase
- Fase 3
Contactos y Ubicaciones
Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.
Ubicaciones de estudio
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Berlin, Alemania, 13353
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Köln, Alemania, 50937
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München, Alemania, 80638
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New South Wales
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Camperdown, New South Wales, Australia, 2015
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Queensland
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Woolloongabba, Queensland, Australia, 4102
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South Australia
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Ashford, South Australia, Australia, 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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Hradec Kralove, Chequia, 500 05
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Praha 2, Chequia, 128 08
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Praha 4, Chequia, 140 21
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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
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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, Francia, 44093
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Paris Cedex 13, Francia, 75651
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Vénissieux, Francia, 69200
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Bologna, Italia, 40138
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Cagliari, Italia, 09134
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Cinisello Balsamo (MI), Italia, 20092
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Ferrara, Italia, 44100
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Perugia, Italia, 06129
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Pisa, Italia, 56124
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Oslo, Noruega, 0373
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Ålesund, Noruega, 6003
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Christchurch, Nueva Zelanda, 8011
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Amsterdam, Países Bajos, 1105 AZ
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Rotterdam, Países Bajos, 3045 PM
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Zwijndrecht, Países Bajos, 3331 LZ
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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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Gauteng
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Johannesburg, Gauteng, Sudáfrica, 2157
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Midrand, Gauteng, Sudáfrica, 1685
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Western Cape
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Observatory, Western Cape, Sudáfrica, 7925
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Parow, Western Cape, Sudáfrica, 7505
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Criterios de participación
Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.
Criterio de elegibilidad
Edades elegibles para estudiar
18 años a 80 años (Adulto, Adulto Mayor)
Acepta Voluntarios Saludables
No
Géneros elegibles para el estudio
Todos
Descripción
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
Plan de estudios
Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Cuadruplicar
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Otro: 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
Otros nombres:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Otro: 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
Otros nombres:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Comparador activo: 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.
Otros nombres:
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)
Otros nombres:
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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)
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Periodo de tiempo |
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Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Periodo de tiempo: 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
Periodo de tiempo: Baseline and week 24
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Baseline and week 24
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Medidas de resultado secundarias
Medida de resultado |
Periodo de tiempo |
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Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: 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
Periodo de tiempo: Baseline and week 24
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Baseline and week 24
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Colaboradores e Investigadores
Aquí es donde encontrará personas y organizaciones involucradas en este estudio.
Patrocinador
Publicaciones y enlaces útiles
La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.
Publicaciones Generales
- 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.
Enlaces Útiles
Fechas de registro del estudio
Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.
Fechas importantes del estudio
Inicio del estudio (Actual)
10 de diciembre de 2013
Finalización primaria (Actual)
10 de noviembre de 2015
Finalización del estudio (Actual)
21 de noviembre de 2017
Fechas de registro del estudio
Enviado por primera vez
8 de noviembre de 2013
Primero enviado que cumplió con los criterios de control de calidad
8 de noviembre de 2013
Publicado por primera vez (Estimar)
14 de noviembre de 2013
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
29 de noviembre de 2018
Última actualización enviada que cumplió con los criterios de control de calidad
1 de noviembre de 2018
Última verificación
1 de noviembre de 2018
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Enfermedades metabólicas
- Trastornos del metabolismo de los lípidos
- Dislipidemias
- Hiperlipidemias
- Efectos fisiológicos de las drogas
- Mecanismos moleculares de acción farmacológica
- Inhibidores de enzimas
- Antimetabolitos
- Factores inmunológicos
- Agentes Anticolesterolémicos
- Agentes hipolipidémicos
- Agentes reguladores de lípidos
- Inhibidores de la hidroximetilglutaril-CoA reductasa
- Atorvastatina
- Anticuerpos Monoclonales
- Evolocumab
- Ezetimiba
Otros números de identificación del estudio
- 20120332
- 2013-000935-29 (Número EudraCT)
Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .