Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)
1 novembre 2018 mis à jour par: 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).
Aperçu de l'étude
Statut
Complété
Les conditions
Description détaillée
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).
Type d'étude
Interventionnel
Inscription (Réel)
511
Phase
- Phase 3
Contacts et emplacements
Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.
Lieux d'étude
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Gauteng
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Johannesburg, Gauteng, Afrique du Sud, 2157
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Midrand, Gauteng, Afrique du Sud, 1685
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Western Cape
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Observatory, Western Cape, Afrique du Sud, 7925
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Parow, Western Cape, Afrique du Sud, 7505
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Berlin, Allemagne, 13353
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Köln, Allemagne, 50937
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München, Allemagne, 80638
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New South Wales
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Camperdown, New South Wales, Australie, 2015
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Queensland
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Woolloongabba, Queensland, Australie, 4102
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South Australia
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Ashford, South Australia, Australie, 5035
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Quebec, Canada, G1V 4M6
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British Columbia
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Vancouver, British Columbia, Canada, V5Z 1M9
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Ontario
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Hamilton, Ontario, Canada, L8L 2X2
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London, Ontario, Canada, N6A 4V2
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Peterborough, Ontario, Canada, K9J 0B2
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Quebec
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Montreal, Quebec, Canada, H2W 1R7
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St-Charles-Borromee, Quebec, Canada, J6E 6J2
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Aarhus N, Danemark, 8200
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Glostrup, Danemark, 2600
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Nantes Cedex 1, France, 44093
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Paris Cedex 13, France, 75651
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Vénissieux, France, 69200
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Bologna, Italie, 40138
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Cagliari, Italie, 09134
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Cinisello Balsamo (MI), Italie, 20092
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Ferrara, Italie, 44100
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Perugia, Italie, 06129
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Pisa, Italie, 56124
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Oslo, Norvège, 0373
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Ålesund, Norvège, 6003
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Christchurch, Nouvelle-Zélande, 8011
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Amsterdam, Pays-Bas, 1105 AZ
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Rotterdam, Pays-Bas, 3045 PM
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Zwijndrecht, Pays-Bas, 3331 LZ
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Birmingham, Royaume-Uni, B15 2TH
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Glasgow, Royaume-Uni, G12 8TA
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Newcastle upon Tyne, Royaume-Uni, NE1 4LP
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Hradec Kralove, Tchéquie, 500 05
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Praha 2, Tchéquie, 128 08
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Praha 4, Tchéquie, 140 21
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California
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Beverly Hills, California, États-Unis, 90211
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Huntington Beach, California, États-Unis, 92648
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Los Angeles, California, États-Unis, 90048
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San Pedro, California, États-Unis, 90732
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Georgia
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Atlanta, Georgia, États-Unis, 30322
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Illinois
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Sterling, Illinois, États-Unis, 61081
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Kansas
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Kansas City, Kansas, États-Unis, 66160
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Maryland
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Baltimore, Maryland, États-Unis, 21201
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Towson, Maryland, États-Unis, 21204
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Michigan
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Ann Arbor, Michigan, États-Unis, 48106
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Minnesota
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Rochester, Minnesota, États-Unis, 55905
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Missouri
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Saint Louis, Missouri, États-Unis, 63110
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New York
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New York, New York, États-Unis, 10029
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North Carolina
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Durham, North Carolina, États-Unis, 27710
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Ohio
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Cleveland, Ohio, États-Unis, 44195
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Pennsylvania
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York, Pennsylvania, États-Unis, 17405
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South Carolina
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Charleston, South Carolina, États-Unis, 29425
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Texas
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Houston, Texas, États-Unis, 77030
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Critères de participation
Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.
Critère d'éligibilité
Âges éligibles pour étudier
18 ans à 80 ans (Adulte, Adulte plus âgé)
Accepte les volontaires sains
Non
Sexes éligibles pour l'étude
Tout
La 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
Plan d'étude
Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Quadruple
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
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Autre: 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
Autres noms:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Autre: 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
Autres noms:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Comparateur actif: 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.
Autres noms:
Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)
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Expérimental: 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)
Autres noms:
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Expérimental: 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)
Autres noms:
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Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Délai |
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Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Délai: 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
Délai: Baseline and week 24
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Baseline and week 24
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Mesures de résultats secondaires
Mesure des résultats |
Délai |
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Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: 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
Délai: Baseline and week 24
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Baseline and week 24
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Collaborateurs et enquêteurs
C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.
Parrainer
Publications et liens utiles
La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.
Publications générales
- 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.
Liens utiles
Dates d'enregistrement des études
Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.
Dates principales de l'étude
Début de l'étude (Réel)
10 décembre 2013
Achèvement primaire (Réel)
10 novembre 2015
Achèvement de l'étude (Réel)
21 novembre 2017
Dates d'inscription aux études
Première soumission
8 novembre 2013
Première soumission répondant aux critères de contrôle qualité
8 novembre 2013
Première publication (Estimation)
14 novembre 2013
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
29 novembre 2018
Dernière mise à jour soumise répondant aux critères de contrôle qualité
1 novembre 2018
Dernière vérification
1 novembre 2018
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
- Maladies métaboliques
- Troubles du métabolisme lipidique
- Dyslipidémies
- Hyperlipidémies
- Effets physiologiques des médicaments
- Mécanismes moléculaires de l'action pharmacologique
- Inhibiteurs d'enzymes
- Antimétabolites
- Facteurs immunologiques
- Agents anticholestérolémiants
- Agents hypolipidémiants
- Agents de régulation des lipides
- Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase
- Atorvastatine
- Anticorps monoclonaux
- Évolocumab
- Ézétimibe
Autres numéros d'identification d'étude
- 20120332
- 2013-000935-29 (Numéro EudraCT)
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .