Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)
1 november 2018 bijgewerkt door: 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).
Studie Overzicht
Toestand
Voltooid
Conditie
Gedetailleerde beschrijving
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).
Studietype
Ingrijpend
Inschrijving (Werkelijk)
511
Fase
- Fase 3
Contacten en locaties
In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.
Studie Locaties
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New South Wales
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Camperdown, New South Wales, Australië, 2015
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Queensland
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Woolloongabba, Queensland, Australië, 4102
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South Australia
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Ashford, South Australia, Australië, 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, Denemarken, 8200
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Glostrup, Denemarken, 2600
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Berlin, Duitsland, 13353
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Köln, Duitsland, 50937
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München, Duitsland, 80638
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Nantes Cedex 1, Frankrijk, 44093
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Paris Cedex 13, Frankrijk, 75651
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Vénissieux, Frankrijk, 69200
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Bologna, Italië, 40138
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Cagliari, Italië, 09134
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Cinisello Balsamo (MI), Italië, 20092
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Ferrara, Italië, 44100
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Perugia, Italië, 06129
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Pisa, Italië, 56124
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Amsterdam, Nederland, 1105 AZ
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Rotterdam, Nederland, 3045 PM
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Zwijndrecht, Nederland, 3331 LZ
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Christchurch, Nieuw-Zeeland, 8011
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Oslo, Noorwegen, 0373
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Ålesund, Noorwegen, 6003
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Hradec Kralove, Tsjechië, 500 05
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Praha 2, Tsjechië, 128 08
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Praha 4, Tsjechië, 140 21
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Birmingham, Verenigd Koninkrijk, B15 2TH
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Glasgow, Verenigd Koninkrijk, G12 8TA
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Newcastle upon Tyne, Verenigd Koninkrijk, NE1 4LP
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California
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Beverly Hills, California, Verenigde Staten, 90211
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Huntington Beach, California, Verenigde Staten, 92648
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Los Angeles, California, Verenigde Staten, 90048
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San Pedro, California, Verenigde Staten, 90732
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Georgia
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Atlanta, Georgia, Verenigde Staten, 30322
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Illinois
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Sterling, Illinois, Verenigde Staten, 61081
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Kansas
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Kansas City, Kansas, Verenigde Staten, 66160
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Maryland
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Baltimore, Maryland, Verenigde Staten, 21201
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Towson, Maryland, Verenigde Staten, 21204
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Michigan
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Ann Arbor, Michigan, Verenigde Staten, 48106
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Minnesota
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Rochester, Minnesota, Verenigde Staten, 55905
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Missouri
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Saint Louis, Missouri, Verenigde Staten, 63110
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New York
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New York, New York, Verenigde Staten, 10029
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North Carolina
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Durham, North Carolina, Verenigde Staten, 27710
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Ohio
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Cleveland, Ohio, Verenigde Staten, 44195
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Pennsylvania
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York, Pennsylvania, Verenigde Staten, 17405
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South Carolina
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Charleston, South Carolina, Verenigde Staten, 29425
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Texas
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Houston, Texas, Verenigde Staten, 77030
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Gauteng
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Johannesburg, Gauteng, Zuid-Afrika, 2157
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Midrand, Gauteng, Zuid-Afrika, 1685
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Western Cape
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Observatory, Western Cape, Zuid-Afrika, 7925
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Parow, Western Cape, Zuid-Afrika, 7505
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Deelname Criteria
Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
18 jaar tot 80 jaar (Volwassen, Oudere volwassene)
Accepteert gezonde vrijwilligers
Nee
Geslachten die in aanmerking komen voor studie
Allemaal
Beschrijving
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
Studie plan
Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.
Hoe is de studie opgezet?
Ontwerpdetails
- Primair doel: Behandeling
- Toewijzing: Gerandomiseerd
- Interventioneel model: Parallelle opdracht
- Masker: Verviervoudigen
Wapens en interventies
Deelnemersgroep / Arm |
Interventie / Behandeling |
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Ander: 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
Andere namen:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Ander: 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
Andere namen:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Actieve vergelijker: 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.
Andere namen:
Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)
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Experimenteel: 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)
Andere namen:
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Experimenteel: 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)
Andere namen:
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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Tijdsspanne |
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Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Tijdsspanne: 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
Tijdsspanne: Baseline and week 24
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Baseline and week 24
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Secundaire uitkomstmaten
Uitkomstmaat |
Tijdsspanne |
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Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: 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
Tijdsspanne: Baseline and week 24
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Baseline and week 24
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Medewerkers en onderzoekers
Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.
Sponsor
Publicaties en nuttige links
De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.
Algemene publicaties
- 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.
Nuttige links
Studie record data
Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.
Bestudeer belangrijke data
Studie start (Werkelijk)
10 december 2013
Primaire voltooiing (Werkelijk)
10 november 2015
Studie voltooiing (Werkelijk)
21 november 2017
Studieregistratiedata
Eerst ingediend
8 november 2013
Eerst ingediend dat voldeed aan de QC-criteria
8 november 2013
Eerst geplaatst (Schatting)
14 november 2013
Updates van studierecords
Laatste update geplaatst (Werkelijk)
29 november 2018
Laatste update ingediend die voldeed aan QC-criteria
1 november 2018
Laatst geverifieerd
1 november 2018
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
- Metabole ziekten
- Stoornissen in het metabolisme van lipiden
- Dyslipidemie
- Hyperlipidemie
- Fysiologische effecten van medicijnen
- Moleculaire mechanismen van farmacologische werking
- Enzymremmers
- Antimetabolieten
- Immunologische factoren
- Middelen tegen cholesterol
- Hypolipidemische middelen
- Vetregulerende middelen
- Hydroxymethylglutaryl-CoA-reductaseremmers
- Atorvastatine
- Antilichamen, monoklonaal
- Evolocumab
- Ezetimibe
Andere studie-ID-nummers
- 20120332
- 2013-000935-29 (EudraCT-nummer)
Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .