Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3 (GAUSS-3)
1 november 2018 uppdaterad av: 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).
Studieöversikt
Status
Avslutad
Betingelser
Detaljerad beskrivning
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).
Studietyp
Interventionell
Inskrivning (Faktisk)
511
Fas
- Fas 3
Kontakter och platser
Det här avsnittet innehåller kontaktuppgifter för dem som genomför studien och information om var denna studie genomförs.
Studieorter
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New South Wales
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Camperdown, New South Wales, Australien, 2015
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Queensland
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Woolloongabba, Queensland, Australien, 4102
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South Australia
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Ashford, South Australia, Australien, 5035
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Aarhus N, Danmark, 8200
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Glostrup, Danmark, 2600
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Nantes Cedex 1, Frankrike, 44093
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Paris Cedex 13, Frankrike, 75651
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Vénissieux, Frankrike, 69200
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California
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Beverly Hills, California, Förenta staterna, 90211
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Huntington Beach, California, Förenta staterna, 92648
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Los Angeles, California, Förenta staterna, 90048
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San Pedro, California, Förenta staterna, 90732
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Georgia
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Atlanta, Georgia, Förenta staterna, 30322
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Illinois
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Sterling, Illinois, Förenta staterna, 61081
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Kansas
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Kansas City, Kansas, Förenta staterna, 66160
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Maryland
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Baltimore, Maryland, Förenta staterna, 21201
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Towson, Maryland, Förenta staterna, 21204
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Michigan
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Ann Arbor, Michigan, Förenta staterna, 48106
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Minnesota
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Rochester, Minnesota, Förenta staterna, 55905
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Missouri
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Saint Louis, Missouri, Förenta staterna, 63110
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New York
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New York, New York, Förenta staterna, 10029
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North Carolina
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Durham, North Carolina, Förenta staterna, 27710
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Ohio
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Cleveland, Ohio, Förenta staterna, 44195
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Pennsylvania
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York, Pennsylvania, Förenta staterna, 17405
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South Carolina
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Charleston, South Carolina, Förenta staterna, 29425
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Texas
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Houston, Texas, Förenta staterna, 77030
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Bologna, Italien, 40138
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Cagliari, Italien, 09134
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Cinisello Balsamo (MI), Italien, 20092
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Ferrara, Italien, 44100
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Perugia, Italien, 06129
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Pisa, Italien, 56124
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Quebec, Kanada, G1V 4M6
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British Columbia
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Vancouver, British Columbia, Kanada, V5Z 1M9
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Ontario
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Hamilton, Ontario, Kanada, L8L 2X2
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London, Ontario, Kanada, N6A 4V2
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Peterborough, Ontario, Kanada, K9J 0B2
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Quebec
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Montreal, Quebec, Kanada, H2W 1R7
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St-Charles-Borromee, Quebec, Kanada, J6E 6J2
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Amsterdam, Nederländerna, 1105 AZ
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Rotterdam, Nederländerna, 3045 PM
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Zwijndrecht, Nederländerna, 3331 LZ
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Oslo, Norge, 0373
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Ålesund, Norge, 6003
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Christchurch, Nya Zeeland, 8011
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Birmingham, Storbritannien, B15 2TH
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Glasgow, Storbritannien, G12 8TA
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Newcastle upon Tyne, Storbritannien, NE1 4LP
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Gauteng
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Johannesburg, Gauteng, Sydafrika, 2157
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Midrand, Gauteng, Sydafrika, 1685
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Western Cape
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Observatory, Western Cape, Sydafrika, 7925
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Parow, Western Cape, Sydafrika, 7505
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Hradec Kralove, Tjeckien, 500 05
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Praha 2, Tjeckien, 128 08
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Praha 4, Tjeckien, 140 21
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Berlin, Tyskland, 13353
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Köln, Tyskland, 50937
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München, Tyskland, 80638
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Deltagandekriterier
Forskare letar efter personer som passar en viss beskrivning, så kallade behörighetskriterier. Några exempel på dessa kriterier är en persons allmänna hälsotillstånd eller tidigare behandlingar.
Urvalskriterier
Åldrar som är berättigade till studier
18 år till 80 år (Vuxen, Äldre vuxen)
Tar emot friska volontärer
Nej
Kön som är behöriga för studier
Allt
Beskrivning
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
Studieplan
Det här avsnittet ger detaljer om studieplanen, inklusive hur studien är utformad och vad studien mäter.
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Behandling
- Tilldelning: Randomiserad
- Interventionsmodell: Parallellt uppdrag
- Maskning: Fyrdubbla
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
|---|---|
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Övrig: 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
Andra namn:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Övrig: 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
Andra namn:
Placebo matching to atorvastatin supplied as over-encapsulated tablets
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Aktiv komparator: 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.
Andra namn:
Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s)
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Experimentell: 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)
Andra namn:
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Experimentell: 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)
Andra namn:
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Vad mäter studien?
Primära resultatmått
Resultatmått |
Tidsram |
|---|---|
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Percent Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Tidsram: 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
Tidsram: Baseline and week 24
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Baseline and week 24
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Sekundära resultatmått
Resultatmått |
Tidsram |
|---|---|
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Change From Baseline in LDL-C at the Mean of Weeks 22 and 24
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: 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
Tidsram: Baseline and week 24
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Baseline and week 24
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Samarbetspartners och utredare
Det är här du hittar personer och organisationer som är involverade i denna studie.
Sponsor
Publikationer och användbara länkar
Den som ansvarar för att lägga in information om studien tillhandahåller frivilligt dessa publikationer. Dessa kan handla om allt som har med studien att göra.
Allmänna publikationer
- 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.
Användbara länkar
Studieavstämningsdatum
Dessa datum spårar framstegen för inlämningar av studieposter och sammanfattande resultat till ClinicalTrials.gov. Studieposter och rapporterade resultat granskas av National Library of Medicine (NLM) för att säkerställa att de uppfyller specifika kvalitetskontrollstandarder innan de publiceras på den offentliga webbplatsen.
Studera stora datum
Studiestart (Faktisk)
10 december 2013
Primärt slutförande (Faktisk)
10 november 2015
Avslutad studie (Faktisk)
21 november 2017
Studieregistreringsdatum
Först inskickad
8 november 2013
Först inskickad som uppfyllde QC-kriterierna
8 november 2013
Första postat (Uppskatta)
14 november 2013
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
29 november 2018
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
1 november 2018
Senast verifierad
1 november 2018
Mer information
Termer relaterade till denna studie
Ytterligare relevanta MeSH-villkor
- Metaboliska sjukdomar
- Lipidmetabolismstörningar
- Dyslipidemier
- Hyperlipidemier
- Läkemedels fysiologiska effekter
- Molekylära mekanismer för farmakologisk verkan
- Enzyminhibitorer
- Antimetaboliter
- Immunologiska faktorer
- Antikolesteremiska medel
- Hypolipidemiska medel
- Lipidreglerande medel
- Hydroximetylglutaryl-CoA-reduktashämmare
- Atorvastatin
- Antikroppar, monoklonala
- Evolocumab
- Ezetimib
Andra studie-ID-nummer
- 20120332
- 2013-000935-29 (EudraCT-nummer)
Denna information hämtades direkt från webbplatsen clinicaltrials.gov utan några ändringar. Om du har några önskemål om att ändra, ta bort eller uppdatera dina studieuppgifter, vänligen kontakta register@clinicaltrials.gov. Så snart en ändring har implementerats på clinicaltrials.gov, kommer denna att uppdateras automatiskt även på vår webbplats .