Universität zu Köln

Raal, Frederick J., Stein, Evan A., Dufour, Robert, Turner, Traci, Civeira, Fernando, Burgess, Lesley, Langslet, Gisle, Scott, Russell ORCID: 0000-0002-2107-6480, Olsson, Anders G., Sullivan, David, Hovingh, G. Kees, Cariou, Bertrand ORCID: 0000-0002-1580-8040, Gouni-Berthold, Ioanna, Somaratne, Ransi, Bridges, Ian, Scott, Rob, Wasserman, Scott M. and Gaudet, Daniel (2015). PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet, 385 (9965). S. 331 - 341. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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Abstract

Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19,2013.331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2.6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4.1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. Findings Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59.2% reduction [95% CI 53.4-65.1], monthly dose: 61.3% reduction [53.6-69.0]; both p<0.0001) and at the mean of weeks 10 and 12 (60.2% reduction [95% CI 54.5-65.8] and 65.6% reduction [59.8-71.3]; both p<0.0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). Interpretation In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Raal, Frederick J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stein, Evan A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dufour, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Turner, Traci UNSPECIFIED UNSPECIFIED UNSPECIFIED Civeira, Fernando UNSPECIFIED UNSPECIFIED UNSPECIFIED Burgess, Lesley UNSPECIFIED UNSPECIFIED UNSPECIFIED Langslet, Gisle UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Russell UNSPECIFIED orcid.org/0000-0002-2107-6480 UNSPECIFIED Olsson, Anders G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sullivan, David UNSPECIFIED UNSPECIFIED UNSPECIFIED Hovingh, G. Kees UNSPECIFIED UNSPECIFIED UNSPECIFIED Cariou, Bertrand UNSPECIFIED orcid.org/0000-0002-1580-8040 UNSPECIFIED Gouni-Berthold, Ioanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Somaratne, Ransi UNSPECIFIED UNSPECIFIED UNSPECIFIED Bridges, Ian UNSPECIFIED UNSPECIFIED UNSPECIFIED Scott, Rob UNSPECIFIED UNSPECIFIED UNSPECIFIED Wasserman, Scott M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaudet, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-414366
DOI:	10.1016/S0140-6736(14)61399-4
Journal or Publication Title:	Lancet
Volume:	385
Number:	9965
Page Range:	S. 331 - 341
Date:	2015
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-547X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DENSITY-LIPOPROTEIN CHOLESTEROL; SUBTILISIN/KEXIN TYPE 9; MONOCLONAL-ANTIBODY; RECEPTOR GENE; LDL-C; EFFICACY; REDUCTION; GUIDANCE; DISEASE; UPDATE Multiple languages Medicine, General & Internal Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41436