BACKGROUND: Heterozygous @entity4310 is characterised by low cellular uptake of LDL @entity165 , increased plasma LDL @entity165 concentrations, and premature @entity65 . Despite intensive statin therapy, with or without ezetimibe, many @entity1 are unable to achieve recommended target levels of LDL @entity165 . We investigated the effect of @entity756 inhibition with evolocumab (AMG 145) on LDL @entity165 in @entity1 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 @entity1 (18-80 years of age), who met clinical criteria for heterozygous @entity4310 and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL @entity165 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 @entity165 concentration at screening (higher or lower than 4  1 mmol/L) and by baseline @entity3709 use (yes/no). @entity1 , 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 @entity165 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 @entity1 , 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 @entity1 received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL @entity165 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 @entity1 than in the placebo groups were @entity11266 (in 19 @entity1 [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten @entity1 [5%] vs 1 [1%]). INTERPRETATION: In @entity1 with heterozygous @entity4310 , evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL @entity165 compared with placebo. FUNDING: Amgen Inc.

XXXX inhibition with evolocumab (AMG 145) in heterozygous @entity4310 (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.

@entity1 :: ('9606', 'Species') :: ['Patients', 'patients'] @entity11266 :: ('MESH:D009304', 'Disease') :: ['nasopharyngitis'] @entity756 :: ('255738', 'Gene') :: ['PCSK9'] @entity3709 :: ('MESH:C108606', 'Chemical') :: ['ezetimibe'] @entity4310 :: ('MESH:D009386', 'Disease') :: ['familial hypercholesterolaemia'] @entity65 :: ('MESH:D002318', 'Disease') :: ['cardiovascular disease'] @entity165 :: ('MESH:D002784', 'Chemical') :: ['cholesterol']
@entity756 :: (255738,Gene) :: ['PCSK9']
