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Background: Fatigue is a very common,disabling symptom in cancer,and particularly severe in lung cancer.Modafinil is a novel central nervous system stimulant,which,along with methylphenidate,is cautiously recommended by the 2013 National Comprehensive Cancer Network Guidelines for fatigue.In this phase Ⅳ randomized placebo-controlled trial,we assessed the efficacy of modafinil for managing fatigue in lung cancer.Methods: Adults with locally advanced or metastatic non small cell lung cancer(stages Ⅲ and Ⅳ),ECOG performance status(PS)0-2 and suffering from fatigue(score 5/10 or greater)were randomised 1:1 to modafinil or matched placebo,100mg daily for 14 days and 200mg daily for a further 14 days.The primary outcome measure was change in the Functional Assessment of Chronic Illness Therapy fatigue subscale(FACIT-fatigue)at 28 days.The trial was powered to detect a 5-point difference with 80%power and 5%significance allowing for 25%attrition.Dose-response,patient satisfaction and safety were also evaluated.Results: 208 patients were recruited from 24 UK centres.Baseline characteristics were well-balanced.160 patients completed both baseline and 28 day questionnaires and were included in the modified-ITT analysis.FACIT-fatigue mean change from baseline was modafinil=5.28,placebo=5.11,difference=0.17,(95%CI-4.17,3.82).Adjustment for baseline fatigue and PS had no impact on outcome.No dose response was seen; the majority of improvement on all scales was seen at 14 days and sustained to 28 days.47%of the modafinil group and 23%of the placebo group stated the study treatment was not helpful(p=0.132).Adverse events were equal.Conclusions: Both modafinil and placebo led to a clinically significant 5-point improvement in FACIT-fatigue score,but there was no significant difference between the two groups.This well-powered study suggests that there is a large placebo effect and NCCN guidelines should be reviewed.