HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis

Objective: To reassess the effect of modafinil, a wakefulness-promoting artificial psychostimulant, on fatigue and neuropsychological measures in patients with multiple sclerosis. Methods: Multiple sclerosis (MS) patients with a baseline score of >= 4 on the Fatigue Severity Scale (FSS) and an Expanded Disability Status Scale score <7 were eligible for the 8-week randomized, double-blind, placebo-controlled study. Modafinil was dosed up to 200 mg/day within 1 week. Assessments were performed at baseline and after 4 and 8 weeks. The primary outcome parameter was the mean change of the FSS mean score. Secondary outcome variables were other questionnaires covering fatigue, daytime sleepiness and sleep quality. Cognitive impairment was assessed by the oral version of the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT). Results: The study included 121 MS patients. Dropout rate was 9%. Both treatment groups showed improvements through time. While mean FSS at 8 weeks showed a trend difference between groups in the intention-to-treat analysis, the primary endpoint was not met. Assessment of cognitive impairment by SDMT and PASAT showed contradictory results. All other secondary endpoints were not met. There was no major safety concern. Conclusions: In general, the study does not support modafinil as an effective treatment for MS fatigue. However, the study shows the need for new study designs and endpoints in MS fatigue studies.