Efficacy and safety of modafinil (Provigil®) for the treatment of fatigue in multiple sclerosis:: a two centre phase 2 study

Objective: To assess the efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis (MS). Methods: Patients aged 18-65 years with a diagnosis of MS, a stable disability level less than or equal to6 on the Kurtzke extended disability status scale (EDSS), and a mean score >4 on the fatigue severity scale (FSS) were eligible for the 9 week, single blind, phase 2, two centre study. Exclusion criteria included a diagnosis of narcolepsy, sleep apnoea, or clinically significant major systemic disease and recent use of medications affecting fatigue. All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day modafinil during weeks 3-4, 400 mg/day modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators. Efficacy was evaluated by self rating scales, using the FSS, the modified fatigue impact scale (MFIS), a visual analogue scale for fatigue (VAS-F), and the Epworth sleepiness scale (ESS). Adverse events were recorded. Results: Seventy two patients (MS type: 74% relapsing-remitting; 7% primary progressive; 19% secondary progressive) received treatment. After treatment with 200 mg/day modafinil for 2 weeks, a significant improvement in fatigue versus placebo run in was demonstrated. Mean scores after treatment with 200 mg/day modafinil were: FSS, 4.7 versus 5.5 for placebo (p<0.001); MFIS, 37.7 versus 44.7 (p<0.001); and VAS-F, 5.4 versus 4.5 (p=0.003). Fatigue scores for 400 mg/day modafinil were not significantly improved versus placebo run in. Mean ESS scores were significantly improved (p<0.001) with 200 mg/day modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5). Serious adverse events were not found at either dose. The most common adverse events were headache, nausea, and aesthenia. Sixty five patients (90%) completed the study. Conclusions: These data suggest that 200 mg/day modafinil significantly improves fatigue and is well tolerated in patients with MS.