For one of the most prevalent a specific symptoms of MS, fatigue, methylphenidate, modafinil, and amantadine are commonly prescribed. Substantial evidence supporting their efficacy is lacking, however. In the randomized crossover TRIUMPHANT-MS trial, none of the 3 agents was superior to placebo in improving MS-related fatigue, but they did cause more adverse events.

The goal of the TRIUMPHANT-MS trial was to compare the efficacy of twice-daily oral methylphenidate, modafinil, and amantadine against each other and placebo. Eligible patients had MS-related fatigue with a Modified Fatigue Impact Scale (MFIS) of >33. Their Expanded Disability Status Scale (EDSS) score at the time of screening was between 0.0 and 7.0. Participants were allocated to one of four treatment sequences: 1) amantadine, placebo, modafinil, methylphenidate; 2) placebo, methylphenidate, amantadine, modafinil; 3) modafinil, amantadine, methylphenidate, placebo; and 4) methylphenidate, modafinil, placebo, amantadine. Each medication was titrated over 4 weeks to the participants’ highest tolerated dose or the pre-defined highest dose. Each intervention was given up to 6 weeks, with a 2-week washout period between each treatment. The primary outcome measure was the MFIS score when the highest tolerated dose was used (in week 5). A total of 141 patients of 18 years and older were enrolled and randomized. Data from 136 participants were included in the intent-to-treat analysis of the primary outcome.

The estimated mean value of MFIS total score at baseline was 51.3. In week 5 of treatment, MFIS total score was 41.2 with amantadine, 39.0 with modafinil, 38.7 with methylphenidate, and 40.7 with placebo (P=0.20 for the overall medication effect). However, in a pre-planned post-hoc analysis, both modafinil and methylphenidate were superior to placebo in improving MFIS score (-4.1 for both interventions) in the subgroup of patients with a higher baseline daytime sleepiness (ESS) score.

In the placebo group, 30.6% of participants reported adverse events. In all 3 active intervention groups, a higher percentage of participants reported adverse events: 38.6%, 40.0%, and 39.5% while taking amantadine, modafinil, and methylphenidate, respectively. All in all, these agents should not be used indiscriminately for the treatment of MS-related fatigue.


  1. Nourbakhsh B, et al. MSVIRTUAL2020, Abstract PS13.03.