Highlights from

MS Virtual 2020

8th Joint ACTRIMS and ECTRIMS Meeting

Virtual 11 - 13 September 2020

Amantadine, modafinil, and methylphenidate for MS-related fatigue

For one of the most prevalent aspecific symptoms of MS, fatigue, methylphenidate, modafinil, and amantadine are commonly prescribed. Substantial evidence supporting their efficacy is lacking, however. In the randomised 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 randomised. 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.

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