The TRIUMPHANT study found no difference between the effects of amantadine, modafinil, methylphenidate, and placebo in the Modified Fatigue Impact Scale (MFIS) in a study involving 141 patients with MS.
There was also no difference between any of the drugs and placebo in any of the preplanned subgroups which included different Expanded Disability Status Scale scores, depressive scores, use of disease-modifying therapy, or type of MS (relapsing remitting or progressive).
The research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
“These three drugs are used very commonly used for MS fatigue by neurologists, psychiatrists, and primary care doctors, but they don’t seem to be any better than placebo. They were all associated with increased side effects compared with placebo even with short-term use,” said lead investigator Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins University, Baltimore.
However, in a post hoc analysis there was an improvement in daytime sleepiness with two of the drugs – methylphenidate and modafinil. “These two agents reduced daytime sleepiness in patients with high daytime sleepiness scores at baseline, with about a 4-point difference versus placebo, which was significant. But as this was not a preplanned analysis, we have to be cautious in its interpretation,” Dr. Nourbakhsh said. “However, this finding may not be too surprising as both these drugs are licensed as stimulants for use in narcolepsy patients with excessive daytime sleepiness.”
“Our recommendations are that as amantadine was not better than placebo in any subgroup its use should be discouraged in MS fatigue,” Dr. Nourbakhsh commented. “Modafinil and methylphenidate may possibly be considered for MS patients with excessive daytime sleepiness, but this should really be confirmed in further studies.”
Fatigue is a common and debilitating symptom of MS, occurring in about 70%-80% of patients with MS. There is no approved drug treatment. However nonpharmacologic therapies have shown some success: studies of exercise and cognitive-behavioral therapy (CBT) have shown these may be effective without causing side effects, Dr. Nourbakhsh noted. “So we should be getting patients to try exercise and CBT before jumping to medication.”
Dr. Nourbakhsh said he was disappointed with the results of the study but not terribly surprised. “We use these three medications frequently in the clinic and we have not been seeing great benefits so we wondered whether they were actually effective.”
He said that the trial was adequately powered and the question has been answered. “These are valuable results – they will hopefully encourage doctors to think twice before prescribing these medications that could be harmful and have no clear benefit,” Dr. Nourbakhsh concluded.
For the randomized, double-blind, placebo-controlled, four-sequence, four-period crossover trial, 141 patients with MS and fatigue received twice-daily oral amantadine (maximum 200 mg/day), modafinil (maximum 200 mg/day), methylphenidate (maximum 20 mg/day), or placebo, each given for up to 6 weeks with a 2-week washout between each medication.
Patients had a mean baseline MFIS score of 51.3 and were randomly assigned to one of four medication administration sequences. Data from 136 participants were available for the analysis of the primary outcome (change in MFIS score), and 111 participants completed all four medication periods.
In the intent-to-treat analysis, the least-squares means of total MFIS scores at the maximally tolerated dose were as follows: 40.7 with placebo, 41.2 with amantadine, 39.0 with modafinil, and 38.7 with methylphenidate (P = .20 for the overall medication effect; P > .05 for all pairwise comparisons). “All medications and placebo reduced the MS fatigue score by 10-12 points from baseline, so there was quite a substantial placebo effect,” Dr. Nourbakhsh noted. There was no statistically significant difference in the physical and cognitive subscales of MFIS and quality of life measures between any of the study medications and placebo. All three drugs were associated with an increase in adverse effects versus placebo.
Dr. Nourbakhsh says he is hopeful that this negative study may stimulate further research into new targets and medications for MS fatigue.
His group has recently conducted a pilot study of intravenous ketamine in MS fatigue with some encouraging results, but he stressed it needs to be tested in a larger study before it can be recommended for use in clinical practice. “While an IV medication is not ideal, the effect did seem to be quite long-lived with a difference still evident at 28 days, so it could perhaps be dosed once a month, which could be feasible,” he said.
Commenting on the TRIUMPHANT study, Jeffrey Cohen, MD, of the Cleveland Clinic, said that “fatigue is a common, often disabling, symptom of MS. It is poorly understood and probably encompasses several mechanisms. There currently is no generally effective treatment for MS-related fatigue.”
“These results are not surprising and confirm previous studies,” Dr. Cohen said. “Despite no benefit from these medicines for patients as a group, they are occasionally helpful for individual patients, so they are frequently tried empirically.
“It also is important to address any factors besides MS that may be causing or contributing to fatigue, for example, sleep disruption, medication side effects, depression, other medical conditions such as anemia or hypothyroidism,” he added.
Dr. Nourbakhsh has reported receiving personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities for Jazz Pharmaceuticals.
A version of this article originally appeared on Medscape.com.