Patient-Reported Outcomes of MS Fatigue Understudied in Drug Development Trials

Most trials that reported on MS-related fatigue measured its change from baseline and whether that change was statistically significant.

Despite the known burden fatigue has on multiple sclerosis (MS), a Systematic Literature Review (SLR) of trials evaluating disease-modifying therapies (DMTs) for these patients showed a low priority to patient-reported outcomes (PRO) specific to understanding the impact these medications may have on fatigue. These findings, presented at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, February 24-26, in West Palm Beach, Florida, highlight the need for future research to include these PROs, considering their effect on daily living.1

"What we see in clinical trials are relapses in the primary end points, imaging, and disability assessments because these are clinical assessments and measures that are objective,” senior author Maria Ait-Tihyaty, PhD, Global Medical Affairs Leader, Janssen, told NeurologyLive®. “Symptoms like fatigue, depression, and cognition are of importance for patients and their neurologists and they are complimenting the data regarding relapses, lesion load, and disability."

Ait-Tihyaty and her colleagues searched databases from 2000 to 2021 that included only trials where MS fatigue was a study outcome. In total, 739 abstracts and 96 clinical trials were manually screened, resulting in 73 articles for full text screening and 48 identified studies that were thus used in the analysis.

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Of those 48 studies, 20.8% (n = 10) were randomized controlled rials that viewed MS fatigue as a secondary outcome. Four of the studies identified were phase 3 studies, and 2 were direct comparison studies. Fatigue Scale for Motor and Cognitive Functions, Fatigue Impact Scale (FIS), Modified FIS, Fatigue Severity Scale, and Fatigue Symptoms and Impacts Questionnaire – Relapsing Multiple Sclerosis (FSIQ-RMS), were among the PRO instruments found in these studies.

In addition to using the previously mentioned instruments, the remaining 38 studies also used Visual Analogue Scale for Fatigue, the Fatigue Descriptive Scale, and the Wurzburger Fatigue Inventory for MS. All these studies were open-label, longitudinal, and nonrandomized in design. Overall, the studies had a median follow-up of 12 months (range, 1-36) in time from baseline to PRO measurement.

"MS-associated fatigue is a complex symptom. We need to put research in motion to better understand its pathophysiology and reasons for why we see fatigue in patients with MS. Just to see the whole hollistic aspect, from relapses to lesions, to fatigue and depression. All that would be a good idea," Ait-Tihyaty added.

The study authors noted that most studies focused on MS fatigue in terms of its change from baseline and whether the change was statistically significant, although 5 studies did report on the clinical meaningfulness of their results. Today, fatigue remains one of the most debilitating symptoms for patients with MS. Analyses from 2 studies presented at the ACTRIMS Forum 2021 showed that fatigue can significantly influence patient’s daily functioning and ability to work productively.2

Using a score range from 0 to 100 (higher score equaling greater severity), fatigue was rated as severe, indicated by a mean score of 57.3 for the FSIQ-RMS symptom domain. The 3 impact sub-domain scores were 42.3, 43.4, and 50.1, which accounted for physical, cognitive/emotional, and coping, respectively. This was the first of the analyses, which included 300 participants with relapsing MS who answered questionnaires on disease history, disease status, sleep, social and emotional functioning, and the FSIQ-RMS, each of which were administered daily for 7 days.

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1. Le HH, Stock S, Ait-Tihyaty M. A systematic literature review of the measurement of patient-reported fatigue in studies of disease modifying therapies for multiple sclerosis. Presented at: ACTRIMS Forum 2022; West Palm Beach, Florida. Abstract P387.
2. Azoulai M, Levy-Heidmann T, Morisseau, et al. Measuring the symptoms and impacts of fatigue in adults with relapsing multiple sclerosis using a novel disease specific scale: a real-world study in US population. Presented at ACTRIMS Forum 2021; February 25–27, 2021. Poster P206