Impact of Fatigue Overlooked in Disease-Modifying Therapy Trials for Multiple Sclerosis


A recent systematic review identified that only 5% of disease-modifying therapy trials for patients with multiple sclerosis assessed fatigue as an outcome, with only 28% among 7 trials showing statistically significant results in the measurement.

Samantha Cruz Rivera, PhD, MSc, a research fellow at the University of Birmingham, UK,

Samantha Cruz Rivera, PhD, MSc

A newly published systematic review in Multiple Sclerosis and Related Disorders revealed limited trial-based evidence on the impact of disease-modifying therapies (DMTs) on fatigue in patients with multiple sclerosis (MS), meaning fatigue assessment was underrepresented and patient-reported outcomes (PROs) data were suboptimal. These findings suggest the importance of considering the impact of the different DMTs on fatigue and conducting randomized controlled trials (RCTs) that include fatigue as an outcome to support the MS community.1

Investigators identified 130 RCTs of DMTs of which 7 (5%) assessed fatigue as an outcome. Among the 7 trials, only 2 (28%) had an assessment of fatigue as an outcome and had fatigue as an adverse event as reported by the clinician. In 1 of the trials, OPTIMUM (NCT02425644), ponesimod 20 mg had a significantly better stabilization of fatigue than teriflunomide 14 mg.2 In contrast, in the other trial, TENERE (NCT00883337), teriflunomide 7 mg significantly improved fatigue results among patients with MS compared with interferon beta-1a.3

“It is important to highlight that both trials presented concerning levels of PRO missing data, thus, careful consideration should be given when interpreting the PRO results. Furthermore, the interpretation of the PRO data was limited because of the lack of discussion around the clinically meaningfulness of the PRO data,” lead author Samantha Cruz Rivera, PhD, MSc, a research fellow at the University of Birmingham, UK, and colleagues wrote.1 “Furthermore, it was not possible to compare the changes in fatigue as both trials used different PRO-measures (PROMs). Standardizing the use of PROMs to measure fatigue would help to facilitate comparison of PRO trial data.”

Clinical Takeaways

  • Fatigue is a prevalent and debilitating symptom in patients with multiple sclerosis (MS), yet disease-modifying therapy (DMTs) trials have limited evidence on their impact on fatigue.
  • Only 5% of DMT trials assessed fatigue as an outcome, with only 2 of them demonstrating statistically significant results.
  • Adherence to reporting standards and the risk of bias in trials addressing fatigue as an outcome need improvement, emphasizing the need for more comprehensive research.

In the review, investigators had 2 independent researchers systematically search MEDLINE, EMBASE and between January 1993 and 2023 for RCTs that measured fatigue as an outcome. Then they assessed adherence to reporting standards with the CONSORT-PRO, and the risk of bias (RoB) was assessed with the RoB 2 tool by the Cochrane Handbook for Systematic Reviews of Interventions. Fatigue was measured with 3 different PROMs in the 7 trials, 4 (57%) had assessed fatigue with the Fatigue Impact Scale, 2 (28%) had the Modified Fatigue Impact Scale subscale, and 1 (14%) trial had the Fatigue Symptoms and Impacts Questionnaires–Relapsing-Remitting MS.

READ MORE: Remote Exercise and Physiotherapy Programs Show Benefit for Depressive Symptoms in MS

All the included trials of the review measured fatigue as a secondary outcome and had a mean of 0.26 (SD, 0.13; range, 0.14-0.64) of the Consolidated Standards of Reporting Trials (CONSORT)-PRO Extension checklist items. In addition, the reporting of fatigue among RCTs was suboptimal with a mean adherence to the CONSORT-PRO Statement of 36% across the 7 trials. In the 7 trials, 3 (42%) presented an overall score of ‘some concern’ with the RoB, and 4 trials (57%) presented ‘high concern.’ Missing outcome data with bias was scored as ‘high’ among 4 trials and 3 trials were scored as ‘no information.’ In addition, 4 trials presented ‘some concerns’ in the domain ‘bias in selection of the reported results.’

“It is important to mention that the RoB tool does not assess bias because of selective reporting. Assessment of selective reporting is essential to ensure that trial results are not excluded based on their direction, magnitude or statistical significance,” Rivera et al noted.1

The authors noted the potential exclusion of relevant studies in the review as a limitation since some studies did not clearly report their study design. Researchers had the reviewers discuss articles with the research team when it was unclear whether an RCT was conducted to ensure that all the studies identified were relevant to the review. Additionally, the authors noted another limitation with the databases as indexing errors could have led to the exclusion of relevant studies, however, they attempted to avoid this by searching through

“The assessment of fatigue as an outcome is underrepresented in trials of DMTs even though fatigue is one of the most common and detrimental symptoms of MS, with only 5% of RCTs of DMTs assessing this outcome using PROMs. As fatigue has a profound effect on the quality of life of individuals with MS further consideration should be given to inclusion of fatigue as a secondary outcome in future MS trials,” Rivera et al noted.1

1. Cruz Rivera S, Aiyegbusi OL, Piani Meier D, et al. The effect of disease modifying therapies on fatigue in multiple sclerosis. Mult Scler Relat Disord. 2023;79:105065. doi:10.1016/j.msard.2023.105065
2. Kappos L, Fox RJ, Burcklen M, et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial. JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405
3. Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705-716. doi:10.1177/1352458513507821
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