A systematic literature review of the measurement of patient-reported fatigue in studies of disease modifying therapies for multiple sclerosis.

Background: Fatigue is the most commonly experienced symptom among people with multiple sclerosis (MS) and has the greatest impact in reducing quality of life. It is important to measure change in MS-related fatigue (MS-fatigue) in response to treatment, particularly the more recent disease modifying therapies (DMTs). To date there has been no systematic literature review of the patient reported outcome (PRO) tools used to measure MS- fatigue specifically in the context of DMTs.

Methods: MEDLINE, Embase and Clinicaltrials.gov were searched from 01 January 2000 to 13 April 2021 to identify published studies of the treatment of MS with DMTs. Studies where MS-fatigue was measured as an outcome using a PRO tool were included in the review. Further literature searches were undertaken to provide information about the development and validation of each PRO tool.

Results: 739 abstracts and 96 clinical trials were manually screened resulting in 68 articles for full text screening. 48 studies were identified for the review; 10 of these were RCTs that considered MS-fatigue as a secondary outcome (4 were Phase 3 trials). The PRO instruments used in the 10 RCTs were the Fatigue Scale for Motor and Cognitive Functions, Fatigue Impact Scale, Modified Fatigue Impact Scale, Fatigue Severity Scale, and Fatigue Symptoms and Impacts Questionnaire - Relapsing Multiple Sclerosis. The other 38 studies were all open-label, longitudinal, non-randomized studies and used the following PRO instruments in addition to those listed above: the Visual Analogue Scale for Fatigue, the Fatigue Descriptive Scale, Modified Fatigue Impact Scale (5 items) and the Würzburger Fatigue Inventory for MS. All these PRO tools were specifically developed for MS-fatigue. Of these 9 PRO tools, 7 were of good methodological quality according to the existing validation studies using the Consensus-based standards for the selection of health measurement instruments (COSMIN) check list and were used in the majority of the MS DMT studies (44/48, 92%). The median follow-up time from baseline to PRO measurement was 12 months (range 1-36 months). Most studies reported on MS fatigue in terms of its change from baseline and whether the change was statistically significant. 5 studies also reported what they considered to be a clinically meaningful difference.

Conclusions: Although fatigue has the greatest impact on quality of life in people with MS, few studies have rigorously investigated the impact of DMTs on fatigue. Comparisons between study outcomes using different PRO tools is challenging due to the variety of psychometric constructs addressed by the questionnaires and differences in the recall period for fatigue symptoms and the measurement scale. Furthermore most of the PRO tools used to quantify MS-fatigue in studies of DMTs are descended from PRO tools developed during the 1990s before DMTs emerged and before widespread patient involvement in PRO development. New PRO tools should involve patients in their development as recommended by the US Food and Drug Administration and the validation process should consider the sensitivity of the PRO tool to change in fatigue over time or between groups.