Assessing the clinical- and cost-effectiveness of REFUEL-MS, a digital therapeutic for multiple sclerosis-related fatigue: study protocol for a randomised controlled trial

Fatigue is a common and disabling symptom affecting up to 90% of people living with multiple sclerosis (MS). Cognitive-behavioural, exercise and balance interventions are effective in reducing MS fatigue, but there is currently no standardised, accessible treatment in the UK healthcare system. REFUEL-MS is an app-based, healthcare professional (HCP)-supported intervention designed to reduce MS fatigue using cognitive-behavioural, exercise and balance principles. This trial aims to test the efficacy, safety and cost-effectiveness of REFUEL-MS compared to treatment as usual. This is a two-arm, parallel-group superiority randomised controlled trial. Adults with confirmed MS, who experience fatigue (scoring > 4 on the Chalder Fatigue Questionnaire [CFQ]), and are not on a new disease-modifying treatment (< 6 months) will be eligible. Participants will be recruited across the UK via the UK MS Register, NHS clinics, and community networks/organisations. Participants will be randomised 1:1 at the individual level using a centralised web-based system, stratified by MS type and recruitment source, to receive the REFUEL-MS intervention or treatment as usual. Participants receiving REFUEL-MS will complete weekly app sessions and four online HCP appointments over 16 weeks. All participants will complete online assessments at baseline, and 4, 6 and 12 months post-randomisation. Participants and HCPs will be unblinded, while the outcome assessors and senior statistician will be blinded. The primary outcome is fatigue severity (CFQ) at 6 months post-randomisation. Secondary outcomes include fatigue impact and improvement, mood, quality of life, service use, physical activity, and adverse events, assessed at multiple timepoints. The target sample is 378 to detect a minimal clinically important difference on the CFQ between groups. Safety and cost-effectiveness will also be evaluated and interviews will be conducted with a subset of participants to explore user and healthcare professionals’ experiences with the intervention. If effective and safe, REFUEL-MS has the potential to be a scalable intervention. Implementation will be tested in a real-world multiple-case study following this trial. The trial was pre-registered on the UK’s Clinical Study Registry on 20/06/2025 (ISRCTN82686286; https://doi.org/10.1186/ISRCTN82686286 ).