Comparative effectiveness of cognitive behavioural therapy, modafinil, and their combination for treating fatigue in multiple sclerosis (COMBO-MS): a randomised, statistician-blinded, parallel-arm trial.

Background: Fatigue is one of the most disabling symptoms reported by people with multiple sclerosis. Although behavioural and pharmacological interventions might be partly beneficial, their combined effects have not been evaluated for multiple sclerosis fatigue, or examined with sufficient consideration of characteristics that might affect treatment response. In this comparative effectiveness research trial, we compared the effectiveness of cognitive behavioural therapy (CBT), modafinil, and their combination for treating multiple sclerosis fatigue.
Methods: This randomised, analyst-blinded, parallel-arm, comparative effectiveness trial was done at two universities in the USA. Adults (aged ≥18 years) with multiple sclerosis and problematic fatigue (Fatigue Severity Scale [FSS] score ≥4) were randomly assigned (1:1:1), using a web-based treatment assignment system with minimisation, to receive CBT, modafinil, or both for 12 weeks. Statisticians were masked to group assignment, but participants, study neurologists, CBT interventionalists, and coordinators were not masked to treatment assignment. The primary outcome was the change in Modified Fatigue Impact Scale (MFIS) from baseline to 12 weeks, assessed using multiple linear regression, adjusted for age, sex, study site, anxiety, pain, baselines MFIS score, and physical activity. Analyses were done by intent to treat. The trial was registered with clinicaltrials.gov, NCT03621761, and is completed.
Findings: Between Nov 15, 2018, and June 2, 2021, 336 participants were randomly assigned treatment (114 assigned to CBT, 114 assigned to modafinil, and 108 assigned to combination therapy). At 12 weeks, CBT (n=103), modafinil (n=107), and combination therapy (n=102) were associated with clinically meaningful within-group MFIS reductions of 15·20 (SD 11·90), 16·90 (15·90), and 17·30 (16·20) points, respectively. Change in MFIS scores from baseline to 12 weeks did not differ between groups: relative to combination therapy, the adjusted total mean difference in MFIS change score was 1·88 (95% CI -2·21 to 5·96) for CBT and 1·20 (-2·83 to 5·23) for modafinil. Most common adverse events for modafinil-containing treatment groups included insomnia (eight [7%] for modafinil and eight [7%] for combination therapy) and anxiety (three [3%] for modafinil and nine [8%] for combination therapy).
Interpretation: Modafinil, CBT, and combination therapy were associated with similar reductions in the effects of multiple sclerosis fatigue at 12 weeks. Combination therapy was not associated with augmented improvement compared with the individual interventions. Further research is needed to determine whether effects of these interventions on multiple sclerosis-related fatigue is influenced by sleep hygiene and sleepiness. No serious adverse events related to the study drug were encountered.
Funding: Patient-Centered Outcomes Research Institute and National Multiple Sclerosis Society.
Competing Interests: Declaration of interests TJB reports current or recent grants from the National Institutes of Health, the International Progressive MS Alliance, and the National MS Society, and an award from the Patient-Centered Outcomes Research Institute. She has received support from Michigan Humane for her research. She has received travel and meeting support from Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the American Academy of Neurology. She reports a patent held by the University of Michigan related to treatment of sleep apnoea. She receives material support, but no financial compensation, from Jazz Pharma for a National Institutes of Health-funded investigator-initiated trial. She holds unpaid service and leadership positions for the National MS Society and the ACTRIMS Program Committee. She has served as site principal investigator for trials of multiple sclerosis therapeutics sponsored by Genentech, Genyzme, and Novartis, but received no direct compensation for this work. KNA reports grants from the National Institutes of Health and the National MS Society and an award from the Patient-Centered Outcomes Research Institute. He has received royalties for licensing of materials to Actelion Pharmaceuticals. DME reports grants from the National Institutes of Health, the National MS Society, the National Institute of Disability, Independent Living, and Rehabilitation Research, Administration for Community Living, and the State of Washington, and an award from the Patient-Centered Outcomes Research Institute. She receives honoraria from the American Psychological Association for her role as Editor for the journal Rehabilitation Psychology. She has received royalties for licensing of materials to Actelion Pharmaceuticals. She serves without compensation in leadership and service roles for the National MS Society National Advisory Board on Medical Rehabilitation Research and on the editorial board for Archives of Physical Medicine and Rehabilitation. GvG reports grants from the Patient-Centered Outcomes Research Institute and the National MS Society and a contract from Novartis; she also serves on a National Institute for Neurological Disorders and Stroke board. TRV reports a grant from the National MS Society. ARR reports research effort support from the National Institutes of Health and travel and meeting support from ACTRIMS. RDC reports grants from the National Institutes of Health and the National MS Society, and an award from the Patient-Centered Outcomes Research Institute. He receives royalties from UpToDate for roles as an editor and author and is a paid Eli Lilly consultant (contract through University of Michigan). He reports patents and copyrighted material held by the University of Michigan for screening, diagnosis, and treatment of sleep disorders. He has held unpaid leadership positions on the board of directors and as treasurer and president elect for the International Pediatric Sleep Association. He serves on the advisory board of The Pajama Program. BMS reports grants from the National Institute of Health and Wings for Life Foundation. He has received travel support from ACTRIMS and International Society for Neuroimmunology for speaking engagements and programmatic activities. He serves as Secretary and Director for the ACTRIMS Program Committee. He has participated on a data and safety monitoring board for Data Safety Monitoring Committee, AACI Trailblazer Clinical Trial, Eli Lilly (2020–21). He holds filed or issued patents for an immune cell based neuroregenerative therapy, a treatment for sleep apnoea, and lymphoid chemokines, through the Ohio State University, University of Michigan, and University of Rochester, respectively. ALK reports grants from the National Institutes of Health, the National MS Society, the Craig H Neilsen Foundation, the National Institute of Disability, Independent Living, and Rehabilitation Research, Administration for Community Living, and the State of Michigan, and an award from the Patient-Centered Outcomes Research Institute. She receives honoraria from the American Psychological Association for her role as Editor for the journal Rehabilitation Psychology. She has received royalties for licensing of materials to Actelion Pharmaceuticals and she served as a paid consultant for Twill Health. She serves without compensation on committees for the United State Association for The Study of Pain and Society for Ambulatory Assessment and on the editorial boards for Journal of Pain and Arthritis Care & Research. RL, YTN, AJ, MH, MS, NL, YZ, and DC report no competing interests.
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