A randomized pragmatic trial of telephone-delivered cognitive behavioral-therapy, modafinil, and combination therapy of both for fatigue in multiple sclerosis: The design of the "COMBO-MS" trial

Background: Fatigue is one of the most common and disabling chronic symptoms in multiple sclerosis (MS). Optimization of available treatments for MS-related fatigue has been stymied by lack of comparative effectiveness research that focuses on real-world treatment delivery methods and potential modification of treatment effect by other chronic MS symptoms or disability level. This report describes the design of a patient centered, comparative effectiveness trial of cognitive behavioral-therapy (CBT), modafinil, and combination therapy of both for fatigue in MS ("COMBO-MS"). Methods: We describe the methods of this pragmatic comparative effectiveness trial that is guided by a team of patient, family, provider, community, and payer stakeholders. Eligible participants with MS and significant fatigue severity are randomly assigned (1:1:1) to received either CBT, modafinil, or a combination of CBT and modafinil for 12 weeks. The primary outcome is change in fatigue impact as measured by the Modified Fatigue Impact Scale (MFIS) at 12 weeks. Secondary outcome measures include ecological momentary assessment (EMA) measures of fatigue intensity, fatigue interference, and fatigability (measured over 7 days' time at baseline and at 12 weeks), and change in MFIS score at 24 weeks. Projected outcomes: We hypothesize that combination therapy will more effectively ameliorate fatigue severity than either monotherapy, and that heterogeneity of treatment effects will be found based on depression status, presence of known or suspected sleep disorder, and disease severity. Study findings will assist patients, providers, payers, and policy makers to provide more effective care for managing fatigue in MS.