CAFE-MS will assess the effectiveness of two online programs for fatigue in multiple sclerosis (MS). Although they differ, both of these online programs contain information about MS and fatigue intended to help people with MS understand and manage their fatigue.

This large-scale, decentralized clinical trial is projected to enroll 2,000 people with MS. The collaboration between iConquerMS and 5 Veterans Affairs (VA) sites in the MS Centers of Excellence is designed to ensure sufficient representation of people with MS from populations traditionally under-represented in MS clinical trials.

The study is a 3-arm, randomized controlled clinical trial with study participation lasting 1 year. Two of the trial arms will include one of two online programs for managing fatigue in MS added to the trial participants' usual MS treatment, and the third arm will include usual MS treatment alone. The online program phase of the trial lasts for 6 months after randomization followed by a final study visit at 12 months. Participants in the usual MS treatment alone arm for the first 6 months will have an opportunity to choose one of the online programs for the final 6 months of the trial.

Inclusion Criteria:

• Informed consent by person with MS
• Living in the US
• Age ≥ 22
• Confirmed diagnosis of MS by a physician, who is a neurologist or has access to a neurologist's statement of diagnosis
• Fatigue Severity Scale score at or above eligibility threshold
• Fluent in English
• Willingness to engage in self-administration of an online intervention for 24 weeks and complete follow-up assessments
• Access to the internet and e-mail with a compatible device (smartphone, computer, or tablet)
• No MS relapse / no steroid treatment in the 4 weeks prior to answering the screening questionnaire (self-reported)
• No disease-modifying therapeutic (DMT) started in the 4 weeks prior to answering the screening questionnaire (self-reported)

Exclusion Criteria:

• Unwilling or unable to consent
• Refusal to saving, processing and forwarding of pseudonymized data
• Concurrent participation in another interventional trial

Participants will be blinded with respect to Program A and Program B. However, the third arm of the trial, Treatment as Usual, will not be blinded. Since outcome assessments are collected online via surveys, the outcome assessor is a blinded entity.