Discussion
MS-related fatigue, fatigue
This is the first study testing non-inferiority of blended CBT to face-to-face CBT in treating MS-related fatigue. Both the ITT and per-protocol analysis show blended CBT (MS Fit) to be non-inferior to face-to-face CBT according to the predefined non-inferiority margin. Blended CBT was more efficient, requiring 3 hours less therapist time per patient to deliver. In both CBT formats, the majority of patients reported a clinically relevant change in fatigue. Results further indicate that patients profit more from CBT when they received the CBT format they preferred.Patients in the face-to-face condition were more adherent to the treatment compared to patients in the blended condition. Adherence was larger when patients received the preferred treatment format. Content of CBT was mentioned more often as reason for non-adherence in the blended condition compared to the face-to-face condition. Since the content of the online modules is written more general, as opposed to a personalized rationale by a therapist, this may appeal stronger to the ability of patients to translate the rationale to their personal situation. Despite the larger treatment drop-out, the proportion of clinically relevant responders in the blended CBT was similar to the face-to-face condition. Face-to-face CBT apparently enhances adherence, with no discernible larger effect on fatigue compared to blended CBT. Studying which patient characteristics predict adherence and effectiveness of both face-to-face and blended CBT would be of great clinical relevance and helpful in personalizing treatment.One important assumption in a non-inferiority RCT is that the effectiveness of the standard treatment (i.e. face-to-face CBT) is preserved in the non-inferiority RCT. Therefore, the same treatment protocol, and the same enrolment criteria should be used.