Induction of Cure in Early Arthritis (I CEA): study protocol for an investigator-initiated randomized single-blind clinical trial with open-label extension to compare three treatment strategies in patients with newly diagnosed undifferentiated arthritis.

Background: Undifferentiated arthritis (UA) is a term used to describe patients with inflammatory arthritis that has not differentiated into a specific rheumatic disease. UA may be a pre-stage of rheumatoid arthritis (RA) or another inflammatory disease or remain undifferentiated, but a substantial proportion of patients may also achieve spontaneous remission. As UA may be an early presentation of RA, rheumatologists often start methotrexate (or another csDMARD) as early as possible. There are however very little data on the potential benefits of early DMARD treatment, and longitudinal data suggests that long-term outcomes such as physical functioning hardly improved in these patients in the past decades. In the I CEA trial, we investigate if it is beneficial to start early treatment with MTX or baricitinib, a more rapidly acting drug with a broader mechanism of action, compared to waiting for spontaneous remission with symptomatic therapy in patients with UA.

Methods: The I CEA is a multicenter single-blind (independent assessor) randomized clinical trial with a 3-month interventional and 9-month observational follow-up period. The study includes patients with early (< 1 year symptom duration) DMARD-naïve undifferentiated arthritis. Patients with an increased risk of AEs with baricitinib treatment are excluded. Participants are randomized 1:1:1 to (1) symptom relief with NSAIDs and a single injection of glucocorticoids and (waiting for spontaneous remission); (2) methotrexate and a single injection of glucocorticoids, and NSAIDs are optional; and (3) baricitinib and a single injection of glucocorticoids and NSAIDs are optional. During the observational follow-up period, patients are treated in shared decision with their rheumatologist. The primary outcome will be the change in DAS at 3 months. Secondary outcomes include radiographic progression, physical functioning, patient-reported outcomes, cost utilities, safety, progression to classifiable RA, and disease activity over time.

Discussion: The 12-month I CEA trial studies early treatment of patients with UA with methotrexate, baricitinib, or NSAIDs. The study initially had a more complex design. Emerging safety warnings about baricitinib necessitated adjustment of the trial protocol including more extensive exclusion criteria. The number of included patients was lower than initially planned, supported by an updated sample size calculation.

Trial registration: Dutch trial register NL73202.058.20, EudraCT 2019-004359-35, registered 10-06-2020. Protocol version 1Q, 06-05-2024.