The Induction of Cure in Early Arthritis (I CEA) trial is underway to evaluate different treatment strategies for patients with early, DMARD-naïve undifferentiated arthritis. This multicenter, investigator-initiated, single-blind randomized clinical trial is designed to assess the efficacy of early intervention in achieving clinical improvement and potential remission. The trial, conducted across two academic and five peripheral hospitals in the Netherlands, aims to determine the optimal approach for managing early arthritis and preventing progression to rheumatoid arthritis (RA).
Study Design and Protocol
The I CEA trial randomizes patients with early unclassified arthritis to one of three treatment arms for a 3-month interventional period followed by a 9-month observational period. The three treatment strategies are:
- Symptom relief with analgesics, NSAIDs, and glucocorticoid injection.
- Initiation of methotrexate (MTX) with a glucocorticoid injection.
- Initiation of baricitinib with a glucocorticoid injection.
After the initial 3-month treatment period, patients enter a 9-month observational phase where treatment decisions are made jointly by the rheumatologist and patient, allowing for adjustments based on individual needs and responses.
Eligibility and Exclusion Criteria
The trial includes patients aged 18 to 65 with clinical early unclassified arthritis of at least two joints, symptom duration of less than one year, and a Disease Activity Score (DAS) greater than 1.6. Key exclusion criteria include:
- Current smoking or a long history of smoking.
- Increased risk for arterial or venous thrombosis.
- Increased risk of malignancy.
- Active or ongoing chronic infection.
These criteria ensure a focused study population with early-stage arthritis while minimizing potential confounding factors.
Intervention Details
Patients in the NSAID arm receive symptom relief with analgesics, NSAIDs, and a single dose of intramuscular or intra-articular glucocorticoids. The choice of NSAID is determined by shared decision-making between the rheumatologist and patient. MTX is initiated at 15 mg/week, with a possible increase to 25 mg/week, or the maximum tolerated dose. Baricitinib is administered at 4 mg/day. Co-treatment with NSAIDs is allowed but not required in the MTX and baricitinib arms. A single additional intra-articular or intramuscular injection of glucocorticoids is permitted in case of a disease flare.
Outcomes and Assessments
The primary outcome measure is the change in Disease Activity Score (DAS) at 3 months. Secondary outcomes include:
- Percentage in clinical remission at 3, 6, 9, and 12 months.
- Time to clinical improvement.
- Functional ability over time, measured by HAQ-DI.
- Progression to classifiable RA over time.
- Toxicity, defined by the number and severity of adverse events.
Exploratory outcomes include illness perceptions, cost-utilities, patient satisfaction, depressive feelings, and daily functioning in preferred activities.
Statistical Analysis
The primary analysis will compare the change in DAS at 3 months between the three treatment arms using ANCOVA, adjusting for baseline DAS. A gatekeeping analysis will be employed, first comparing baricitinib to NSAIDs, then MTX to NSAIDs, and finally MTX to baricitinib, if statistical significance is achieved in the preceding steps. Secondary outcomes will be analyzed using GEE or ANCOVA, as appropriate, with NSAIDs as the reference arm. Time-to-event outcomes will be analyzed using Kaplan-Meier curves and Cox regression.
Safety Monitoring
Safety monitoring includes regular assessments of blood counts, liver and renal function, and lipid panels. Patients are screened for latent tuberculosis and viral hepatitis before treatment initiation with baricitinib. A Data Safety Monitoring Board (DSMB) meets every 6 months to review toxicity data and advise on study continuation and potential protocol adjustments.
Current Status and Implications
Patient inclusion concluded earlier than expected, with 111 patients enrolled. Follow-up is ongoing and planned until the end of 2024. The results of this trial are expected to provide valuable insights into the optimal early treatment strategies for undifferentiated arthritis, potentially leading to improved outcomes and reduced progression to RA.
