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Objectives: To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt., Methods: CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups., Results: Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%)., Conclusion: Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104., Trial Registration Number: NCT03649061., Ctr Pilot Approval Belgium: S59474, EudraCT number: 2017-004054-41., Competing Interests: Competing interests: RJ received consulting fees from Novartis, Pfizer, Amgen, AbbVie; speakers fee from Novartis; support for meeting/travel from Fresenius Kabi; and participation on advisory board from AbbVie, Amgen, Novartis and Fresenius Kabi. KT received consulting fees and payment/honoraria for speakers/manuscript writing/education from Eli Lilly, AbbVie, Amgen, Novartis, Pfizer, Celgene, Otsuka, Celltrion, Galapagos, Viatris, UCB and Sandoz. JV received support for meeting/travel from UCB and Novartis. SA received support for meeting/travel from Eli Lilly, payment/honoraria for speakers/manuscript writing/education from Eli Lilly, and was member of Research Foundation – Flanders (FWO) expert panel. AD received consulting fees from Amgen, support for meeting/travel from Galapagos, Eli Lilly, Sanofi and UCB; participation on data safety monitoring board/advisory board from Agmen. MD reported a grant from Research Foundation – Flanders (FWO), and support for meeting/travel from AbbVie, Novartis, Galapagos and UCB. EDM reported a grant from Research Foundation – Flanders (FWO). RW received consulting fees from Galapagos, and payment/honoraria for speakers/manuscript writing/education from Galapagos and Celltrion. PV received institution grants from Pfizer, Galapagos; consulting fees from Galapagos, Sidekick Health, Pfizer and Boehringer Ingelheim; payment/honoraria for speakers/manuscript writing/education from Eli Lilly, Galapagos and Roularta; support for meeting/travel from AbbVie; participation on data safety monitoring board/advisory board from Eli Lilly, Galapagos, Pfizer, AbbVie, Celltrion and vice president of the Royal Belgian Society for Rheumatology. The remaining authors declared no disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)