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Objectives: To evaluate the safety, efficacy and response duration of four different dosing regimens of dazodalibep (DAZ), a non-antibody biological antagonist of CD40L, in patients with rheumatoid arthritis (RA)., Methods: This double-blind study included adult patients with moderate-to-severe active RA with a positive test for serum rheumatoid factor and/or anticitrullinated protein antibodies, an inadequate response to methotrexate, other conventional disease-modifying antirheumatic drugs or tumour necrosis factor-α inhibitors, and no prior treatment with B-cell depleting agents. Eligible participants were randomised equally to five groups receiving intravenous infusions of DAZ or placebo. The primary endpoint was the change from baseline in the Disease Activity Score-28 with C reactive protein (DAS28-CRP) at day 113. Participants were followed through day 309., Results: The study randomised 78 eligible participants. The change from baseline in DAS28-CRP (least squares means±SE) at day 113 was significantly greater for all DAZ groups (-1.83±0.28 to -1.90±0.27; p<0.05) relative to PBO (-1.06±0.26); significant reductions in DAS28-CRP were also observed for all DAZ groups at day 309. The distribution of adverse events was generally balanced among DAZ and PBO groups (74% and 63%, respectively). There were four serious adverse events deemed by investigators to be unrelated to study medication., Conclusions: DAZ treatment for all dosage regimens significantly reduced DAS28-CRP at day 113 relative to PBO. The safety data suggest an acceptable safety and tolerability profile. Treatment effects at day 113 and the prolonged duration of responses after DAZ cessation support the use of longer dosing intervals., Trial Registration Number: NCT04163991., Competing Interests: Competing interests: AK has received study funding, medical writing support, and article processing charges from Amgen. He has received consulting fees from AXDEV Group, Pfizer, Janssen, Boehringer Ingelheim, AbbVie, Flexion, Gilead, Grunenthal, Orion, Regeneron, Sun Pharma Advance Research, and ECOR1. He has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck & Co, Eli Lilly, Novartis, Pfizer, Flexion, AbbVie, Amgen, Genentech, Regeneron, UCB, Horizon, and GSK. He has participated in a data safety monitoring board for AbbVie and Amgen. He has been part of a board or advisory board for AbbVie, Bendcare, Boehringer Ingelheim, ChemoCentryx, Flexion, Gilead, Grunenthal, Horizon, Eli Lilly, Janssen, Pfizer, Regeneron, UCB, and Novartis. He has stock or stock options in Pfizer, GSK, Gilead, Novartis, and Amgen. LW, IA are current employees of Horizon Therapeutics and own stock. MG, JF and GI are former employees of Horizon Therapeutics and own stock. EWS has consulted for Horizon Therapeutics, Bristol Myers Squibb, CSL Behring, Resolve Therapeutics, and Sonoma Biotherapeutics, and receives royalties from UpToDate., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)