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Objective: Dipeptidase-1 (DPEP-1) is a recently discovered leucocyte adhesion receptor for neutrophils and monocytes in the lungs and kidneys and serves as a potential therapeutic target to attenuate inflammation in moderate-to-severe COVID-19. We aimed to evaluate the safety and efficacy of the DPEP-1 inhibitor, LSALT peptide, to prevent specific organ dysfunction in patients hospitalised with COVID-19., Design: Phase 2a randomised, placebo-controlled, double-blinded, trial., Setting: Hospitals in Canada, Turkey and the USA., Participants: A total of 61 subjects with moderate-to-severe COVID-19., Interventions: Randomisation to LSALT peptide 5 mg intravenously daily or placebo for up to 14 days., Primary and Secondary Outcome Measures: The primary endpoint was the proportion of subjects alive and free of respiratory failure and/or the need for renal replacement therapy (RRT). Numerous secondary and exploratory endpoints were assessed including ventilation-free days, and changes in kidney function or serum biomarkers., Results: At 28 days, 27 (90.3%) and 28 (93.3%) of subjects in the placebo and LSALT groups were free of respiratory failure and the need for RRT (p=0.86). On days 14 and 28, the number of patients still requiring more intensive respiratory support (O 2 ≥6 L/minute, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation) was 6 (19.4%) and 3 (9.7%) in the placebo group versus 2 (6.7%) and 2 (6.7%) in the LSALT group, respectively (p=0.14; p=0.67). Unadjusted analysis of ventilation-free days demonstrated 22.8 days for the LSALT group compared with 20.9 in the placebo group (p=0.4). LSALT-treated subjects had a significant reduction in the fold expression from baseline to end of treatment of serum CXCL10 compared with placebo (p=0.02). Treatment-emergent adverse events were similar between groups., Conclusion: In a Phase 2 study, LSALT peptide was demonstrated to be safe and tolerated in patients hospitalised with moderate-to-severe COVID-19., Trial Registration Number: NCT04402957., Competing Interests: Competing interests: DRL, DS, KG and AL are employed by Arch Biopartners Inc. DRL, AL, SMR and DLS hold equity positions in Arch Biopartners. SMR, DLS, AL and DM have patents issued and pending in the areas of dipeptidase-1 and the LSALT peptide. DM is the acting chief science officer for Arch Biopartners and is compensated with an equity position. DM has received research funding from Arch Biopartners. All other authors have no competing interests., (© 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.)