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Background: Glenzocimab is a novel antithrombotic agent which targets platelet glycoprotein VI (GPVI) and does not induce haemorrhage. SARS-CoV-2 triggers a prothrombotic state and lung injury whose mechanisms include coagulopathy, endothelial dysfunction, and inflammation with dysregulated platelets., Methods and Patients: GARDEN was a randomised double-blind, exploratory phase II study of glenzocimab in SARS-CoV-2 respiratory failure (NCT04659109). PCR+ adults in Brazil and France (7 centres) were randomized to standard-of-care (SOC) plus glenzocimab (1000 mg/dayx3 days) or placebo, followed for 40 days. Primary efficacy endpoint was clinical progression at Day 4. All analyses concerned the intention-to-treat population., Results: Between December 2020 and August 2021, 61 patients received at least one dose (30 glenzocimab vs 32 placebo) and 58 completed the study (29 vs 29). Clinical progression of COVID-19 ARDS was not statistically different between glenzocimab and placebo arms (43.3% and 29.0%, respectively; p = 0.245). Decrease in the NEWS-2 category at D4 was statistically significant (p = 0.0290) in the glenzocimab arm vs placebo. No Serious Adverse Event (SAE) was deemed related to study drug; bleeding related events were reported in 6 patients (7 events) and 4 patients (4 events) in glenzocimab and placebo arms, respectively., Conclusions: Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications., Competing Interests: The authors are declaring the following links of interest. JP was a part of GARDEN study scientific committee and worked as a consultant for Acticor Biotech, he also has link with AOP Orphan, Baxter, Edwards Lifseciences, Masimo, LFB, RDS and Takeda outside the scope of this work. FR has consultancy agreement with Astra Zeneca, Gilead, MSD, Roche and ViiV Healthcare. MJP is a scientific co-founder, consultant and shareholder of Acticor-Biotech. GA is a co-founder, CEO and shareholder of Acticor-Biotech. SB is the CSO and GM of Acticor Biotech. YP is the CMO and GM of Acticor Biotech as a consultant and has stock interest in Acticor Biotech. SB, AC, DF, ML, AM and ET are employees and have stock interest in Acticor Biotech. SG, VDH and GA are consultant for Acticor Biotech. Other authors have no links to disclose. Acticor Biotech is a commercial company currently developing GARDEN study drug, glenzocimab, and holds several related patents/rights. GARDEN study was an industry sponsored trial, and Acticor Biotech was involved, or provided support, for study design, data collection and analysis, decision to publish, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials. , (Copyright: © 2024 Pottecher et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)