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SummaryBackgroundHospitalised patients with severe COVID-19 have an increased risk of developing acute respiratory distress syndrome (ARDS) and death from severe systemic inflammatory response. Acetylcholine modulates the acute inflammatory response through a neuro-immune mechanism known as the inflammatory reflex. Pyridostigmine, an acetylcholine-esterase inhibitor, increases the half-life of endogenous ACh, reducing lung and systemic inflammation in murine sepsis. This trial aimed to evaluate whether pyridostigmine could decrease invasive mechanical ventilation (IMV) and death in patients with severe COVID-19.MethodsWe performed a parallel-group, multicentre, double-blinded, placebo-controlled, randomised clinical trial in two COVID-19-designated hospitals in Mexico City, Mexico. Adult (≥ 18-year-old), hospitalised patients with confirmed SARS-CoV-2 infection based on a positive RT-PCR test in a respiratory specimen, a computed tomography compatible with pneumonia, as well as requiring supplementary oxygen were included. Patients were randomly assigned (1:1) to receive oral pyridostigmine (60 mg per day) or placebo for a maximum of 14 days. The intention-to-treat analysis included all the patients who underwent randomisation. The primary endpoint was the composite outcome of initiation of IMV and 28-day all-cause mortality. The trial is registered in ClinicalTrials.gov, NCT04343963.FindingsBetween May 5, 2020, and Jan 29, 2021,188 participants were randomly assigned to placebo (n=94) or pyridostigmine (n=94). The composite outcome occurred in 22 (23·4%) vs. 11 (11·7%) participants, respectively (hazard ratio 0·46, 95% CI 0·22-0·96, p=0·03). The most frequent adverse event was diarrhoea (5 [5·3%] in the pyridostigmine group vs 3 [3·2%] in the placebo group). Most of the adverse events were mild to moderate, with no serious adverse events related to pyridostigmine.InterpretationOur data indicates that the addition of pyridostigmine to standard treatment reduces significantly the fatality rate among patients hospitalized for severe COVID-19.FundingConsejo Nacional de Ciencia y Tecnología, México.