Pyridostigmine in adults with severe SARS-CoV-2 infection: the PISCO trial

Fragoso-Saavedra, S.; Nunez, I.; Audelo-Cruz, B. M.; Arias-Martinez, S.; Manzur-Sandoval, D.; Quintero-Villegas, A.; Garcia-Gonzalez, H. B.; Carbajal-Morelos, S. L.; Ponce de Leon-Rosales, S.; Gotes-Palazuelos, J.; Caro-Vega, Y.; Maza-Larrea, J.; Batina, I.; Islas-Weinstein, L.; Calva, J. J.; Iruegas-Nunez, D. A.; Belaunzaran-Zamudio, P. F.; Sierra-Madero, J.; Crispin, J. C.; Valdes-Ferrer, S. I.

Background: Hospitalized patients with severe COVID-19 have an increased risk of developing severe systemic inflammatory response, pulmonary damage, and acute respiratory distress syndrome (ARDS), resulting in end-organ damage and death. 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, chemically stimulating the inflammatory reflex. This trial aimed to evaluate whether pyridostigmine could decrease invasive mechanical ventilation (IMV) and death in patients with severe COVID-19. Methods: We performed a parallel-group, multicenter, double-blinded, placebo-controlled, randomized clinical trial to evaluate if add-on pyridostigmine to standard treatment reduced the composite outcome of initiation of IMV and 28-day all-cause mortality among hospitalized patients with severe COVID-19. Results: 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% confidence interval 0.22-0.96, p=0.03). Most of the adverse events were mild to moderate, with no serious adverse events related to pyridostigmine; discontinuation of the study drugs was similar in both groups. Conclusions: We provide evidence indicating that the addition of pyridostigmine to standard treatment resulted in a clinically significant reduction in the composite outcome (IMV/death) among patients hospitalized for severe COVID-19. (Funded by Consejo Nacional de Ciencia y Tecnologia, Mexico; ClinicalTrials.gov number: NCT04343963).