Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 28; no. 1; pp. 1 - 131
• Main Authors: Fragoso-Saavedra, Sergio, Núñez, Isaac, Audelo-Cruz, Belem M., Arias-Martínez, Sarahi, Manzur-Sandoval, Daniel, Quintero-Villegas, Alejandro, Benjamín García-González, H., Carbajal-Morelos, Sergio L., PoncedeLeón-Rosales, Sergio, Gotés-Palazuelos, José, Maza-Larrea, José A., Rosales-de la Rosa, J. Javier, Diaz-Rivera, Dafne, Luna-García, Edgar, Piten-Isidro, Elvira, Del Río-Estrada, Perla M., Fragoso-Saavedra, Mario, Caro-Vega, Yanink, Batina, Isabella, Islas-Weinstein, León, Iruegas-Nunez, David A., Calva, Juan J., Belaunzarán-Zamudio, Pablo F., Sierra-Madero, Juan, Crispín, José C., Valdés-Ferrer, Sergio Iván
• Format: Journal Article
• Language: English
• Published: New York BioMed Central 08.11.2022; BMC
• Subjects: Collaboration; COVID-19; Hospitals; Immunomodulation; Infections; Inflammation; Invasive mechanical ventilation; Laboratories; Mortality; Pyridostigmine; Sample size; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Steroids; Mexico
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1186/s10020-022-00553-x

Background: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. Methods: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. Results: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44–64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24–0.9; P  = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). Conclusion: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.