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

José A Maza-Larrea, Sergio Iván Valdés-Ferrer, José C Crispín, Juan J Calva, David A Iruegas-Nunez, León Islas-Weinstein, Isabella Batina, Mario Fragoso-Saavedra, Perla M Del Río-Estrada, Elvira Piten-Isidro, Edgar Luna-García, Dafne Diaz-Rivera, J Javier Rosales-de la Rosa, Pablo F Belaunzarán-Zamudio, José Gotés-Palazuelos, Sergio PoncedeLeón-Rosales, Sergio L Carbajal-Morelos, H Benjamín García-González, Alejandro Quintero-Villegas, Daniel Manzur-Sandoval, Sarahi Arias-Martínez, Belem M Audelo-Cruz, Isaac Núñez, Sergio Fragoso-Saavedra, Juan Sierra-Madero, Yanink Caro-Vega

Journal: Molecular medicine (Cambridge, Mass.) 2022;28(1):131

PMID: 36348276

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Abstract

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.

Address: Plan de Estudios Combinados en Medicina (MD/PhD Program), Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.; Programa de Residencia en Medicina Interna, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Departamento de Neurología y Psiquiatría, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, BM, Mexico.; Instituto Nacional de Cardiología Ignacio Chávez (INCICh), Mexico City, Mexico.; Departamento de Educación Médica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Mexico City, Mexico.; División de Medicina, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Facultad de Medicina, Universidad Autónoma de Coahuila, Torreón, Mexico.; Departamento de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.; Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Departamento de Infectómica y Patogénesis Molecular, Mexico City, Mexico.; Departamento de Infectología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Departamento de Patología Experimental, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Mexico.; Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.; Plan de Estudios Combinados en Medicina (MD/PhD Program), Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico. [email protected].; Departamento de Neurología y Psiquiatría, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. [email protected].; Departamento de Infectología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico. [email protected].

DOI: 10.1186/s10020-022-00553-x

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MeSH Terms: Adult, Male, Humans, Middle Aged, Female, Pyridostigmine Bromide, SARS-CoV-2, Respiration, Artificial, Inflammation, Treatment Outcome, COVID-19 Drug Treatment