A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol

Sergio Fragoso-Saavedra, David A Iruegas-Nunez, Alejandro Quintero-Villegas, H Benjamín García-González, Isaac Nuñez, Sergio L Carbajal-Morelos, Belem M Audelo-Cruz, Sarahi Arias-Martínez, Yanink Caro-Vega, Juan José Calva, Verónica Luqueño-Martínez, Alejandra González-Duarte, Brenda Crabtree-Ramírez, José C Crispín, Juan Sierra-Madero, Pablo F Belaunzarán-Zamudio, Sergio I Valdés-Ferrer, Sergio Fragoso-Saavedra, David A Iruegas-Nunez, Alejandro Quintero-Villegas, H Benjamín García-González, Isaac Nuñez, Sergio L Carbajal-Morelos, Belem M Audelo-Cruz, Sarahi Arias-Martínez, Yanink Caro-Vega, Juan José Calva, Verónica Luqueño-Martínez, Alejandra González-Duarte, Brenda Crabtree-Ramírez, José C Crispín, Juan Sierra-Madero, Pablo F Belaunzarán-Zamudio, Sergio I Valdés-Ferrer

Abstract

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19.

Methods: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19.

Discussion: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19.

Trial registration: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).

Keywords: ACh; COVID-19; Immunomodulation; Inflammatory reflex; Invasive mechanical ventilation; Mortality; Placebo-controlled trial; Pyridostigmine; SARS-Cov-2.

Conflict of interest statement

Pablo F Belaunzarán-Zamudio is an Associated Editor for the HIV and co-infections section of BMC Infectious Diseases.

Figures

Fig. 1
Fig. 1
The PISCO trial (Pyridostigmine in Severe COVID-19) study design and schedule of follow-up visit
Fig. 2
Fig. 2
Protocol Activities. All timepoints are counted from enrollment (Baseline). Arrows indicate specific actions to be performed at each predefined timepoint. Patients who are discharged from hospital before day 14 are not required to return for blood sampling. Abbreviations: ABG: arterial blood gases; IL-6: interleukin 6

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