Pyridostigmine in the treatment of adults with severe SARS-CoV-2 infection (PISCO): a randomised, double-blinded, phase 2/3, placebo-controlled trial
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Abstract
Background
Hospitalised 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.
Methods
We 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 .
Findings
Between 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.
Interpretation
Our data indicates that the addition of pyridostigmine to standard treatment reduces significantly the fatality rate among patients hospitalized for severe COVID-19.
Funding
Consejo Nacional de Ciencia y Tecnología, México.
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SciScore for 10.1101/2021.04.28.21255834: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization We performed a double-blinded, placebo-controlled, parallel randomized clinical trial. Blinding Due to an observed difference in the primary outcome between groups (still blinded to investigators, but unblinded to the DSMB), as well as difficulty recruiting new participants due to a reduction in eligible patients and a swell in competing studies, we decided to stop the trial after 188 participants had been recruited (94 in each group). Power Analysis Thus, we calculated a sample size of 436 participants considering an event rate of 25% in the control group, considering a 10% absolute reduction (40% relative reduction) in the … SciScore for 10.1101/2021.04.28.21255834: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization We performed a double-blinded, placebo-controlled, parallel randomized clinical trial. Blinding Due to an observed difference in the primary outcome between groups (still blinded to investigators, but unblinded to the DSMB), as well as difficulty recruiting new participants due to a reduction in eligible patients and a swell in competing studies, we decided to stop the trial after 188 participants had been recruited (94 in each group). Power Analysis Thus, we calculated a sample size of 436 participants considering an event rate of 25% in the control group, considering a 10% absolute reduction (40% relative reduction) in the primary outcome as clinically significant, and 80% power to detect a difference in the primary outcome using a two-sided significance level of α=0.0517. Table 2: Resources
Software and Algorithms Sentences Resources Statistical analysis was conducted with Prism GraphPad software, version 9.1.0 (GraphPad Software, San Diego, CA), and R version 4.0.0. Prism GraphPadsuggested: NoneGraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Our study has important limitations. The originally planned sample size could not be achieved. Still, a significant difference was observed because of a greater than expected effect. Also, it is possible that some patients requiring IMV could not receive it because of either, a pre-existing living will; last-minute patient (or proxy) refusal of intubation; or, intermittently throughout the study period, hospital saturation of critical-care beds19,20. Our outcome included starting, but not necessarily the requirement of, IMV. This is reflected in the fact that the bulk of the primary outcome was due to deaths without receiving IMV, most likely due to lack of critical care space. Thus, our results may not be generalizable to places that do not have this problem. Importantly, we do not have a disease severity measure at randomization, so groups could be imbalanced in this sense. Nonetheless, both groups should be equally affected by this limitation. As a proof-of-concept, this study needs to be replicated or refuted in independent clinical trials. Also, at this point, our results cannot be extrapolated to patients with less severe disease, or those already receiving IMV, without prior verification in clinical trials. Finally, medium-term outcomes (90 days) will be reported at a later time point. The strengths of the study include that it is a double-blinded placebo-controlled multicentric randomized clinical trial that evaluated an inexpensive treatment, has a positive pharmacol...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04343963 Recruiting Pyridostigmine in Severe SARS-CoV-2 Infection Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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