Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19)

Abstract

Background A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by SARS-CoV-2 may induce a redox imbalance in alveolar epithelium cells, causing apoptosis, increased inflammation and, consequently, impaired gas exchange. We hypothesized that N-acetylcysteine (NAC) administration could restore this redox homeostasis and suppress unfavorable evolution in Covid-19 patients. Objective To determine whether NAC in high doses can avoid respiratory failure in patients with Covid-19. Methods It was a double-blind, randomized, placebo-controlled, unicentric trial, conducted at the Emergency Department of Hospital das Clínicas, São Paulo, Brazil. We enrolled 135 patients with severe Covid-19 (confirmed or suspected), with an oxyhemoglobin saturation of less than 94% or respiratory rate higher than 24 breaths/min. Patients were randomized to receive NAC 21 g (approximately 300 mg/kg) for 20 hours, or dextrose 5%. Primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to ICU, time in ICU, and mortality. Results Baseline characteristics were very similar in the two groups, with no significant difference in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest CT scan findings. Sixteen patients (23.9%) in the Placebo group were submitted to endotracheal intubation and mechanical ventilation, compared to 14 patients (20.6%) in the NAC group (p=0.675). No difference was observed in secondary endpoints. Conclusion Administration of NAC in high doses did not affect the evolution of severe Covid-19.

Open Clinical Trial of the Use of Antioxidants and Pentoxifylline as Coadjuvant Measures to Standard Therapy to Improve Prognosis of Patients with Pneumonia and Septic Shock due to Covid-19

“…The effect of NAC in COVID-19 in a double-blind, randomized, placebocontrolled and unicentric trial, conducted in 135 patients with the severe disease (confirmed or suspected), having as a primary endpoint the need for mechanical ventilation was recently published. Time of mechanical ventilation, admission to ICU, time in ICU, and mortality were secondary endpoints of this paper and it was found that administration of NAC in high doses did not affect the evolution of severe form of COVID-19 [69]. The difference with our study resides in the studied populations, the doses of NAC and in the fact that the authors did not explain whether the therapy was an adjuvant to standard comprehensive management.…”

Spike protein disulfide disruption as a potential treatment for SARS-CoV-2

“…Current usage of NAC in a clinical setting against the coronavirus infection shows controversial results. While in some clinical cases a positive outcome was reported (Ibrahim et al, 2020;Alamdari et al, 2020), a recent double-blinded clinical study conducted in Brazil did not find a significant difference between placebo and experimental groups (de Alencar et al, 2020). More evidence for the effectiveness of NAC in SARS-CoV-2 treatment should be obtained from newly established clinical trials: "Efficacy of N-Acetylcysteine (NAC) in Preventing COVID-19 from Progressing to Severe Disease," identifier NCT04419025 and "A Study of N-acetylcysteine in Patients with COVID-19 Infection," NCT04374461 (clinicaltrials.gov).…”

Current evidence for COVID-19 therapies: a systematic literature review

“…In another small trial (n=20), administration of enoxaparin significantly reduced the median number of ventilator-free days compared with low molecular weight/ unfractionated heparin (0 versus 15 days; p=0.028) and resulted in a higher ratio of successful liberation from mechanical ventilation after respiratory failure (HR 4.0 (95% CI 1.035-15.053); p=0.031) in patients with severe COVID-19 (supplementary table 4) [54]. Trials of ruxolitinib, N-acetylcysteine and rhG-CSF (n=43-200) showed no significant efficacy in reducing need for ventilation in patients with severe COVID-19 [32,48,49] ( figure 4b and supplementary table 4).…”

“…Other therapies Trials (n=20-135) investigating the kinase inhibitor, ruxolitinib [32], the calcium release-activated calcium channel inhibitor, auxora [56], the anticoagulant, enoxaparin [54], and N-acetylcysteine, a mucolytic drug with anti-oxidant properties [49], in patients with severe COVID-19 reported no significant difference in mortality versus the comparator groups (figure 2c). One trial (n=200) reported a reduced 21-day mortality with recombinant human granulocyte colony-stimulating factor (rhG-CSF) added to standard care versus standard care alone (HR 0.19 (95% CI 0.04-0.88)) in patients with severe COVID-19 [48].…”

“…Other therapies Among trials of other therapies, one trial (n=103) reported numerical but nonsignificant trends towards reduced hospitalisation duration and increased numbers of patients discharged with convalescent plasma versus standard care [38] ( figure 3b and table 1). Trials of rhG-CSF (n=200), N-acetylcysteine (n=135), enoxaparin (n=20) and ruxolitinib (n=43) reported no significant impact of these interventions on hospitalisation outcomes versus standard care or placebo [32,48,49,54] (figure 3b and table 1).…”