Double-blind, Randomized, Placebo-controlled Trial With N-acetylcysteine for Treatment of Severe Acute Respiratory Syndrome Caused by Coronavirus Disease 2019 (COVID-19)
Authors: de Alencar Julio Cesar Garcia , Moreira Claudia de Lucena , Müller Alicia Dudy , Chaves Cleuber Esteves , Fukuhara Marina Akemi , da Silva Elizabeth Aparecida , Miyamoto Maria de Fátima Silva , Pinto Vanusa Barbosa , Bueno Cauê Gasparotto , Lazar Neto Felippe , Gomez Gomez Luz Marina , Menezes Maria Clara Saad , Marchini Julio Flavio Meirelles , Marino Lucas Oliveira , Brandão Neto Rodrigo Antônio , Souza Heraldo Possolo ,   COVID Register Group, Valente Fernando Salvetti , Rahhal Hassan , Pereira Juliana Batista Rodrigues , Padrão Eduardo Messias Hirano , Wanderley Annelise Passos Bispos , Marques Bruno , Gomez Luz Marina Gomez , D’Souza Edwin Albert , Bellintani Arthur Petrillo , Miléo Rodrigo Cezar , Toccoli Rodrigo Werner , Silva Fernanda Máximo Fonseca e , Baptista João Martelleto , Silva Marcelo de Oliveira , Costa Giovanna Babikian , Luna Rafael Berenguer , dos Santos Henrique Tibucheski , De Calasans Mariana Mendes Gonçalves Cimatti , Sanches Marcelo Petrof , Takamune Diego Juniti , Boscolo Luiza , Simões Pedro Antonio Araújo , Pandolfi Manuela Cristina Adsuara , Fantinatti Beatriz Larios , Travessini Gabriel , de Faria Matheus Finardi Lima , Lima Ligia Trombetta , Nicolao Bianca Ruiz , Escudeiro Gabriel de Paula Maroni , Nascimento João Pedro Afonso , Caldeira Bruna Tolentino , Campos Laura de Góes , Medeiros Vitor Macedo Brito , Monsalvarga Tales Cabral , Omori Isabela Harumi , Guidotte Diogo Visconti , Bortolotto Alexandre Lemos , Abreu Rodrigo de Souza , Martins Nilo Arthur Bezerra , Juck Carlos Eduardo Umehara , Utiyama Lucas de Oliveira , Bortoleto Felipe Mouzo , Tinel Renan Dourado , Andreola Gabriel Martinez , Cardoso Natalia Paula , Claure Osvaldo Santistevan , Lopes João Vitor Ziroldo , da Costa Ribeiro Sabrina Correa 
Published: September 2020

Abstract

Background
A local increase in angiotensin 2 after inactivation of angiotensin-converting enzyme 2 by severe acute respiratory syndrome coronavirus 2 (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 patients with coronavirus disease 2019 (COVID-19).

Methods
This was a double-blind, randomized, placebo-controlled, single-center trial conducted at the Emergency Department of Hospital das Clínicas, São Paulo, Brazil, to determine whether NAC in high doses can avoid respiratory failure in patients with COVID-19. We enrolled 135 patients with severe COVID-19 (confirmed or suspected), with an oxyhemoglobin saturation &lt;94% or respiratory rate &gt;24 breaths/minute. Patients were randomized to receive NAC 21 g (~300 mg/kg) for 20 hours or dextrose 5%. The primary endpoint was the need for mechanical ventilation. Secondary endpoints were time of mechanical ventilation, admission to the intensive care unit (ICU), time in ICU, and mortality.

Results
Baseline characteristics were similar between the 2 groups, with no significant differences in age, sex, comorbidities, medicines taken, and disease severity. Also, groups were similar in laboratory tests and chest computed tomography scan findings. Sixteen patients (23.9%) in the placebo group received endotracheal intubation and mechanical ventilation, compared with 14 patients (20.6%) in the NAC group (P = .675). No difference was observed in secondary endpoints.

Conclusions
Administration of NAC in high doses did not affect the evolution of severe COVID-19.

Clinical Trials Registration
Brazilian Registry of Clinical Trials (REBEC): U1111-1250-356 (http://www.ensaiosclinicos.gov.br/rg/RBR-8969zg/).