Pre-Clinical and Randomized Clinical Trial with Bromhexine and N-Acetylcysteine for COVID-19

Abstract

Roberto J. Pires-Neto, Marco Clementino, Rafael F. Mesquita, Mariana S. Lima, Ronaldo B. Martins, Iasmin Ferreira, Jose Quirino-Filho, Rafhaella N. D. G. Gondim, Lyvia M. V. C. Magalhaes, Karene F. Cavalcante, Vania A. F. Viana, Liana P. Mello, Jose K. Souza, Xhaulla M.Q.C. Fonseca, Armenio A. Santos, Pedro J. C. Magalhaes, Alexandre Havt, Erico A. G. Arruda, Juliano P. Souza, Marjorie Pontelli, Italo A. Castro, Thais M. Lima, Rosa M. M. Viana, Daniel M. Jorge, Priscyla D. Marcato, Hugo P. Monteiro, Eurico Arruda, Aldo A. M. Lima and Study Group Members - AVANTI

Treatment options for mild to moderate COVID-19 is limited. N-acetylcysteine and bromhexine have antiviral activity and show potential as treatment options against SARS-CoV-2 infections. This study evaluates the in vitro antiviral effect of bromhexine (BMX) for SARS-CoV-2 and determines the efficacy of treatment with BMX in combination with N-acetylcysteine (NAC) to reduce clinical scores in patients with mild to moderate COVID-19. Upon evidence from pre- clinical studies, a single center randomized trial of BMX + NAC (ClinicalTrials.gov Identifier: NCT04928495) with 420 participants in total took place in Fortaleza, CE, Brazil. Out of the 420 participants 140 received placebo, 140 received NAC alone, and 140 received NAC + BMX. Patients were monitored for 10-14 days, where physicians recorded all signs and symptoms reported. Nasopharyngeal swabs and blood samples were collected for SARS-CoV-2 RNA testing during the first visit, as well as 3 and 10 days after. Blood samples were collected at first visit and 10 days after for immuno-inflammatory biomarkers measurements. Treatment with NAC+BMX reduced clinical scores and symptoms when compared to placebo group (2/26; 8% vs 7/18; 39%; p < 0.05). Fever (≥37.8°C) was reduced by NAC + BMX treatment when compared to treatment with NAC alone and placebo. This study was limited by a largely vaccinated population. Our analysis showed that BMX reduces SARS-CoV-2 infection in vitro. Clinical trial results suggested that combinatory treatment with NAC + BMX is beneficial in mild to moderate COVID-19.

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