Nitazoxanide in Patients Hospitalized With COVID-19 Pneumonia: A Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial
Patricia R M Rocco, Pedro L Silva, Fernanda F Cruz, Paulo F G M M Tierno, Eucir Rabello, Jéfiton Cordeiro Junior, Firmino Haag, Renata E De Ávila, Joana D G Da Silva, Mariana M S Mamede, Konrad S Buchele, Luiz C V Barbosa, Anna C Cabral, Antônio A F Junqueira, João A Araújo-Filho, Lucianna A T J Da Costa, Pedro P M Alvarenga, Alexandre S Moura, Ricardo Carajeleascow, Mirella C De Oliveira, Roberta G F Silva, Cynthia R P Soares, Ana Paula S M Fernandes, Flavio Guimarães Fonseca, Vidyleison Neves Camargos, Julia De Souza Reis, Kleber G Franchini, Ronir R Luiz, Sirlei Morais, Carlos Sverdloff, Camila Marinelli Martins, Nathane S Felix, Paula Mattos-Silva, Caroline M B Nogueira, Dayene A F Caldeira, Paolo Pelosi, José R Lapa-E-Silva
Frontiers in Medicine, doi:10.3389/fmed.2022.844728
Background: Nitazoxanide exerts antiviral activity in vitro and in vivo and anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is uncertain. Methods: A multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was intensive care unit admission due to the need for invasive mechanical ventilation. Secondary outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and adverse events within 14 days. Rocco et al.
Nitazoxanide in COVID-19 Pneumonia Patients Results: Of the 498 patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in the analyses. Admission to the intensive care unit did not differ between the groups (hazard ratio [95% confidence interval], 0.68 [0.38-1.20], p = 0.179); death rates also did not differ. Nitazoxanide improved the clinical outcome (2. 75 [2.21-3.43], p < 0.0001), time to hospital discharge (1.37 [1.11-1.71], p = 0.005), and reduced oxygen requirements (0.77 [0.64-0.94], p = 0.011). C-reactive protein, D-dimer, and ferritin levels were lower in the nitazoxanide group than the placebo group on day 7. No serious adverse events were observed. Conclusions: Nitazoxanide, compared with placebo, did not prevent admission to the intensive care unit for patients hospitalized with COVID-19 pneumonia.
ETHICS STATEMENT The studies involving human participants were reviewed and approved by Brazilian National Commission for Research Ethics (CAAE:30662420.0.1001.0008). The patients/participants provided their written informed consent to participate in this study.
AUTHOR CONTRIBUTIONS PR, PS, and FC were involved in the conception and design of the study. PT, ER, JJ, FH, RÁ, JS, MM, KB, LB, AC, AJ, JA-F, LC, PA, AM, RC, MO, RS, and CS were responsible for recruitment and clinical care of the patients. AF was responsible for laboratory analyses. KF, PP, and JL-e-S contributed to data interpretation and critical review of the manuscript. RL, SM, CS, and CM were responsible for the statistical analysis. NF, PM-S, CN, and DC contributed to data collection. All authors reviewed and approved the final version of the manuscript. Authority for Studies and Projects (FINEP), Brasília, Brazil (number: 01.20.0003.00).
SUPPLEMENTARY MATERIAL The The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher...
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of Covid-19 -preliminary report, N Engl J Med,
doi:10.1056/NEJMoa200776Berlin, Gulick, Martinez, Severe Covid-19
Blum, Cimerman, Hunter, Tierno, Lacerda et al., Nitazoxanide superiority to placebo to treat moderate COVID-19 -a pilot prove of concept randomized double-blind clinical trial, EClinicalMedicine,
doi:10.1016/j.eclinm.2021.100981Core, R: A Language and Environment for Statistical Computing
Guan, Ni, Hu, Liang, Ou et al., Clinical characteristics of Coronavirus Disease 2019 in China, N Engl J Med,
doi:10.1056/NEJMoa2002032Haffizulla, Hartman, Hoppers, Resnick, Samudrala et al., Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial, Lancet Infect Dis,
doi:10.1016/S1473-3099(14)70717-0Harris, Taylor, Minor, Elliott, Fernandez et al., The REDCap consortium: building an international community of software platform partners, J Biomed Inform,
doi:10.1016/j.jbi.2019.103208Hong, Kim, Song, Choi, Lee et al., Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice, Int Immunopharmacol,
doi:10.1016/j.intimp.2012.03.002Horby, Lim, Emberson, Mafham, Bell et al., Dexamethasone in Hospitalized Patients with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2021436Kalil, Patterson, Mehta, Tomashek, Wolfe et al., Baricitinib plus Remdesivir for hospitalized adults with Covid-19, N Engl J Med,
doi:10.1056/NEJMoa2031994Munch, Myatra, Vijayaraghavan, Saseedharan, Benfield et al., Effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support in adults with COVID-19 and severe hypoxemia: the COVID STEROID 2 randomized trial, JAMA,
doi:10.1001/jama.2021.18295Raut, Huy, Rising incidence of mucormycosis in patients with COVID-19: another challenge for India amidst the second wave?, Lancet Respir Med,
doi:10.1016/S2213-2600(21)00265-4Rocco, Silva, Cruz, Junior, Tierno et al., Early use of nitazoxanide in mild Covid-19 disease: randomised, placebocontrolled trial, Eur Respir J,
doi:10.1183/13993003.03725-2020Rossignol, Bardin, Fulgencio, Mogelnicki, Bréchot, A randomized double-blind placebo-controlled clinical trial of nitazoxanide for treatment of mild or moderate COVID-19, EClinicalMedicine,
doi:10.1016/j.eclinm.2022.101310Schulz, Altman, Moher, Consort, statement: updated guidelines for reporting parallel group randomised trials, BMJ,
doi:10.1136/bmj.c332Shou, Kong, Wang, Tang, Wang et al., Tizoxanide inhibits inflammation in LPS-activated RAW264.7 macrophages via the suppression of NF-kappaB and MAPK activation, Inflammation,
doi:10.1007/s10753-019-00994-3Singh, Singh, Joshi, Misra, Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India, Diabetes Metab Syndr,
doi:10.1016/j.dsx.2021.05.019Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res,
doi:10.1038/s41422-020-0282-0Wang, Zhang, Du, Du, Zhao et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial, Lancet,
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'abstract': '<jats:sec><jats:title>Background</jats:title><jats:p>Nitazoxanide exerts antiviral activity '
'<jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> and '
'anti-inflammatory effects, but its impact on patients hospitalized with COVID-19 pneumonia is '
'uncertain.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>A '
'multicentre, randomized, double-blind, placebo-controlled trial was conducted in 19 hospitals '
'in Brazil. Hospitalized adult patients requiring supplemental oxygen, with COVID-19 symptoms '
'and a chest computed tomography scan suggestive of viral pneumonia or positive RT-PCR test '
'for COVID-19 were enrolled. Patients were randomized 1:1 to receive nitazoxanide (500 mg) or '
'placebo, 3 times daily, for 5 days, and were followed for 14 days. The primary outcome was '
'intensive care unit admission due to the need for invasive mechanical ventilation. Secondary '
'outcomes included clinical improvement, hospital discharge, oxygen requirements, death, and '
'adverse events within 14 '
'days.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Of the 498 '
'patients, 405 (202 in the nitazoxanide group and 203 in the placebo group) were included in '
'the analyses. Admission to the intensive care unit did not differ between the groups (hazard '
'ratio [95% confidence interval], 0.68 [0.38–1.20], <jats:italic>p</jats:italic> = 0.179); '
'death rates also did not differ. Nitazoxanide improved the clinical outcome (2.75 '
'[2.21–3.43], <jats:italic>p</jats:italic> &lt; 0.0001), time to hospital discharge (1.37 '
'[1.11–1.71], <jats:italic>p</jats:italic> = 0.005), and reduced oxygen requirements (0.77 '
'[0.64–0.94], <jats:italic>p</jats:italic> = 0.011). C-reactive protein, D-dimer, and ferritin '
'levels were lower in the nitazoxanide group than the placebo group on day 7. No serious '
'adverse events were '
'observed.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Nitazoxanide, '
'compared with placebo, did not prevent admission to the intensive care unit for patients '
'hospitalized with COVID-19 pneumonia.</jats:p></jats:sec><jats:sec><jats:title>Clinical Trial '
'Registration</jats:title><jats:p>Brazilian Registry of Clinical Trials (REBEC) RBR88bs9x; '
'<jats:ext-link>ClinicalTrials.gov</jats:ext-link>, NCT04561219.</jats:p></jats:sec>',
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