Remo H M Furtado1, Otavio Berwanger2, Henrique A Fonseca3, Thiago D Corrêa4, Leonardo R Ferraz3, Maura G Lapa3, Fernando G Zampieri5, Viviane C Veiga6, Luciano C P Azevedo7, Regis G Rosa8, Renato D Lopes9, Alvaro Avezum10, Airton L O Manoel11, Felipe M T Piza11, Priscilla A Martins12, Thiago C Lisboa13, Adriano J Pereira14, Guilherme B Olivato14, Vicente C S Dantas15, Eveline P Milan16, Otavio C E Gebara17, Roberto B Amazonas18, Monalisa B Oliveira18, Ronaldo V P Soares3, Diogo D F Moia3, Luciana P A Piano3, Kleber Castilho3, Roberta G R A P Momesso3, Guilherme P P Schettino3, Luiz Vicente Rizzo3, Ary Serpa Neto19, Flávia R Machado20, Alexandre B Cavalcanti5. 1. Hospital Israelita Albert Einstein, São Paulo, Brazil; Instituto do Coração, Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, Brazil. 2. Hospital Israelita Albert Einstein, São Paulo, Brazil. Electronic address: otavio.berwanger@einstein.br. 3. Hospital Israelita Albert Einstein, São Paulo, Brazil. 4. Hospital Israelita Albert Einstein, São Paulo, Brazil; Brazilian Research in Intensive Care Network, São Paulo, Brazil. 5. Brazilian Research in Intensive Care Network, São Paulo, Brazil; HCor Research Institute, São Paulo, Brazil. 6. Brazilian Research in Intensive Care Network, São Paulo, Brazil; BP-A Beneficência Portuguesa de São Paulo, São Paulo, Brazil. 7. Brazilian Research in Intensive Care Network, São Paulo, Brazil; Hospital Sírio Libanês Research and Education Institute, São Paulo, Brazil. 8. Brazilian Research in Intensive Care Network, São Paulo, Brazil; Hospital Moinhos de Vento, Porto Alegre, Brazil. 9. Brazilian Clinical Research Institute, São Paulo, Brazil; Duke University Medical Centre, Duke Clinical Research Institute, Durham, NC, USA. 10. International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil. 11. Hospital Moyses Deustche (MBoi Mirim), São Paulo, Brazil. 12. Hospital Estadual Jayme dos Santos Neves, Serra, Brazil. 13. Hospital de Clínicas, Porto Alegre, Brazil. 14. Hospital Israelita Albert Einstein, São Paulo, Brazil; Hospital Vila Santa Catarina, São Paulo, Brazil. 15. Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil. 16. Hospital Giselda Trigueiro, Natal, Brazil. 17. Hospital Santa Paula, São Paulo, Brazil. 18. EMS Pharma, Hortolândia, Brazil. 19. Hospital Israelita Albert Einstein, São Paulo, Brazil; Brazilian Research in Intensive Care Network, São Paulo, Brazil; Australian and New Zealand Intensive Care Research Centre, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. 20. Brazilian Research in Intensive Care Network, São Paulo, Brazil; Department of Anesthesiology, Pain and Intensive Care Medicine, Universidade Federal de São Paulo, São Paulo, Brazil.
Abstract
BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use ofoxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2 infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS:447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.
RCT Entities:
BACKGROUND: The efficacy and safety of azithromycin in the treatment of COVID-19 remain uncertain. We assessed whether adding azithromycin to standard of care, which included hydroxychloroquine, would improve clinical outcomes of patients admitted to the hospital with severe COVID-19. METHODS: We did an open-label, randomised clinical trial at 57 centres in Brazil. We enrolled patients admitted to hospital with suspected or confirmed COVID-19 and at least one additional severity criteria as follows: use of oxygen supplementation of more than 4 L/min flow; use of high-flow nasal cannula; use of non-invasive mechanical ventilation; or use of invasive mechanical ventilation. Patients were randomly assigned (1:1) to azithromycin (500 mg via oral, nasogastric, or intravenous administration once daily for 10 days) plus standard of care or to standard of care without macrolides. All patients received hydroxychloroquine (400 mg twice daily for 10 days) because that was part of standard of care treatment in Brazil for patients with severe COVID-19. The primary outcome, assessed by an independent adjudication committee masked to treatment allocation, was clinical status at day 15 after randomisation, assessed by a six-point ordinal scale, with levels ranging from 1 to 6 and higher scores indicating a worse condition (with odds ratio [OR] greater than 1·00 favouring the control group). The primary outcome was assessed in all patients in the intention-to-treat (ITT) population who had severe acute respiratory syndrome coronavirus 2infection confirmed by molecular or serological testing before randomisation (ie, modified ITT [mITT] population). Safety was assessed in all patients according to which treatment they received, regardless of original group assignment. This trial was registered at ClinicalTrials.gov, NCT04321278. FINDINGS: 447 patients were enrolled from March 28 to May 19, 2020. COVID-19 was confirmed in 397 patients who constituted the mITT population, of whom 214 were assigned to the azithromycin group and 183 to the control group. In the mITT population, the primary endpoint was not significantly different between the azithromycin and control groups (OR 1·36 [95% CI 0·94-1·97], p=0·11). Rates of adverse events, including clinically relevant ventricular arrhythmias, resuscitated cardiac arrest, acute kidney failure, and corrected QT interval prolongation, were not significantly different between groups. INTERPRETATION: In patients with severe COVID-19, adding azithromycin to standard of care treatment (which included hydroxychloroquine) did not improve clinical outcomes. Our findings do not support the routine use of azithromycin in combination with hydroxychloroquine in patients with severe COVID-19. FUNDING: COALITION COVID-19 Brazil and EMS.
Authors: Renato D Lopes; Ariane V S Macedo; Pedro G M de Barros E Silva; Renata J Moll-Bernardes; Tiago M Dos Santos; Lilian Mazza; André Feldman; Guilherme D'Andréa Saba Arruda; Denílson C de Albuquerque; Angelina S Camiletti; Andréa S de Sousa; Thiago C de Paula; Karla G D Giusti; Rafael A M Domiciano; Márcia M Noya-Rabelo; Alan M Hamilton; Vitor A Loures; Rodrigo M Dionísio; Thyago A B Furquim; Fábio A De Luca; Ítalo B Dos Santos Sousa; Bruno S Bandeira; Cleverson N Zukowski; Ricardo G G de Oliveira; Noara B Ribeiro; Jeffer L de Moraes; João L F Petriz; Adriana M Pimentel; Jacqueline S Miranda; Bárbara E de Jesus Abufaiad; C Michael Gibson; Christopher B Granger; John H Alexander; Olga F de Souza Journal: JAMA Date: 2021-01-19 Impact factor: 56.272
Authors: Matteo Bassetti; Daniele Roberto Giacobbe; Paolo Bruzzi; Emanuela Barisione; Stefano Centanni; Nadia Castaldo; Silvia Corcione; Francesco Giuseppe De Rosa; Fabiano Di Marco; Andrea Gori; Andrea Gramegna; Guido Granata; Angelo Gratarola; Alberto Enrico Maraolo; Malgorzata Mikulska; Andrea Lombardi; Federico Pea; Nicola Petrosillo; Dejan Radovanovic; Pierachille Santus; Alessio Signori; Emanuela Sozio; Elena Tagliabue; Carlo Tascini; Carlo Vancheri; Antonio Vena; Pierluigi Viale; Francesco Blasi Journal: Infect Dis Ther Date: 2021-07-30
Authors: Miguel de Lemos Neto; Rafael Costa Vieira Alexandre; Rafaela Oliveira Gallart Morra; Juliana Aparecida Souza da Paz; Shana Priscila Coutinho Barroso; Angela Castro Resende; Daniel J M de Medeiros-Lima; Pedro Celso Braga Alexandre Journal: Pharmacol Rep Date: 2021-06-04 Impact factor: 3.024