Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
Alexandre B Cavalcanti, Fernando G Zampieri, Regis G Rosa, Luciano C P Azevedo, Viviane C Veiga, Alvaro Avezum, Lucas P Damiani, Aline Marcadenti, Letícia Kawano-Dourado, Thiago Lisboa, Debora L M Junqueira, Pedro G M De Barros E Silva, Lucas Tramujas, Erlon O Abreu-Silva, Ligia N Laranjeira, Aline T Soares, Leandro S Echenique, Adriano J Pereira, Flávio G R Freitas, Otávio C E Gebara, Vicente C S Dantas, Remo H M Furtado, Eveline P Milan, Nicole A Golin, Fábio F Cardoso, Israel S Maia, Conrado R Hoffmann Filho, Adrian P M Kormann, Roberto B Amazonas, Monalisa F Bocchi De Oliveira, Ary Serpa-Neto, Maicon Falavigna, Renato D Lopes, Flávia R Machado, Otavio Berwanger
New England Journal of Medicine, doi:10.1056/nejmoa2019014
BACKGROUND Hydroxychloroquine and azithromycin have been used to treat patients with coronavirus disease 2019 (Covid-19). However, evidence on the safety and efficacy of these therapies is limited.
METHODS We conducted a multicenter, randomized, open-label, three-group, controlled trial involving hospitalized patients with suspected or confirmed Covid-19 who were receiving either no supplemental oxygen or a maximum of 4 liters per minute of supplemental oxygen. Patients were randomly assigned in a 1:1:1 ratio to receive standard care, standard care plus hydroxychloroquine at a dose of 400 mg twice daily, or standard care plus hydroxychloroquine at a dose of 400 mg twice daily plus azithromycin at a dose of 500 mg once daily for 7 days. The primary outcome was clinical status at 15 days as assessed with the use of a seven-level ordinal scale (with levels ranging from one to seven and higher scores indicating a worse condition) in the modified intention-to-treat population (patients with a confirmed diagnosis of Covid-19). Safety was also assessed.
RESULTS A total of 667 patients underwent randomization; 504 patients had confirmed Covid-19 and were included in the modified intention-to-treat analysis. As compared with standard care, the proportional odds of having a higher score on the seven-point ordinal scale at 15 days was not affected by either hydroxychloroquine alone (odds ratio, 1.21; 95% confidence interval [CI], 0.69 to 2.11; P = 1.00) or hydroxychloroquine plus azithromycin (odds ratio, 0.99; 95% CI, 0.57 to 1.73; P = 1.00). Prolongation of the corrected QT interval and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent.
CONCLUSIONS Among patients hospitalized with mild-to-moderate Covid-19, the use of hydroxychloroquine, alone or with azithromycin, did not improve clinical status at 15 days as compared with standard care. (Funded by the Coalition Covid-19 Brazil and EMS Pharma; ClinicalTrials.gov number, NCT04322123.
droxychloroquine plus azithromycin. Patients who received hydroxychloroquine, either with azithromycin or alone, had more frequent events of QTc interval prolongation and elevation of liver-enzyme levels than patients who did not receive either agent. Supported by institutions participating in the Coalition Covid-19 Brazil and by EMS Pharma, which provided partial funding, the trial drugs, and logistic support. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Appendix
References
Borba, Val, Sampaio, Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial, JAMA Netw Open
Boulware, Pullen, Bangdiwala, A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19, N Engl J Med
Cao, Wang, Wen, A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19, N Engl J Med
Core, R: a language and environment for statistical computing
Gautret, Lagier, Parola, Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Int J Antimicrob Agents
Geleris, Sun, Platt, Observational study of hydroxychloroquine in hospitalized patients with Covid-19, N Engl J Med
Grasselli, Zangrillo, Zanella, Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy region, Italy, JAMA
Harris, Taylor, Minor, The REDCap consortium: building an international community of software platform partners, J Biomed Inform
Haybittle, Repeated assessment of results in clinical trials of cancer treatment, Br J Radiol
Liu, Cao, Xu, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov
Rosenberg, Dufort, Udo, Association of treatment with hydroxychloroquine or azithromycin with in-hospital mortality in patients with COVID-19 in New York State, JAMA
Tang, Cao, Han, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ
Vaduganathan, Van Meijgaard, Mehra, Joseph, Donnell et al., Prescription fill patterns for commonly used drugs during the COVID-19 pandemic in the United States, JAMA
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
'L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., '
'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Eveline P.',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Nicole A.',
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
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'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Fábio F.',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Israel S.',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
'L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., '
'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
'R.D.L.), Hospital...'}]},
{ 'given': 'Conrado R.',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Adrian P.M.',
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Roberto B.',
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
'R.D.L.), Hospital...'}]},
{ 'given': 'Monalisa F.',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Ary',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
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'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Maicon',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
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'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
'R.D.L.), Hospital...'}]},
{ 'given': 'Renato D.',
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'sequence': 'additional',
'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
'L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., '
'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
'R.D.L.), Hospital...'}]},
{ 'given': 'Flávia R.',
'family': 'Machado',
'sequence': 'additional',
'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
'L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., '
'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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{ 'given': 'Otavio',
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'affiliation': [ { 'name': 'From HCor Research Institute (A.B.C., F.G.Z., L.P.D., A.M., '
'L.K.-D., T.L., D.L.M.J., P.G.M.B.S., L.T., E.O.A.-S., L.N.L., '
'I.S.M.), Brazilian Research in Intensive Care Network (A.B.C., '
'F.G.Z., R.G.R., L.C.P.A., V.C.V., T.L., F.G.R.F., A.S.-N., '
'F.R.M.), Hospital Sírio Libanês Research and Education Institute '
'(L.C.P.A.), BP–A Beneficência Portuguesa de São Paulo (V.C.V.), '
'International Research Center, Hospital Alemão Oswaldo Cruz '
'(A.A.), Brazilian Clinical Research Institute (P.G.M.B.S., '
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'container-title': 'New England Journal of Medicine',
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'language': 'en',
'link': [ { 'URL': 'http://www.nejm.org/doi/pdf/10.1056/NEJMoa2019014',
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'deposited': { 'date-parts': [[2020, 11, 18]],
'date-time': '2020-11-18T21:59:36Z',
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'subtitle': [],
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'issued': {'date-parts': [[2020, 11, 19]]},
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'journal-issue': {'issue': '21', 'published-print': {'date-parts': [[2020, 11, 19]]}},
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'URL': 'http://dx.doi.org/10.1056/NEJMoa2019014',
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