Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19
Authors: Emerson Boschi da Silva
Sara Mohrbacher
Leandro Echenique
Eveline P Milan
Fernando Merlos
Jimena Eva Barriviera de Torre
Gedealvares Francisco de Souza Junior
Daniel Schneider
Lucas Pereira Mallman
Lucas Tramujas
Hugo Bertpaglia
Adrian P M Kormann
Bruna P Gimenes
Priscilla de Aquino Martins
Regis G Rosa
Conrado Roberto Hoffmann Filho
Jorge Luiz Paranhos
Eduardo Teodoro Gurgel de Oliveira
Gustavo Parfume de Sá
Ary Serpa-Neto
André Luiz Nunes Gobatto
Arthur M E Kummer
Aline Marcadenti
Maicon Falavigna
Alessandra Silva Barros Macedo Costa
Karina Negrelli
Thiago Correa
Evelin C Sanchez
Priscila Freitas das Neves Gonçalves
Adriano J Pereira
Alexandre de Matos Soeiro
Cecília Netto Costa da Fonseca
Michael Bailey
Pedro Isaacsonn Velho
Júlio César de Carvalho
Cintia Magalhães Carvalho Grion
Sandra Nivea Dos Reis Saraiva Falcão
Glauco Adrieno Westphal
Sabrina Sabino
Vinicius Ponzio da Silva
Salomon Rojas
Flávia R Machado
Flavia C S Kojima
Orlando Sandoval Farias Jr
Jacqueline T Silva
Eduardo Fellipe Assef Coelho
Luis Henrique Simões Covello
Nanci Valeis
Camila Ragne Torreglosa
Jordana R Homsi
Artur Martins Codeço
Mariana Martins Dos Santos Leal
Aline Reis de Albuquerque
Fátima Maria Venâncio Porfirio
Denise Paisani
Andrei G Peleias
Coalition Covid-19 Brazil I Investigators
Otavio Celso Eluf Gebara
Fábio de Castro Jorge Racy
Gabriela V Batista
Cristiane Dos Santos Costa
Bruna Martins Pereira Vianna
Viviane B Campos
Flávio G R Freitas
Jádina Spricigo
Priscilla Alves Barreto
Nathaly Fonseca Nunes
Fernanda Esteves Nascimento Barros
Marina Politi Okoshi
Beatriz Arns
Henrique Fonseca
Aline Albuquerque
Viviane Cordeiro Veiga
Vivian Viera Rodrigues
Rinaldo Bellomo
Victor Augusto Hamamoto Sato
Carla Andressa Dal Ponte
Angela C B Ferreira
Sergio Seiji Yamada
Rafael Chaves Ferreira
Leonardo R Ferraz
Cintia Grion
Cláudio Galvão
Lucas Ribeiro Silva
Guilherme Schettino
Leonardo Brauer
Patrícia Oliveira Guimarães
Fábio F Cardoso
Alline S de Souza
Hugo Urbano
Gregory Saraiva Medeiros
Rodrigo C Figueiredo
Conrado R Hoffmann Filho
Glauco Westphal
Aline T Soares
Rosa R M Dos Santos
Rafaela Rádner Reis de Oliveira
Remo Furtado
Israel S Maia
José Francisco Kerr Saraiva
Luciano C P Azevedo
Marcos Eiró
Angela Cristine Bersch Ferreira
Alexandre Teruya
Luiz V Rizzo
Mônica Ribeiro de Campos
Erlon O Abreu-Silva
Rafaela Martelosso Secron
Debora L M Junqueira
Renato D Lopes
Adriano José Pereira
Denise de Souza
Mauro Esteves Hernandes
Audes Diógenes de Magalhães Feitosa
Fábio Fernandes Cardoso
Aline Thomaz Soares
Isabele Berti
Eduardo Sprinz
Felipe Dal-Pizzol
Ricardo D&#x27;Oliveira Vieira
Ligia N Laranjeira
Camila R Torreglosa
Hugo Diógenes de Oliveira Paiva
Andréia Ribeiro da Rocha
Raquel Wanzuita
Bruna M P Vianna
Samara Pinheiro do Carmo Gomes
Eliana V Santucci
Bruno Martins Tomazini
Roberto B Amazonas
José A O Suarez
Bruno M Tomazini
Pedro G M de Barros E Silva
Gabriela Cordeiro de Carvalho
Antônio Tonete Bafi
Daniel Vicente da Silva
Débora M de Oliveira
Aline Braz Pereira
Ricardo Antônio Bonifácio de Moura
Felipe Dal Pizzol
Eveline Pipolo Milan
Remo H M Furtado
Frederico Toledo Campo Dall&#x27;Orto
André Gobatto
Letícia Kawano-Dourado
Tamiris Abait
Flavio G R Freitas
Aline Daiane Schlindwein
Fabricio Assami Borges
Rafael Osellame
Luiz Eduardo Fonteles Ritt
Paul Young
Caroline Cabral Robinson
Priscila Regina Torres Bueno
Manoella do Monte Alves
Odilson Marcos Silvestre
Alexandre B Cavalcanti
Sabrina S da Silva
Leandro Cacciari Cardozo Porto
Remo Holanda Furtado
Luiz Fernando Degrecci Relvas
Thiago Lisboa
Milla Carolina Costa Lafetá Araújo
Renato Barcelos de Oliveira
Gabriel Augusto Cordeiro Dos Santos
Joaquim Squizato Alano
Cássio Zandonai
Natalia Avanzi
Monica Baumgardt Bay
Fernando G Zampieri
Alvaro Avezum
Vicente Cés de Souza Dantas
Rachel Helena Vieira Machado
Thales Aníbal Leite Barros Agostinho
Rachel H V Machado
Flávio Geraldo Rezende de Freitas
Dayanna de Oliveira Quintanilha Palme
Franciele De Bortoli
Nicole Alberti Golin
Glaucia Chaves
Arcangela C Elias do Valle
Rafael M Soares
Danielle Leão
Regis Rosa
Maiko Moura Silveira
Isabella de Andrade Jesuino
Otavio Berwanger
Philip Scheinberg
Otávio C E Gebara
Ana Tarina Alvares Lopes
Flávia Ribeiro Machado
Adrian Kormann
Rodrigo Biondi
Sidiner Mesquita Vaz
Talga Caroline Aires Maciel
Vicente C S Dantas
Leandro S Echenique
Renata da Silva Bolan
Rodrigo Thot Leite
Viviane C Veiga
Alexandre Pereira Tognon
Gabriela Verzolla Gomes da Silva
Juliana Giacomazzi
Ary Serpa Neto
Rodrigo Sacci de Freitas Santos
Rafael Marques Soares
Nicole A Golin
Fernando A Bozza
Renata Vicente da Penha
João Prats
Eduardo Leite
Geraldine Trott
Lucas P Damiani
Adriana Coracini Tonacio de Proença
Monalisa F Bocchi de Oliveira
Journal: New England Journal of Medicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Hydroxychloroquine; azithromycin; Covid-19; randomized trial; clinical status
Affiliations: 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 São Camilo (A.T.S.), Hospital Moriah (L.S.E.), Academic Research Organization of Hospital Israelita Albert Einstein (R.H.M.F., O.B.), Hospital Israelita Albert Einstein (L.S.E., A.J.P., A.S.-N.), Hospital Sepaco (F.G.R.F.), and Hospital Santa Paula (O.C.E.G.), São Paulo, Hospital Moinhos de Vento, Porto Alegre (R.G.R., M.F.), Hospital Naval Marcílio Dias, Rio de Janeiro (V.C.S.D.), Hospital Giselda Trigueiro, Natal (E.P.M.), Instituto Tacchini de Pesquisa em Saúde, Hospital Tacchini, Bento Gonçalves (N.A.G.), Hospital Bruno Born, Lajeado (F.F.C.), Hospital Baia Sul, Florianópolis (I.S.M.), Hospital Regional Hans Dieter Schmidt, Joinville (C.R.H.F.); Angiocor Blumenau, Blumenau (A.P.M.K.), and EMS Pharma, Hortolândia (R.B.A., M.F.B.O.) - all in Brazil; and Duke Clinical Research Institute, Duke University Medical Center, Durham, NC (R.D.L.)., 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...

Abstract:  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.). 

Retracted: No

PubPeer comments:
 Dr. Calvalcanti, Dr. Zampieri, and your valiant doctors of Brazil, Thank you in advance for clarifying a few aspects of your study. u2022 u00a0 Why were ICU patients included in your baseline of mild-to-moderate patients Covid-19 study? At baseline, 13.8% of patients in all study arms were in the ICU. Admission to ICU indicates severeu00a0Covid-19.u00a0(see screen shot of Table 1: Characteristics of the Patients at Baseline (pg 4)) u2022 u00a0 Of the 18 patients (or 13 patients) who died during the study, how many of them were in the ICU at the time of randomization baseline?u00a0 In other words, regardless of which study arm, did those who were the sickest at the time of randomization, die? u2022 u00a0 A contradiction in data: At baseline, 42% of the HCQ Azithromycin arm were hospitalized and receiving supplemental oxygen (level 4).u00a0Yet, 13.8% of the patients in this same arm were in the ICU.u00a0u00a0 Both conditions cannot be true at the same time. If a patient is on supplemental oxygen, then he is NOT intubated in the ICU.u00a0 In the USA, ICU admission protocol implies intubation (which therefore requires ventilation.) Is there a different protocol in Brazil? (Again see screen shot of Table 1: Characteristics of the Patients at Baseline (pg 4)) u2022 u00a0Aside from the HCQ Azithromycin arm, the data of the other two arms of the study were contaminated with patients who received HCQ Azithromycin. u00a0 For example, in the Control Group, 10% of the patients received HCQ azithromycin or HCQ. u00a0 See Screen shot ofu00a0the Supplementary Appendix,u00a0 Figure S1. (Pg 34)u00a0(PLEASE DOUBLECLICK THE IMAGE to see all three arms). u2022 u00a0u201cSome protocol deviations.u201d This is an understatement:u00a0u00a0Since this was not a blinded study, the doctors understandably were not willing to hold back a treatment option for a patient in order to preserve the data integrity of the arm that they were assigned. See attached screen shot of Discussion on page 11. u2022 u00a0 Extremely high doses:u00a0 This trialu2019s HCQ dosage - twice as high as that advocated by protocols for Covid-19 - is extremely high: 800 mg (400 mg bid) of Hydroxychloroquine per day for seven days.u00a0 u00a0 For comparison, 97% of the patients in the Henry Ford study dosed at 400u2005mg twice daily for 2 doses on day 1, followed by 200u2005mg twice daily on days 2u20135. The authorsu2019 definition of u201cearlyu201d is, in fact, really late. u201cHydroxychloroquine was administered relatively early after symptom onset median seven days.u201d Given that all treatment groups were hospitalized on O2 or in the ICU at baseline, the name of the title is misleading. It should have been named,u201dHydroxychloroquine with or without Azithromycin in hospitalized, Moderate-to-Severe COVID-19 patients.u201c Thank you for your consideration. ![file] ![file] ![file] ![](http: ) ,