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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) InfectionA Randomized Clinical Trial

Educational Objective
To understand the risks associated with using chloroquine diphosphate to treat COVID-19
1 Credit CME
Key Points

Question  How safe and effective are 2 different regimens of chloroquine diphosphate in the treatment of severe coronavirus disease 2019 (COVID-19)?

Findings  In this phase IIb randomized clinical trial of 81 patients with COVID-19, an unplanned interim analysis recommended by an independent data safety and monitoring board found that a higher dosage of chloroquine diphosphate for 10 days was associated with more toxic effects and lethality, particularly affecting QTc interval prolongation. The limited sample size did not allow the study to show any benefit overall regarding treatment efficacy.

Meaning  The preliminary findings from the CloroCovid-19 trial suggest that higher dosage of chloroquine should not be recommended for the treatment of severe COVID-19, especially among patients also receiving azithromycin and oseltamivir, because of safety concerns regarding QTc interval prolongation and increased lethality.

Abstract

Importance  There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

Objective  To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

Design, Setting, and Participants  This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

Interventions  Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

Main Outcomes and Measures  Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

Results  Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

Conclusions and Relevance  The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19.

Trial Registration  ClinicalTrials.gov Identifier: NCT04323527

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Article Information

Accepted for Publication: April 20, 2020.

Published: April 24, 2020. doi:10.1001/jamanetworkopen.2020.8857

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Borba MGS et al. JAMA Network Open.

Corresponding Author: Marcus Vinícius Guimarães Lacerda, MD, Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Av. Pedro Teixeira, 25–Dom Pedro, Manaus–AM, 69040-000, Brazil (marcuslacerda.br@gmail.com).

Author Contributions: Drs Lacerda and Monteiro had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Borba, Val, Sampaio, Melo, Mourão, Guerra, Pacheco, Xavier, Croda, Nogueira, Bassat, Fontes, Monteiro, Lacerda.

Acquisition, analysis, or interpretation of data: Sampaio, Alexandre, Brito, Mourão, Brito-Sousa, Baía-da-Silva, Hajjar, Pinto, Balieiro, Santos Jr, Naveca, Xavier, Siqueira, Schwarzbold, Romero, Albuquerque, Daniel-Ribeiro.

Drafting of the manuscript: Sampaio, Brito-Sousa, Baía-da-Silva, Pinto, Balieiro, Santos Jr, Naveca, Xavier, Nogueira, Bassat, Monteiro, Lacerda.

Critical revision of the manuscript for important intellectual content: Borba, Val, Sampaio, Alexandre, Melo, Brito, Mourão, Brito-Sousa, Guerra, Hajjar, Pacheco, Siqueira, Schwarzbold, Croda, Romero, Bassat, Fontes, Albuquerque, Daniel-Ribeiro, Lacerda.

Statistical analysis: Sampaio, Balieiro, Pacheco, Santos Jr, Xavier.

Obtained funding: Hajjar, Monteiro, Lacerda.

Administrative, technical, or material support: Brito, Mourão, Brito-Sousa, Guerra, Naveca, Schwarzbold, Albuquerque.

Supervision: Borba, Val, Alexandre, Melo, Mourão, Baía-da-Silva, Hajjar, Xavier, Siqueira, Croda, Nogueira, Romero, Fontes, Daniel-Ribeiro, Lacerda.

Conflict of Interest Disclosures: Dr Pacheco reported receiving grants from the National Council for Scientific and Technological Development and the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro during the conduct of the study. Dr Naveca reported receiving grants from the National Council for Scientific and Technological Development and the Coordination for the Improvement of Higher Education Personnel during the conduct of the study.

Funding/Support: Many members of the CloroCovid-19 Team are funded by Fundação de Amparo à Pesquisa do Estado do Amazonas and Coordination for the Improvement of Higher Education Personnel. ISGlobal receives support from the Spanish Ministry of Science and Innovation through Centro de Excelencia Severo Ochoa 2019-2023 Program (grant, CEX2018-000806-S) and from Generalitat de Catalunya through the Centres de Recerca de Catalunya Program. Centro de Investigação em Saúde de Manhiça is supported by the Government of Mozambique and the Spanish Agency for International Development. This study was funded by the Government of the Amazonas State, Farmanguinhos (Fiocruz), Superintendência da Zona Franca de Manaus, Coordination for the Improvement of Higher Education Personnel, Fundação de Amparo à Pesquisa do Estado do Amazonas, and federal funds facilitated by the Brazilian Senate.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: Adria Lemos Vasconcelos, BSc; Adriana Ferreira Praia Marins, BSc; Ágatha Kelly Araújo Costa, BSc; Alex Bezerra Silva Maciel, MSc; Alexandre Oliveira Trindade, BSc; Andiana Souza Dias, BSc; André Lima Guerra Corado, MSc; Anna Gabriela Rezende Santos, BSc; Antonny Michael Silva Sousa, BSc; Bleno Leonam Gonçalves Costa, BSc; Carlos Eduardo Padron Morais, BSc; Caroline Santos Soares, BSc; Debora Camila Gomes Duarte, BSc; Christiane Maria Prado Jeronimo, BSc; Ejandre Garcia Negreiros Silva, BSc; Elisângela Fátima Ponte Frota, BSc; Emanuel Medeiros Marinho Almeida, BSc; Emanuelle Lira Silva, BSc; Erick Frota Gomes Figueiredo, BSc; Fábio Manabu Martins Shimizu, BSc; Fabíola Ramalho Ferreira Souza, BSc; Fernando Hugo Jesus Fonseca, BSc; Fernanda Oliveira do Nascimento, BSc; Flor Ernestina Martinez-Espinosa, MD; Francielen Azevedo Furtado, BSc; Gabrielle Silva Pereira, BSc; Hilda Ferreira Melo, BSc; Ingrid Nascimento Oliveira, BSc; João Ricardo Silva Neto, BSc; Josué Nélio Brutus, BSc; Kelry Mazurega Oliveira Dinelly, BSc; Laleyska Deucylane Costa Rodrigues, BSc; Larissa Esthefani Barros Cirino, BSc; Lorenna Pereira Souza, MD; Lucas Barbosa Oliveira, MSc; Luiz Carlos Lima Ferreira, MD, Luiz Henrique Gonçalves Maciel, MSc; Maria Eduarda Leão Farias, BSc; Monique Freire Santana, MD; Nagila Morais Rocha, BSc; Natália Guedes Melo Silva, BSc; Raíssa Soares Freire, BSc; Rebeca Linhares Abreu-Netto, BSc; Rodrigo Saboia Lima, BSc; Rosângela Francisca Tanantas Melo, BSc; Rossicleia Lins Monte, MSc; Sheila Vitor-Silva, PhD; Thaliê Cavalcante Santos, MD; Valdinete Alves Nascimento, MSc; Vitória Silva Printes, BSc; Wanessa Pessoa Sousa Barbosa, BSc.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Former Brazilian Minister of Health Luiz Henrique Mandetta, MD; his former Secretary of Health Surveillance Wanderson Kleber Oliveira, PhD, and the Secretary of Science and Technology Denizar Vianna, PhD, provided remote support. We thank Ms Camile Sachetti, MSc (Department of Science and Technology), and Jorge Souza Mendonça, MSc (Farmanguinhos, a Brazilian public pharmaceutical industry). We thank José Luiz Gasparini, BSc (Hospital e Pronto Socorro Delphina Rinaldi Abdel Aziz), Governor Wilson Lima, BSc (Amazonas), and his former Secretary of Health, Rodrigo Tobias, PhD. Cleinaldo Costa, MD (Universidade do Estado do Amazonas), provided high-quality, locally produced personal protective equipment to the team. We thank the Industrial Pole in Manaus (Zona Franca de Manaus), which donated tablet computers to the team for data collection at bedside, including business executives Wilson Périco and Marcelo Dutra. Judith Recht, PhD, and Donald Skillman, MD (independent consultants), provided thoughtful input on manuscript preparation. Acknowledged people were not compensated for their contributions.

Additional Information: The study included a data and safety monitoring board composed of Drs Romero, Bassat, Albuquerque, Daniel-Ribeiro, and Fontes. Given their day-to-day involvement in the trial’s activities, their close monitoring of safety events, and their role in the decision to halt the study on account of safety issues, Dr Lacerda decided to invite them on an individual basis to coauthor the manuscript. All members agreed to be included. Drs Siqueira and Daniel-Ribeiro are fellows from Fundação de Apoio à Pesquisa do Estado do Rio de Janeiro. Drs Naveca, Croda, Nogueira, Daniel-Ribeiro, Monteiro and Lacerda are research fellows from Conselho Nacional de Desenvolvimento Científico e Tecnológico. The Laboratório de Pesquisa em Malária from Instituto Oswlado Cruz is a National Institute of Science and Technology on Neuro-Immuno-Modulation–associated laboratory.

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