This randomized clinical trial evaluated the safety and efficacy of two chloroquine diphosphate dosages in patients with severe coronavirus disease 2019 (COVID-19).
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 a 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.
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 the 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 endpoints 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 the high-dosage group and 40 [49.4%] to the 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 instances 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.
The full study is available for free through the link below.
Authors: Marcus Vinícius Guimarães Lacerda, M.D., of the Fundação de Medicina Tropical Dr. Heitor Vieira Dourado in Manaus, Brazil, is the corresponding author.
Reference: “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” by Mayla Gabriela Silva Borba, MD; Fernando Fonseca Almeida Val, PhD; Vanderson Souza Sampaio, PhD; Marcia Almeida Araújo Alexandre, MD; Gisely Cardoso Melo, PhD; Marcelo Brito, MSc; Maria Paula Gomes Mourão, MD; José Diego Brito-Sousa, MSc; Djane Baía-da-Silva, PhD; Marcus Vinitius Farias Guerra, MD; Ludhmila Abrahão Hajjar, MD; Rosemary Costa Pinto, BSc; Antonio Alcirley Silva Balieiro, MSc; Antônio Guilherme Fonseca Pacheco, MD; James Dean Oliveira Santos Jr, PhD; Felipe Gomes Naveca, PhD; Mariana Simão Xavier, MSc; André Machado Siqueira, MD; Alexandre Schwarzbold, MD; Júlio Croda, MD; Maurício Lacerda Nogueira, MD; Gustavo Adolfo Sierra Romero, MD; Quique Bassat, MD; Cor Jesus Fontes, MD; Bernardino Cláudio Albuquerque, MD; Cláudio-Tadeu Daniel-Ribeiro, MD; Wuelton Marcelo Monteiro, PhD and Marcus Vinícius Guimarães Lacerda, MD; for the CloroCovid-19 Team, 24 April 2020, JAMA Network Open.