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
Mayla Gabriela Silva Borba, Fernando Fonseca Almeida Val, Vanderson Souza Sampaio, Marcia Almeida Araújo Alexandre, Gisely Cardoso Melo, MSc Marcelo Brito, Maria Paula Gomes Mourão, MSc José Diego Brito-Sousa, PhD; Djane Baía-Da-Silva, Marcus Vinitius Farias Guerra, Ludhmila Abrahão Hajjar, BSc Rosemary Costa Pinto, Antonio Alcirley Silva Balieiro, Antônio Guilherme Fonseca Pacheco, James Dean Oliveira Santos, Felipe Gomes Naveca, MSc Mariana Simão Xavier, André Machado Siqueira, MD Alexandre Schwarzbold, MD; Maurício Júlio Croda, Maurício Lacerda Nogueira, Gustavo Adolfo Sierra Romero, MD; Cor Quique Bassat, Cor Jesus Fontes, Bernardino Cláudio Albuquerque, Cláudio-Tadeu Daniel-Ribeiro, Wuelton Marcelo Monteiro, Marcus Vinícius Guimarães Lacerda
JAMA Network Open, doi:10.1001/jamanetworkopen.2020.8857
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 highdosage 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 highdosage 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 (continued) 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..
Abbreviation: CK, creatine phosphokinase; CKMB, creatinine phosphokinase-MB; COVID-19, coronavirus disease 2019; QTcF, QT interval corrected by the Fridericia method. a Not all patients completed day 13 visit before this article was finalized. b Low-dosage group received chloroquine for 5 days (450 mg twice daily on the first day and 450 mg once daily for 4 days). c High-dosage group received chloroquine for 10 days (600 mg twice daily for 10 days). d Decreases in hemoglobin level of more than 3 g/dL or 30% or greater from baseline are shown. e Increases in creatinine serum levels of 30% or more from baseline are shown. f Serious adverse events related to the trial regimen were prolongation of the QTcF. Lethality among critically ill patients in the present study seemed to be even higher than among similar patients not receiving CQ in a large historical sample-size cohort of patients in Lombardy, Italy. 24 That could reflect the quality of intensive care units in both countries or the possible lack of or deleterious effect of CQ in such patients with COVID-19. The occurrence of myocarditis in our sample, with the confirmed QTcF prolongation, warrants caution regarding this drug's safety, particularly considering the eventual increase in fatal arrythmias, such as ventricular tachycardia.
Strengths and Limitations This study had some strengths. It was double-masked; performed in a public hospital, which will manage most cases in countries like Brazil; compliant with good..
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