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
Authors: Ludhmila Abrahão Hajjar
Júlio Croda
Marcia Almeida Araújo Alexandre
Marcus Vinitius Farias Guerra
Gustavo Adolfo Sierra Romero
Maurício Lacerda Nogueira
Antonio Alcirley Silva Balieiro
Wuelton Marcelo Monteiro
Marcelo Brito
Quique Bassat
Marcus Vinícius Guimarães Lacerda
Djane Baía-da-Silva
Mayla Gabriela Silva Borba
James Dean Oliveira Santos Jr
Vanderson Souza Sampaio
Fernando Fonseca Almeida Val
Cláudio-Tadeu Daniel-Ribeiro
Rosemary Costa Pinto
Bernardino Cláudio Albuquerque
José Diego Brito-Sousa
Mariana Simão Xavier
Felipe Gomes Naveca
CloroCovid-19 Team
Cor Jesus Fontes
Antônio Guilherme Fonseca Pacheco
Alexandre Schwarzbold
Gisely Cardoso Melo
Maria Paula Gomes Mourão
André Machado Siqueira
Journal: JAMA Network Open (2020)
Discipline: CLINICAL MEDICINE
Keywords: antiviral therapy; coronavirus disease 2019; COVID-19; chloroquine diphosphate; CQ dosages
Affiliations: Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil., Universidade do Estado do Amazonas, Manaus, Brazil., Fundação de Vigilância em Saúde do Amazonas, Manaus, Brazil., Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil., Instituto Leônidas and Maria Deane, Fiocruz Amazonas, Manaus, Brazil., Programa de Computação Científica, Fiocruz, Rio de Janeiro, Brazil., Universidade Federal do Amazonas, Manaus, Brazil., Instituto Nacional de Infectologia Carlos Chagas-Fiocruz, Rio de Janeiro, Brazil., Universidade Federal de Santa Maria, Rio Grande do Sul, Brazil., Faculdade de Medicina da Universidade Federal do Mato Grosso do Sul, Campo Grande, Brazil., Fundação Oswaldo Cruz, Mato Grosso do Sul, Campo Grande, Brazil., Faculdade de Medicina de São José do Rio Preto, São Paulo, Brazil., Universidade de Brasília, Brasília, Brazil., ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain., Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique., Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain., Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain., Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain., Universidade Federal de Mato Grosso, Mato Grosso, Brazil., Faculdade de Medicina da Universidade Federal do Amazonas, Manaus, Brazil., Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

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. 

Retracted: No

PubPeer comments:
 Main study conclusions:  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. - Wasn t the medical risk already known from the beginning? Such drugs being already known to interact towards cardiac risk -- as reckoned by the authors to have been acknowledged by the same Chinese experts who recommended the use of chloroquine --, why test that on critical patients. - The  higher dosage might have been better described as superhigh dosage. How does it compare with the official recommended dosages for CQ , adjusted per patients weight? , 
 The study certainly provides no evidence for any benefit of chloroquine, for the usual reasons of (low) power and the absence of a control group not receiving the drug. It was, however, randomised. It did look at clinical outcome (mortality). If it shows anything, it s that the drug is quite toxic. Maybe not surprising, but that reinforces the arguments for great care in its use. According to comparisons with estimated mortality (as considered valid only by groups in Marseille and the White House), the study again provides only (weak) evidence - of toxicity. Zero evidence for any benefit. I guess we ll just have to wait for a properly designed RCT. ,