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
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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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A single dose of either sarilumab or tocilizumab appears to be similarly efficacious.
“A single dose of either sarilumab and tocilizumab appears to be similarly efficacious.37”
From Drug treatments for covid-19: living systematic review and network meta-analysis (2020) · cites this paper as [37]
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A compendium answering 150 questions on COVID‐19 and SARS‐CoV‐2
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- Authors
- Borba, M. G. S., Val, F. F. A., Sampaio, V. S., Alexandre, M. A. A., Melo, G. C., Brito, M., Mourão, M. P. G., Brito-Sousa, J. D., Baía-da-Silva, D., Guerra, M. V. F., Hajjar, L. A., Pinto, R. C., Balieiro, A. A. S., Pacheco, A. G. F., Santos, J. D. O., Naveca, F. G., Xavier, M. S., Siqueira, A. M., Schwarzbold, A., Croda, J., Nogueira, M. L., Romero, G. A. S., Bassat, Q., Fontes, C. J., Albuquerque, B. C., Daniel-Ribeiro, C.-T., Monteiro, W. M., Lacerda, M. V. G., & for the CloroCovid-19 Team
- Affiliations
- Fundação de Medicina Tropical (BR)
- Fundação de Medicina Tropical Dr Heitor Vieira Dourado, Manaus, Brazil
- Universidade de São Paulo (BR)
- Fundação de Vigilância em Saúde do Amazonas, Manaus, Brazil
- Instituto Leônidas and Maria Deane, Fiocruz Amazonas, Manaus, Brazil
- Fundação Oswaldo Cruz (BR)
- Universidade Federal do Amazonas (BR)
- Fiocruz Amazônia (BR)
- Universidade Federal de Santa Maria (BR)
- Universidade Federal de Mato Grosso do Sul (BR)
- Faculdade de Medicina de São José do Rio Preto (BR)
- Universidade de Brasília (BR)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universidade Federal de Mato Grosso, Mato Grosso, Brazil
- Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
- Corresponding author
- Lacerda, Marcus Vinícius Guimarães
- ORCID
- Borba, Mayla Gabriela Silva
- Val, Fernando Fonseca Almeida
- Melo, Gisely Cardoso
- Brito, Marcelo
- Mourão, Maria Paula Gomes
- Brito-Sousa, José Diego
- Baía-da-Silva, Djane
- Hajjar, Ludhmila Abrahão
- Pacheco, Antônio Guilherme Fonseca
- Santos, James Dean Oliveira
- Naveca, Felipe Gomes
- Xavier, Mariana Simão
- Siqueira, André Machado
- Schwarzbold, Alexandre
- Croda, Júlio
- Nogueira, Maurício Lacerda
- Romero, Gustavo Adolfo Sierra
- Bassat, Quique
- Albuquerque, Bernardino Cláudio
- Monteiro, Wuelton Marcelo
- Lacerda, Marcus Vinícius Guimarães
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2020-04-24
- Volume
- 3
- Issue
- 4
- Pages
- e208857
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC12124691
- OpenAlex
- W3020239101
- Cited by
- 1,038
- References
- 35
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 23 · 2023: 37 · 2022: 93 · 2021: 297 · 2020: 575 · 2019: 1
- FWCI
- 32.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Generalitat de Catalunya
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Ministerio de Ciencia e Innovación
- Fundação de Amparo à Pesquisa do Estado do Amazonas
- Topics
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Keywords
- chloroquine phosphate, COVID-19 pandemic, SARS-CoV-2, mortality, viral load, drug safety, adverse events, hospitalized patients, electrocardiographic changes, heart disease comorbidity, viral RNA detection
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, Adult, Aged, Anti-Bacterial Agents, Antiviral Agents, Brazil, Chloroquine, Disease Outbreaks, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Pneumonia, Viral, Azithromycin, Coronavirus Infections, Oseltamivir, Pandemics, Tertiary Care Centers
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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