An open-label randomized controlled trial evaluating the efficacy of chloroquine/hydroxychloroquine in severe COVID-19 patients
Álvaro Réa-Neto, Rafaella Stradiotto Bernardelli, Bruna Martins Dzivielevski Câmara, Fernanda Baeumle Reese, Marcos Vinicius Oliveira Queiroga, Mirella Cristine Oliveira
Scientific Reports, doi:10.1038/s41598-021-88509-9
Despite several studies designed to evaluate the efficacy of chloroquine and hydroxychloroquine in the treatment of coronavirus disease 2019 (COVID-19), there is still doubt about the effects of these drugs, especially in patients with severe forms of the disease. This randomized, open-label, controlled, phase III trial assessed the efficacy of chloroquine or hydroxychloroquine for five days in combination with standard care compared to standard care alone in patients hospitalized with severe COVID-19. Chloroquine 450 mg BID on day 1 and 450 mg once daily from days 2 to 5 or hydroxychloroquine 400 mg BID on day 1 and 400 mg once daily from days 2 to 5 were administered in the intervention group. Patients were enrolled from April 16 to August 06, 2020, in 6 hospitals in southern Brazil. The primary outcome was the clinical status measured on day 14 after randomization with a 9-point ordinal scale. The main secondary outcomes were all-cause mortality; invasive mechanical ventilation use; the incidence of acute renal dysfunction in 28 days; and the clinical status of patients on days 5, 7, 10 and 28. All patients with a positive RT-PCR result for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were analyzed (modified intention to treat (mITT) population). Arrythmias and cardiovascular complications were assessed as safety outcomes. A total of 105 patients were enrolled and followed for 28 days. The trial was stopped before reaching the planned sample size due to harmful effects. Patients in the intervention group had a worse clinical outcome on the 14th day (odds ratio (OR) 2.45 [1.17 to 4.93], p = 0.016) and on the 28th day (OR 2.47 [1.15 to 5.30], p = 0.020). Moreover, the intervention group had higher incidences of invasive mechanical ventilation use (risk ratio (RR) 2.15 [1.05 to 4.40], p = 0.030) and severe renal dysfunction (KDIGO stage 3) (RR 2.24 [1.01 to 4.99], p = 0.042) until the 28th day of follow-up. No significant arrythmia was noted. In patients with severe COVID-19, the use of chloroquine/hydroxychloroquine added to standard treatment resulted in a significant worsening of clinical status, an increased risk of renal dysfunction and an increased need for invasive mechanical ventilation. Trial Registration: ClinicalTrials.gov, NCT04420247. Registered 09 June 2020-Retrospectively registered, https:// www. clini caltr ials. gov/ ct2/ show/ study/ NCT04 420247. The novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has already infected tens of millions of people around the world and killed more than a million people (approximately 3%) 1 . Patients with risk factors or severe forms of COVID-19 have more than a 30% chance of dying. Many antiviral or anti-inflammatory drugs have been studied to find a way to control the poor outcomes of COVID-19 2 . Some drugs have demonstrated in vitro activity against SARS-CoV-2 and potential clinical benefits in small..
Author contributions All authors have approved the submitted version and agreed to be personally accountable for their own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even those in which the author was not personally involved, are appropriately investigated and resolved and that the resolution is documented in the literature.
Competing interests The authors declare no competing interests.
Additional information
Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1038/ s41598-021-88509-9. Correspondence and requests for materials should be addressed to Á.R.-N. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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