Written by Joyce Smith, BS. This study evaluates the safety and efficacy of two chloroquine diphosphate (CQ) doses in patients with severe COVID-19.
Coronavirus 2019 disease (COVID-19) was first diagnosed in Wuhan, China as “pneumonia of unknown etiology” in December of 2019 1. As the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly to other countries 2,3, it was declared a pandemic on March 11, 2020 by the World Health Organization. Recent studies 4 have implicated a possible benefit of two anti-malarial drugs, CQ and hydroxychloroquine (HCQ), (also used to treat systemic lupus erythematosus and rheumatoid arthritis treatment 5), as potential drugs for treating the SARS-CoV-2 infection.
Based on the results of two previous studies 6,7, Borba et al conducted a study in Brazil to determine the safety and efficacy of CQ in two different dosages for the treatment of severe COVID-19 8. The CloroCovid-19 trial had a pre-determined sample size of 440 patients, but had enrolled only 81, of which 41 were assigned to a high-dose group (600 mcg CQ twice daily for 10 days) and 40 to a low-dose group (450 mcg CQ twice daily on day 1, and once daily for 4 days). The mean age of enrolled patients was 51, 75% of patients were men and 18% had heart disease compared to the low-dose group which was free of heart disease.
Patients with COVID-19 coronavirus infection, who were treated with high-dose chloroquine diphosphate (CQ) in conjunction with azithromycin or oseltamivir, experienced higher rates of death and adverse cardiac events compared to the low-dose group. Thus, due to safety concerns, the Independent Data Safety and Monitoring Board (DSMB) recommended the immediate interruption of the high-dosage group for all ages and that all patients be unmasked and moved back to the low-dosage group.
Results showed that drug lethality until day 13 was higher in the high-dose group (11 patients died) compared to four patients in the low-dose group (39% vs 15%, respectively), with more patients in the high-dose group experiencing QTc intervals of greater than 500 milliseconds (18.9% vs 11.1%). QT refers to an interval seen in an electrocardiogram (EKG) test of heart function.
The researchers were not able to independently assess the toxicity of chloroquine because, per the hospital protocol, all the patients were already receiving azithromycin. In addition, most patients were receiving oseltamivir for suspected influenza infection, which could also have impacted QTc interval and caused cardiac effects. According to the research team, while chloroquine could be used to “decrease the viral load in respiratory secretions,” to potentially decrease transmission, patients using CQ failed to present evidence of “substantial viral clearance by day 4″, even with azithromycin.
At the time of this study, Brazil’s health Minister had authorized “compassionate use of CQ and HCQ at clinician’s discretion”, triggering an ethical dilemma that was further compounded by media pressure favoring the continued use of QC. The study was randomized but lacked a placebo. After adjusting for the absence of a placebo, the lethality rates were not lower, yet researchers felt they “could not conclude that QC was of no benefit”. However, they felt that the development of myocarditis in the high-dose group and the prolonged QTcF and potential for fatal arrhythmias such as ventricular tachycardia “warranted caution” regarding this drugs safety.
Adverse events included one patient who developed rhabdomyolysis, the breakdown of damaged muscle, which can cause kidney damage. Two patients had suspected myocarditis potentially related to SARS-CoV-2 infection. Also, both QC and HQC have the potential to prolong OTC interval and cause severe arrhythmias.
Study limitations include the use of an older high-dose group more susceptible to heart disease, a small sample size, the lack of a placebo group, and the single-center design. Randomized controlled trials evaluating the prophylactic and efficacious role of QC in COVID-19 treatment are needed.
Source: Borba, Mayla Gabriela Silva, Fernando Fonseca Almeida Val, Vanderson Souza Sampaio, Marcia Almeida Araújo Alexandre, Gisely Cardoso Melo, Marcelo Brito, Maria Paula Gomes Mourão et al. “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.” JAMA network open 3, no. 4 (2020): e208857-e208857.
© Open Access. This is an open access article distributed under the terms of the CC-BY License.
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Posted May 11, 2020.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
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- Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell research. 2020;30(3):269-271.
- Borba MGS, Val FFA, Sampaio VS, et al. 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. JAMA Netw Open. 2020;3(4):e208857.
