High dosage of chloroquine proves lethal for coronavirus patients, researchers halt clinical trials on drug
Stating a high risk of death, researchers have cut short a clinical trial testing anti-malaria drug chloroquine (CQ) as a potential treatment for COVID-19 after some patients who were taking a higher dose developed irregular heartbeats. The study in the high-dosage group was cut short after 22 patients died.
The study in Brazil aimed to evaluate the safety and efficacy of chloroquine in two different dosages for the treatment of severe COVID-19. A total of 81 patients were part of the trial, of which 40 patients (49.4%) were allotted to the low-dosage group and 41 (50.6%) in the high-dosage group. “The preliminary findings of from the CloroCovid-19 trial suggest that the higher chloroquine dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially among patients also receiving azithromycin and oseltamivir. These findings cannot be extrapolated to patients with non-severe COVID-19,” says the research team from in their findings published in JAMA.
There are currently no proven treatments for COVID-19 and no vaccine. Chloroquine is closely related to the more widely used drug hydroxychloroquine. Hydroxychloroquine and chloroquine have not been shown to be safe and effective for treating or preventing COVID-19 so far. They are being studied in clinical trials for COVID-19. US President Donald Trump had touted them as a potential treatment for the novel coronavirus despite little evidence that they work. In a recent study involving US veterans, hydroxychloroquine was linked to higher rates of death among patients hospitalized with the new coronavirus.
In the current study, enrolled patients had an average age of 51.1 years, and most (60) were men. Eligible participants were given either high-dosage chloroquine of 600 mg, twice daily for 10 days, that is, a total dose of 12g, or low-dosage chloroquine of 450 mg twice daily or a total dose 2.7 g. All patients received azithromycin, and the frequency of oseltamivir use was 86.8% (33 of 38) and 92.5% (37 of 40) in the low- and high-dosage groups, respectively.
Within three days, researchers started noticing heart arrhythmias in patients taking the higher dose. A preliminary analysis was done on April 5, when 11 patients had died (7 or 63.6%) in the high-dosage group and 4 (36.4%) in the low-dosage group.
By day 13, 16 of the 41 patients in the high-dose group had died, as did six of the 40 patients in the low-dose group. Heart abnormalities were seen in 11 of the 81 patients. Besides, two patients in the high-dose group experienced ventricular tachycardia, a heart rhythm disorder. “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) compared with the low-dosage group (4 of 36),” says the study.
“Overall, 19 of 22 deaths (86.4%) had virologic confirmation of SARS-CoV-2 infection antemortem. Based on these findings, in which a higher dosage of chloroquine showed the opposite of the study’s hypothesis, the DSMB (data safety and monitoring board) recommended the immediate interruption of the high-dosage group for all ages and that all patients be unmasked and reverted to the low-dosage group,” the findings state.
According to the researchers, global recommendations for COVID-19 are being made based on “unpowered studies, and because of the chaotic urgency of the situation, drugs are being prescribed in a compassionate manner” given the severity of the disease. “CQ is a safe drug, used for more than 70 years to treat malaria. However, in the context of patients with severe COVID-19, our study raises enough red flags to stop the use of a high-dosage regimen (that is, 12 g of CQ during 10 days) because the risks of toxic effects overcame the benefits,” says the team.
The researchers said the study did not have enough patients in the lower-dose portion of the trial to conclude if chloroquine was effective in patients with severe disease. “To better understand the role of CQ or HCQ in the treatment of COVID-19, we recommend randomized clinical trials evaluating its role as a prophylactic drug and randomized clinical trials evaluating its efficacy against the progression of COVID-19 when administered to patients with mild or moderate disease,” say researchers.
FDA warns against chloroquine use outside of clinical trials
Chloroquine and hydroxychloroquine are not FDA-approved for the treatment of COVID-19. On March 28, the US Food and Drug Administration (FDA) issued a notice authorizing the emergency use of chloroquine phosphate and hydroxychloroquine sulfate from the national stockpile for treatment of COVID-19 when clinical trials are not available, or participation is not feasible. However, on April 24, the FDA issued a statement, warning against the use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to the risk of heart rhythm problems.
“Hydroxychloroquine and chloroquine can cause abnormal heart rhythms such as QT interval prolongation and a dangerously rapid heart rate called ventricular tachycardia. These risks may increase when these medicines are combined with other medicines known to prolong the QT interval, including the antibiotic azithromycin, which is also being used in some COVID-19 patients without FDA approval for this condition. Patients who also have other health issues such as heart and kidney disease are likely to be at increased risk of these heart problems when receiving these medicines,” says the FDA notice.
“We recommend initial evaluation and monitoring when using hydroxychloroquine or chloroquine under the emergency use authorization (EUA) or in clinical trials that investigate these medicines for the treatment or prevention of COVID-19,” it adds.