CloroCovid-19 Trial of High-Dose Chloroquine Halted Early Due to Toxicity, Deaths

By Megan Brooks

April 29, 2020

NEW YORK (Reuters Health) - The Brazilian CloroCovid-19 trial testing the safety and efficacy of a high dose of chloroquine in patients with severe COVID-19 has been terminated early after an interim analysis showed it was associated with more toxic effects and deaths, particularly affecting heart rhythms, than a lower dose.

Of the 81 randomized patients, 41 in the high-dose group received 600 mg of the antimalarial drug twice daily for 10 days and 40 in the low-dose group received 450 mg twice daily for one day and then once daily for four days.

After 13 days of treatment, 16 patients (39.0%) in the high-dose group had died compared to six patients (15.0%) in the low-dose group. In addition, more patients in the high-dose group experienced prolongation of QTc interval (18.9% vs. 11.1%).

Two patients in the high-dose group (2.7%) suffered ventricular tachycardia. Three of five patients (60.0%) in the high-dose group with underlying heart disease died.

All patients were already using azithromycin (as per hospital protocol), so the researchers could not independently assess the toxic role of chloroquine. Most patients were also taking oseltamivir for suspected influenza, which also increases QTc interval and could have adverse cardiac effects.

"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," Dr. Mayla Gabriela Silva Borba of the Tropical Medicine Foundation Dr Heitor Vieira Dourado in Manaus and colleagues conclude in their paper online in JAMA Network Open April 24.

That same day the U.S. Food and Drug Administration (FDA) cautioned against the use of hydroxychloroquine or chloroquine for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems (https://bit.ly/3cNzzHH).

"Chloroquine 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 (ie, 12 g of CQ during 10 days), because the risks of toxic effects overcame the benefits," Dr. Borba and colleagues note in their article.

In email to Reuters Health, corresponding author Dr. Marcus Vinicius Guimaraes Lacerda noted that "in vitro studies show that only high CQ doses are able to kill the virus. The highest dose already used in humans was tested in our study, and it presented more toxicity, which was the reason to halt this group. The concomitant use of azithro/tamiflu might be an issue, but we could not do the study without them, because it was the standard of care. Low doses are apparently safer, but evidence of efficacy is still pending."

The researchers are continuing to enroll patients in the low-dose group and the safety-data generated in this group could be "extremely useful for designing better guidelines for the rational use of chloroquine as compassionate treatments for severe COVID-19 until the conclusion of placebo-controlled trials."

In a linked editorial, Dr. Stephan Fihn of Harborview Medical Center, University of Washington, in Seattle, and colleagues note that several other trials in progress, including a large multicenter trial in the U.S., "hopefully will provide additional crucial information about the efficacy and safety of hydroxychloroquine."

"In the interim, the results of this trial by Borba et al should prompt some degree of skepticism toward the enthusiastic claims about chloroquine and perhaps serve to curb the exuberant use. For the time being, prudent clinicians should discuss with patients and their families, when feasible, the potential risks of this drug and the uncertain benefits before initiating it," they write.

Dr. Fihn and colleagues add, "In the current torrent of data, the half-life of information is short. A novel observation from a week earlier rapidly becomes common knowledge or is superseded by more definitive studies. That so much research is being conducted and published underscores the robustness of the scientific publishing enterprise and should be heartening to the world population as we all wait anxiously for information and signs of progress."

SOURCE: https://bit.ly/3cTugGJ and https://bit.ly/2W2sw7b JAMA Network Open, online April 24, 2020.

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