COVID-19 Clinical Trial Questions High Doses of Chloroquine

A recent COVID-19 clinical trial found that higher dosages of 2 chloroquine diphosphate should not be recommended for critically ill coronavirus patients because of its potential safety hazards. 

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The double-masked, randomized clinical trial was conducted from March 23 to April 5, 2020. It provided 81 patients with 600mg of chloroquine diphosphate (CQ) twice daily for ten days, and 40 patients with a low-dosage of 450mg twice daily on day one and once daily for four days.

The primary outcome of the clinical trial was a reduction in lethality by nearly 50 percent in the high-dosage group compared with the low-dosage group. Specifically, lethality was 39 percent in the high-dosage group and 15 percent in the low-dosage group on the last day of the trial.

Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28.

“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,” researchers stressed.

“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 because the risks of toxic effects overcame the benefits.”

Despite the smaller sample size, high-dosage CQ was not associated with death when controlled by age.

Out of five patients with chronic cardiac disease, three individuals, or 60 percent, died. Out of 12 patients with prolonged QTcF and/or ventricular tachycardia, no notable association was seen between the first day of prolonged QTcF and day of death and the cumulative dosages did not appear higher among those who died.

Researchers highlighted that based on these outcomes, they recommended an interruption of the high-dosage group for all ages and that all patients be unmasked and reverted to the low-dosage group.

“We recommend that similar dosages no longer be used for the treatment of severe COVID-19, especially because treatment based on older patients with previous cardiac diseases who are receiving concomitant cardiotoxic drugs should be the rule.”

“The safety data obtained from the low-dosage group would be extremely useful for designing better guidelines for the rational use of CQ as compassionate treatment for severe COVID-19 until the conclusion of placebo-controlled trials,” they said. “All the patients remaining in the study were asked to provide updated informed consent, and the informed consent form was properly modified.”

The Health Commission recommended the use of phosphate CQ tablets at a dose of 500 mg twice daily for 10 days for the treatment of patients aged 18 to 65 years with mild, moderate, or severe pneumonia due to COVID-19. 

Additionally, hospital protocol requires that all patients in the study who had respiratory distress syndrome receive 1g of intravenous ceftriaxone twice daily for seven days, plus 500mg of azithromycin once daily for five days. Seventy-five milligrams of Oseltamivir was also given twice daily for five days when influenza infection was suspected.

“Most patients (89.6%) in our study were also receiving oseltamivir for suspected influenza infection, which also increases QTc interval and could have adverse cardiac effects. The data presented here refer to patients in whom CQ, azithromycin, and oseltamivir were concomitantly used because of the atypical circumstances of an unknown disease,” researchers said. 

Researchers now recommend randomized clinical trials evaluating the role of CQ or HCQ as a prophylactic drug and if the drugs can help stop the progression of COVID-19 when given to patients with mild or moderate disease.

“Even if we fail to generate good evidence in time to control the current pandemic, the information will affect how we deal with coronavirus outbreaks in the future,” they concluded.