COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

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Treatment 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 Apr 24;3(4):e208857. doi: 10.1001/jamanetworkopen.2020.8857.

Importance: There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug.

Objective: To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19.

Design, Setting, and Participants: This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon.

Interventions: Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days).

Main Outcomes and Measures: Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4.

Results: Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. 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 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%).

Conclusions and Relevance: The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19.

Trial Registration: Identifier: NCT04323527.

Discipline / Specialty Area Score
Infectious Disease
Intensivist/Critical Care
Hospital Doctor/Hospitalists
Internal Medicine
Comments from MORE raters

Cardiology rater

Needs a control/placebo group.

Cardiology rater

High-dose chloroquine (more toxic form than hydroxychloroquine) with 2 other QT-prolonging medications, so unsurprising to see the large toxicity due to QTc prolongation and death. Average age was young at 50 years and the study appropriately prematurely terminated because of high mortality and low viral clearance. Renal/liver dose adjustments were not made and routine daily or twice-daily ECG was not done, so safety surveillance may have been under performed. Informing front-line practitioners of the danger of high-dose CQ accompanied by other drugs has the potential for QT prolongation is a scientific and social responsibility.

Hospital Doctor/Hospitalists rater

It is important to have data regarding treatment options for Covid-19. Although there are many limitations to this study (stopped early, concomitant treatment with azithromycin and oseltamivir, low number of participants), safety issues were seen with high-dose CQ. Hopefully as more data come out from countries across the world, we can gather insight into treating this disease.

Infectious Disease rater

This randomized trial was stopped early because of increased numbers of adverse events in the high-dose group before any conclusions could be drawn about efficacy. The paper adds to the growing evidence of toxicity that is so far not outweighed by evidence of benefits. It reinforces the recommendations that chloroquine should only be used within clinical trials.

Intensivist/Critical Care rater

In this trial of high- vs low-dose chloroquine for presumed severe COVID, an interim analysis showed a trend toward harm and in the opposite direction expected among the high-dose group. These findings were consistent based on final confirmation of SARS-CoV-2 infection. Although the sample size was too small to be interpreted as evidence of harm, the decision to terminate the high-dose arm appears appropriate based on physiologic correlates of harm (higher rates of ventricular tachycardia and QTc prolongation in the high-dose group) along with higher observed deaths, making an ultimate finding of benefit very unlikely.

Intensivist/Critical Care rater

An excellent study in view of current events.

Intensivist/Critical Care rater

The useful information from this study is that high-dose hydroxychloroquine should not be used in the treatment of COVID-19, especially with azithromycin and olsetamivir. The overall prolongation of QTc was higher in the high-dose group, but still only 18.9% (compared with 11.1% for the low-dose group).

Intensivist/Critical Care rater

Given the emotion and politics injected into this process, this is a very important study in advancing understanding of CQ and HCQ utility and value in COVID-19 treatment. As noted, further study is indicated. This emphasizes the need to enroll patients treated with CQ and HCQ in formal studies.

Internal Medicine rater

Without a placebo, this is not useful at all. A small number of participants with unequal groups. Very flawed.

Internal Medicine rater

It is natural and good to be hopeful. Science helps us add realism to hope.