The results of an eagerly anticipated randomized controlled trial indicate the antimalaria drug hydroxychloroquine was ineffective at preventing symptoms of COVID-19 in people after they were exposed to patients infected with the coronavirus.
The results, which appeared yesterday in the New England Journal of Medicine, are the first from a large-scale controlled trial testing the efficacy of the drug against SARS-CoV-2—the virus that causes COVID-19—to be published. The findings showed that when given to participants within 4 days of close exposure to someone with confirmed COVID-19, hydroxychloroquine was no better than a placebo at preventing symptoms compatible with the novel coronavirus.
"This randomized trial did not demonstrate a significant benefit of hydroxychloroquine as postexposure prophylaxis for COVID-19," the authors of the study, a team of US and Canadian researchers, wrote in the paper.
No significant difference
While many observational studies and clinical trials are investigating the use of hydroxychloroquine in patients already sick with COVID-19, this trial aimed to find out whether the drug could play a role in breaking the chain of coronavirus transmission by preventing infection in people after high- or moderate-risk exposure to the virus. This was defined as being within 6 feet of someone with confirmed COVID-19 for more than 10 minutes while wearing neither a mask nor an eye shield (high-risk exposure) or while wearing a mask but not an eye shield (moderate-risk exposure).
For the trial, researchers from the University of Minnesota, McGill University, the University of Manitoba, and the University of Alberta recruited and enrolled 821 asymptomatic participants from Canada and the United States who'd reported household or workplace exposure to an infected person within the previous 3 days. The objective was to intervene before the median COVID-19 incubation period of 5 or 6 days.
The investigators randomly assigned participants on a 1:1 basis to receive hydroxychloroquine (800 milligrams [mg] once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 days) or a placebo. Neither the investigators nor the participants knew who received hydroxychloroquine or a placebo. The drugs were shipped to participants, and email surveys were sent to them on days 1, 5, 10, and 14 to report symptoms and adherence to the treatment.
The primary outcome of the trial was symptomatic illness confirmed by molecular testing or, if testing was unavailable, COVID-19–related symptoms.
Of the 821 participants, 87.6% (719 of 821) reported a high-risk exposure to a confirmed COVID-19 patient, and 66.4% (545/821) were healthcare workers. A total of 27.4% of participants (225/821) reported chronic health conditions. The median age of participants was 40 years.
Overall, new COVID-19 illness (either confirmed by polymerase chain reaction [PCR] or symptomatically compatible) developed in 13% of participants (107/821). Analysis of the two treatment groups showed that the difference in the incidence of new illness compatible with COVID-19 was not statistically significant—11.8% of those receiving hydroxychloroquine (49 of 414) got sick, compared with 14.3% of those receiving placebo (58 of 407). The absolute difference was –2.4 percentage points (95% confidence interval [CI], –7.7 to 2.2).
The analysis also found no meaningful difference in effectiveness according to the time of starting postexposure prophylaxis or in any prespecified subgroups.
Adherence among trial participants was moderate, with 75.4% of the hydroxychloroquine recipients (312/414) and 82.6% of those in the placebo group (336/407) taking the entire drug regimen. The most common reason for stopping hydroxychloroquine was side effects. Overall, 40.1% of those who took any hydroxychloroquine (140 of 349) reported a side effect by day 5, compared with 16.8% of the placebo group (59 of 351). No serious adverse events were reported.
Limitations of the study
Among the limitations noted by the investigators is that, because of the lack of COVID-19 diagnostic testing available during the trial, the vast majority of participants were unable to get a test. As a result, only 20 of the 107 patients reporting COVID-19 symptoms had a lab-confirmed diagnosis.
In the rest, the presence of a combination of symptoms—such as cough, shortness of breath, difficulty breathing, fever, chills, diarrhea, and olfactory and taste disorders—were classified as COVID-19–related illness based on US Council of State and Territorial Epidemiologists criteria for probable and possible cases.
"The U.S. case definition is how probable COVID-19 cases are nationally reportable," the authors wrote. "However, the predictive power of this case definition is unknown, particularly in the younger populations that we studied; given the small number of PCR tests, it remains theoretically possible that hydroxychloroquine therapy limits proven infection. Reproduction of our results in other, ongoing trials would confirm our findings."
They also noted that the participants, who had a median age of 40 years, were generally younger than those at risk for severe COVID-19.
"Although a marginal possible benefit from prophylaxis in a more at-risk group cannot be ruled out, the potential risks that are associated with hydroxychloroquine may also be increased in more at-risk populations, and this may essentially negate any benefits that were not shown in this large trial involving younger, healthier participants," they wrote.
An editorial that accompanies the study brought up these limitations and also pointed out the delay between exposure and the initiation of treatment in the trial.
"In the current trial, the long delay between perceived exposure to SARS-CoV-2 and the initiation of hydroxychloroquine (≥ 3 days in most participants) suggests what was being assessed was prevention of symptoms or progression of COVID-19, rather than prevention of SARS-CoV-2 infection," Myron Cohen, MD, of the Institute for Global and Infectious Diseases at the University of North Carolina, wrote.
Cohen said these limitations suggest that the potential prevention benefits of hydroxychloroquine remain to be determined.