- Hydroxychloroquine, the malaria drug thrust into the global spotlight as a potential COVID-19 treatment, doesn't prevent people who have been exposed to the new coronavirus from getting sick any better than does a placebo, results from a highly anticipated study show.
- About 12% of study participants taking hydroxychloroquine developed symptoms characteristic of COVID-19, compared to 14% of those who received placebo, a difference that was not statistically significant. Unlike some previous, less rigorous tests, this study did not show hydroxychloroquine to be associated with higher rates of heart arrhythmia.
- The findings are the first to come from a randomized and placebo-controlled trial and are therefore more trustworthy than earlier data. But the study has important weaknesses, meaning the results are unlikely to end debate over the drug, which President Donald Trump has frequently touted as beneficial. Other clinical trials in hospitalized patients, healthcare workers and people who haven't yet been exposed to the virus are underway.
Clinical evidence for and against use of hydroxychloroquine has, up until now, failed to meet the "gold standard" of medical research: Comparing a drug against a placebo while both doctors and study participants remain unaware of who received which pill.
This trial, conducted by researchers at the University of Minnesota and with results published in the New England Journal of Medicine, finally meets that test.
The study goes the furthest in answering the question of whether a decades-old, repurposed drug can help treat COVID-19, at least when considering early use after coronavirus exposure.
"There was not a clinically meaningful benefit," said Caleb Skipper, an infectious disease postdoctoral fellow and an author on the NEJM paper, in an interview. The 2% difference observed between groups was "not beyond random chance," he added.
The trial's findings, as well as its limitations, will be closely scrutinized, as its publication follows many weeks of back-and-forth among researchers, physicians and government officials over the treatment's potential role. In the U.S., the drug was granted emergency authorization by the Food and Drug Administration on scant data, and was used more frequently following regular promotion by President Trump and television pundits.
"We ended up having a warped view of the both the safety of the drug and the efficacy of the drug," said University of Pittsburgh professor Walid Gellad in a recent interview.
The University of Minnesota study begins to offer more conclusive answers, and is the first of a handful of larger and higher-quality clinical tests of the drug. But it's not a definitive verdict on hydroxychloroquine and leaves room for further evidence to be gathered.
Researchers at the University of Minnesota enrolled into their trial 821 people who had been exposed to the virus either through household contact or as a healthcare worker, and followed them for two weeks. Forty-nine of 414 people taking hydroxychloroquine and 58 of 407 people taking placebo developed symptoms consistent with COVID-19. One person in each group was hospitalized, and none died.
Only 20 participants, 11 on hydroxychloroquine and nine on placebo, were confirmed to have COVID-19 through laboratory testing, due in part to the limited availability of viral tests during the study period. The others were all diagnosed symptomatically — a limitation that could mean some patients didn't actually have coronavirus disease.
Notably, the trial reported no cases of cardiovascular arrhythmias, a side effect of concern because of hydroxychloroquine's known effect on heartbeat patterns. However, because the trial was conducted remotely, the investigators couldn't perform the tests that would detect cardiovascular signs pointing to the potential for arrhythmia.
Still, 40% of participants who took hydroxychloroquine reported side effects, most commonly nausea, diarrhea or abdominal discomfort, compared to only 17% on placebo.
The investigators acknowledged their findings may have been weakened by the trial's design, which relied on using social media to recruit participants and have them self-report outcomes. Both the drug and placebo were shipped to participants overnight by mail.
The social media approach meant the trial enrolled younger and healthier patients, with a median age of around 40. Because hospitalization and death from COVID-19 occurs more frequently in older adults, hydroxychloroquine could potentially have helped those individuals had the trial been able to enroll them.
Study researchers, however, thought that possibility unlikely to outweigh the higher chance of drug-related complications in more at-risk individuals.
The University of Minnesota is also conducting trials of hydroxychloroquine as a preventive therapy among healthcare workers who don't have a known exposure to the coronavirus, and as a treatment for diagnosed COVID-19 patients. The former study has completed enrollment and should be published soon.
International trials run by researchers in the U.K., France and at the World Health Organization are ongoing and should report results in the coming weeks and months. Other medical centers in the U.S. are conducting studies as well.
"If you look at our paper as a piece of the total equation, it's an important piece, but not an exhaustive, end-of-story piece," said University of Minnesota's Skipper.