HIodroxychloroquine did not lead to a faster improvement in symptoms among patients who had symptoms of Covid-19 and were not hospitalized, according to a new study published Thursday in the Annals of Internal Medicine.
The study, a randomized controlled trial led by researchers from the University of Minnesota, adds to the evidence that the antimalarial drug, advertised as a data-poor treatment at the start of the pandemic, has little use in treating Covid-19. It is likely to add to the latent political conflict around the drug, which President Trump said he took to prevent Covid-19 infection. But the study itself has significant limitations that prevent it from being a last word on the subject.
On Tuesday, Peter Navarro, the president’s business adviser, made his faith in hydroxychloroquine part of an offensive against Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, on USA Today. “[W]When Fauci was telling the White House Coronavirus Task Force that there was only anecdotal evidence in support of hydroxychloroquine to fight the virus, I confronted him with scientific studies that provided evidence of safety and efficacy, “Navarro wrote.
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Three high-quality randomized controlled trials, the gold standard in drug evaluation, have been discontinued because hydroxychloroquine provided no benefit to patients. The results of one, the RECOVERY study by researchers from the UK, were published on a prepress server on Wednesday and show that not only was there not a statistically significant difference between the arms of the trial, but that patients with hydroxychloroquine tended to worsen.
But advocates, including Navarro, have argued that the drug should be used first in the disease. The Minnesota study represents the first trial of drug use among patients who have not been hospitalized.
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The Minnesota study is part of a triad of randomized controlled trials, organized by David Boulware, aimed at evaluating the efficacy of hydroxychloroquine. One tried administering the drug to people after they were exposed to patients with Covid-19; That trial also failed. This trial tested the use of the drug just after symptoms started. A third study, the results of which have yet to be reported, administered hydroxychloroquine to doctors and others at high risk of contracting Covid-19 before being exposed to the virus.
To perform these studies, the researchers made significant commitments. They were unable to obtain diagnostic tests for all patients, so people who had symptoms were included but were unable to obtain the test result. In the end, only 58% of people in this study had diagnostic test results. The researchers mailed a study drug or placebo to patients without examining them after they enrolled via the Internet, meaning they used self-reported patient data. Ultimately, the study randomized 491 patients, 432 of whom contributed data to the final analysis.
Hydroxychloroquine patients recovered 12% faster, or 0.27 points on a 10-point scale, but this difference was far from statistically significant. Patients treated with hydroxychloroquine also had side effects: 31% had an upset stomach and 21% had diarrhea, both of which doubled the rates in the placebo group, although no patient reported cardiac arrhythmias. Overall, 43% of hydroxychloroquine patients and 22% of placebo patients reported adverse effects.
The question is, given the limitations of the study, what weight should be given to the results?
“The study was of such low quality that it was fundamentally uninterpretable,” said Steven Nissen, a veteran clinical investigator at the Cleveland Clinic. Still, he said, the evidence against hydroxychloroquine is increasing. “In this study there is no evidence of a benefit for hydroxychloroquine, and it is probably time to go ahead and start trying other therapies,” he said.
The main problem, Nissen said, is that the evidence for hydroxychloroquine should come from large, well-funded studies that were large enough to give clear answers. “Instead of focusing on one or two rigorous, well-developed and well-run trials, we have a lot of observational studies, low-quality randomized controlled trials with no response.”
