New Covid-19 study, despite flaws, adds to case against hydroxychloroquine

Hydroxychloroquine did not lead to faster symptom improvement among patients who had Covid-19 symptoms 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 at the University of Minnesota, adds to the evidence that the malaria drug, heralded as a treatment based on scant data early in the pandemic, has little utility in treating Covid-19. It is likely to add to the smoldering 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 final word on the subject.

On Tuesday, Peter Navarro, the president’s trade adviser, made his faith in hydroxychloroquine part of a broadside against Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, in USA Today. “[W]hen 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 providing evidence of safety and efficacy,” Navarro wrote.

Three high-quality randomized controlled studies, the gold standard in evaluating medicines, have been stopped because hydroxychloroquine was providing no benefit at all for patients. Results from one, the RECOVERY study run by U.K. researchers, were released on a preprint server Wednesday and show that not only was there no statistically significant difference between the arms of the trial, the patients on hydroxychloroquine tended to do worse.

But proponents, including Navarro, have argued that the drug needs to be used earlier in the disease. The Minnesota study represents the first test of using the drug among patients who have not been hospitalized.

The Minnesota study is one of a triad of randomized controlled trials, organized by David Boulware, that aimed to test hydroxychloroquine’s efficacy. One tested giving the drug to people after they were exposed to patients with Covid-19; that trial also failed. This trial tested using the drug right after symptoms began. A third study, for which results have not yet been reported, gave hydroxychloroquine to doctors and other people at high risk of getting Covid-19 before they were exposed to the virus.

To conduct these studies, the researchers made significant compromises. They could not obtain diagnostic testing for all patients, so included people who had symptoms but couldn’t get a test result. In the end, only 58% of the people in this study had diagnostic test results. The researchers mailed study drug or placebo to patients without examining them after they enrolled over the internet, meaning they used data patients self-reported. In the end, the study randomized 491 patients, 432 of whom contributed data to the final analysis.

The patients on hydroxychloroquine recovered 12% faster, or 0.27 points on a 10-point scale, but this difference was far from statistically significant. Patients on hydroxychloroquine also had side effects: 31% had upset stomachs and 21% diarrhea, both about double the rates in the placebo group, though no patients reported cardiac arrhythmias. Overall, adverse effects were reported by 43% of hydroxychloroquine patients and 22% of placebo patients.

The question is, given the study’s limitations, 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 trialist at the Cleveland Clinic. Still, he said, the evidence against hydroxychloroquine is mounting. “In this study there is no evidence of a benefit for hydroxychloroquine, and it is probably time to move on and start testing other therapies,” he said.

The main problem, Nissen said, is that the evidence on hydroxychloroquine should be coming from large, well-funded studies that were big enough to give clear answers. “Instead of focusing on one or two large, well-powered, well-run rigorous trials, we’ve got a bunch of observational studies, low quality randomized controlled trials, and no answers.”