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The malaria drug hydroxychloroquine did not help prevent people who had been exposed to others with Covid-19 from developing the disease, according to the results of an eagerly awaited study that was published Wednesday in the New England Journal of Medicine.

Despite a lack of evidence, many people began taking the medicine to try to prevent infection early in the Covid-19 pandemic, following anecdotal reports it could be effective and claims by President Trump and conservative commentators. Trump, too, said he took hydroxychloroquine to prevent infection.

But the new study, the first double-blind randomized, placebo-controlled trial of hydroxychloroquine, found otherwise.

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“I think in the setting of post-exposure prophylaxis, it doesn’t seem to work,” said Sarah Lofgren, an assistant professor at the University of Minnesota who is a co-author of the study.

Other studies of hydroxychloroquine are ongoing. Also Wednesday, the World Health Organization said it is resuming a clinical trial testing hydroxychloroquine as a treatment after pausing it over safety concerns.

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“This is not the end of the story with hydroxychloroquine,” said Ashish Jha, the director of the Harvard Global Health Institute. But given the data, he said, if there is any benefit to giving the drug to prevent infection, “it’s going to be small.”

The same group of researchers is also planning to publish the results of trials testing the drug as a treatment and as a “pre-exposure prophylaxis” — that is, before any exposure to SARS-CoV-2, the virus that causes Covid-19.

The latest trial enrolled 821 patients who were either living in the same household as someone with Covid-19 or who were health care workers who had been exposed to someone with Covid-19 without adequate protective gear. While the initial infections had to be confirmed with a diagnostic test, the researchers also counted patients who had symptoms consistent with disease, in part because testing wasn’t available.

Approximately 12% of those given hydroxychloroquine developed Covid-19, compared to 14% who were given the vitamin folate as a placebo. There was no further benefit among patients who chose to take zinc or vitamin C. Nearly 40% of patients on hydroxychloroquine experienced side effects such as nausea, upset stomach, or diarrhea. However, the study did not see a significant increase in disturbances of heart rhythms, or an imbalance of deaths.

Even though the study used the gold standard methodology of conducting clinical research, outside researchers saw significant limitations. The study was conducted in an unusual way: over the internet, without patients being seen by study doctors. 

“It just continues to extend the case that the drug is lacking significant efficacy,” said Eric Topol, the director of the Scripps Research Translational Institute. He said that the results are consistent with small randomized trials that were conducted in China and with most observational studies. But while he said that the safety results are encouraging, he worried that the study, because of size and other limitations, might not completely rule out such issues.

Steven Nissen, a cardiologist and veteran clinical trialist at the Cleveland Clinic, was much harsher. The fact that patients self-reported their data and that one in five did not take all their doses of the study drug, as well as the study’s small size, made him less than confident that the study could entirely rule out that hydroxychloroquine had some preventative effect. He emphasized that more studies of the drug, which was widely prescribed during the initial months of the Covid-19 pandemic, have not been completed.

“Absence of evidence is not evidence of absence,” Nissen said. “Poor quality data does not help it only confuses the world. That’s exactly where we find ourselves, in a state of confusion.”

David Boulware, a professor of medicine at the University of Minnesota Medical School, said he thought up the study, which was also far cheaper to run than a conventional clinical trial, precisely because he saw a need to get something done with minimal resources.

On March 8, as it became clear that the U.S. was about to face the brunt of the pandemic, he was in the airport on the way back from a grant meeting at the National Institutes of Health in Washington. His team had been scheduled to go to a major meeting on HIV, but the meeting was canceled. With four days of uninterrupted work time, he set his team to creatively working out how to get a trial up and running. He bought $5,000 worth of hydroxychloroquine, and borrowed the self-reporting methodology from randomized studies that have been run in the social sciences. He said he requested a U.S. government grant to support the study, but was rebuffed.

Robert Califf, the former Food and Drug Administration commissioner who now works at Alphabet, said there were “lots of flaws” in the study but it was still “a great effort,” providing the best evidence yet about hydroxychloroquine’s utility. He said he would favor doing another study with viral testing. The dozens of other clinical trials being conducted may give a clearer answer.

  • Currently, this study can be seen here:
    https://www.nejm.org/doi/pdf/10.1056/NEJMoa2016638?articleTools=true

    This study doesn’t seem to be a very ‘strong’ study, apparently depending on remote surveys and self-reporting, and not actually directly testing for infections, etc…

    And it is not really about the usual prophylactic use of Hydroxychloroquine. Instead it is specifically about post-exposure use, i.e. giving Hydroxychloroquine several days after exposure to Covid-19. Additionally, the drug was only given for 5 days. Even under these conditions it had a beneficial effect (though the authors consider it insignificant).

    14.3% control group got covid
    11.8% hydroxyl group got covid

  • Prophylaxis ideally should be composed of supplements or OTC medicines that do not require a prescription. I am looking forward to Famotidine related trials. Quercetin, zinc, and Pterostilbene have interesting possibilities.

  • This story should at least mention and link to the debacle of the Surgispehere papers given the topic overlap. @matthewherper and STAT please dig more into Surgisphere and how did papers using its data get past peer review for the Lancet and NEJM???

    I also have concerns about any other Surgishpere products that may be in use:

    Also from STAT
    Top medical journals raise concerns about data in two studies related to Covid-19
    By Matthew Herper and Andrew Joseph June 2, 2020
    Two of the world’s leading medical journals on Tuesday expressed concern about potential flaws in the data produced by a small company to draw major conclusions about Covid-19.

  • This feels completely irresponsible saying there was no statistical impact with the known high percentage of asymptomatic cases and no final testing (self-reporting based on symptoms). How do we know the difference, really?!

  • So much misinformation to confuse people rather than a posit study to help manage the spread of the virus… I am sure it can help in a way otherwise it would never have been mentioned…

  • Hydroxychloroquines primary efficacy is acting as an ionophore for Zinc which has viral replication blocking effect. Both should be studied for complete efficacy.

  • It is broadly observed by Rheumatologists that people already on hydroxychloroquine do not seem to get COVID, or significant cases of it. I look forward to seeing the pre-exposure-prophylaxis data. John Day MD, Austin

  • The Mayo Clinic study is nonsense. It should not have been reported do to too many methodological errors. I think if a physician or group publishes misleading studies due to obvious methodological errors they should be banned from publishing or the minimal is that every article that is published afterwards should always include the moniker “untrustworthy source regardless of institutional credentials”

  • But they didn’t study it while pairing it WITH zinc? When that’s what has shown promise? Statnews might as well be CNN now, publishing such trash.

  • Why is Stat publishing misinformation? Did you ever publish the fact that the Lancet & NEJM studies on HCQ have been debunked? Sensible people & physicians all knew the HCQ deadly was a nonsensical hoax because it has been used safely by millions of people for years!

    • The stories I have read on warnings about hydroxychloroquine are mind-blowing. I live in Kenya and I have taken chloroquine close to 20 times. In 2017, at least 5 millions doses of hydroxychloroquine were used in the US alone. It was not deadly then. But hydroxychloroquine is now one of the most dangerous drug in the world – and that is when the world needs it. It is shocking people are buying into that dangerous nonsense.

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