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.

  • What this study showed was that people who took hydroxychloroquine were 17.5% less likely to get Covid. However, the difference wasn’t statistically significant. That means that the benefit of hydroxychloroquine may have been due to chance. The other possibility is that the study was underpowered to detect a difference.

  • Hydroxychloroquine usage is purposefully being demonized by the liberal left just because Trump mentioned it. With that said, please do your research on the mechanism behind what it does. It is a zinc ionophore and has no direct effect on the virus, just allows Zinc to be absorbed into the cells so it can help slow or stop the reproduction of the virus. In no way shape or form does it prevent you from catching the virus, but has the ability to reduce the effects and give the body time to build anti-bodies.

    • Exactly. When Quinine was provided for malaria prophylaxie it was not preventing mosquitoes to bite and infect. But when infected, severity of the disease was very attenuated.

    • Then tell the world because there is absolutely no data to it’s mechanism of action. It isn’t even used for malaria anymore because of drug resistance to it decades ago.
      When it was used it was used for uncomplicated malaria. Meaning if you had other health issues then it was considered too toxic to use.

    • I can send you a bottle if you dont mind night blindness, skin and hair bleaching, cerebral edema, skin sores, etc and so forth.

    • To the people trying to claim this medication is too dangerous to even use: Plaquenil is the go-to treatment for Lupus, and having it myself, I cannot put words to how sick I am during flares. The side effects are rare even after taking it for years; some Lupus patients take it for decades. When taken at prescribed doses those side effects are rare. So stop with the fear-mongering, this is a drug that was used in Vietnam by 10s of 1000s for years as well, in any tropic location with malaria. I cannot believe people are spreading such gross disinfo, frightening people who take it for lupus and potentially putting enough fear into the newly diagnosed that they may be too scared to take it all for a progressive incurable degenerative disease. Lupus is horrible, what it does to a person is disfiguring and painful and it destroys lives. Stop with the talking points downing this drug, when it is the only hope for so many seriously ill people. And incidentally, since the concern trolling is so irresistible for some people, you might want to go around warning people of the dangers of aspirin and tylenol, as far more are damaged by those drugs than by plaquenil.

  • From what I understand HQ with zinc supplement will not stop you contracting the virus but taken in the early stages will block the ace2 receptors and stop the rapid progression of an over reaction of immune system. Being In, a at risk group for sure I might catch Covid 19 but if HQ prevents my death that’s great. So please report issues concerning the recovery rates and the prevention of pneumonia and the need for a ventilator.
    Who cares about the side effects, being alive after the infection is what’s important.
    So please report the whole study ie from infection to recovery not what the media wants to hear.
    I await your comments
    Regards
    John

  • This umptieth story on HCQ underscores the chaos in studies, opinions, preferences, likes and dislikes. What IS clear for sure is that it is NOT a great drug (even the President who promoted it is no longer taking it either – haha), and clearly R&D should focus on other much more effective drug candidates. So STAT News : please dig into those far better options and deliver the readers some much more worthwhile material.

    • The President took the drug to demonstrate it was safe on a 75 years old. He does not need to keep taking it because the White House has put in place extraordinary sanitation’s barriers to ensure his safety.

  • In the STATISTICAL ANALYSIS subsection of the Methods Section in today’s NEJM article it mentions that the Kruskal-Wallis test was employed in a secondary analysis. Given that this study compared two arms — a treatment versus a control — it is not clear why that statistical procedure, designed for comparing differences among more than two arms when the data outcomes are at least ordinal in measurement, was selected.

  • To John Day’s Comments and others… For Shame… Since when do properly trained and licensed medical professionals make such ridiculous statements starting with “it seems…” especially when referring to a potentially deadly, highly communicable disease such as COVID-19?

  • To John Day’s Comments and others… For Shame… Since when do properly trained and licensed medical professionals make such ridiculous statements starting with “it seems…” especially when referring to a potentially deadly, highly communicable disease such as COVID-19? And, to John Day’s comment about people already on hydroxychloroquine for rheumatological problems who don’t “seem” to get COVID-19… give me a break… what kind of scientifically constructed phrase is that?

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