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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.

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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.

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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.”

  • I love how most posters here have suddenly become clinical trialists. Not every trial is perfectly executed but rest assured the trialists who do these things for a living know much, much more than you dumb, dumb posters.

    The drug works excellent for what it is currently approved for which is the treatment of lupus and malaria and not for covid19.

    Don’t like it? Go back to school, get your ba, mba and phd in biology or chemistry, go to work as bench scientist for a pharma company for 5 years and report back.

    Otherwise, stop it with the idiocratcy as you have no credibility whatsoever.

    • Not a dotard. Please rea the reports by Dr who have used HCQ +Zn+ ABX correctly and reported excellent results. We don;t have time for double blind placebo trials people are dying now. IF this protocol saves one patient it is worth it.
      Yopur negativity is killing patients.

    • Again, i’ll rely on clinical scientists who do this for a living. You, “dr tedone” should just worry about those knee and hip replacements down in FL. If there is a clinical protocol where you want to prescribe the cocktail to a patient then go for it. You are clearly the expert.

    • I am not impressed how some posters here have suddenly become clinical trialists. Nor how some feel elitist and utterly fail to appreciate they do not comprehend everything in any particular field, let alone better than the vast numbers of people in multidisciplinary fields which have a better handle on the realities of the world. Often, people not directly involved in a project can see past limiting paradigms and can interpret study data and statistics more clearly. Experts in a particular arena are best equipped to work in their chosen field, but only a fool would discount input from all others. Cluster mentality at the exclusion of independent opinions is by definition arrogance.

  • Why is it, every time I read a “study” report that shows not effect of HCQ, the use of supplemental zinc (and azithromycin) is not mentioned? Is it because the researchers do not know that tissue zinc prevents the reproduction of the SARS-CoV2 virus in infected cells but does not replenish the necessary compound without supplement?

  • This study is so horrible that it borders on suspicious. You don’t even know which patients actually had COVID.
    If it wasn’t so sad it would be comical.
    The fact is that Drs have already proven that this medication works. Why are these trials so screwball. The Henry ford trial shows that it reduced death by 50 percent!!! Come on guys, you can do better than this.

  • I have not looked at this study, but suggest we need to take note of vitamin D levels and add zinc to any treatment protocol. Data from whole countries using HCQ routinely show much lower death rates than USA; is that demographic, or benefit?

  • How are these ‘high quality’ studies if they’re stopped before the medicine has had a chance to provide its effects? There are so many testimonials of the positive effects of HCQ that something smells here.

  • Another possible major flaw – among many – in the Minnesota ‘trial’ :

    Most patients received folic acid as a placebo

    But folic acid may itself be active against the disease :

    https://chemrxiv.org/articles/preprint/The_Role_of_Folic_Acid_in_the_Management_of_Respiratory_Disease_Caused_by_COVID-19/12034980

    This could essentially negate the study –
    aside from its other flaws – and indeed add positivity to the HCQ treatment arm

    • From the paper: “Additional post-hoc analyses showed that self-reported use of zinc or vitamin C in addition to hydroxychloroquine did not improve symptoms over use of hydroxychloroquine alone.”

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