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COVID-19 patients are treated using a noninvasive ventilation system at a field hospital in Manaus, Brazil.

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‘Too good to be true’: Doubts swirl around trial that saw 77% reduction in COVID-19 mortality

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

It would be the best news by far in COVID-19 treatment: According to a preprint published on 22 June, an experimental prostate cancer drug named proxalutamide reduced deaths in hospitalized COVID-19 patients by 77% in a clinical trial in Brazil. The preprint also claims the drug, which blocks the activity of androgens—male hormones such as testosterone—cut patients’ average hospital stay by 5 days, far more than any other treatment yet tested. Interim results of the study, announced at a press conference in March, led President Jair Bolsonaro to tout proxalutamide as a wonder cure and spurred Brazilian doctors to dose patients with similar drugs.

But many scientists are wary. Alleged irregularities in the clinical trial have reportedly triggered an investigation by a national research ethics commission in Brazil. Top medical journals have rejected a paper about the study, and its main author, Flavio Cadegiani, an endocrinologist at the biotech company Applied Biology, has previously touted unproven COVID-19 medications, such as ivermectin, azithromycin, and antiworm compounds. And to many, the claims simply seem implausible.

“These results are too good to be true,” says Eric Topol, executive vice president of Scripps Research Translational Institute. “There are almost no medical interventions in the history of medicine that have this magnitude of benefit, no less with COVID-19.”

But the idea behind the study makes sense, some scientists say. Men are more susceptible to hospitalization and death from COVID-19, and androgens may play a role. Although other studies with antiandrogens have come up empty, some researchers are keeping an open mind about the Brazilian trial. “It seems pretty convincing,” says Christina Jamieson, a prostate cancer researcher at the University of California (UC), San Diego. “If they did what they say they did, it looks really good.” Matthew Rettig, a prostate cancer oncologist at  UC Los Angeles who is leading a similar trial with another drug, says the oversize impact gives him pause, but “If this can be confirmed it would be a home run for sure,” he says.

Proxalutamide is not approved in any country for any condition, but its manufacturer, Kintor Pharmaceuticals in China, is recruiting patients to test it for prostate cancer at multiple centers in the United States. For the COVID-19 study, Kintor teamed up with Applied Biology, a hair loss treatment company based in California where Cadegiani is a clinical director. In February, Cadegiani's team reported an encouraging early finding: Proxalutamide helped nonhospitalized patients with mild to moderate symptoms clear the virus much faster than those given a placebo.

The new study tested the drug in hospitalized patients in COVID-19’s later stages. Doctors at eight hospitals in Brazil's Amazonas state enrolled 645 patients, according to the preprint. None initially required mechanical ventilation, and all were receiving “usual care,” which included approved anti-inflammatory drugs such as dexamethasone but sometimes also unproven compounds such as ivermectin. Roughly half also got proxalutamide; the other half got a placebo for 14 days.

In March, little more than a month after the trial began, Cadegiani and his colleagues announced their stunning interim results at a press conference. “A doctor has to see their patients with proxalutamide to truly understand what we have seen. It is unfeasible to describe through words or translation into scientific language the dramatic response,” Cadegiani tweeted around that time. The final analysis is in the new preprint, which reports that almost half of patients in the placebo group died, versus only 11% in the treatment arm, a 77% reduction in mortality. Patients on proxalutamide also had shorter hospital stays and less need for mechanical ventilators throughout the course of their treatment, and nearly 81% recovered after 2 weeks, compared with 36% of those not on the drug.

But on 8 June, the Brazilian newspaper O Globo reported that the Brazilian National Research Ethics Commission was investigating the study because the authors failed to report trial deaths as quickly as required by clinical trial rules in Brazil, and at different times reported a total of 170 and more than 200 deaths during the trial. The agency would not confirm the investigation, noting that “all data from the research protocols under analysis are confidential,” but Cadegiani confirms to Science that the commission is expected to issue a report on the trial.

Numerous researchers, including Topol and Jason Pogue, an infectious diseases clinical pharmacist at the University of Michigan, Ann Arbor, caution that the number of deaths in the trial is startling. In the placebo group the fatality rate was 49.4%, which made the drug look better but is far larger than the less than 10% of hospitalized COVID-19 patients who die in the United States. The speed of the trial, which only began in early February yet reported interim results in March, is suspicious as well, says Ana Carolina Peçanha, an intensive care physician at the Federal University of Rio Grande do Sul. “To [recruit] and monitor about 600 patients in a study in less than 30 days is unbelievable,” she says.

Cadegiani says it isn’t surprising so many people died in the trial because the Gamma variant (also known as P.1) was widespread in northern Brazil at the time and overwhelming hospitals. According to official data, about 43% of hospitalized COVID-19 patients in Amazonas state were dying when the study started in February. And as for the rapid recruitment, Cadegiani says as word got out in hospitals that patients in the proxalutamide trial were recovering within days and being released, others clamored to get into the trial.

Cadegiani believes the criticism stems from the fact that Bolsonaro and other officials have praised the drug. That "made it quite political," he says. He says it also explains why he has had trouble getting the data published, he says. “Bolsonaro made [journal] editors afraid to publish positive results,” Cadegiani says. He submitted the full results to The New England Journal of Medicine in the spring but says the paper was rejected despite what he calls "extremely constructive" reviews. When Cadegiani asked for the reason, Eric Rubin, the journal’s editor-in-chief, responded in an email, “It’s simple—the results are unexpectedly good. Given how good they are, the reviewers felt the data needed a primary review,” meaning they needed to see not just the analysis, but also the original data. “We simply don’t have the capacity to do that,” Rubin wrote in his email, which Cadegiani shared with Science. The Lancet rejected the paper as well.

The study is already having an impact in Brazil, however. Because proxalutamide is not yet approved or sold in Brazil, some doctors have begun to treat COVID-19 with other antiandrogens and prostate cancer drugs, such as dutasteride and bicalutamide. They are adding to a tide of unproven drugs being used to treat COVID-19 in Brazil, alarming infectious disease experts. "We cannot put the health of the Brazilian population at risk with guidelines without scientific evidence," Clóvis Arns da Cunha, who heads the Brazilian Society for Infectious Dieases, wrote in a statement last year.

There are almost no medical interventions in the history of medicine that have this magnitude of benefit, no less with COVID-19.

Eric Topol, Scripps Research Translational Institute

Yet there is good reason to hope antiandrogens could combat COVID-19, some scientists say. According to the latest monthly statistics compiled by Global Health 50/50, which tracks gender disparities in COVID-19 patients, men account for 56% of COVID deaths worldwide. That disparity has prompted speculation that androgens may promote COVID-19 and encouraged studies of whether anti-androgen drugs can curb the disease.

Antiandrogens have been studied for decades as a treatment for prostate cancer, a disease fueled by androgens. In the prostate, when male hormones bind to receptor molecules, cells boost their production of a membrane protein called TMPRSS2 and divide more rapidly. Androgens also increase production of another protein, the angiotensin converting enzyme 2 (ACE2) receptor. Both molecules play key roles in coronavirus infections: TMPRSS2 cuts the virus’ outer spike protein, which enables it to bind to ACE2 receptors and slip into cells’ interiors.

With the exception of the Brazilian trial, tests of antiandrogens in COVID-19 patients so far have not been encouraging. A February study in the Journal of Urology, led by prostate cancer researcher Nima Sharifi of the Cleveland Clinic, found that in 1779 men with prostate cancer, androgen-deprivation therapy (ADT) had no effect on their risk of being infected with SARS-CoV-2. Another study, led by researchers from Vanderbilt University and presented at a recent meeting of the American Society of Clinical Oncology, found ADT treatment in nearly 600 prostate cancer patients had no effect on the number who died from COVID-19.

“I’m not saying [the proxalutamide results] are not true,” Sharifi says. “But it’s hard to make complete sense of them.” It's also not clear why a drug that acts on SARS-CoV-2's receptors and should be best at preventing early stage viral infection would be effective at late stages of disease, when the surge of infection is largely over and a hyperactive immune system causes the problems. Cadegiani and co-authors believe proxalutamide tamps down cytokines that stimulate immune responses and encourage the production of estrogen, which lowers them further.

Other clinical trials may soon provide additional data. Kintor is currently recruiting male, nonhospitalized patients in California for a U.S. phase 3 trial of proxalutamide. Cadegiani says his colleagues in Brazil hope to soon test bicalutamide, a similar U.S. Food and Drug Administration-approved androgen receptor blocker to see whether it produces comparable results.

Separate clinical trials of bicalutamide are ongoing at the University of Florida and Johns Hopkins University. Swedish researchers are testing a similar drug called enzalutamide. And Rettig says his team is now conducting an interim analysis of trial results on degarelix, another antiandrogen. For now, most researchers are waiting to see what, if anything, is real in the seemingly improbable results from the heart of the Amazon.

With reporting by Sofia Moutinho in Brazil.

Correction, 9 July 2021, 8:00 a.m.: A previous version of this story identified Ana Carolina Peçanha as a pulmonologist. She is an intensive care physician.