WHO’s megastudy of COVID-19 treatments

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Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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Remdesivir and interferon fall flat in
WHO’s megastudy of COVID-19
treatments
By Kai KupferschmidtOct. 16, 2020 , 3:45 AM
Patients get tested for COVID-19 in India, one of 30 countries that took part in the Solidarity trial.
AP Photo/Altaf Qadri
Science’s COVID-19 reporting is supported by the Pulitzer Center and
the Heising-Simons Foundation.
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One of the world’s biggest trials of COVID-19 therapies released its long
Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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awaited interim results yesterday—and they’re a letdown. None of the four
treatments in the Solidarity trial, which enrolled more than 11,000 patients in
400 hospitals around the globe, increased survival—not even the muchtouted antiviral drug remdesivir. Scientists at the World Health Organization
(WHO) released the data as a preprint on medRxiv last night, ahead of its
planned publication in The New England Journal of Medicine.
Yet scientists praised the unprecedented study itself and the fact that it
helped bring clarity about four existing, ”repurposed” treatments that each
held some promise against COVID-19. “It’s disappointing that none of the
four have come out and shown a difference in mortality, but it does show
why you need big trials,” says Jeremy Farrar, director of the Wellcome Trust.
“We would love to have a drug that works, but it’s better to know if a drug
works or not than not to know and continue to use it,” says WHO’s chief
scientist, Soumya Swaminathan.
Related
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The prospects of two of the four treatments—the malaria drug
hydroxychloroquine and the HIV drug combination ritonavir/lopinavir—had
faded after another large study, the United Kingdom’s Recovery
trial, showed they did not increase survival in June. After analyzing that
study and its own data up until then, WHO decided to drop both from the
study.
There was still hope for remdesivir and for interferon-beta, which had
initially been given in combination with ritonavir/lopinavir but was tested as
a standalone drug after the Recovery data came out. But neither of those
treatments lowered mortality or delayed the moment patients needed
ventilation to help them breathe. The results in these two treatment arms
are likely to be the most scrutinized.
Remdesivir, which attacks a specific enzyme in several RNA viruses and
was previously tested against Ebola, was initially seen as a promising
candidate. In a U.S. trial with more than 1000 COVID-19 patients published
last week, those who received remdesivir had a shorter recovery time than
patients in the control group, but there was no significant difference in
mortality. Two smaller trials found few significant benefits. Remdesivir
received an emergency use authorization from the U.S. Food and Drug
Administration (FDA) in May for severe COVID-19 patients that was later
expanded to include all patients.
But the Solidarity trial suggests the drug does little in severe cases. Of 2743
Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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hospitalized patients who received the drug, 11% died, versus 11.2% in a
control group of roughly the same size. The difference is so small it could
have arisen by chance.
When the authors pooled Solidarity’s data with those from the three other
trials, they found a slight reduction in mortality that wasn’t statistically
significant either. “This absolutely excludes the suggestion that remdesivir
can prevent a substantial fraction of all deaths,” the authors write. “The
confidence interval is comfortably compatible with prevention of a small
fraction of all deaths but is also comfortably compatible with prevention of
no deaths.”
“This trial doesn’t help remdesivir, that’s for sure,” says Eric Topol, director
of the Scripps Research Translational Institute. “It’s not a dead duck as
much as hydroxychloroquine, but it certainly is not the hope that was
initially signaled.”
But the drug’s manufacturer, Gilead Sciences, casts doubt on the study.
“The trial design prioritized broad access, resulting in significant
heterogeneity in trial adoption, implementation, controls and patient
populations,” the company says in a statement, “and consequently, it is
unclear if any conclusive findings can be drawn from the study results.”
Gilead received the manuscript about Solidarity on 28 September,
according to WHO. On 8 October, before the results became public, the
company signed a $1 billion deal with the European Commission for a 6-
month supply of the drug.
Solidarity’s “most disappointing results,” however, are those for interferonbeta, Topol says. Mortality among the 2050 people who received that drug
(either alone or in combination with lopinavir/ritonavir) was 11.9%, versus
10.5% in the control group. Prior studies have suggested interferon can only
Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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help if given early, however, and not once patients have been hospitalized.
“So I think that’s still an open question,” Topol says.
“Treating COVID late is very difficult,” Benjamin tenOever, a virologist at the
Icahn School of Medicine at Mount Sinai, wrote in an email to Science. “At
this point in the disease the issue is more about inflammation and clotting,
which is likely why these four drug regimens showed little value.”
The silver lining may be that the trial itself, unprecedented in several ways,
succeeded. Set up in a short time in March as the pandemic engulfed the
world, it used a simple protocol that allowed doctors in overstretched
hospitals anywhere to randomize their patients to whatever study drug was
available or to standard care. “To get four different drug strategies nailed
down, and in this short period of time and across the world, is just
fantastic,” Topol says. “I give them a lot of praise for getting us these results
with extraordinary velocity.” “I think that Recovery and the Solidarity trial
between them have set the standard of the scale that’s required in order to
give you clear answers,” Farrar adds.
To get four different drug strategies nailed down, and in this short
period of time and across the world, is just fantastic.
Eric Topol, Scripps Research Translational Institute
The biggest hurdle was the long time it took to get regulatory approval for
the study in some countries, says WHO’s Marie-Pierre Preziosi. “Regulators,
as well as the ethics committees for that matter, need to rethink their
approaches in pandemics and need to be much more ready to cope with
this because sometimes the duration for authorization is really not
appropriate.”
Still, the trial has ramped up to more than 11,000 patients from 30
Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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countries, including Argentina, Peru, India, the Philippines, and Spain, with
more slated to join. About 2000 patients are now included every month. For
the moment, the remdesivir arm will continue “to get more precise
evidence,” says John-Arne Røttingen, CEO of the Research Council of
Norway, who heads the executive group of Solidarity’s steering committee.
But new drugs will be added, he says.
As early as next week, Solidarity participants could start to receive
acalabrutinib, a cancer drug that inhibits an enzyme that plays an important
role in the human immune system. The hope is to soon include targeted
therapies such as monoclonal antibodies as well because they are more
likely to be successful than repurposed drugs. “Trying to find off-target
benefits from FDA-approved drugs is not a great strategy (although
arguably the best we can do under these conditions),” tenOever wrote.
Solidarity built on experience from the 2014–16 Ebola epidemic in West
Africa, says Ana Maria Henao Restrepo, who heads the Research and
Development Group at WHO. Back then, there were many debates about
whether it was even ethical to do randomized clinical trials—which withhold
a potential therapy from patients in control groups—during a deadly
outbreak. “Now, you don’t see any debate” on that question, she says. “The
community, all of us, we have moved, we have learned a lot since West
Africa.”
The study’s global reach has important benefits, says Nahid Bhadelia, a
physician at Boston Medical Center. Conducting a trial in many places
simultaneously means more patients can be included, leading to faster
results but also to more robust data, she says. “You’re including many
different types of subgroups and populations in different parts of the
world.”
Remdesivir and interferon fall flat in WHO’s megastudy of COVID-19 treatments | Science | AAAS 11/5/20, 3:15 PM
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Another advantage: The 1300 participating doctors worldwide will have a
sense of ownership of the results, Henao Restrepo says. “When they see
the results in The New England Journal of Medicine, [they will] say, ‘I’ve
contributed to that and I understand why that drug works or doesn’t work. I
know, I trust it,’” she says. “That is different from some Northern
Hemisphere group publishing, and they say: ‘Somewhere in a rich country
they did a trial and now we all have to believe the results.’”

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