[Ip-health] Science: WHO launches global megatrial of the four most promising coronavirus treatments

Thiru Balasubramaniam thiru at keionline.org
Sun Mar 22 22:32:07 PDT 2020


WHO launches global megatrial of the four most promising coronavirus

By Kai Kupferschmidt <https://www.sciencemag.org/author/kai-kupferschmidt>, Jon
Cohen <https://www.sciencemag.org/author/jon-cohen>Mar. 22, 2020 , 3:28 PM

A drug combo already used against HIV. A malaria treatment first tested
during World War II. A new antiviral whose promise against Ebola fizzled
last year.

Could any of these drugs hold the key to saving COVID-19 patients from
serious harm or death? On Friday, the World Health Organization (WHO)
announced a large global trial, called SOLIDARITY, to find out if any can
treat infections with the new coronavirus for the dangerous respiratory
disease. It’s an unprecedented effort—an all-out, coordinated push to
collect robust scientific data rapidly during a pandemic. The study, which
could include many thousands of patients in dozens of countries, has been
designed to be as simple as possible so that even hospitals overwhelmed by
an onslaught of COVID-19 patients can participate.

With around 15% of COVID-19 patients suffering from severe disease and
hospitals being overwhelmed, treatments are desperately needed. So rather
than coming up with compounds from scratch that may take years to develop
and test, researchers and public health agencies are looking to repurpose
drugs already approved for other diseases and known to be largely safe.
They’re also looking at unapproved drugs that have performed well in animal
studies with the other two deadly coronaviruses, which cause severe acute
respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

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Drugs that slow or kill the novel coronavirus, called SARS-CoV-2, could
save the lives of severely ill patients but might also be given
prophylactically, to protect health care workers and others at high risk of
infection. Treatments may also reduce the time patients spend in intensive
care units, freeing critical hospital beds.

Scientists have suggested dozens of existing compounds for testing but WHO
is focusing on what it says are the four most promising therapies: an
experimental antiviral compound called remdesivir; the malaria medications
chloroquine and hydroxychloroquine; a combination of two HIV drugs,
lopinavir and ritonavir; and that same combination plus interferon-beta, an
immune system messenger that can help cripple viruses. Some data on their
use in COVID-19 patients has already emerged—the HIV combo failed in a
small study in China-but WHO believes a large trial with a greater variety
of patients is warranted.

Enrolling subjects in SOLIDARITY will be easy. When a person with a
confirmed case of COVID-19 is deemed eligible, the physician can enter the
patient’s data into a WHO website, including any underlying condition that
could change the course of the disease, such as diabetes or HIV infection.
The participant has to sign an informed consent form that is scanned and
sent to WHO electronically. After the physician states which drugs are
available at his or her hospital, the website will randomize the patient to
one of the drugs available or to the local standard care for COVID-19.

“After that, no more measurements or documentation are required,” says Ana
Maria Henao-Restrepo, a medical officer at WHO’s Department of Immunization
Vaccines and Biologicals.  Physicians will record the day the patient left
the hospital or died, the duration of the hospital stay, and whether the
patient required oxygen or ventilation, she says. “That's all.”

The design is not double-blind, the gold standard in medical research, so
there could be placebo effects from patients knowing they received a
candidate drug. But WHO says it had to balance scientific rigor against
speed. The idea for SOLIDARITY came up less than two weeks ago, says
Henao-Restrepo, and the agency hopes to have supporting documentation and
data management centers set up next week. “We are doing this in record
time,” she says.

Arthur Caplan, a bioethicist at New York University Langone Medical Center,
says he likes the study’s design. “No one wants to tax the frontline
caregiver who's overwhelmed and taking risks anyway,” says Caplan.
Hospitals that aren’t overburdened might be able to record more data on
disease progression, for instance by following the level of virus in the
body, Caplan suggests. But for public health, the simple outcomes WHO seeks
to measure are the only relevant ones for now, says virologist Christian
Drosten of the Berlin University Clinic Charité: “We don’t really know
enough about this disease to be sure what it means when the viral load
decreases in the throat, for instance.”

On Sunday, the French National Research Institute for Medical Research
(INSERM) announced it will coordinate an add-on trial in Europe, named
Discovery, that will follow WHO’s example and will include 3200 patients
from at least 7 countries, including 800 from France. That trial will test
the same drugs, with the exception of chloroquine. Other countries or
groups of hosptals could organize add-on studies as well, says Heneo
Restrepo. They are free to do additional measurements or observations, for
instance on virology, blood gases, chemistry, and lung imaging. "While
well-organized additional research studies of the natural history of the
disease or of the effects of the trial treatments could well be valuable,
they are not core requirements," she says.

The list of drugs to test first was put together for WHO by a panel of
scientists who have been assessing the evidence for candidate therapies
since January, says Restrepo. The group selected drugs that had the highest
likelihood of working; had the most safety data from previous use; and are
likely to be available in supplies sufficient to treat substantial numbers
of patients if the trial shows they work.

Here are the treatments that SOLIDARITY will test:

The new coronavirus is giving this compound a second chance to shine.
Originally developed by Gilead to combat Ebola and related viruses,
remdesivir shuts down viral replication by inhibiting a key viral enzyme,
the RNA-dependent RNA polymerase.

Researchers tested remdesivir last year during the Ebola outbreak in the
Democratic Republic of the Congo, along with three other treatments. It did not
show any effect
(Two others did.) But the enzyme it targets is similar in other viruses,
and in 2017 researchers at the University of North Carolina in Chapel Hill
showed in test tube and animal studies that the drug can inhibit the
coronaviruses that cause SARS and MERS

The first COVID-19 patient diagnosed in the United States—a young man in
Snohomish County, Washington—was given remdesivir when his condition
worsened; he improved the next day, according to a case report in the *New
England Journal of Medicine* *(NEJM)*
<https://www.nejm.org/doi/full/10.1056/NEJMoa2001191>*.* A Californian
patient who received remdesivir—and who doctors thought might not
as well

Such evidence from individual cases doesn’t prove a drug is safe and
effective. Still, from the drugs in the SOLIDARITY trial, “remdesivir has
the best potential to be used in clinics” says Jiang Shibo, of Fudan
University in Shanghai, China, who has long worked on coronavirus
therapeutics. Jiang particularly likes that high doses of the drug can
likely be given without causing toxicities.

However, it may be much more potent if given early in an infection, like
most other drugs, says Stanley Perlman, a coronavirus researcher at the
University of Iowa. “What you really want to do is give a drug like that to
people who walk in with mild symptoms,” he says. “And you can't do that
because it's an [intravenous] drug, it’s expensive and 85 out of 100 people
don’t need it.”
Chloroquine and hydroxychloroquine

At a press conference on Friday, President Donald Trump called chloroquine
and hydroxychloroquine a “game changer.” “I feel good about it,” Trump
said. His remarks have led to a rush in demand for the decades-old
antimalarials. (“It reminds me a little bit of the toilet paper phenomenon
and everybody's running to the store,” says Caplan.)

The WHO scientific panel designing SOLIDARITY had originally decided to
leave the duo out of the trial  but had a change of heart at a meeting in
Geneva on 13 March, because the drugs “received significant attention” in
many countries, according to the report of a WHO working group
looked into the drugs’ potential. The widespread interested prompted “the
need to examine emerging evidence to inform a decision on its potential

The available data are thin. The drugs work by decreasing the acidity in
endosomes, compartments inside cells that they use to ingest outside
material and that some viruses can coopt to enter a cell. But the main
entryway for SARS-Cov-2 is a different one, using its so-called spike
protein to attach to a receptor on the surface of human cells. Studies in
cell culture have suggested chloroquines have some activity against
SARS-CoV-2, but the doses needed are usually high—and could cause serious

Encouraging cell study results with chloroquines against two other viral
diseases, dengue and chikungunya, didn’t pan out in people in randomized
clinical trials. And non-human primates infected with chikungunya did worse
when given chloroquine. “Researchers have tried this drug on virus after
virus, and it never works out in humans. The dose needed is just too high,”
says Susanne Herold, an expert on pulmonary infections at the University of
Giessen, Germany.

Results from COVID-19 patients are murky. Chinese researchers who report
treating more than 100 patients with chloroquine touted its benefits in a
 letter in *BioScience*
but the data underlying the claim have not been published. All in all, more
than 20 COVID-19 studies in China used chloroquine or hydroxychloroquine,
WHO notes, but their results have been hard to come by. “WHO is engaging
with Chinese colleagues at the mission in Geneva and have received
assurances of improved collaboration; however, no data has been shared
regarding the chloroquine studies.”

Researchers in France have published a study in which they treated 20
COVID-19 patients with hydroxychloroquine
They concluded that the drug significantly reduced viral load in
nasal swabs. But it was not a randomized controlled trial and it didn’t
report clinical outcomes such as deaths. In guidance published on Friday
the US Society of Critical Care Medicine said that “there is insufficient
evidence to issue a recommendation on the use of chloroquine or
hydroxychloroquine in critically ill adults with COVID-19.”

Hydroxychloroquine in particular might do more harm than good. The drug has
a variety of side effects and can in rare cases harm the heart. Since
people with heart conditions are at higher risk of severe COVID-19, that is
a concern, says David Smith, an infectious disease physician at the
University of California, San Diego. “This is a warning signal, but we
still need to do the trial,” he says. What’s more, a rush to use the drug
for COVID-19 might make it harder for the people who need it to treat their
rheumatoid arthritis or malaria.

This combination drug, sold under the brand name Kaletra, was approved in
the US in 2000 to treat HIV infections. Abbott Laboratories developed
lopinavir specifically to inhibit the protease of HIV, an important enzyme
that cleaves a long protein chain into peptides during the assembly of new
viruses. Because lopinavir is quickly broken down in the human body by our
own proteases, it is given with low levels of ritonavir, another protease
inhibitor, that lets lopinavir persist longer.

The combination can inhibit the protease of other viruses as well,
specifically coronaviruses. It has shown efficacy in marmosets infected
with the MERS virus
<https://academic.oup.com/jid/article/212/12/1904/2911949>, and has also
been tested in SARS and MERS patients, though results from those trials are

The first trial with COVD-19 was not encouraging, however. Doctors in
Wuhan, China, gave 199 patients two pills of lopinavir/ritonavir twice a
day plus standard care, or standard care alone. There was no significant
difference between the groups, they reported in *NEJM *on 15 March
<https://www.nejm.org/doi/full/10.1056/NEJMoa2001282>. But the authors
caution that patients were very ill—more than a fifth of them died—and so
the treatment may have been given too late to help.  While the drug is
generally safe it may interact with drugs usually given to severely ill
patients, and doctors have warned it could cause significant liver damage.
Ritonavir/lopinavir + interferon beta

SOLIDARITY will also have an arm that combines the two antivirals with
interferon-beta, a molecule involved in regulating inflammation in the body
that also has shown an effect in marmosets infected with MERS. A
combination of the three drugs is now being tested in in MERS patients in
Saudi-Arabia in the first randomized controlled trial for that disease

But the use of interferon-beta on patients with severe COVID-19 might be
risky, says Herold. “If it is given late in the disease it could easily
lead to worse tissue damage instead of helping patients,” she cautions.
Thousands of patients

The design of the SOLIDARITY trial can change at any time. A global data
safety monitoring board will look at interim results at regular intervals
and decide whether any member of the quartet has a clear effect, or whether
one can be dropped because it clearly does not. Several other drugs,
including the influenza drug favipiravir, produced by Japan’s Toyama
Chemical, may be added to the trial.

To get robust results from the study, several thousands of patients will
likely have to be recruited, says Henao-Restrepo. Argentina, Iran, South
Africa, and several other non-European countries have already signed up.
WHO is also hoping to do a prevention trial to test drugs that might
protect health care workers from infection, using the same basic protocol,
says Henao-Restrepo.

The trial’s European counterpart, Discovery, will recruit patients from
France, Spain, the United Kingdom, Germany, and the Benelux countries,
according to an INSERM press release today. The trial will be led Florence
Ader, an infectious diseases researcher at the University Hospital Center
in Lyon.

Doing rigorous clinical research during an outbreak is always a challenge,
says Henao-Restrepo, but it’s the best way to make headway against the
virus: “It will be important to get answers quickly, to try to find out
what works and what doesn't work. We think that randomized evidence is the
best way to do that.”

Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International
41 22 791 6727
thiru at keionline.org

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