
WHO launches global megatrial of the four most promising coronavirus treatments - MichaelMoser123
https://www.sciencemag.org/news/2020/03/who-launches-global-megatrial-four-most-promising-coronavirus-treatments
======
bitL
I am missing Fujifilm's Avigan/Favipiravir here - Chinese reported success
using it:

"On 17 March 2020, Chinese officials suggested that Favipiravir seemed to be
effective in treating COVID-19 in Wuhan and Shenzhen.[31][32][33]

A study on 80 patients comparing it to lopinavir/ritonavir found that it
significantly reduced viral clearance time to 4 days, compared to 11 for the
control group, and that 91.43% of patients had improved CT scans with few side
effects."

[https://en.wikipedia.org/wiki/Favipiravir](https://en.wikipedia.org/wiki/Favipiravir)

~~~
vikramkr
The four drugs they are testing seem to be already developed/approved in
humans for other uses so expanding the label is easy, while avigan is still
experimental (some limited approval in Japan, but worldwide acceptance not
there yet) and would have to go through much more testing before being
unleashed at coronavirus scale.

~~~
yosito
Surely if it's already being used in Japan it's been tested enough to use
globally in an emergency.

~~~
vikramkr
It's very limited approval, it's not something that's just approved and
available to be prescribed to anyone. According to the wiki it's only approved
in an emergency (presumably meaning individual, not societal, emergency)
because of concerns with toxicity and alll. And countries don't automatically
trust other countries to approve drugs correctly - Europe did not buy what the
FDA was saying about opioids for chronic pain which saved a lot of lives on
Europe. The damage that would come from releasing a half baked drug into the
world with terrible side effects would vastly outweigh the benefits of
mitigating coronavirus, and that's a mistake you only get to make once.

I'm sure they'll test the drug in the future though, there are likely plans to
test it as we speak, and if it works really well there are lots of ways to get
expedited approval, especially in a state of emergency

[https://en.m.wikipedia.org/wiki/Favipiravir](https://en.m.wikipedia.org/wiki/Favipiravir)

------
DocSavage
Stage of disease also is important. In the first symptomatic stage, makes
sense to try antivirals and HCQ to reduce or eliminate the virus, and prevent
a cascade into the next stage. The problematic second stage - ARDS, a subset
of patients who really go critical, seems to call for different approach
because at that time, it’s the cytokine storm and our own immune reaction
killing us.

~~~
vhvjkyhkogvv
Do you have a source for the last part?

~~~
DocSavage
A good synopsis of current understanding (as of last Friday) was a UCSF
Medicine Grand Rounds broadcast. I've bookmarked the most relevant slide to
our discussion in particular: [https://youtu.be/bt-
BzEve46Y?t=2349](https://youtu.be/bt-BzEve46Y?t=2349)

Significant lung and myocardial injury and papers have honed in on ARDS as a
real problem.

~~~
bluenose69
This is a wonderful resource. Thank you for pointing it out.

------
ignoramous
The drugs on trial are:

1\. Remdesivir (Ebola drug).

2\. Chroloquine and Hydroxychroloquine (Malaria drug).

3\. Ritonavir/lopinavir (AIDS drug).

4\. Ritonavir/lopinavir + interferon beta (virus signaling protein).

~~~
tosser0001
Interesting to see interferon on here. I remember it being hailed as some sort
of wonder drug back in the 80s, but then sort of fell off the radar.

[https://books.google.com/ngrams/graph?content=interferon](https://books.google.com/ngrams/graph?content=interferon)

~~~
chasil
Covid disables the innate immune response by preventing the expression of
interferon alpha & beta.

This allows it to engage in uncontrolled replication for up to two weeks
before the adaptive response brings it under control.

This massive viral load greatly contributes to transmission.

(Or at least SARS does this.)

[https://cmr.asm.org/content/20/4/660.long](https://cmr.asm.org/content/20/4/660.long)

------
jaynetics
Can anyone comment about the worldwide production capacity and possible lower
price limits for these drugs?

It should be possible to supply a large part of the worlds population with
(hydroxy)chloroquinine _if_ that is deemed a solution, but the others seem
less ideal candidates for that, or am I wrong?

~~~
rscho
What I can personally comment on is that if people go on with hoarding on
quinine derivatives, we're gonna have a massive problem whether it's found
effective or not.

The hoarding is even happening among my lesser scientifically-reasonable md
colleagues. This has to stop. Now.

~~~
matsemann
Norwegian doctors have also been hoarding this for themselves lately. Enough
that the Norwegian government had to step in and put it on a list so those
that actually need it day-to-day can get hold of it.

I hope when this is over, someone will look into this behaviour from the MDs.
It's eroding trust in the system when they claim potentially vital resources
for themselves.

~~~
XaspR8d
I don't know what the situation is like in Norway, but I 100% don't blame MDs
in the US for trying to find their own treatments, because they're generally
being left high and dry by the extreme rationing of the PPE. Doctors
themselves have taken to personally reaching out to the communities near me so
that they can find masks.

Obviously I don't want anyone with lupus / malaria / etc to be adversely
affected, but I think the people being forced to work the front lines _do_
deserve to be somehow prioritized just from a "how do we keep the system
operating efficiently" standpoint, and it doesn't really seem like the people
who could manage supplies to make sure both parties needs are balanced, e.g.
hospital administrations and regional governments, are going to take much
responsibility for that.

------
nil-sec
Anyone knows why serum is not sufficient to completely solve all our issues? I
applaud this trial but this confuses me. It seems like we already have the
capacity to do this on large scale, it's considered very safe and as far as I
understand is highly effective. There was an article about it here a few days
back, but besides that I don't hear much about it in the general discussion,
why?

~~~
raverbashing
One thing I couldn't find a source for is how many donors could potentially
help how many people. Is it 1 to 1? 1 donor can help multiple people? Or one
patient needs the amount of multiple donors?

~~~
ajross
That's exactly it. If the virus is exploding exponentially the number of
recovered cases is a tiny, tiny fraction of the active ones. This treatment
doesn't work until things are under control, basically.

~~~
Ajedi32
But if the death rate is "only" 1 in 10 (approximately) then doesn't that mean
there are ~9 survivors for every terminally ill patient? It doesn't seem like
the number of survivors would be the limiting factor here.

~~~
ajross
No, because the virus takes time. Survivors aren't "survivors" until they've
recovered, so they reflect the people who "would have been" critical cases
maybe 10-15 days ago. But 10-15 days ago the number of cases was (depending on
which doubling statistic you use) 4x-32x _smaller_ than what it is today.

Exponential growth messes everything up, basically. All our intuition about
how things work tends to be wrong in subtle ways.

~~~
nil-sec
e^(c _t) /e^(c_(t - 14days)) = e^(c*14days) = k = constant, with c the growth
rate. While you are right that, in an exponential growth scenario, the number
of recovered cases is smaller than the number of currently active cases, the
factor is proportional to the growth rate which is worst case constant, but
likely going down over time due to quarantine measures. As such we have
theoretically enough recovered cases if n_infected/n_critical > k. For the
most critical age group an estimated 10% of infected require ICU care [1].
Thus we need k < 10\. With a 1:2 ratio for serum we get k < 20\. Likely not
everyone will donate though and constant factors in this equation will end up
mattering but the exponential nature does not kill the idea in the manner you
indicate. However, it still requires scaling production exponentially. This is
true for all other drugs as well though.

[1] [https://www.imperial.ac.uk/media/imperial-
college/medicine/s...](https://www.imperial.ac.uk/media/imperial-
college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-
modelling-16-03-2020.pdf)

~~~
amluto
You don’t need 80-year-old serum to treat an 80-year-old patient.

------
subsubzero
Its interesting to note they did not mention antibiotics as something that was
being tested. I know for a fact that a major bay area hospital is treating
covid-19 patients with a course of antibiotics(unsure which type), which is
strange as its a virus. The nurse I know said they are seeing good results,
the antibiotics are administered right away(they didn't say if anything else
is administered) and 5 of 6 patients are being sent home with none coming back
with worse symptoms. The sample size is small, maybe 30-40 and I wonder if
these patients are already healthy enough that the virus is not affecting them
greatly. It looks like other countries are looking into it as well:

[https://techcrunch.com/2020/03/19/french-study-finds-anti-
ma...](https://techcrunch.com/2020/03/19/french-study-finds-anti-malarial-and-
antibiotic-combo-could-reduce-covid-19-duration/)

~~~
rossdavidh
One theory I've heard is that it is not the virus itself that kills you, but
your immune system overreaction causing secondary damage which leads to
infections. So the antibiotic might be aimed at that part? Just a guess.

~~~
Dahoon
If that is true (it is theorised that was how the 1918 flu killed people) it
would primarily kill people with strong immune systems, not people with weak
immune systems. I saw an epidemiology specialist (Michael T. osterholm maybe?)
say that luckily this isn't how COVID-19 behaves or we would see millions
dead.

------
MichaelMoser123
this information might become relevant if anybody dear to you is hospitalized
with Corona virus related symptoms: The WHO is running a randomized trial to
check the effect of existing medications:

"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."

------
haybanusa
I find it curious that favipiravir isn't in the list. Are they just leaving it
for Japan to test, so it wasn't mentioned?

~~~
Mvandenbergh
Most likely, yes. It's not generally available outside of Japan (and China
where it has also been tested) so not much point in adding it to a global
trial.

~~~
funklute
Is that due to licensing issues or manufacturing capacity?

~~~
dis-sys
more to do with the side effect. it causes birth defects in pretty alarming
rate.

Japanese government only allows it to be used as a backup, Chinese licensed
the design but the government only allows it to be used when all other avenues
are exhausted.

~~~
Grue3
Aren't most severe patients elderly? Why would birth defects be a problem at
this point?

~~~
vonmoltke
That isn't the issue; it's that this drug is not available at all outside of
those two countries. Side effects are the reason it isn't. The WHO is
prioritizing drugs with worldwide availability.

~~~
KIFulgore
If it's effective, I'd hope it would become widely available for future
pandemics.

------
salimmadjd
UCSF had a great video conference call with several of their experts
essentially covering these drugs and the two different stages of the disease.
I highly recommend watching the first half at least. [https://youtu.be/bt-
BzEve46Y](https://youtu.be/bt-BzEve46Y)

~~~
alexitosrv
thanks man, very informative and without doubt well condensed and explained
info on the presentation of the disease and treatment options.

------
pbreit
I’m wondering what took so long? Shouldn’t we be ready to do something like
this almost immediately?

Still seems chloroquine is required to meet a higher bar than the others which
continues to be odd.

~~~
endorphone
The fact that this particular treatment has a booster club is odder still.
People are acting like they have a personal stake in which treatment wins.

I mean...it seems likely that some of the boosters who have been astroturfing
it do actually have a stake.

~~~
IAmEveryone
Look at this thread: everyone has their “one weird trick” (substance) which
they believe is the silver bullet. Including garlic.

I doubt that these people have financial stake in any of these products.
Sometimes, the substance might be relevant to some opinion they hold dear. The
guy recommending garlic might consider all modern medicine a conspiracy of the
pharmaceutical industry. A significant number of people on HN and reddit have
also been really into cytokines for the last few years, the reason for which
eludes me (maybe it’s the one bit of biology they heard of at some point and
they are still enamored by their smartitude and want everyone to take notice).

Quinine and similar might have just been popular for the funny Gin&Tonic tie-
in. Then, the US president read about, called it “the biggest discovery in
medicine” or similar on Twitter, and now the alt-right has a stake in its
success.

~~~
davidw
Now people are dying from taking that stuff:

[http://bannerhealth.mediaroom.com/trending-now-at-
banner?ite...](http://bannerhealth.mediaroom.com/trending-now-at-
banner?item=122999)

------
vhvjkyhkogvv
Kinda makes you wonder why they aren't using methods from the multi armed
bandit literature.

~~~
btilly
Multi armed bandit methods work best with immediate success-fail metrics. This
one has time delays.

An example of how machine learning goes wrong is if a treatment slows down the
progression but increases the death rate. Given exponential ramp up in the
incoming cases, it will look good until the final horrifying numbers are in.
You need to slice and dice the numbers by cohort to detect/react to this.

~~~
jerf
"Multi armed bandit methods work best with immediate success-fail metrics.
This one has time delays."

Well, sure, but _everything_ works best with immediate success-fail metrics.
That's one of the most basic results from learning theory is that the longer
the latency between stimulus and response the slower the learning rate can be.
I'm not sure how multi-armed bandit is special in this regard in any
particular dimension. All learning techniques are going to be susceptible to
the problem you outline in your second paragraph.

This is one of those "there is no perfect solution" situations. It's really
easy to say that out loud. It's quite difficult to internalize it.

(Also, just as a note to your other post, bear in mind that our hard-core
"social distancing" efforts in the US are just about to reach approx. 1
incubation period. It is only just this week that we're going to start seeing
the results of that, and it'll phase in as slowly as our efforts 1-2 weeks ago
did. My state just went to full lockdown today, though we've been on a looser
lockdown for a week before that.)

~~~
btilly
Everything works better with immediate success/fail metrics. However the
simplest approach is easiest to analyze, and is easiest to analyze after the
fact in as many ways as you want. The more complex the decision making, the
less we should be willing to put it under the control of a computer program.
(Unless that program has been well-studied for our exact problem so that we
trust it more.)

Which medicine looks effective? Which medicine gets people out of the hospital
faster? What underlying conditions interacted badly with given medicines?
These questions do not have to be asked up front. But they can be answered
afterwards. And knowing the answers, matters.

Here is an example. Suppose that we find one medication that gets people out
of bed faster but kills some. In areas with overwhelmed hospitals, cycling
people through the bed may save net lives. If your hospital is not
overwhelmed, you wouldn't want to give that medicine. Now I'm not saying that
any of these medicines will come to a conclusion like that. But they _could_.
And if one did, I _definitely_ want human judgement to be applied about when
to use it

~~~
jerf
I don't think anyone is proposing actually removing all humans from the loop,
so I think that's an argument against a strawman.

Even if they were proposing it, there's no realistic chance of it happening.

I don't want people blindly copying "standard" scientific procedures either,
where we run high-stastistical-power studies for months with double-blind
scenarios then carefully peer-review it and come up with some result somewhere
in 2022.

~~~
disgruntledphd2
So, hopefully there will be blinded researchers who analyse the data.

They'll probably use sequential stopping rules to take samples of incoming
data.

If one of the treatments works much much better, then they'll almost certainly
recommend that (but doctors will probably figure this out first, anyway).

------
dharma1
Is the expectation that SARS-CoV-2 will become a seasonal virus, permanently
with us, like the other 4 coronaviridae (which we don't have a vaccine for)?

[https://www.cdc.gov/coronavirus/general-
information.html](https://www.cdc.gov/coronavirus/general-information.html)

It seems that those keep coming back each year either because they mutate, or
the antibodies produced by our bodies are no longer produced/effective after a
year or so.

So even if we had a vaccine for SARS-CoV-2, would it lose its' potency after a
year, and people need annual booster shots? Or would the virus mutate so that
the specific vaccine no longer works?

Also, is the expectation that the mortality rate of SARS-CoV-2 will reduce
over time because of evolutionary pressure? Is that really the case, given
that much of the spreading happens in the first 1-2 weeks, before the host is
potentially dead?

~~~
satanspastaroll
There is research going into their more fundamental structure to try and
defeat their whole family at once

~~~
freeone3000
So out of this mess, we might end up with a cure for the common cold?

~~~
petschge
Not really. The majority of cases of the common cold are caused by
rhinoviruses, not coronaviruses. Then again I would gladly take a 10% cut in
the common cold...

------
electriclove
When are the results expected?

~~~
bsaul
From what i've heard in the news about this trial, not until 6 weeks minimum

------
ggm
Combinations need to be tested.

------
drited
Seems strange that they're not going to use a control group that receives a
placebo.

------
primrose
Would this new global mechanism be useful for other diseases like cancer or
AIDS?

------
teddyvangogh
Forbes: Coronavirus Patient Dodged A Bullet With Hydroxychloroquine.

Mar 22, 2020,01:43pm EDT

"Two scientists at major university centers reviewed the French trial for me.
They agreed, separately, that while the study is preliminary, small, and not
without flaws, its findings were strong enough, given the drugs’ known safety
records, to guide treatment decisions in a crisis.

“Despite the limitations of this study, in the absence of any effective
treatment, in this urgent situation, this Plaquenil and Azithromycin
combination therapy should be given to patients with COVID-19 as a treatment
option,” Ying Zhang, a professor of microbiology at Johns Hopkins Bloomberg
School of Public Health, wrote in an email. “For now, there is no time to
wait."

Brian Fallon, a research scientist and clinical trials investigator at the
Columbia University Irving Medical Center, agreed on the study’s overall merit
despite the patients who dropped out. After analyzing the data and counting
all six dropouts as treatment failures, he said the overall rate of
improvement was still statistically significant for the entire group, though
not for the hydroxychloroquine group alone."

[https://www.forbes.com/sites/marybethpfeiffer/2020/03/22/one...](https://www.forbes.com/sites/marybethpfeiffer/2020/03/22/one-
patient-dodges-a-covid-bullet-is-she-a-harbinger-or-outlier/)

~~~
1980phipsi
It's not just hydroxychlroquine, the best results in the (albeit small) study
were when it was paired with a Z-pack. A WSJ editorial had also talked about
the same thing, but the Forbes article you posted has more details:

"The just-released French study reported that 70 percent of
hydroxychloroquine-treated patients, or 14 of 20, were negative for the virus
at day 6, as were all six patients who were treated with hydroxychloroquine
and the antibiotic azithromycin (which Novins also received). But the study
was small – 20 treated patients and 16 controls – and had other serious
limitations."

~~~
chimichangga
Agree. This is interesting.

Covid-19: India Recommends Hydroxychloroquine As Prophylaxis For Healthcare
Providers, Patient Family Members

[https://swarajyamag.com/insta/covid-19-india-recommends-
hydr...](https://swarajyamag.com/insta/covid-19-india-recommends-
hydroxychloroquine-as-prophylaxis-for-healthcare-providers-patient-family-
members)

