
Chloroquine trial halted after 11 patients die on high dose - colinprince
https://nationalpost.com/news/world/covid-19-brazil-trial-for-drug-chloroquine-touted-by-trump-stopped-after-11-patients-die
======
hinkley
When this clusterfuck first started revealing itself, the forsythia plants in
my town had just started flowering.

Every time this chloroquine stuff comes up I just hear Jude Law's character
from Contagion in my head saying "forsythia" over and over again in different
sentence fragments.

Unfortunately the SEC isn't going to send men to arrest anybody this time.

~~~
klenwell
I had the same thought. Here's the clip from Contagion where Jude Law's
character, an internet crank, promotes it on national television:

[https://www.youtube.com/watch?v=CHZ8wx6J36Q](https://www.youtube.com/watch?v=CHZ8wx6J36Q)

~~~
andy_ppp
Man I really need to watch Contagion then...

~~~
ornornor
It’s interesting watching it now. I watched it last month and it felt like it
was a documentary for what hasn’t happened yet in this epidemics.

~~~
libria
1 year ago, I'd have thought this movie was typical Hollywood hyperbole.

Watching it recently, the scene where Sanjay Gupta is facilitating an
interview about the virus was like deja vu. He was literally on TV doing the
same thing recently, but for real this time.

------
martingoodson
This title is misleading. They didn't halt the _trial_ , they halted one
treatment arm (the arm with a very high dose). They continued with the 'low'
dose (2.7g - about the same dose as used to treat malaria). The high dose was
over 4x more of the drug, at 12g.

~~~
post_below
I haven't looked farther than the linked article, but assuming their reporting
is accurate:

> However, higher dose use of chloroquine (600 milligrams as opposed to 450
> milligrams) was stopped after just six days, after 11 of patients who were
> given the greater dose died.

To me that reads as an increase of about 1.35x rather than 4x.

~~~
bagacrap
600 mg chloroquine twice daily for 10 days or total dose 12g

450 mg for 5 days, twice daily only on the first day, or total dose 2.7 g

~~~
post_below
That 600mg part of the study ended at 6 days. The potential total dose in a
future that didn't happen seems irrelevant.

------
bearcobra
COVID-19 is obviously very scary and I fully understand why we'd want to
lessen some restrictions to allow novel treatments to be tried. But as bad as
things are, I think people underestimate how much worse they could be if
aren't careful when easing those restrictions. There seems to be a mentality
that people are going to die anyway so we should be trying anything. That
seems to underestimate the potential to make things worse, not just in terms
of deaths but also in terms of quality of life for patients.

~~~
dionian
This is why FDA is not recommending it as a treatment for everyone, only off-
label.

~~~
0xff00ffee
Here's some clarification I googled because I was a little confused by your
comment:

TL;DR - The FDA only approved it for emergency investigation, not treatment.
(as of 2020-03-31):

[https://www.forbes.com/sites/rachelsandler/2020/03/30/fda-
ap...](https://www.forbes.com/sites/rachelsandler/2020/03/30/fda-approves-
anti-malarial-drugs-chloroquine-and-hydroxychloroquine-for-emergency-
coronavirus-treatment/#3d0c01045e5d)

------
jonplackett
This is this the more toxic variant though right? It’s meant to be
hydroychloroquine

~~~
simtel20
Here in Brazil, for whatever reason, the president has been talking up
chloroquine, while Trumps talking point is hydroxychloroquine.

I don't know how people who have no medical training or experience who are
actively trying to undermine their advisors with such experience determine
which of these medicines they're going to place their bets on, but given the
lack of good results in either, it seems like either bet is as bad as the
other.

~~~
merpnderp
China had more luck treating COVID with chloroquine phosphate (which is more
toxic), but hydrochloroquine sulfate is more available in the US.

~~~
addicted44
COVID-19 kills anywhere between 0.7-4% of the people it infects. (Some
countries like Italy saw a much higher mortality rate, nearing 15% in Italy, I
believe, but that was due to the breakdown of the overwhelmed health
services).

How would one even tell if any of the chloroquinine derivatives have been
effective without a systematic study when 96 out of 100 people (at worst)
would have recovered anyways? That's another thing that makes the 20 person
French study which kicked off all this so much more ridiculous.

There was a 44% chance that they would have all recovered without any
intervention. But it was probably higher for this group since they did have
intervention, and they clearly had a high level of medical assistance.

~~~
rootusrootus
> COVID-19 kills anywhere between 0.7-4% of the people it infects. (Some
> countries like Italy saw a much higher mortality rate, nearing 15% in Italy,
> I believe, but that was due to the breakdown of the overwhelmed health
> services).

That is mixing up IFR and CFR. We don't have any good way of knowing IFR yet,
and it may be quite a while before we can get a good estimate. The denominator
in CFR is confirmed cases, so Italy's inflated CFR could be (and probably is)
entirely related to the lack of sufficient testing.

~~~
rurban
Italy has a very high IFR of 1%, the same rate as their every year flu
epidemic. Or better very two years. The flu comes every two years. Italy has
traditionally the highest flu death rates in the world. This year, with
COVID-19, it is still lower than in a bad flu year.

When you read 15% this might be the CFR, the case fatality rate. But only
about a tenth is getting tested. So it means nothing. You can only look the
death numbers, and after it settled down at the excess death rate. From there
you get the real IFR. So far we are at an IFR of 0.3 - 0.6. A little bit
higher than the flu, but in absolute numbes lower than a bad flu year.

~~~
rootusrootus
IIRC, Italy had a health care professional study that put their IFR at
something around .35% or so. Similar for Germany, and the CDC just did a study
of HCP's here and came up with 0.26% IFR (but the sample was 75% women).

------
tannerbrockwell
I wonder what happened with the WHO study: "20,000 healthcare workers [will
receive] #chloroquine [and] will be tested daily as currently used in the
treatment of rheumatoid arthritis for three months or until they are diagnosed
with COVID-19."

[https://www.who.int/blueprint/priority-diseases/key-
action/R...](https://www.who.int/blueprint/priority-diseases/key-action/RD-
Blueprint-expert-group-on-CQ-call-Mar-13-2020.pdf)

~~~
sdenton4
Maybe it will be discontinued, now that the loudest promoter of
hydrochloroquine has decided to pull their WHO funding...

(The city is on fire! Those hacks at the fire department failed to predict the
earthquake! Fire them all!)

------
giardini
The researchers gave whopping doses of chloroquine to both groups: (a) high
dose chloroquine (600 mg chloroquine twice daily for 10 days or total dose
12g);

(b) low dose chloroquine (450 mg for 5 days, twice daily only on the first
day, or total dose 2.7 g)

In addition, all patients received ceftriaxone and azithromycin.

So group (a) got 1200 mg chloroquine the first day and group (b) got 900 mg
chloroquine the first day. No wonder they had irregular heart rates! Luckily a
review board stopped group (a) treatment before they killed all the patients.

In contrast, the regimen for Covid-19 _successfully_ used by Dr. Zev Zelenko
on ~700 patients is:

1\. Hydroxychloroquine 200mg twice a day for 5 days,

2\. Azithromycin 500 mg once a day for 5 days,

3\. Zinc sulfate 220 mg once a day for 5 days.

[https://www.freerepublic.com/focus/f-news/3829492/posts](https://www.freerepublic.com/focus/f-news/3829492/posts)

The zinc sulfate is _important_ because it raises the blood level of zinc
(Zn++ ion). Chloroquine is a zinc Zn++ "ionophore" which marshals Zn++ across
the cell's outer wall into the cytoplasm where the Zn++ can halt viral
replication.

"Chloroquine Is a Zinc Ionophore":

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/)

(PDF)
[https://journals.plos.org/plosone/article/file?id=10.1371/jo...](https://journals.plos.org/plosone/article/file?id=10.1371/jo..).

Some researchers seem to be missing the point that chloroquine and its analogs
may play a different role here than in malaria, acting not directly against
covid-19 but as a facilitator for Zn++, which then halts covid-19 replication.

Zelenko's use of an antibiotic(azithromycin = Z-Pak) is a prophylaxis against
potential secondary bacterial infection; the antibiotic would not likely play
a role against the viral infection directly.

Once again we see that randomized, double-blinded clinical trials can be more
deadly and less informative than ad-hoc studies performed on the battlefield
of medicine.

~~~
cycrutchfield
> In contrast, the regimen for Covid-19 _successfully_ used by Dr. Zev Zelenko
> on ~700 patients is:

For all we know, it was a successful placebo. Anecdotal evidence does not
constitute scientific fact.

~~~
12elephant
A single piece of anecdotal evidence does not constitute scientific fact.

~700 pieces of anecdotal evidence is a study.

~~~
cycrutchfield
If there's no randomly selected control group then the value of the results
are fairly minimal.

~~~
12elephant
The remaining population of COVID patients is a good control group. Or, if you
prefer, randomly select sub-populations with similar demographic statistics.

~~~
cycrutchfield
Yeah sorry, I don’t think you understand how control groups work.

~~~
12elephant
Yes, let's throw out valuable field evidence just because it doesn't fit some
narrow definition of "valid experiment".

Compare 700 people who received a treatment to 700 demographically similar
people who received the standard treatment in the same or similar hospital and
you're going to get a useful result.

We can do your fancy RCT later when we aren't dying en masse from a novel and
highly lethal virus.

~~~
cycrutchfield
I mean, people have tried doing studies like that for CQ/HCQ. They are riddled
with questionable assumptions (that patient groups are similar or treatment
regimens are equivalent) that make their conclusions completely unreliable.

In the end we will most likely find that all positive anecdotal evidence found
was just confirmation bias. That's why RCTs are so important.

~~~
cbxyp
That's ridiculous

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/)

~~~
cycrutchfield
In vitro is not the same as in vivo

------
the_mitsuhiko
Austria stopped all uses of chloroquine/hydroxychloroquine for covid-19 a few
weeks back citing bad outcomes and from what I can tell it's not the only
country. I feel like the only reason trials are kept alive are the popularity
in the US.

------
shadowprofile77
To be clear, because the title makes it ambiguous, 11 patients died because of
the treatment, or 11 paitents died of covid-related/suspected causes despite
elevated treatment? It's a crucial distinction. The article doesn't perfectly
specify which either. Covid-19 is already becoming known for causing cardiac
problems in some patients, so if they were killed by a fatal heart arrhythmia,
how to be sure that the medication caused it to be fatal instead of the
disease progression itself due to myocarditis or something related combining
with said arrhythmia.

------
tgafpc2
Arrhythmia is a well know complication and contraindication of Chloroquine.
This should have been identified by the doctors prescribing it and NOT
PRESCRIBED IT for at risk patients.

~~~
HillRat
Unfortunately, COVID may also be associated with hypokalemia, so even patients
without comorbidities could be at risk for TdP. HCQ may have therapeutic or
prophylactic benefits, but it’s definitely not without serious risks.

------
Carpetsmoker
Also interesting read on some more background of the drug:
[https://blogs.sciencemag.org/pipeline/archives/2020/03/20/ch...](https://blogs.sciencemag.org/pipeline/archives/2020/03/20/chloroquine-
past-and-present)

------
rurban
Horrible article. Now what was the problem? CQ or HCQ? Major difference in
those two.

------
lenkite
Those dosage numbers are completely OFF the charts. Thats ridiculously high
dosage. In India, it's 200mg for treatment of Covid 19.

600mg WILL kill you. I don't even understand who approved that!

------
stevev
I think a high dose of any reactive medication or drug is deadly.

~~~
samatman
This is a meaningless statement.

For starters, to call a compound "reactive" means it's eager to participate in
chemical reactions. I'm unable to discern what you were trying to say, but I'm
betting it isn't that.

To continue, yes, at the limit, a sufficient dose of anything will kill you.
The difference between the therapeutic dose and the lethal dose is referred to
as the therapeutic index: wide is good, narrow is dangerous.

(hydroxy)chloroquine has a fairly narrow therapeutic index at the doses being
tested for acute COVID-19 intervention. That's not a property you want in a
medicine. It would have to be that much more effective to make up for the risk
it poses to the patient.

------
ph0rque
It irks me to see chloroquine and hydroxychloroquine being used
interchangeably in the media. This study used chloroquine. Trump touted
hydroxychloroquine.

"Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in
inhibiting SARS-CoV-2 infection in vitro"
[https://www.nature.com/articles/s41421-020-0156-0](https://www.nature.com/articles/s41421-020-0156-0)

~~~
morninglight
Hydroxy what? You mean I bought the wrong stuff?
[https://leafbrands.com/hydrox/](https://leafbrands.com/hydrox/)

~~~
ineedasername
Just wait till the stories of imbibing hydrogen peroxide start coming in! /s

~~~
Avshalom
Well know quack Dr Joseph Mercola has been pitching this for a couple weeks
now.

~~~
ineedasername
Wow, that's disturbing. The typical household variety isn't strong enough to
do much more than give you a nasty upset stomach and maybe vomit a bit. I
guess drinking a lot might cause irritation. But if quacks are peddling this,
it's only a matter of time before someone gets creative and finds some of the
12% stuff in some hair dye kits and other beauty products. Internal chemical
burns are pretty nasty stuff, and surviving the ordeal is option

------
droithomme
They were giving 1.2 grams a day to the patients that died. That is
significantly higher than what is known to be a safe dose. CQ is also not
indicated for anyone with underlying heart conditions. Since COVID-19 is known
to cause heart damage as well as lung damage in the late stage of the disease
using these drugs in the late stage of the disease has built in problems.

The article doesn't mention anyone in the lower dose group dying of heart
problems, though heart attacks and related problems are things that are known
to happen to people with COVID-19. The lower dose study is continuing and was
not halted. Presumably there will be a subsequent study published with those
results. I agree that it is a bad idea to be taking 1.2 grams a day of CQ.
During the century of widespread CQ use the fatality rate due to side effects
was certainly no where near what they managed to obtain by overdosing patients
in this reckless study.

------
GenerocUsername
From the article:

"The Brazil study was undertaken with 81 patients at a hospital in Manaus, in
Amazonas state. As well as chloroquine, patients were also given azithromycin,
an antibiotic also being used in the U.S., often paired with chloroquine.
However, higher dose use of chloroquine (600 milligrams as opposed to 450
milligrams) was stopped after just six days, after 11 of patients who were
given the greater dose died."

So they canceled a test with higher doses, not tests with regular doses.

Meanwhile they touched several times on the fact that Trump touted the drug.
If trump recommended hugs, the media would write an article about how choking
people is bad.

~~~
nick_kline
It's not that trump said he likes to breath air, so everyone became fixated on
that. It's that this is one of many (dozens at least) of things he has said
were solutions, cures, miracles that would deal with covid-19. These went
through the fox news world and now my elderly relatives are fixated on getting
it (they are otherwise healthy). Because fox news and all these other non-
medical people keep harping on it, the elderly people, the same ones preyed
upon by certain news sources get the wrong idea about this.

~~~
ghostpepper
There are two stories here: One is whether one of the most promising drugs to
stop the pandemic is actually dangerous, and the other is what Trump said and
whether he was right to say it blah blah blah.

Thanks to the inclusion of Trump in this article by National Post, anyone who
has strong views about Trump (most people in North America) are now focused on
the second story, instead of the first.

~~~
m0zg
Best I can tell, the article doesn't even mention the cause of death. :-) Did
they die because they were given HCQ or did they die in spite of being given
HCQ? We'll never know.

And the paper itself
([https://web.archive.org/web/20200413181618/https://www.medrx...](https://web.archive.org/web/20200413181618/https://www.medrxiv.org/content/10.1101/2020.04.07.20056424v1.full.pdf))
doesn't say that either, and mentions that this study's randomization was
flawed in that older patients with heart disease were assigned to the high
dosage arm of the experiment.

~~~
tehjoker
They saw people were getting heart arrhythmias in the original Brazil study.
Anecdotally, a doctor I know has been seeing an increase in arrhythmias on
patients treated with HCQ at lower doses if they already have a pre-existing
circulatory problem. What is really irking me is that we still don't even know
if it's really doing anything.

At the same time, my elderly parent is taking HCQ for arthritis and appears to
think she is invincible, going to the store each day in the middle of Queens,
the world epicenter. She tried to send me links to Trump's touted Dr. Zelenko
about how it's a miracle cure.

~~~
m0zg
We don't even know if eggs and butter are "good for you" so I'm not surprised
we know jack squat about HCQ beyond anecdotal evidence, which most studies you
will find in the press seem to either ignore, or set their studies up s.t.
they fail. In particular, per anecdotal evidence HCQ+Zpak+Zinc is the most
effective combination, and only if given at the onset of symptoms. Yet
routinely we see either just HQ or HCQ alone, or HCQ (with or without Zpak)
given to patients that are so far gone it's unlikely to make any difference.
Just read the original study fer chrissakes, it's publicly accessible. Sure
it's not "randomized" or "principled", but at the very least _try_ what Raoult
did in the first place, maybe? Exactly as he did it?

~~~
tehjoker
It looks like Azithromycin is for clearing bacterial pneumonia. Certainly this
is a possible and probably common complication of viral pneumonia caused by
COVID-19, but I'm sure doctors are well aware of ways to treat secondary
bacterial pneumonia.

Just looking at what doctors are saying about Zinc, it seems like there could
be something to it, especially if an individual is Zinc deficient, but it's
not at all clear it's anything like a silver bullet.

[https://www.medicinenet.com/script/main/art.asp?articlekey=2...](https://www.medicinenet.com/script/main/art.asp?articlekey=228691)

We have no idea what the mechanism of action if for HCQ. My doctor friend
tried looking it up and it seemed like there are many possible pathways, many
of which are still being researched, that modify immune response. There was
one statement that speculated if HCQ could act directly on viral particles by
changing pH near a key molecule. My attitude is, great if it works, but we
still are very far from knowing that for certain.

One thing that I think is worth keeping in mind is that if a medicine kills 1%
of the people we give it to, and we give it to a large number of people
relatively indiscriminately, it's about as bad as COVID, which kills 1-5% of
victims (though as much as 15% for high risk patients).

~~~
giardini
tehjoker says _> "_We have no idea what the mechanism of action if for HCQ. "<

Here's one paper showing that chloroquine allows Zn++ ions to pass into the
cell cytoplasm where viral replication takes place. Zinc halts viral
replication:

"Chloroquine Is a Zinc Ionophore":

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182877/)

(PDF version)
[https://journals.plos.org/plosone/article/file?id=10.1371/jo...](https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0109180&type=printable)

~~~
tehjoker
Thanks for the link. I looked around and I saw that 2 uM Zinc inhibited SARS-
CoV-1 in vitro, while human cellular concentrations of zinc are typically in
the tens to hundreds mM range.

As a non-expert, there are two things that occur to me. That either something
weird is going on, or zinc is very tightly controlled by the body and the
range is really important. This means that taking extra dietary zinc without
an ionophore probably wouldn't do much. So maybe CQ would help promote
additional Zinc. According to one review article I was reading, Zinc
concentration is naturally increased during immune response unless the virus
hijacks the Zinc system.

This information makes me open to the possibility CQ is doing something, but
so far the real world results have been unclear. One study showed that CQ had
no effect on patients in France. If it's the Zinc that's making the difference
and they didn't give Zinc, that would possibly explain the results, but the
body also has abundant supplies of Zinc and adjusting intracellular
concentration by 2/1000 of the ambient concentration shouldn't be a big deal.

------
DoreenMichele
I'm going to note this:

The body is the landscape where this battle gets fought. "Nuke it from orbit.
It's the only way to be sure." is a treatment policy that should be expected
to result in some patients dying.

 _Trump has been vociferous on the drugs’ potential benefits, but among those
to contradict his views are his own top expert Anthony Fauci_

Edit: I stand corrected. The above still horrifies me. I've edited out the
inaccurate framing. It's absolutely not intended to make replies to me look
dumb. Quite the contrary.

This comment has been extensively edited. Hopefully, this is the least worst
handling of blurting something out that expresses my concerns badly.

~~~
pdonis
_> this is being tested not because medical professionals think it's a good
idea, but because the US president has been loudly promoting it_

The article is describing a trial in Brazil, not the US.

Also, the trial used chloroquine, not hydroxychloroquine. They're not the
same.

~~~
12elephant
Furthermore, the studies on chloroquine started at least a month before the US
president ever mentioned hydroxycholoroquine in mid March. E.g. this one from
early Feb:
[https://www.nature.com/articles/s41422-020-0282-0](https://www.nature.com/articles/s41422-020-0282-0)

So the research is not only being conducted because of the US president's
promotion.

