> The proportion of patients that had negative PCR results in nasopharyngeal samples significantly differed between treated patients and controls at days 3-4-5 and 6 post-inclusion (Table 2). At day6 post-inclusion, 70% of hydroxychloroquine-treated patients were virologicaly cured comparing with 12.5% in the control group (p= 0.001).
The effect size is huge, even considering the potential biases.
One of the issues with the study is that they didn't use the clinical outcome as an endpoint, they just measured the virus concentration in the throat (and even that not properly for all cases as far as this HN post says).
Huge effect size doesn't matter at all when the effect is not the correct one. There is a significant risk that this surrogate endpoint is not telling the true story as the virus migrates to the lung, measuring in the throat could be very misleading.
Funny how the super-rational HN crowd throws science out the window as soon as it starts to actually matter. I guess there really are no atheists in foxholes, nor statisticians in a pandemic.
The authors of this study excluded one patient from the study because they died, and several other because they were admitted to ICU.
Assuming the dead patient did not get run over by a car, not considering death as relevant information for your study seems... bold.
They switched outcomes from what they pre-registered.
They did not even measure viral load, their primary outcome, in the control group. They looked at the patient and went like “she’s really sick, that’s a 23 at least”.
This, and the other problems mentioned, make this study suspect. And at the point where actual fraud is a possibility, the top line numbers stop being meaningful.
So in that sense your comment is like my Grandmother’s insistence on Pascal’s wager: “I know there’s no God, but paradise sound too good not to try”
The control group is not randomized, and most of it was in others hospitals, so it's not clear that they have the same treatment and some prognosis.
They are not counting the 6 patients that they lost in the treatment group (1 just leave, 1 had too much nausea, 3 where transfer to ICU, 1 died). It is more strange that they didn't lost any patient in the control group.
You can't assume the top line effect size is real without critiquing the study design in detail. A lot of experienced drug developer think the data suggests that HCQ may be marginally effective, but Azt + HCQ seems promising. THere are others who are more skepticl
"we are not talking about some marginal level of efficacy here:"
Your above-statement, and then the quote suggests you have no idea how this actually works in the real world. The reality is that NO-ONE KNOWS whether there is great efficacy, no efficacy, or marginal efficacy. No one. And we will not until we have a properly designed trial. That link direct us to is horrifyingly badly designed (well, not designed at all). There are all sorts of confounding issues in their results.
> With my team, we believe we have found a cure. And in terms of medical ethics, I believe that I have no right as a doctor not to use the only treatment that has so far proven successful. I am convinced that in the end everyone will use this treatment. It's just a matter of time before people agree to eat their hats and say, this is the thing to do.
And in the Irish times:
>“In my field, I am a star, worldwide,” he boasted to La Provence newspaper.
Why are we so excited about the French trial? What about the Chinese treatment guidelines [0]?
The Chinese recommend chloroquine phosphate. They've had more experience than anyone else in this area and have had time to conduct actual trials. The disease has a ~2-4 week course so it should take about that long to gather compelling evidence; and they've been dealing with it since January.
The French are clever people, but we really should be looking to Asia for this information. People should be finding and quoting Chinese studies.
Another anti-malaria drug, methylene blue had been proven to work against coronavirus in blood plasma in 2005 [1].
It is used in photodynamic therapy to selectively kill some viruses (see below) / bacteria (e.g. mycoplasma) [2].
When entering the bloodstream, it binds selectively to the nucleus of the viruses it is effective against. It's the same mechanism why it's effective as a dye to stain microbes under microscope. Methylene blue best absorbs light at 660nm wavelength, which at the same time penetrates into human tissues deeply. When light is absorbed, methylene blue disintegrates to harmless molecules while releasing reactive oxygene species, killing the virus.
It is a very safe drug, so the same logic that bsaul mentioned could be applied, and therefore would be a responsible move. It is also beneficial to mitochondria and effective against fungus.
it also literally turns your bodily emissions blue, needs to be administered intravenously, and has some ugly side effects:
Common side effects include headache, vomiting, confusion, shortness of breath, and high blood pressure.[1] Other side effects include serotonin syndrome, red blood cell breakdown, and allergic reactions.[1] Use often turns the urine, sweat, and stool blue to green in color.[3]
The numerous* stories that I have read recently about medical professionals writing themselves prescriptions for hydroxychloroquine so that they can have it available for themselves and their families suggests to me that the French trial is not the only reason to be hopeful about hydroxychloroquine's efficacy against COVID-19.
Sure, medical professionals are not necessarily any kind of super-rational savants, but I think it's unlikely that all of the medical professionals who are trying to hoard hydroxychloroquine are being irrational hysterics. They might be engaging in ethically questionable acts by hoarding hydroxychloroquine, but that doesn't mean that they don't know what they're doing from a self-preservation standpoint.
That said, it's not that I think they are necessarily trying to hoard hydroxychloroquine because they are convinced that it works - it's probably more that they want it on hand in case it turns out that it works. However, some of them may also have directly seen it help people, or may have heard or read about it helping.
Given that hydroxychloroquine has already been used for, as I understand it, weeks in treating people ill with COVID-19, I am actually surprised that there is not more anecdotal evidence about its efficacy. But I probably have just not been reading in the right places.
*Edit: I probably shouldn't have said "numerous stories", since "numerous" implies more than the number that I actually have seen.
The vast majority of medical professionals are not researchers, and are not trained in evaluating clinical trial data. They are notoriously poor at assessing such information.
You can be a remarkable clinician without ever interacting with the primary literature. These are simply different things.
I feel like they'd start doing that even if they thought the chances were ~10% of it working. Its relatively inexpensive and they know its availability would drop dramatically as soon as more data is available.
> The numerous* stories that I have read recently about medical professionals writing themselves prescriptions for hydroxychloroquine
A doctor friend of mine showed me a Facebook group consisting entirely of prepper medical professionals trying to decide whether or not to buy guns (in Australia!) for self-defense.
Medical school tends to select for a personality type that is, shall we say, somewhat obsessive?
The doctors are likely doing the intelligent thing, not necessarily hoarding. They should know that antivirals tend to work only at disease onset or as preventives. The production of these drugs can be ramped up very quickly so the amount these doctors took from the supply should be immaterial - esp. in the US where testing is limited to later stage patients when antivirals are less likely to help.
I see many problems with all the caution around that study:
1/ chloroquine is a very well known cheap drug. There is no new risk associated to using it that doctors arent already aware of.
2/ we do have a lot of statistics now on the outcome of patient not treated with that drug. There's no need for establishing a benchmark. Just proper categorization of existing patient should be enough to compare.
3/ people are oversaturating ICU right now. And as such, it is an emergency situation. We should take the reverse reasoning we usually take : if there's no suscipicion this drug could cause new problems, we should have people massively use it whenever possible and look at the result after 6 days (since that's the time the original study says it takes for the first results to show).
> 3/ people are oversaturating ICU right now. And as such, it is an emergency situation.
From what I can gather chloroquine is already used as a first line treatment in Italian hospitals (at least it is indicated as such by the COVID treatment guidelines published by the society of Italian infectious disease specialists [0], and has been for quite some time - this document is from 10 days ago, but an earlier revision was not different regarding chloroquine). If this is the case, it's pretty clear that this is no miracle cure - it has at best a marginal effect.
> we do have a lot of statistics now on the outcome of patient not treated with that drug. There's no need for establishing a benchmark. Just proper categorization of existing patient should be enough to compare.
This is very wrong; we have good aggregate statistics across lots of different hospitals, but for a study with a small number of sites where the patients are treated with the drug, there's enough inter-site variability that may obscure any effect, or create a false effect.
This is doubly true as health care varies as sites get overwhelmed, and healthcare workers get increasingly strained from long shifts. There will be far more variability as time goes on.
And for how small we expect the effect to be, based on the data in the paper, we really should include controls.
All that said, I think that the publication of this flawed study is very good, and why pop-science takes that excoriate science as "most research finding are false" really communicate the wrong way to think about science, and limit its applicability. Flawed datasets like this still give us clues, and publishing flawed data is still useful to others to accelerate the pace of science. Which is why we need to take the attitude that publications are point in time guesses at what's going on, and only rarely does one come out that can be considered on its own as definitive, and that it's good to have mostly "here's some data and analysis but we don't have a complete theory yet"-type-papers. Without those intermediate publications, science would grind to a halt.
Opinions like this seem to be popular these days, but they're dangerous. Because this is an emergency we want reliable information.
Think about it like this: If these researchers had done a proper trial - and there's absolutely no reason to think that they couldn't have done that in the same amount of time with the same amount of effort - then we'd actually know something useful now. With that trial - we don't.
> chloroquine is a very well known cheap drug. There is no new risk associated to using it that doctors arent already aware of.
I mean, you could say the same of practically any older drug. It's a fairly well-understood, cheap, somewhat dangerous drug.
> we do have a lot of statistics now on the outcome of patient not treated with that drug.
Sure. We also have a lot of statistics on the outcome of patients not treated with thalidomide, and morphine, and basically any other cheap somewhat dangerous drug you care to mention.
> if there's no suscipicion this drug could cause new problems
While I don't think there are, there's the certainty that it will cause the usual old problems that this drug causes. Which you probably don't want when you also have covid-19.
This is irresponsible. This drug has severe side effects, it makes absolutely no sense to prescribe it for a completely different disease without first confirming in clinical trials that it has positive effects.
> if there's no suscipicion this drug could cause new problems, we should have people massively use it
That's not how evidence-based medicine works. The drug is known to cause new problems because of the side effects. Clinical trials are needed to determine whether these are outweighed in patients by positive health effects.
You do not prescribe medicine on the basis of hunches.
Exactly. Since the risks and side-effects are well-established, it’s more ethical at this point to experiment on humans with an “off label” usage. Doctors do that all the time with other meds.
Being sick with a disease like Covid-19 could absolutely alter how a medication works on a person. The drug might be safe to a person with a certain profile and it has been tested against those, but each underlying issue is a new profile which it should be tested against as separately as possible.
2) It complicates the treatment of the patients who will experience the worst cases of COVID-19 causing panic... people above 65 with diabetes and heart conditions.
3) Again this drug has well known precautions that reads like the all the people who will experience the worst of COVID-19
Having Grandpa John walk in for COVID-19 and roll out for death by QT elongation is not something the public will have to litigate.
It isn't vitamin C. It has a lot of side effects, including serious psychiatric ones in limited cases. If you give it to 100 people you're going to get new health issues that you didn't have before in that population.
You cannot pour a drug into the populace that will cause side effects on a mass scale that might also overwhelm the healthcare system. It is nice to imagine we have the medicine already, that we can simply wave our hands distribute the pills and everything can go on as it was before this. But we do not and can not go back.
I have 0 clues about clinical trials and the procedures. My questions is: Why are so few studies done on this?
I think so far we have 2 studies. (from China and France).
However, we've had hundreds of hospitals around the world with thousands of patients. And the drug is cheaply available.
What is preventing us to have studies around this in tens of different hospitals? Wouldn't WHO be able to budget this, or actually send people to conduct these studies all across the globe and report back day to day, so within 2 weeks we get a pretty significant set of data?
I like facts. Article says only French study exists but at least a couple of other studies exist from China. I wish when someone makes a very important argument to check all internet sources.
This is the kind of idiocy that pie-in-the-sky theatrical crap like this causes. People are going to end up seriously harming if not killing themselves by taking this stuff.
Regarding randomization, the HCQ + Azithromycin study showed good results despite the control group being 14 years younger. Sex was about equal so no male/female imbalance. It’s clear that older patients have worse outcomes, but this study measures viral load which also can change depending on the stage of the disease.
[+] [-] ekianjo|6 years ago|reply
https://www.medrxiv.org/content/10.1101/2020.03.16.20037135v...
> The proportion of patients that had negative PCR results in nasopharyngeal samples significantly differed between treated patients and controls at days 3-4-5 and 6 post-inclusion (Table 2). At day6 post-inclusion, 70% of hydroxychloroquine-treated patients were virologicaly cured comparing with 12.5% in the control group (p= 0.001).
The effect size is huge, even considering the potential biases.
[+] [-] fabian2k|6 years ago|reply
Huge effect size doesn't matter at all when the effect is not the correct one. There is a significant risk that this surrogate endpoint is not telling the true story as the virus migrates to the lung, measuring in the throat could be very misleading.
[+] [-] IAmEveryone|6 years ago|reply
The authors of this study excluded one patient from the study because they died, and several other because they were admitted to ICU.
Assuming the dead patient did not get run over by a car, not considering death as relevant information for your study seems... bold.
They switched outcomes from what they pre-registered.
They did not even measure viral load, their primary outcome, in the control group. They looked at the patient and went like “she’s really sick, that’s a 23 at least”.
This, and the other problems mentioned, make this study suspect. And at the point where actual fraud is a possibility, the top line numbers stop being meaningful.
So in that sense your comment is like my Grandmother’s insistence on Pascal’s wager: “I know there’s no God, but paradise sound too good not to try”
[+] [-] gus_massa|6 years ago|reply
They are not counting the 6 patients that they lost in the treatment group (1 just leave, 1 had too much nausea, 3 where transfer to ICU, 1 died). It is more strange that they didn't lost any patient in the control group.
[+] [-] aaavl2821|6 years ago|reply
Check out this analysis: https://twitter.com/AppleHelix/status/1240495937522368512
[+] [-] hcknwscommenter|6 years ago|reply
Your above-statement, and then the quote suggests you have no idea how this actually works in the real world. The reality is that NO-ONE KNOWS whether there is great efficacy, no efficacy, or marginal efficacy. No one. And we will not until we have a properly designed trial. That link direct us to is horrifyingly badly designed (well, not designed at all). There are all sorts of confounding issues in their results.
[+] [-] tim333|6 years ago|reply
and r/coronavirus discussion https://www.reddit.com/r/Coronavirus/comments/fncs5c/didier_...
Quote:
> With my team, we believe we have found a cure. And in terms of medical ethics, I believe that I have no right as a doctor not to use the only treatment that has so far proven successful. I am convinced that in the end everyone will use this treatment. It's just a matter of time before people agree to eat their hats and say, this is the thing to do.
And in the Irish times:
>“In my field, I am a star, worldwide,” he boasted to La Provence newspaper.
>“I don’t give a damn what others think. I am not an outsider. I’m streaks ahead of the others.” https://www.irishtimes.com/news/world/europe/coronavirus-fra...
Not the most modest of guys...
[+] [-] DanBC|6 years ago|reply
[+] [-] roenxi|6 years ago|reply
The Chinese recommend chloroquine phosphate. They've had more experience than anyone else in this area and have had time to conduct actual trials. The disease has a ~2-4 week course so it should take about that long to gather compelling evidence; and they've been dealing with it since January.
The French are clever people, but we really should be looking to Asia for this information. People should be finding and quoting Chinese studies.
[0] http://kjfy.meetingchina.org/msite/news/show/cn/3337.html 10(b)(4)
[+] [-] unknown|6 years ago|reply
[deleted]
[+] [-] klmadfejno|6 years ago|reply
It claims many clinical trials have been done in China that show chloroquine works. However... there's nothing to actually read with any data.
[+] [-] lez|6 years ago|reply
It is used in photodynamic therapy to selectively kill some viruses (see below) / bacteria (e.g. mycoplasma) [2].
When entering the bloodstream, it binds selectively to the nucleus of the viruses it is effective against. It's the same mechanism why it's effective as a dye to stain microbes under microscope. Methylene blue best absorbs light at 660nm wavelength, which at the same time penetrates into human tissues deeply. When light is absorbed, methylene blue disintegrates to harmless molecules while releasing reactive oxygene species, killing the virus.
It is a very safe drug, so the same logic that bsaul mentioned could be applied, and therefore would be a responsible move. It is also beneficial to mitochondria and effective against fungus.
[1] https://europepmc.org/article/cba/518857 [2] https://www.sciencedirect.com/science/article/abs/pii/S15721...
[+] [-] hprotagonist|6 years ago|reply
Common side effects include headache, vomiting, confusion, shortness of breath, and high blood pressure.[1] Other side effects include serotonin syndrome, red blood cell breakdown, and allergic reactions.[1] Use often turns the urine, sweat, and stool blue to green in color.[3]
[+] [-] tootie|6 years ago|reply
[+] [-] nikolay|6 years ago|reply
[+] [-] axguscbklp|6 years ago|reply
Sure, medical professionals are not necessarily any kind of super-rational savants, but I think it's unlikely that all of the medical professionals who are trying to hoard hydroxychloroquine are being irrational hysterics. They might be engaging in ethically questionable acts by hoarding hydroxychloroquine, but that doesn't mean that they don't know what they're doing from a self-preservation standpoint.
That said, it's not that I think they are necessarily trying to hoard hydroxychloroquine because they are convinced that it works - it's probably more that they want it on hand in case it turns out that it works. However, some of them may also have directly seen it help people, or may have heard or read about it helping.
Given that hydroxychloroquine has already been used for, as I understand it, weeks in treating people ill with COVID-19, I am actually surprised that there is not more anecdotal evidence about its efficacy. But I probably have just not been reading in the right places.
*Edit: I probably shouldn't have said "numerous stories", since "numerous" implies more than the number that I actually have seen.
[+] [-] Obi_Juan_Kenobi|6 years ago|reply
You can be a remarkable clinician without ever interacting with the primary literature. These are simply different things.
[+] [-] brm|6 years ago|reply
[+] [-] _ea1k|6 years ago|reply
[+] [-] EdwardDiego|6 years ago|reply
A doctor friend of mine showed me a Facebook group consisting entirely of prepper medical professionals trying to decide whether or not to buy guns (in Australia!) for self-defense.
Medical school tends to select for a personality type that is, shall we say, somewhat obsessive?
[+] [-] fspeech|6 years ago|reply
[+] [-] johnrgrace|6 years ago|reply
[+] [-] bsaul|6 years ago|reply
1/ chloroquine is a very well known cheap drug. There is no new risk associated to using it that doctors arent already aware of.
2/ we do have a lot of statistics now on the outcome of patient not treated with that drug. There's no need for establishing a benchmark. Just proper categorization of existing patient should be enough to compare.
3/ people are oversaturating ICU right now. And as such, it is an emergency situation. We should take the reverse reasoning we usually take : if there's no suscipicion this drug could cause new problems, we should have people massively use it whenever possible and look at the result after 6 days (since that's the time the original study says it takes for the first results to show).
[+] [-] lultimouomo|6 years ago|reply
From what I can gather chloroquine is already used as a first line treatment in Italian hospitals (at least it is indicated as such by the COVID treatment guidelines published by the society of Italian infectious disease specialists [0], and has been for quite some time - this document is from 10 days ago, but an earlier revision was not different regarding chloroquine). If this is the case, it's pretty clear that this is no miracle cure - it has at best a marginal effect.
[0] http://www.simit.org/medias/1569-covid19-vademecum-13-03-202...
[+] [-] epistasis|6 years ago|reply
This is very wrong; we have good aggregate statistics across lots of different hospitals, but for a study with a small number of sites where the patients are treated with the drug, there's enough inter-site variability that may obscure any effect, or create a false effect.
This is doubly true as health care varies as sites get overwhelmed, and healthcare workers get increasingly strained from long shifts. There will be far more variability as time goes on.
And for how small we expect the effect to be, based on the data in the paper, we really should include controls.
All that said, I think that the publication of this flawed study is very good, and why pop-science takes that excoriate science as "most research finding are false" really communicate the wrong way to think about science, and limit its applicability. Flawed datasets like this still give us clues, and publishing flawed data is still useful to others to accelerate the pace of science. Which is why we need to take the attitude that publications are point in time guesses at what's going on, and only rarely does one come out that can be considered on its own as definitive, and that it's good to have mostly "here's some data and analysis but we don't have a complete theory yet"-type-papers. Without those intermediate publications, science would grind to a halt.
[+] [-] wpietri|6 years ago|reply
> There is no new risk associated to using it that doctors arent already aware of.
You're imagining that their might be an unknown benefit using it with a novel disease, but you're confident that there won't be unknown risks?
Drugs just have effects. Risk/benefit is a human construction we apply over the top. There's no reason to expect only good surprises here.
[+] [-] hannob|6 years ago|reply
Think about it like this: If these researchers had done a proper trial - and there's absolutely no reason to think that they couldn't have done that in the same amount of time with the same amount of effort - then we'd actually know something useful now. With that trial - we don't.
[+] [-] rsynnott|6 years ago|reply
I mean, you could say the same of practically any older drug. It's a fairly well-understood, cheap, somewhat dangerous drug.
> we do have a lot of statistics now on the outcome of patient not treated with that drug.
Sure. We also have a lot of statistics on the outcome of patients not treated with thalidomide, and morphine, and basically any other cheap somewhat dangerous drug you care to mention.
> if there's no suscipicion this drug could cause new problems
While I don't think there are, there's the certainty that it will cause the usual old problems that this drug causes. Which you probably don't want when you also have covid-19.
We'd be better off waiting on a proper trial.
[+] [-] jonathanstrange|6 years ago|reply
> if there's no suscipicion this drug could cause new problems, we should have people massively use it
That's not how evidence-based medicine works. The drug is known to cause new problems because of the side effects. Clinical trials are needed to determine whether these are outweighed in patients by positive health effects.
You do not prescribe medicine on the basis of hunches.
[+] [-] henriquez|6 years ago|reply
[+] [-] httpsterio|6 years ago|reply
[+] [-] jcrubino|6 years ago|reply
3) Again this drug has well known precautions that reads like the all the people who will experience the worst of COVID-19
Having Grandpa John walk in for COVID-19 and roll out for death by QT elongation is not something the public will have to litigate.
[+] [-] jpz|6 years ago|reply
[+] [-] kingkawn|6 years ago|reply
[+] [-] herf|6 years ago|reply
Has side effects in patients with G6PD deficiency (10-15% in some populations)
Cardiotoxicity, retinopathy, and these are especially likely in older patients.
https://www.bloomberg.com/news/articles/2020-03-20/virus-dru...
Disclaimer: am not a MD or public health person, but I talk to both.
[+] [-] emilsedgh|6 years ago|reply
I think so far we have 2 studies. (from China and France).
However, we've had hundreds of hospitals around the world with thousands of patients. And the drug is cheaply available.
What is preventing us to have studies around this in tens of different hospitals? Wouldn't WHO be able to budget this, or actually send people to conduct these studies all across the globe and report back day to day, so within 2 weeks we get a pretty significant set of data?
[+] [-] jansan|6 years ago|reply
https://www.thelancet.com/journals/lancet/article/PIIS2213-2...
Looking at the drug cocktail that the patient received, this seems to be pretty heavy artillery:
- methylprednisolone
- moxifloxacin
- lopinavir plus ritonavir
- interferon
- meropenem
Holy shit, is this a recommended medication for severe Covid-19 cases?
[+] [-] biolurker1|6 years ago|reply
[+] [-] MisterBastahrd|6 years ago|reply
This is the kind of idiocy that pie-in-the-sky theatrical crap like this causes. People are going to end up seriously harming if not killing themselves by taking this stuff.
[+] [-] jeffdavis|6 years ago|reply
Given how the virus is moving now, couldn't we have a pretty nice study completed in a few weeks?
[+] [-] Bhilai|6 years ago|reply
https://www.novartis.com/news/media-releases/novartis-commit...
[+] [-] DocSavage|6 years ago|reply
[+] [-] Cantbekhan|6 years ago|reply
http://www.chictr.org.cn/showprojen.aspx?proj=48880
[+] [-] sanxiyn|6 years ago|reply
[+] [-] max_|6 years ago|reply
Are its downsides worth the upsides when used as a COVID-19 treatment?
[+] [-] unknown|6 years ago|reply
[deleted]
[+] [-] Avshalom|6 years ago|reply
well that took what, two days?
[+] [-] ekianjo|6 years ago|reply
Erm, even poorly designed studies tell you if there's any efficacy to expect or not. And it leads to better studies afterwards.
Science is iterative.
[+] [-] unknown|6 years ago|reply
[deleted]
[+] [-] vsmhn|6 years ago|reply
Testing will be randomized apparently.