Well, there should be plenty of patients for studies soon.
The timing actually makes some sense. Getting it into the field in a "can't hurt" way allows us to start studying its effectiveness quickly, before the medical system gets totally overwhelmed and studies become nearly impossible.
That's a much lower bar than most drug trials impose.
Given the severity of the situation, trying anything that might work and isn't obviously worse than the disease makes sense right now. But equally, given the side effects of chloroquines and also the postulated mechanism of action for an antiparasitic against a virus being literally just "zinc stuff? idk lol ¯\_(ツ)_/¯" right now, I think it's no less reasonable to want to see some more rigorous evaluation before regarding it as the panacea it's been claimed in many quarters to be.
Ok, if you feel things are still in such a good shape, great for you. At my distant vantage point, it seems it could be difficult to keep up with all the ways the WH (we do not speak its name) is or could be interfering with just about anything it has a tangential interest in.
Also your reassurance hinges on that every federal bureaucrat would complain to media in every circumstance. From my experience of bureaucracies you have to pick your battles and resisting or leaking is not always in the cards if you want to keep your job or career prospects. ("Live and let live.")
Do you know the CDC has been "silent", or have you just not seen anything about this before? Two weeks is pretty rapid to push through a decision like this, even in an emergency.
Yes the CDC has been silent in the sense that whenever the public was looking for urgent leadership, they found foreign agencies and scientists developing consensus before they did.
Then the CDC wants to chip in, but by then they were no longer ahead of the narrative.
The CDC did Not give people sufficient forewarning of what’s to come, and foreign agencies, scientists, business leaders, and news media took control because they were in fact providing more signal. America is normally a beacon of confidence during crisis.
I mean, they have not held a press conference since March 14. In these times, you'd think they'd have something to say since then. But maybe this is not to be expected, I can only compare to the rough equivalents in England, the one for the EU, and the one in Sweden, all of which communicate much more frequently.
Yeah, I can see reason for the CDC to have daily press conferences now, not be routing it all through the White House. But that starts to lean toward political pressure from the White House silencing them to prevent mixed messages.
I'm guessing it's more like "There's some hints that it might work so if a doctor wants to try it, we promise we won't say that they're crazy, committing malpractice, or breaking any regulations around off-label use."
These articles both seem to summarize the same set of evidence, and it primarily consists not of studies where it doesn't work but evidence that Mr. Raoult is untrustworthy. Which he does seem to be, don't get me wrong, but that's very different than affirmative evidence it's ineffective.
In terms of clinical trials, you can run a non-superiority trial. They aren’t run as part of the drug approval process but can be and are run by clinicians and health services.
>national authorities including French government decided to deploy chloroquine as the medicine to treat COVID19. All based on Trump’s tweets which in turn was based on Fox News promotion of this study by Raoult.
This is absurd, and is insulting to every health official in any of the countries using this treatment. The idea that the French government is taking medical advice from Trumps twitter, or from Fox News is ridiculous. Moreso when the doctor and researcher they are talking about is a French citizen and infectious disease expert.
I think they the article is implying that because of all the attention that Trump gave the article, they decided to put it on the fore front of their approach.
And also raoult is a major liar. If you look at the study he omits a lot of information and refuses to release 14 day endpoint data. Plus he's been a co-author to several papers which have had their results manipulated
A French infectious disease expert publishes a paper which outlines the results of a small clinical trial and which is in agreement with anecdotal experiences in China, and with evidence gathered in vitro. The French authorities ignore their expert until Donald Trump posts about it on twitter, which they take as medical advice.
That seems insulting to France, and also like complete fantasy. In fact I would go so far as to say it sounds like something somebody with an obvious agenda would say.
re your edit/medrxiv link: note that the control group and experimental group were also both receiving standard-care, which includes a pile of antiviral and antibacterial drugs. So it's still an interesting signal, but there's a confounder with potential drug-drug interactions.
US physicians have already been able to prescribe and administer those drugs to COVID-19 patients. This order merely opens distribution from the government stockpile to mitigate current supply shortages while production ramps up. So it's a good move. The efficacy in treating COVID-19 is still being studied but in the meantime patients who need the drugs for other conditions have had trouble filling their prescriptions.
I can't help but feel that people are bending over backwards now to deny the potential efficacy of this treatment because Trump tweeted about it.
The potentially positive results are some 2 months old now, there have been multiple (admittedly nonideal) reports out of China first, then Europe, that these drugs may work, and we have a theorized mechanism of action.
These drugs were also reported to work on SARS.
A tweet may not be an appropriate venue but it was absolutely a good idea to give people hope, and these drugs undeniably do show promise. Any other president would have been lauded.
>Would have the appropriate agency issue recommendations.
POTUS operates Twitter as a direct line to the people. This would be akin to an announcement at a press conference or a daily briefing. This particular tweet was neither glory-hogging or blowharding, and for some reason people are unable to treat it appropriately.
>It's natural to doubt, when random things come out that channel everyday
There's no excuse to doubt this when you have access to multiple journal articles going back to January. It was merely a mention of a promising treatment. You can verify the multiple studies yourself, instead of just blindly dismissing it because you don't like Trump. Imagine if we pass over a possible treatment because people can't stifle their bias against the president?
>In any case, this is a political act. Or a hail mary, one or the other. Not credible medical advice, not at this point
What? Every move by the POTUS is a political act. This isn't supposed to be "credible advice." The POTUS is letting the country know there's at least one promising treatment available, and that's not a lie.
This hysteria is irrational. Pure emotional bias. You don't have to like the guy but a psychologically healthy person should be able to evaluate his statements individually - not literally ignore everything he says because you think he's racist or sexist or xenophobic or whatever.
It's not akin to any of those things, as there's no give-and-take or question period. Its a travesty of honest communications.
Why use tweets, do you suppose? So that pronouncements cannot be challenged? Certainly they do that. So there's no filter, no adviser in the way? The randomness of the messages confirm that.
Doubt is normal when instead of a coordinated communication, its a random thought bursting out his phone with no filter.
Go ahead and read journals. There's the sketchiest of support and lots of null results. Making this not credible. So then what is it? If solely an utterance to make it look like the big man is doing something, then that fits 'blowhard' precisely.
Your bias is keeping you from parsing my comments appropriately.
One can single out individual positive actions without defending the overall presidency. I also feel that tweets are inapropriate, but what I'm arguing is that this particular tweet was not the misstep that it's being made out to be.
I'm not trying to defend the president, I'm trying to explain that, as your comment demonstrates, people let their hatred of the president get in the way of rationally evaluating his actions and statements.
I guess I'll have to echo your sentiment back at you. For some reason, the guy's supporters seem utterly blind to, what to the rest of us, is the obvious fact that he's a regular doofus who finagled his way into the highest office in the land. He's floundering around, not really trying, defensive and petulant most of the time. Totally unready for the rigors of the task, and not willing to learn.
So if we give only the most cursory attention to his incoherent remarks, its obvious why. To some. To others, we're "not giving the guy a chance" or for some astonishing reason, we should "rationally evaluate his actions and statements". Like maybe this time, he's said something that by some accident can be construed as reasonable.
To those who think this is bad: why? What is the downside to trying this, or at least manufacturing a stockpile, that all of the health officials seem to be missing.
Essentially: if you could talk directly to the FDA, what new information would you give them that would cause them to reverse course on this? Same question for any of the countries who have made this a part of their standard treatment. What do you know about this that they don’t, why are they wrong to have done what they are doing?
We don't know if it works, so if they're going to try it they can at least run it as an RCT.
We do know that chloroquine and hydroxychloroquine can have significant side effects, especially if combined with azithromycin. This combination requires careful monitoring. That monitoring is harder to achieve during the current very highly pressured treatment environment, where we have a bunch of people with less experience in very busy wards and field hospitals using unfamiliar equipment.
• Safety considerations for inpatient and outpatient use of hydroxychloroquine-azithromycin in clinical practice are outlined below. Additional sources of expert guidance are also available here.
• The intensity of QT and arrhythmia monitoring should be considered in the context of risk level, resource availability and quarantine considerations.
• Hydroxychloroquine or chloroquine therapy should occur in the context of a clinical trial or registry, until sufficient evidence is available for use in clinical practice.
• IRB-approved protocols should guide use of hydroxychloroquine or chloroquine for pandemic research; suggestions for researchers are outlined below.
• Hydroxychloroquine or chloroquine use outside of a clinical trial should occur at the direction of an infectious disease or COVID-19 expert, with cardiology input regarding QT monitoring.
>The heart problems are from short term use in combination with azithromycin.
Is this true? I keep hearing this but it is not supported by your source. It seems that it is the azithromycin that is of concern, and with a death rate of 47 per million. Is there any data suggesting this is worse when co-administered?
>Chloroquine, and its more contemporary derivative hydroxychloroquine, have remained in clinical use for more than a half-century as an effective therapy for treatment of some malarias, lupus, and rheumatoid arthritis. Data show inhibition of iKr and resultant mild QT prolongation associated with both agents. Despite these suggestive findings, several hundred million courses of chloroquine have been used worldwide making it one of the most widely used drugs in history, without reports of arrhythmic death under World Health Organization surveillance.4 Nonetheless, the absence of an active drug safety surveillance system in most countries limits reassurance from these observations.
Azithromycin, a frequently used macrolide antibiotics lacks strong pharmacodynamic evidence of iKr inhibition. Epidemiologic studies have estimated an excess of 47 cardiovascular deaths which are presumed arrhythmic per 1 million completed courses, although recent studies suggest this may be overestimated.6-7 There is limited data evaluating the safety of combination therapy, however in vivo studies have shown no synergistic arrhythmic effects of azithromycin with or without chloroquine.
> We do know that chloroquine and hydroxychloroquine can have significant side effects, especially if combined with azithromycin.
What side effects? Could you expand on this for a layman? And at what doses and are there drug interaction requirements to get these side effects? What percentage of people experience these side effects?
I’m not an expert on this like you appear to be so my experience is anecdotal. Basically that I know multiple people who take this drug for various reasons. And the claim of it being some dangerous drug doesn’t seem consistent with their experience.
Obviously if used improperly that is true, but the same is true for anything, so I’m not sure that that fact rises above the rhetorical noise floor for me.
It talks about the hopefulness of this treatment, but also asks for better quality research to happen, and warns against blanket use of an experimental treatment especially in a group of patients that includes people who were often pretty ill even without covid-19.
> Basically that I know multiple people who take this drug for various reasons. And the claim of it being some dangerous drug doesn’t seem consistent with their experience.
With any medication we do a balancing exercise. "Do the risks of taking the meds outweigh the harm I experience from not taking the meds?" (One of the most important questions you can ask your doctor is "What happens if we do nothing?")
We don't really know what that balance is with covid-19 yet, and the only way we find out is by running good quality science.
(Downvoting on HN is currently pretty weird. I upvoted you.)
It appears that the FDA agrees with both of these points and specifically addresses them in the authorization. From the original post:
"The hydroxychloroquine sulfate may only be used to treat adult and adolescent patients who weigh 50 kg or more hospitalized with COVID-19 for whom a clinical trial is not
available, or participation is not feasible."
"Public health authorities about the need to have a process in place for performing adverse event monitoring and compliance activities designed to ensure that adverse events and all medication errors associated with the use of the authorized chloroquine phosphate or hydroxychloroquine sulfate are reported to FDA, to the extent practicable given emergency circumstances"
Personally my money is on Favipiravir if I had to bet on which of the drugs in trial is mostly likely to turn out to be the best treatment but there are lots of drugs in trial and we still need to know much more about all of them. In the meantime we're advancing our understanding of how to treat Covid-19 in other ways as well, such as finding out that proning patients can help in some circumstances.
The preliminary clinical trail results seem to be the best so far, that's all. I haven't been following it that systematically and reporting is noisy so I'm not confident it'll be the best, it just seems to be in front at the moment.
Favipiravir looks like a fairly simple molecule: C₅H₄FN₃O₂. Would any organic chemists care to comment on how difficult it would be to synthesize for large-scale medical grade production?
They don't publish demographics that I could find, but certainly the fact that 1,283 people have been given that treatment and only 1 person that received it for at least three days has died, that strongly suggests it's better than "nothing".
IMO the impact of the drugs should be, more than preventing deaths, in reducing hospitalization or even prevent going into the ICU, which can mean removing load off the healthcare system and make infections manageable (far more than waiting out for a vaccine).
In fact, some the remdesivir trials which will end next month (end of April) measure also the time spent in the hospital.
I guess we never learn from history. I suggest looking into temiflu fiasco.
I even got it prescribed recently when I got diagnosed with influenza. Basically, the US and European governments have spent massive amounts of money on this drug to help with the flu. People soon learned that temiflu is very close to placebo in efficacy.
67 comments
[ 3.1 ms ] story [ 111 ms ] threadhas any double blind study with more than 100 participants actually reported yet?
The timing actually makes some sense. Getting it into the field in a "can't hurt" way allows us to start studying its effectiveness quickly, before the medical system gets totally overwhelmed and studies become nearly impossible.
the double blind study, or the number of participants?
Given the severity of the situation, trying anything that might work and isn't obviously worse than the disease makes sense right now. But equally, given the side effects of chloroquines and also the postulated mechanism of action for an antiparasitic against a virus being literally just "zinc stuff? idk lol ¯\_(ツ)_/¯" right now, I think it's no less reasonable to want to see some more rigorous evaluation before regarding it as the panacea it's been claimed in many quarters to be.
"Don't be snarky."
https://news.ycombinator.com/newsguidelines.html
good plan
"Don't be snarky."
https://news.ycombinator.com/newsguidelines.html
Edit: why would I wonder? Not only because the commander in chief is quickly flipping between standpoints, but why is the CDC silent since March 14?
If the WH was directing them to approve something against their judgment there would have been headlines on major news sites.
Also your reassurance hinges on that every federal bureaucrat would complain to media in every circumstance. From my experience of bureaucracies you have to pick your battles and resisting or leaking is not always in the cards if you want to keep your job or career prospects. ("Live and let live.")
Then the CDC wants to chip in, but by then they were no longer ahead of the narrative.
The CDC did Not give people sufficient forewarning of what’s to come, and foreign agencies, scientists, business leaders, and news media took control because they were in fact providing more signal. America is normally a beacon of confidence during crisis.
https://forbetterscience.com/2020/03/26/chloroquine-genius-d...
https://blogs.sciencemag.org/pipeline/archives/2020/03/29/mo...
EDIT: Hmm I haven't seen this one before, that actually looks better https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v...
There's no such thing as affirmative evidence of ineffectiveness. You can't prove a negative.
Drug trials are designed to prove effectiveness, because the null hypothesis is always that your therapy is ineffective.
>national authorities including French government decided to deploy chloroquine as the medicine to treat COVID19. All based on Trump’s tweets which in turn was based on Fox News promotion of this study by Raoult.
This is absurd, and is insulting to every health official in any of the countries using this treatment. The idea that the French government is taking medical advice from Trumps twitter, or from Fox News is ridiculous. Moreso when the doctor and researcher they are talking about is a French citizen and infectious disease expert.
And also raoult is a major liar. If you look at the study he omits a lot of information and refuses to release 14 day endpoint data. Plus he's been a co-author to several papers which have had their results manipulated
[1] https://forbetterscience.com/2020/03/26/chloroquine-genius-d...
A French infectious disease expert publishes a paper which outlines the results of a small clinical trial and which is in agreement with anecdotal experiences in China, and with evidence gathered in vitro. The French authorities ignore their expert until Donald Trump posts about it on twitter, which they take as medical advice.
That seems insulting to France, and also like complete fantasy. In fact I would go so far as to say it sounds like something somebody with an obvious agenda would say.
Here’s a Recent promising study.
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v...
The potentially positive results are some 2 months old now, there have been multiple (admittedly nonideal) reports out of China first, then Europe, that these drugs may work, and we have a theorized mechanism of action.
These drugs were also reported to work on SARS.
A tweet may not be an appropriate venue but it was absolutely a good idea to give people hope, and these drugs undeniably do show promise. Any other president would have been lauded.
It's natural to doubt, when random things come out that channel everyday.
In any case, this is a political act. Or a hail mary, one or the other. Not credible medical advice, not at this point.
POTUS operates Twitter as a direct line to the people. This would be akin to an announcement at a press conference or a daily briefing. This particular tweet was neither glory-hogging or blowharding, and for some reason people are unable to treat it appropriately.
>It's natural to doubt, when random things come out that channel everyday
There's no excuse to doubt this when you have access to multiple journal articles going back to January. It was merely a mention of a promising treatment. You can verify the multiple studies yourself, instead of just blindly dismissing it because you don't like Trump. Imagine if we pass over a possible treatment because people can't stifle their bias against the president?
>In any case, this is a political act. Or a hail mary, one or the other. Not credible medical advice, not at this point
What? Every move by the POTUS is a political act. This isn't supposed to be "credible advice." The POTUS is letting the country know there's at least one promising treatment available, and that's not a lie.
This hysteria is irrational. Pure emotional bias. You don't have to like the guy but a psychologically healthy person should be able to evaluate his statements individually - not literally ignore everything he says because you think he's racist or sexist or xenophobic or whatever.
Why use tweets, do you suppose? So that pronouncements cannot be challenged? Certainly they do that. So there's no filter, no adviser in the way? The randomness of the messages confirm that.
Doubt is normal when instead of a coordinated communication, its a random thought bursting out his phone with no filter.
Go ahead and read journals. There's the sketchiest of support and lots of null results. Making this not credible. So then what is it? If solely an utterance to make it look like the big man is doing something, then that fits 'blowhard' precisely.
One can single out individual positive actions without defending the overall presidency. I also feel that tweets are inapropriate, but what I'm arguing is that this particular tweet was not the misstep that it's being made out to be.
I'm not trying to defend the president, I'm trying to explain that, as your comment demonstrates, people let their hatred of the president get in the way of rationally evaluating his actions and statements.
Even Hitler was capable of positive deeds.
So if we give only the most cursory attention to his incoherent remarks, its obvious why. To some. To others, we're "not giving the guy a chance" or for some astonishing reason, we should "rationally evaluate his actions and statements". Like maybe this time, he's said something that by some accident can be construed as reasonable.
Essentially: if you could talk directly to the FDA, what new information would you give them that would cause them to reverse course on this? Same question for any of the countries who have made this a part of their standard treatment. What do you know about this that they don’t, why are they wrong to have done what they are doing?
We don't know if it works, so if they're going to try it they can at least run it as an RCT.
We do know that chloroquine and hydroxychloroquine can have significant side effects, especially if combined with azithromycin. This combination requires careful monitoring. That monitoring is harder to achieve during the current very highly pressured treatment environment, where we have a bunch of people with less experience in very busy wards and field hospitals using unfamiliar equipment.
Here's some guidance from the American College of Cardiology:
https://www.acc.org/latest-in-cardiology/articles/2020/03/27...
• Safety considerations for inpatient and outpatient use of hydroxychloroquine-azithromycin in clinical practice are outlined below. Additional sources of expert guidance are also available here.
• The intensity of QT and arrhythmia monitoring should be considered in the context of risk level, resource availability and quarantine considerations.
• Hydroxychloroquine or chloroquine therapy should occur in the context of a clinical trial or registry, until sufficient evidence is available for use in clinical practice.
• IRB-approved protocols should guide use of hydroxychloroquine or chloroquine for pandemic research; suggestions for researchers are outlined below.
• Hydroxychloroquine or chloroquine use outside of a clinical trial should occur at the direction of an infectious disease or COVID-19 expert, with cardiology input regarding QT monitoring.
There aren't any of those.
Is this true? I keep hearing this but it is not supported by your source. It seems that it is the azithromycin that is of concern, and with a death rate of 47 per million. Is there any data suggesting this is worse when co-administered?
>Chloroquine, and its more contemporary derivative hydroxychloroquine, have remained in clinical use for more than a half-century as an effective therapy for treatment of some malarias, lupus, and rheumatoid arthritis. Data show inhibition of iKr and resultant mild QT prolongation associated with both agents. Despite these suggestive findings, several hundred million courses of chloroquine have been used worldwide making it one of the most widely used drugs in history, without reports of arrhythmic death under World Health Organization surveillance.4 Nonetheless, the absence of an active drug safety surveillance system in most countries limits reassurance from these observations.
Azithromycin, a frequently used macrolide antibiotics lacks strong pharmacodynamic evidence of iKr inhibition. Epidemiologic studies have estimated an excess of 47 cardiovascular deaths which are presumed arrhythmic per 1 million completed courses, although recent studies suggest this may be overestimated.6-7 There is limited data evaluating the safety of combination therapy, however in vivo studies have shown no synergistic arrhythmic effects of azithromycin with or without chloroquine.
What side effects? Could you expand on this for a layman? And at what doses and are there drug interaction requirements to get these side effects? What percentage of people experience these side effects?
I’m not an expert on this like you appear to be so my experience is anecdotal. Basically that I know multiple people who take this drug for various reasons. And the claim of it being some dangerous drug doesn’t seem consistent with their experience.
Obviously if used improperly that is true, but the same is true for anything, so I’m not sure that that fact rises above the rhetorical noise floor for me.
It talks about the hopefulness of this treatment, but also asks for better quality research to happen, and warns against blanket use of an experimental treatment especially in a group of patients that includes people who were often pretty ill even without covid-19.
> Basically that I know multiple people who take this drug for various reasons. And the claim of it being some dangerous drug doesn’t seem consistent with their experience.
With any medication we do a balancing exercise. "Do the risks of taking the meds outweigh the harm I experience from not taking the meds?" (One of the most important questions you can ask your doctor is "What happens if we do nothing?")
We don't really know what that balance is with covid-19 yet, and the only way we find out is by running good quality science.
(Downvoting on HN is currently pretty weird. I upvoted you.)
>This combination requires careful monitoring.
It appears that the FDA agrees with both of these points and specifically addresses them in the authorization. From the original post:
"The hydroxychloroquine sulfate may only be used to treat adult and adolescent patients who weigh 50 kg or more hospitalized with COVID-19 for whom a clinical trial is not available, or participation is not feasible."
"Public health authorities about the need to have a process in place for performing adverse event monitoring and compliance activities designed to ensure that adverse events and all medication errors associated with the use of the authorized chloroquine phosphate or hydroxychloroquine sulfate are reported to FDA, to the extent practicable given emergency circumstances"
https://www.mediterranee-infection.com/covid-19/
They don't publish demographics that I could find, but certainly the fact that 1,283 people have been given that treatment and only 1 person that received it for at least three days has died, that strongly suggests it's better than "nothing".
In fact, some the remdesivir trials which will end next month (end of April) measure also the time spent in the hospital.
I even got it prescribed recently when I got diagnosed with influenza. Basically, the US and European governments have spent massive amounts of money on this drug to help with the flu. People soon learned that temiflu is very close to placebo in efficacy.