About that Hydroxychloroquine for Covid-19 trial
betterscience.org
betterscience.org
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.
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.
> It has been reported that oral absorption of CQ and HCQ in humans is very efficient. In animals, both drugs share similar tissue distribution patterns, with high concentrations in the liver, spleen, kidney, and lung reaching levels of 200–700 times higher than those in the plasma10. It was reported that safe dosage (6–6.5 mg/kg per day) of HCQ sulfate could generate serum levels of 1.4–1.5 μM in humans11. Therefore, with a safe dosage, HCQ concentration in the above tissues is likely to be achieved to inhibit SARS-CoV-2 infection.
> We have a lot of experience. We have made the most precise description of an untreated patient cohort among the Munich patients. And at the Munich group, we saw how the virus concentration in both the throat and lungs behaved over time. And we can say that at the beginning of the disease the virus is in the throat and it goes away on its own through the - let's say - the first ten days of the disease. After that, many patients in the throat have little or only irregular evidence of the virus.
But that has nothing to do with how the virus behaves in the lungs. The virus is then really replicative in the lungs, especially in severe cases. And we can also say what the patient has in his throat, it has nothing to do with how the clinical development of the disease continues, whether the patient quickly gets well or only goes through a difficult phase. So what is being measured in this entire clinical study has nothing to do with the outcome of the disease, with the symptoms, but is only an initial indicator of how the disease starts. For all patients, the virus concentration drops in the first week, but if you now imagine that the group being treated will be included a little later and the untreated group being included earlier in this study, it is in nature the thing that with this group that was later included - they are already further in eliminating the virus from the throat - that the virus then goes down in the throat, faster. This disappears faster because they have simply been in the course of the disease for a long time. Whether this is due to the fact that they are treated, cannot be said at all from this entire study. Perhaps it would have been so if the groups had been put together as here, but if they hadn't given them chloroquine, but some headache pill, the study would have been the same.
It's difficult to due true double blind random studies in these cases because doctors are there to give everyone the best chance at recovery, not to pick half of a group to potentially do worse.
Hopefully we can ethically do well design studies on controlled groups with moderate symptoms, but until then this imperfect clinical data is very interesting.
But that's not what these doctors were doing, is it? They weren't looking at whether the patient got better or not. They were looking at viral load only.
https://twitter.com/GaetanBurgio/status/1241201751916568576
> Outcome from the study is based on viral load only and not on clinical outcome and I can see a major flaw here as clinical outcome critical.
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.
Toxicity is typically tied to dosage rates or drug interactions. The bigger concern from the french study was the additional use of Azithromycin which is more dangerous/toxic. The dosage rates and toxicity of HCQ by itself is well known.
The other big risk is panicky people ignoring the recommended guidelines. Fortunately in the US (and Canada) both drugs require a prescription where both a doctor and pharmacist will provide this information, and it will be printed on the pillcase. What's more worrying is people buying it in countries where it's over the counter then not reading the side of the box and taking far too much (or worse reading the correct dose and thinking 2x the drug = 2x more effective or some nonsense).
Check out this analysis: https://twitter.com/AppleHelix/status/1240495937522368512
the goal of studies like this are to strengthen the evidence base and remove those unknowns, so physicians can make evidence-based decisions. if the study is sufficiently poorly designed, it does not accomplish this goal, and can even lead to misinformation
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”
By the same logic, you must stop eating carrots if I tell you that doing so will be infinitely rewarded after you die.
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.
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...
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)
It claims many clinical trials have been done in China that show chloroquine works. However... there's nothing to actually read with any data.
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...
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]
It doesn't need to be administered intravenously (only for methemoglobenia) - although more effective that way.
serotonin syndrome, rbc breakdown and allergic reactions occur when you drink a glass of what few drops are enough.
As said, it is extremely safe drug in low dosages (4-16 drops of 0.1% solution).
Edit: Also see the Kevin Rose Show episode https://podcast.kevinrose.com/dr-peter-attia-longevity-compo... starting @ 1:16:20
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.
https://old.reddit.com/r/medicine/comments/flor5z/please_sto...
https://www.mahoningmatters.com/regional-news/ohio-doctors-a...
* https://journals.plos.org/plospathogens/article?id=10.1371/j...
* https://journals.plos.org/plosone/article/file?id=10.1371/jo...
https://twitter.com/chroniclycranky/status/12418326784727244...
You can be a remarkable clinician without ever interacting with the primary literature. These are simply different things.
Citation, please. This is a very strong statement.
Seem less ridiculous?
Understanding, designing and executing clinical trials is an entire specialty within medicine. Your average doctor will be familiar with the concepts, but not necessarily adept at evaluating a clinical trial.
It may not still be a thing, but I happened to run across the factoid while reading the wikipedia page of a middle-aged and famous doctor that just got the coronavirus.
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?
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).
If it turns out to shorten the illness, everyone sick, and also everyone taking it prophylactically who is actually infected but asymptomatic, will reduce their contagion rate by joining the ranks of the non-contagious sooner, reducing everyone's risk. If it does not turn out to shorten the illness, no harm done.
Chloroquine is well-known. If it caused an unacceptable rate of liver failure we would already know.
I see suggestions that it takes a very high doses to work. But that might be so only for the already severe infections they are using it on. It should be easy enough to discover whether low doses work prophylactically, and safe enough to try them while waiting on results.
What should not happen now is, that the general public starts taking the drug as a precaution, just because it might work. The known side-effects are too severe (e.g. blindness) and also, there are already shortages of the drug for those who already require it as part of their medical treatment (e.g. immune-supressed).
This side effect occurs if you take chloroquine for extended periods of time. Look at the data.
https://eyewiki.aao.org/Hydroxychloroquine_toxicity
"Risk for toxicity is less with <5.0 mg/kg real weight/day for hydroxychloroquine and <2.3 mg/kg real weight/day for chloroquine[2]. Patients are at low risk during the first 5 years of treatment."
And management is as simple as stopping the drug if it starts affecting your vision:
"At the first signs of retinal toxicity, hydroxychloroquine should be stopped to prevent further retinal damage and visual loss[2]. "
Common (1-10%): rash, itching, diarrhea, vomiting, loss of appetite, headache, blurred vision, "Affect liability" (got no idea what that is).
This is not some crazy experimental new drug that was unknown until past week. It's an experimental treatment, it's not an experimental drug, with unknown side effects. For a condition where time is critical.
Of course, we should also be quick to discard unpromising drugs, and not only focus on one promising drug.
WHO is starting a megratrial of several drugs now https://www.sciencemag.org/news/2020/03/who-launches-global-... (including CQ/HCQ)
> 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.
What are you talking about? The severe side effects are known and are usually associated with chronic usage of that drug. Chloroquine is taken for prophylaxis against malaria (daily) in many places in the southern hemisphere. Usual regimen is at least for 8 continuous weeks!
EDIT: Toxicity here: as you can see it's very well tolerated. https://eyewiki.aao.org/Hydroxychloroquine_toxicity
What health authorities want to do is to allow physicians to use the drug if the patient agrees, but only in a controlled setting in which data is collected and there is a control group. So at least afterwards we could draw conclusions about whether it killed more people or helped saving people. Does that not make sense to you?
It does, but why can't one can have the control groups at the same as blanket prescribtion? In times like this when the health care apparatus is overwhelmed, is it a good alternative to do that, since side effects are well-known and given the fact that the drug might be ineffective if used late in the infection cycle [0]?
First is prophylaxis for front line health care workers, who are suffering grave infections likely exacerbated by long hours and low morale. Long term use of chloroquine or alternatives is a concern for this audience. There were fatalities last time, just like this time.
The second is for the patients themselves, who will otherwise endure uncontrolled viral replication for up to two weeks until the adaptive immune response recognizes the pathogen. Reducing transmission requires an earlier end to this stage.
Is the data from the previous studies worthless for these goals?
And you just described the reason for a control group. We simply do not have that information. Things are moving too fast and treatments have not been standardized yet, not to mention the built in variability between locations. If you want to know if a treatment is effective, you must have to comparable groups. The point of the control group is to gather that information. Just because there are many, many, global cases doesn’t mean you actually have been able to capture the data for a control. Things are moving that fast.
> But if a doctor wants to prescribe all its patient with it, he should be allowed to
And what about the supply of these drugs? There are people who do need these drugs for other conditions (I’ve read Lupus patients sometimes need it). These patients need the drug and the supply is getting scooped up by people who don’t know (a) if they have the virus and (b) if the treatment is effective. And if it is effective, is it effective for treatment of infection or prophylactically? Just because a drug is widely used does not mean that there is enough supply to distribute it to anyone who wants to try it.
These are major issues that can be answered with proper clinical trials. We know how to do this and they can (and are) being done as fast as possible.
The goal here is to get enough evidence the treatment works or doesn't work. Conducting double blind studies is not the most efficient and fastest way to do that when you already have a lot of preexisting knowledge about both the patients not receiving any drugs and the safety profile of the drug in question.
This is again a situation where statisticians should be asked for help as medical professionals very often operate on very simplistic model (double blind or gtfo) which we just don't have time for this time around.
And yet trials for new medication against these diseases always include a control group.
I’d suggest we need to get it to people before they end up in the hospital to try to keep the resources available.
No. Likely needs to be given closer to onset of symptoms.
"The suggestion was to massively prescribe it."
No. The suggestion is to generate more evidence as fast as possible since it looks promising.
Cannot wait for full clinical trials. 1500+ deaths per day in the mean time.
Why are you fighting it so hard? If this is a useful treatment, don't you want us to find out? Let the doctors do their thing.
Doctors have the authority in many countries to prescribe it off label based on their own review of the evidence and their patient's consent. That's the best we can do right now without risking something much worse.
See https://www.drugs.com/sfx/hydroxychloroquine-side-effects.ht...
And it's not just for drugs. It's also why DDT continues used in some countries but is illegal in others.
Nor on the basis of panic; we should be able to manage this pandemic as long as people stick to the measures in place. Stay at home, limit your shopping, don't take the piss. I mean panic right now is causing more problems - e.g. hoarding and people trying to make a quick buck.
This thing is mainly a big problem because people can't keep calm and rational. Or they think they're rational, as in, "I should buy enough toilet paper because I should stay indoors for a while".
These are very real concerns for which no one has answers. People are stockpiling because of the uncertainty, which could be seen as a very rational stance in hindsight if this goes on for quite some time.
To clarify, hydroxychloroquine has far fewer side effects than chloroquine.
I would only want this drug given to me if there was no hope of recovery.
Advil has probably killed more people than hydroxychloroquine.
The drug is 90 years old, has been used by millions, has relatively modest side effects, is relatively well-understood, has shown efficacy against coronavirus in vitro.
Hydroxycholoquine is very safe and is prescribed to lupus patients daily. The Korean recommended dose (400mg/day) is the same as what is prescribed to lupus patients. Chloroquine is a bit more dangerous, but only in high doses and over long periods of time. Patients would be on either for 10-20 days maximum which is much less than what it takes to be dangerous.
Both are less toxic than Tylenol.
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.
If we want to deal with covid we should have started years ago. As ever, we didn't.
So much for that given the president was recommending chloroquine to be used off the cuff.
There is EVERY reason to think they were not in a position to a "proper" test. They are in the middle of an epidemic!
Most SLE/Lupus patients take HCQ, and reportedly none in the cohort of the doctor I know have sufficiently severe symptoms to qualify for pCR testing to even establish if they have Covid19. This is Spain with (currently) 708 cases per MM. Of course, caveats like absence of evidence is not (necessarily sufficient) evidence of absence. It may be that SLE or other immuno-modulation treatments have some effect - someone should do analysis with matched non-SLE HCQ and non-HCQ prophylaxis cohorts. But back to my main point with the house burning metaphor for exponential infection - the risk landscape demands we take more risk, give HCQ widely instead of waiting for the conclusion of prospective studies. We can withdraw it if it is shown to be no better than placebo or worsens outcomes when enough data is available to conclude.
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...
> Il trattamento deve essere accompagnato da trattamento antivirale (lopinavir/ritonavir o remdesivir + clorochina/idrossiclorochina) e/o steorideo (desametasone)
This is from the 13th of March so I guess there will be still some days until we see results of this (either positive or negative)
That seems like pretty strong evidence that the new treatment protocol is drastically decelerating the pandemic in Italy.
I believe with the number of patients they have, they would've updated the guideline if it wasn't effective at all. But how effective it is we don't know. If a large percentage of some areas is already infected but the health system is still in the state it's in now, it could actually be a good sign. If the current numbers are realistic (which I don't believe at a positive test rate of >30%), it's probably not. We simply cannot know.
Per some interview with some Chinese doctors who battled COVID19, they said that for many critical patients, their viral load is actually low, but the virus had caused damages to all parts of their bodies thus antiviral isn't going to do anything significant at that stage.
This might suggest chloroquine could be helpful at earlier stage of COVID19, to help prevent patients developing into server/critical stage, which would still be a very good thing if hold true.
What are you basing "it has at best a marginal effect" on?
> 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.
Coughing your lungs out but feel like CNN is not lying to you? Easy! Refuse the drug. Nobody can force you to take it.
Worst thing that can happen with a chloroquine and azithromycin combination is that it causes heart arrhythmia and sudden death in a patient that would not have otherwise died.
Studies of patients taking this combination of meds include daily EKGs, which is something the general population at home isn't going to have access to.
https://twitter.com/search?q=azithromycin%20qt&src=typed_que...
I bet it can, if FDA is beat over the head with a shovel, which it will be if the need arises. It's a real ECG verifiably capable of detecting irregular hearth rhythm, and it costs a tiny fraction of what a big-ass ECG machine would, and therefore can be deployed at a much larger scale. Just because it could only get approval to detect atrial fibrillation duing "peacetime" doesn't mean it can't be pressed into service for other things.
This is very difficult to do. In this study all the patients in the treatment group are from a hospital and most of the patients in the other hospital are from other hospital. Do the population of both hospitals have the same median income? Usually a low income cause a bad diet that may cause bad health that has a worse prognosis.
Are the patients in the other countries classified by income? Does the difference in income cause more/less consumption of milk? Bottled milk has an additional amount of vitamin D, and some unconfirmed reports say that the lack of vitamin D is bad for covid19. Does this difference depend on the country? For historical/genetic reason, French drink more milk that Chinese. What about wine, is the consumption of wine important?
What is the effect of temperature and humidity in the no-hydroxychloroquine group? The average climate conditions change from country to country and from place to place and from month to month.
To be included in the testing group the patient must give consent. Probably they have not to be too wasted to be able to read it. Probably not been to wasted is a good sign.
There are a lot of factors, and not all of them are known, not all of them are easy to measure, not all of them are measured. So you need a control group.
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.
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.
Except those precautions are at least two orders of magnitude less than the case fatality rate for coronavirus infection.
Equivalently, there are scenarios where a seatbelt can decapitate you or trap you in a drowning car. But you'd still be a fool to drive without one, because buckling is a thousand times more likely to save you than kill you.
The most serious cases of COVID-19 affect all the people who have the underlying conditions that have precautions listed using H-Chloroquine.
That makes the normal ICU case of COVID-19 more difficult (time consuming) to manage because now you have to spend time managing / monitoring: The condition, COVID-19, the side effects of H-Chloroquine on vital body systems already impaired, already being attacked by COVID.
Throw the magnitude two out the window like a lucky car crash victim while these patients suffer the crash in the hospital. Not even Bernie was going to pay for the specialty concierge care needed to manage such a patient and yet you some how assume that is how it works.
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.
The simple solution is to spread it over enough sites so that the law of large numbers quantifies that variability into the dataset. For example if we run trials over 10 hospitals in 20 different states, 200 sites in the dataset would almost certainly capture inter-site variance.
There are a bunch of "contract research organizations" all over the world, quite a few of them making billions of dollars a year, who specialize only in running clinical trials because these things are so complicated. The documentation for clinical trials are often thousands of pages long describing tiny details like device calibration across hospitals trying to eliminate as many risks as possible. These organizations tend to have long standing relationships with hospitals and host many different trials in each one with a bunch more subcontractors who do patient selection.
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.
The point of these studies is to help the evidence catch up to improvised clinical practice. If the studies are poorly designed, that goal is not achieved
Prayer? Meditation? Garlic? Red wine? Cannabis?
...I mean it is a big loophole. Something I've wondered about for years is V-8 juice. Seems healthy, but what about the psoralens in celery?
I'm not saying that everything does need to be tested, but if you don't, you don't really know and no mental gymnastics can change that.
You can't possibly know whether this drug would have adverse interactions with a new illness.
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?
https://cmr.asm.org/content/20/4/660.long
Despite the role of the pH-sensitive endosomal protease cathepsin L in the entry pathway (151, 300), viral culture does not require pretreatment with trypsin. However, this pH-sensitive cathepsin L may be a target for agents such as chloroquine, which elevates endosomal pH (174, 341).
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?
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282?query=fe...
It also seems some EU countries are now stopping the use of lopinavir due to this study.
Not sure what to make of this. Can this to some extent explain the huge differences in death rate between Italy and Germany?
Source: https://www.medpagetoday.com/infectiousdisease/covid19/85499
Source (in Dutch): https://swab.nl/nl/covid-19
But yes in Italy the current guidelines (which are still dated 13 February still mention lopinavir).
Source (in Italian): http://www.simit.org/medias/1569-covid19-vademecum-13-03-202...
It has also been removed from guidelines from Belgium: source (English) : https://epidemio.wiv-isp.be/ID/Documents/Covid19/COVID-19_In...
I think the odd case is France wich I think is still not having Chloroquine/Hydroxichloroquine in their guidelines as of today.
I was not able to find the german guidelines.
Italy has a couple severe disadvantages compared to Germany:
- since the financial crisis young ppl are forced to live with their parents and often enough grandparents in cramped conditions due to exploded rents - which means that symptomless infected can spread coronavirus in their families
- Italy's healthcare system has been wrecked by forced austerity after the financial crisis - it's exactly what everyone warned of back at the time.
- many young nurses and other medical staff have fled to Germany and other countries for better pay
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.
Given how the virus is moving now, couldn't we have a pretty nice study completed in a few weeks?
https://www.novartis.com/news/media-releases/novartis-commit...
According to the register, the study execution time should be "2020-01-31 To 2020-02-29"
But nobody seems to have any insight on the final results. But I would recommend this article with comments of the study leader (Dr Zhang Zhan). The article also explains how they initially discovered the efficiency of the drug by just noticing there were no lupus patients (who were under chronic treatment of hydroxichloroquine) infected with covid19.
https://www.jqknews.com/news/388543-The_novel_coronavirus_pn...
I assume that means it's either too small of a sample size or it doesn't make enough of an affect?
(this is more or less also why vaccine timelines are so long; chicken eggs take a bit of time to get going, and that's the best breeding ground we have!)
"As of 23 March 2020, it seems that Japan and China have issued an export ban on the substance. Japan and China are the only countries in which favirapir is produced and approved as a medical compound." [1]
Apparently a 1-month dose costs £5 in the UK, so there doesn't seem to be a large hurdle to produce it.
If you dig around in the other exceptions in the document I've linked you'll see there are multiple places where patent protection and protection of human life are discussed.
I know where I sit on the patent validity continuum already, but I also know other people are furiously bouncing on the other end of that seesaw.
1. https://www.wto.org/english/docs_e/legal_e/gatt47_02_e.htm#a...
https://www.nytimes.com/2001/02/19/business/patents-health-e...
Are its downsides worth the upsides when used as a COVID-19 treatment?
well that took what, two days?
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.
The way the authors have analyzed their data it tells us this is a promising drug. Had they done an intention to treat analysis very likely the opposite would've been the result.
The only thing that trial tells us is that if you do a bad trial you're as clueless as before.
Testing will be randomized apparently.
1) 6 / 26 of the individuals in the experimental group got removed from the stats because their condition got worse and the treatment ceased. One of them died.
2) The metric used to test the efficacy is viral load. You can get a negative on this and still have the disease. This is going to be a function of how long you've had the disease, which isn't controlled in the study.
If you have a gripe with the author because they're not a medical scientist, read the peer review comments here: https://pubpeer.com/publications/B4044A446F35DF81789F6F20F8E...
They are easy to understand as a layman I feel.
Other noteworthy takeaways:
1) The combination of HCQ and AZ was hyped as superior because all 6 patients did better. But looking at the data there is no significant difference in viral load outcomes between both drugs and just HCQ.
2) Many of the author's claims of statistical significance disappear if you use more conservative estimates for when people were supposed to be PCR positive except for Day 6 (now 0.01 instead of 0.001).
3) The paper turnaround was incredibly fast, with less than 24 hours for peer review. One of the authors of the paper is an editor of the journal in which it was published. Could be indicative of poor study controls.
I hope this turns out to be useful. I would not be surprised if it did not. Regardless, the best case takeaway of THIS information does not inform us about how the drug performs in the most critical area (severe ICU patients).
If you're a non-bio programmer please try to recognize that saying the current paper is good enough to justify mass distribution of chloroquine tablets to everyone is about on par with the cliche clueless product manager making bold decisions about how to move forward with your codebase despite having no clue how it works themselves.
Unfortunately, all those waiting patiently for "confirmed results of double blind trials" will make up a significant percentage of those visiting the pearly gates by the time those trials are ever completed.
Look, the risk is fairly low for chloroquine, mild side effects in a very well done Danish study were only ~15%, serious side effects were ~1.5%.
Reported Side Effects to Chloroquine, Chloroquine plus ... academic.oup.com › jtm › article-pdf › jtm7-0079
Now, what's the risk of serious side effects/death from coronavirus for those over 70 years old ? Like >10%.
And a recent report out of Hong Kong is stating that lung scarring from coronavirus is being found in all ages (radiological imaging), like 20 to 30% loss of lung function, shortness of breath reported by recovered patients just from fast walking - - - is that going to be permanent in all ages ? Are you willing to take that risk ?
A glaring fact is that chloroquine / hydroxychloroquine have been on the WHO's list of essential medicines for decades . . . . why so, if they were too toxic to recommend ?
Just like the rush on buying ammo, would you prefer to have "the likely treatment" before the problems comes to you - - or, would you prefer to fail to find it after all the shops and stores are completely sold out and the unemployed "zombies" are all over your property and smashing down your door while your family is cowering under the table screaming and crying for help ? I already got my supply of it, best of luck for all the naysayers.
https://www.foxnews.com/health/florida-man-with-coronavirus-...
https://video.foxnews.com/v/6143849011001
BTW, what is your Gov't offering you right now in the way of proven drugs ? Nothing. All the while the rich in NY are reported in the news media as cashing in on favors to secure reservations for hospital beds in case they need them - - and buying ventilators . . . under the counter.
"While I understand the basics of a clinical trial, I’d like to point out that I am no medical scientists. Most of the issues here were spotted by other people and I have linked to the sources."
You cannot make this s@#t up!
Put on your critical thinking caps folks -- there's a lot of bad info out there.