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First hydroxychloroquine randomized controlled trial: results disappointing (twitter.com)
199 points by aaavl2821 8 days ago | hide | past | web | favorite | 89 comments





For people that didn't read: it's "disappointing" because both the control and study groups largely tested negative (93% and 87% respectively). That 87% figure sounds worse than the control but it actually is better than in the French study.

What happened in essence is that almost all cases were mild so the patients almost all got better after a while, with or without medication. This doesn't mean HCQ is ineffective, only that its efficacy couldn't be measured in this instance. And I wouldn't call a study where almost everyone gets better at the end "disappointing".


"That 87% figure sounds worse than the control but it actually is better than in the French study."

This is a moot point, because the French study was not a randomized control trial, on 6 people, at different stages of the disease from this study.


It's disappointing because it's no better than placebo.

In this case (as with many others) placebo is pretty effective, but also, these folks didn't get sick enough to need it, as with the overwhelming majority of young and healthy people. Another, broader study is required. I'm sure we'll find out more soon -- this reads like a mulligan though.

> In this case (as with many others) placebo is pretty effective

Where do you get that idea from? In the study it looks like everyone got better, but that may just be regression to the mean (i.e. the normal progression of covid-19 in those patients).

If you'd want to know if placebo is effective on covid-19 you'd have to do a completely different study, comparing placebo to doing nothing. Though the likelyhood that placebo therapy is "pretty effective" here is very low. Placebos usually work best in things that have a strong subjective factor, e.g. pain treatment.


any data on what percentage of “young healthy” people die/get hospitalized? also, what’s the definition of young and healthy?

I mean, I’ve been saying this for a while and I don’t want to tire y’all out but, young being defined as under 40 and healthy being defined as without comorbid conditions.

The median age of the dead in Italy is 80.5 and 99.2% of them were sick, averaging 3 comorbid conditions [3]. So basically the opposite of that.

[1] https://twitter.com/AndyBiotech/status/1241741127205572609?s...

[2] https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e2.htm

[3] https://www.google.com/amp/s/www.bloomberg.com/amp/news/arti...


I keep reading this statistic about deaths in Italy, but how much of it is shaped by doctors desperately deciding to withhold care from the sickest in order to save others?

i.e., would the age curve be different in an ideal situation where everyone was getting optimal care, and is the statistic thus misleadingly suggesting that younger people are less at risk?


Would the curve be different in an ideal situation where the hospitals weren't completely overrun and out of resources? Yes, of course. However, I would guess that if care was withheld, it was based on disease state and patient robustness. Age is part of that equation so it is hard to separate it out. In other words, a fit healthy, no comorbidity senior whose immune system is fighting hard is probably not having treatment withheld just because of age. I'm not there of course, but based on accounts I think this is right. At least I hope so.

As an aside, you were certainly not being judgmental about the clinicians in Italy and I applaud you for that. Those professionals are doing incredible work in unbelievably difficult and personally dangerous situations, so I hope we can all agree not to second guess their decisions from the cheap seats.


I was not suggesting that Italian doctors might be withholding treatment "just because of age." Clearly, as you state, there will always be a strong correlation between age and overall health.

I was trying to point out that some people using the statistics about age and mortality from Italy are trying to use them as justification for doing less to combat the disease's spread, and that might be a dangerously misleading gambit.


Point taken and well made. Sorry if I misunderstood.

Data: https://covid19.colorado.gov/sites/covid19/files/COVID%20-%2...

This is a summary of all cases in Colorado. All of our state's (small handful of) fatalities have been among residents aged 60 and over. The hospitalization rate is ~5% or so for adults in the 30-50 year old range, and it rises to about 20% in the elderly age groups.

Caveats: with only 600 cases to draw inferences from, there's a little less than one digit of precision in those estimates. Testing availability is also still somewhat limited in the state with a little more than a 10% positive rate.


The Imperial College paper that was being passed around said about 1% of 20somethings, 3% of 30somethings, and 5% of 40somethings wind up hospitalized.

I think if your population trends younger this can mean pretty high absolute numbers even if low percentages. A number of news sites in various places said the under 50 crowd is using significant portions of hospital resources.


Across the United States, 38 percent of those hospitalized were between the ages of 20 and 54.

Nationally, 12 percent of the intensive care patients were between the ages of 20 and 44.

https://www.nytimes.com/2020/03/23/nyregion/nyc-coronavirus-...


I keep hearing statistics like this and I yell at my TV every time. Counting up the people in the hospital is pretty easy, but it doesn't answer the more important question of how many infected 20-54 require hospitalization. Even comparing those numbers to the larger demographics would be helpful.


> Across the United States, 38 percent of those hospitalized were between the ages of 20 and 54.

> Nationally, 12 percent of the intensive care patients were between the ages of 20 and 44.

Versus 26 percent of the ICU patients being aged 45 to 54, and 62 percent of the ICU patients being 55 or older.


You mean "not worse". If almost everyone got cured there's hardly any leeway to be even better.

The difference is not statistically significant is what I mean.

There's a really important distinction to be made here though. "No better than placebo, and half the control group died" would mean it probably doesn't work. "No better than placebo, but no one needed to be hospitalized" presumably means that no medical care was required in the first place. If no medical care was required, then it will be impossible to demonstrate a positive drug effect by definition.

I think what you are trying to say is that we cannot measure the difference.

It’s actually worse than placebo...

Why are we amplifying someone posting a compressed jpeg to 3,000 followers who lists no name, has a photo of George Costanza, and claims to be a virologist?

Perhaps they are infinitely more qualified than some of the public figures pushing this treatment as a "game-changer"? Either way, hopefully we'll hear from some well-identified, qualified experts in time.

The best early information was on 4chan while the authoritative sources were downplaying it. Pseudo anonymous social media has most of the chaff but all of the wheat.

It is a 30 patients test and almost everybody’s fever was gone right after enrollment. Even the swab test results turned negative in 2-4 days. Why is medicine ever needed for such group of patients?

The results are disappointing because they are useless. That's how I interpret the headline.

I am sorry, but isn't the mechanism of action that hydroxychloroquine is simply a zinc ionophore, i.e. you need enough free zinc in the blood for this to work? I read doctors suggesting using hydroxychloroquine along with 50mg of ionic zinc.

CQ (and HCQ, etc) have multiple potential mechanisms of action. I don't believe we know how it works in this particular case yet, or if it even works at all. It is indeed a zinc ionophore, [1] and those are known to impair the replication of a number of RNA viruses. [2] However, there are a number of other mechanisms at play here as well. [3]

> Both CQ and HCQ are weak bases that are known to elevate the pH of acidic intracellular organelles, such as endosomes/lysosomes, essential for membrane fusion5. In addition, CQ could inhibit SARS-CoV entry through changing the glycosylation of ACE2 receptor and spike protein6. Time-of-addition experiment confirmed that HCQ effectively inhibited the entry step, as well as the post-entry stages of SARS-CoV-2, which was also found upon CQ treatment (Supplementary Fig. S2).

[1] https://journals.plos.org/plosone/article?id=10.1371/journal...

[2] https://journals.plos.org/plospathogens/article?id=10.1371/j...

[3] https://www.nature.com/articles/s41421-020-0156-0


Like Reelin said, it's effectiveness may be related to it's ability to modulate immune activity by affecting pH.

https://www.ncbi.nlm.nih.gov/pubmed/27927040

Course, that'll only work if the symptoms are being caused by an overactive immune system and it's able to mediate that immune response in time.


> Course, that'll only work if the symptoms are being caused by an overactive immune system and it's able to mediate that immune response in time.

Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome [1]. HCQ is known to moderate this reaction.

[1] https://www.thelancet.com/journals/lancet/article/PIIS0140-6...


I'm not sure if it would be able to mitigate a cytokine storm, but it could prevent it. When DW was on it for sepsis due to an auto-inflammatory condition, her progression was much slower than what I've read about cytokine storm.

Thanks, I misspoke.

I've read about benefits not related to zinc, in addition to the zinc-related mechanism. It helps zinc get into the cell which prevents the replication of the virus, but there are additional benefits of this chemo medication. I'd have to take some time to find the particulars, if you read the original French study I think it details all the theoretical benefits.

With any chemo drug I suspect it won't have a huge effect on patients who are mild, in fact it could have a negative effect, but I'm no expert.


Hydroxychloroquine is not a chemo drug

It's a chemosensitizer, I'd say it is.

https://en.wikipedia.org/wiki/Chemosensitizer

edit: It's still being researched, but it is an anti-cancer drug, just like how chemo drugs get classed.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2...

Chemo drugs aren't really a technical category, but it seems like chloroquine will become part of the anti-cancer family soon.

Given our recent discovery that chemotherapy has only gives you a 2% greater chance of survival (again, your immune system fights of cancer just like it fights off viruses), I'm not so hopeful here.

https://www.thelancet.com/journals/lanonc/article/PIIS1470-2...

(summary: chemotherapy actively kills people, some people would have survived without it)


Don't believe everything you watch on youtube.


Peer reviewed papers are great, and that’s obviously where medcram got their info from. Whether or not this is the actual mechanism of action for covid-19 has not been demonstrated however.

Has anyone found the study they're talking about? This tweet is only a screenshot of the abstract.

And the trials registry entry says "No results published": https://clinicaltrials.gov/ct2/show/NCT04261517

Update: I asked the person on twitter and here it is: http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43... Apparently it's in chinese.


Yes. Two issues...

Median age for the control group and test group was 24yrs and 18yrs respectively. This isn't the ideal sample group for testing this drug for COVID-19 indication.

But more importantly... Dosing was only 400mg once per day versus recommended 500mg twice per day as performed in the French trial.

Taken together, this trial tells us very little on how this drug would perform at proper dosing on severe subjects in vulnerable age range and/or with prior co-morbidities.


didnt find a link to the abstract, seems the results are just being published

link to the trial on clinicaltrials.gov is here: https://clinicaltrials.gov/ct2/show/NCT04261517

patients in both tx and control arm fared better than in the french study from earlier this week, suggesting patients were healthier / lower risk at baseline

patients got slightly lower dose in this study (400 mg / day) vs the french study (600 mg / day)


Someone on the Twitter thread linked to this, which seems to be not exactly the same document but contains very similar text in the abstract:

http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43...

I think it helps if you can read Chinese, though Google Translate seems to do a pretty ok job on it.


No need to read Chinese, the abstract is on page 2. Conclusion: at current trial size no better than placebo. More study is needed to tease out an effect, if there is any.

It does help if you read the translation.

By now everybody should know that the successful dosis is 2x500mg per day for 10 days. Not 1x 400mg per day, which is the old dosis for Malaria prevention. This dosis needs at least 2-3 weeks to be effective (saturate the cell membranes with zinc), and by then the infection is already over. And the Chinese treatment plan contained much more.

A study with zero value.


What's the source of this?

The official chinese treatment recommendation. https://old.reddit.com/r/COVID19/comments/fd28s6/preprint_ar...

Amongst doctors both hydroxychloroquine sulfate and chloroquine phosphate run under broadband antiviral.


Kind of crazy these are not in the open. Especially when we are used to work in software.

It may be that they just presented an abstract and the manuscript has not yet been submitted for publication or peer reviewed

[flagged]


scientists have increasingly been doing this during covid by publishing on biorxiv and then discussing on other channels (twitter etc)

for ex, this paper [0] by UCSF analyzing 26 of the 29 viral proteins expressed by the virus was posted on biorxiv and publicized further via twitter [1]. they identified 69 FDA approved drugs that target these proteins, giving the medical and scientific community a massive head start on studying drugs that could potentially be near-term treatments

there are some parts of academic science that are stuck in the last century but scientists themselves are certainly not

for those interested in learning more about how science works and how scientists operate, the covid situation is a great way to see how its done. modern science is amazing

[0] https://www.biorxiv.org/content/10.1101/2020.03.22.002386v1

[1] https://twitter.com/kevansf/status/1241936588164063233


Yeah, I'm following a bunch of scientists on Twitter and have been watching from the sidelines with awe and admiration. The contrast to the seeming hordes of dumbfucks could hardly be more remarkable; sometimes it's hard to keep in mind the same platform is host to both sets of people.

This Doctor in NY seems to have had great results so far https://www.thegatewaypundit.com/2020/03/stunning-ny-doctor-...

This Doctor, Health Commissioner of NYC, Oxiris Barbot, seemed to take a lot of joy in proclaiming: Today our city is celebrating the #LunarNewYear parade in Chinatown, a beautiful cultural tradition with a rich history in our city. I want to remind everyone to enjoy the parade and not change any plans due to misinformation spreading about #coronavirus. https://on.nyc.gov/377LlcH

https://t.co/bwCnIb7j8H

Which Dr deserves awe and admiration and which brings with the seeming hordes of dumbfucks?

https://www.amny.com/editorial/city-leaders-seek-to-allay-fe...


> This Doctor in NY seems to have had great results so far https://www.thegatewaypundit.com/2020/03/stunning-ny-doctor-....

Let's stick with legitimate news sources.

Either way no data is provided there, but the case fatality rate for folks under 10 is 0% and under 29 is between 0.1% and 0%. If this hypothetical doctor even exists, it wouldn't be hard to pick 350 people, give them some HCQ and Azithromycin and have 100% of them recover -- as they would have even if they hadn't received anything. That's more or less what this study shows.

In fact, as the fatality rate for under-29s is 0.1%, you have a 70% ((1-0.001)^12) chance that any randomly selected 350 of them will recover.


I don't really know what point you're trying to make here. Neither doctor would come anywhere near my list of experts. The real experts are highly critical of both those offering miracle cures and public health people who are slow to respond.

There are dumbfucks with MD after their name too, unfortunately.


Would you mind linking a couple here that are worth a follow?

Even better, I have a very carefully curated list: https://twitter.com/i/lists/1239639611694911489

Every single person on this list is brilliant at what they do and a good communicator, with excellent s/n in their tweets. I've also removed people (like Jeremy Konyndyk, who otherwise I would recommend highly) who have a lot of insight but also a high emotional tone or a tendency to lean into politics. I've also tried to represent a wide range of expertise, from immunology to sequencing-based virology to public health specialists to frontline ER doctors.

So it's as close to a golden source of information as I could make it. I hope it's useful to some people, though I know the reach of it is a tiny fraction as if I made some dumb clickbait that happened to go viral.


Thanks!

Wikipedia style is unreliable. I'm aware of quite a few errors. Why I don't fix them then? Because my edits would be reverted. Or because the page has been locked.

Academic literature in contrast, has multiple parallel journals. If one is suppressing you, you can go to the next. Of course if you go to a less reliable one, then people might not trust your research.



> That was a first run trial without the Zpak. The following trial with both showed 100% efficacy after 5-6 days.

Is that twitter reply accurate?


No, that trial has some glaring flaws. Several threads go into them way better than I could.

https://twitter.com/GaetanBurgio/status/1241201751916568576

https://twitter.com/MicrobiomDigest/status/12414295448478638...


Thank you for the links! I didn’t know about those gremlins in the supplementary info. Hopefully the WHO trials recently announced will give us a better answer soon.

Both trials have glaring flaws: they're tiny.

What's wrong with the size of the 30 patient experiment?

The French study? Aside from the fact that it wasn't a randomized study and 6 patients dropped out from the treatment group (1 died, 3 went to ICU)?

30 patients would be statistically significant. Problem is that they were non randomized, open-label, and they seemingly discarded some of the bad results. They also measured viral load, not cure, and the measurement was not done correctly in all cases.

It's basically a "there could potentially be a causal link here; needs way more research" type of study.


30 was the size of the study in the linked tweet.

In late January 2020 during the 2019–20 coronavirus outbreak, Chinese medical researchers stated that exploratory research into chloroquine and two other medications, remdesivir and lopinavir/ritonavir, seemed to have "fairly good inhibitory effects" on the SARS-CoV-2 virus, which is the virus that causes COVID-19. Requests to start clinical testing were submitted.[43] Chloroquine had been also proposed as a treatment for SARS, with in vitro tests inhibiting the SARS-CoV virus.[44][45] However, at least one case of self-medication with chloroquine for COVID-19 has caused a fatality, and the Nigeria Centre for Disease Control has stated that such self-medication "will cause harm and can lead to death."

Chloroquine has been recommended by Chinese, South Korean and Italian health authorities for the treatment of COVID-19.[47][48] These agencies noted contraindications for people with heart disease or diabetes.[49] Both chloroquine and hydroxychloroquine were shown to inhibit SARS-CoV-2 in vitro, but a further study concluded that hydroxychloroquine was more potent than chloroquine, with a more tolerable safety profile.[50] Preliminary results from a trial suggested that chloroquine is effective and safe in COVID-19 pneumonia, "improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course."[51] Self-medication with chloroquine has caused one known fatality.

https://en.wikipedia.org/wiki/Chloroquine#COVID-19


Thank goodness that we are actually getting some RCT results. There has been a huge confirmation bias towards any positive results for chloroquine, no matter how specious or flawed the underlying science was. Everybody wants this to work because the drug is well-tested on humans, cheap, and broadly available. It would be a panacea, a miracle drug. My concern is that the desire for this drug to be effective has clouded people's judgment (even seasoned researchers) and led to bad science.

>It would be a panacea, a miracle drug.

Not really, a panacea is a drug that cures everything. If chloroquine was found to be an effective antiviral, it would only be a drug that cured two things. That's common enough to not warrant excessive skepticism taken alone.


While that may be the precise definition of a panacea, the vernacular definition is a breakthrough or unexpected good thing.

This study really isn’t sufficient proof for anything. Not even weak evidence. We need far better studies before deciding to give up on a drug.

It is definitely orders of magnitudes better than that flawed French study.

Don't forget the time pressure. It's a real balance act. The ideal panacea would be an already approved drug that is easy to manufacture, scale and distribute.

If fighting covid means we need new drugs then we look at a long development time that will likely stretch the availability of a therapeutic behind the availability of a vaccine.

Obviously everyone knows that these things are needed NOW, all bureaucratic road blocks are removed save the really important and necessary ones. You cannot just hand out a drug to millions of people or inject them with vaccines without thoroughly testing their safety first.

Imagine if the "cure" to covid was long term harmful in a broad population, e.g. it affects 5% of the people negatively. The health, societal and economic impact could wipe the floor with covid.


It's two samples of 15. 13/15 and 14/15 successes. Much too small to draw any conclusions. It's even noted a larger sample size is needed

Wait. I thought that hydroxychloroquine was hypothesized to protect against wet lung, as an anti-inflammatory, and not as an antiviral.

Did I just make that up?


No, HCQ is the Antiviral. Anti-inflammatories are also in the plan, but not Iboprofen.

Not exactly. HCQ has anti-inflammatory action as well as immune moderating action [1] the latter of which may help protect against cytokine storm which occurs in some serious COVID-19 infections. It also has antiviral action in some situations but it's not clear that that's actually relevant to COVID-19 yet.

[1] https://en.wikipedia.org/wiki/Hydroxychloroquine


Thanks. Upon reflecting, I meant to say immune moderating as well as anti-inflammatory. Which is why it's become so popular for treating arthritis.

I wonder about the antiviral activity, though. What I've read is about possibly faster drop in virus levels. And I suppose that HCQ could be interfering with some stage of intracellular virus production. But time will tell.


You're mixing it up: CQ Phosphat is the rheuma/arthritis treatment, HCQ Sulfat the malaria prevention drug. CQ has much more severe side-effects, esp. in blacks. HCQ can lead to temporal blindness after years of use. We are talking 10 days here.

Not unexpected. A week or two ago a Chinese treatment protocol made the rounds where hydroxychloroquine was suggested as an alternative to HIV protease inhibitors. Since we now know that ritonavir/lopinavir doesn't work well, one wouldn't expect hydroxychloroquine to do any better. If it had remarkable clinical effects it would be the first-line treatment.

This is evidence; it isn't great but it also isn't conclusive. We'll need to wait longer for something a little more decisive. A twitter link is also unhelpful because we only get a blurry abstract to go off.

The happy dream is maybe hydroxychloroquine has prophylactic tendencies since it is something people can take long term to be at a substantially lower risk vs catching COVID. The abstract doesn't really show much either way on that front.

Spitballing as an amateur, I suspect once someone has actual symptoms or is verging on a serious case it is too late to help - what is a drug supposed to do, regrow a busted lung? It comes to a point where the virus isn't what is killing you, it is the damage the virus did while breeding and/or the immune system overreacting fighting back and going haywire. Antivirals should help but aren't expected to be magic for either of those things.


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

https://swarajyamag.com/insta/covid-19-india-recommends-hydr...


> The happy dream is maybe hydroxychloroquine has prophylactic tendencies since it is something people can take long term to be at a substantially lower risk vs catching COVID.

It's an immune system inhibitor, so this seems like a bad plan.


> It's an immune system inhibitor, so this seems like a bad plan.

Not unless the cytokine storm is what ends up killing the patient in the end.

https://www.vox.com/2020/3/12/21176783/coronavirus-covid-19-...

Then it may be a good idea. The immune system is a very complex _system_ so some parts may be active and some parts suppressed at the same time and that may be what’s need for the fastest recovery.


often times your immune system kicking into overdrive is what kills you — not the virus itself.

It seems like the study was conducted on the complete wrong set of patients.

The reported dosage is less than half what the Chinese Government recommends (500mg x 2 (BID)). So it's possible that they didn't hit the effective dose. https://medium.com/@balajis/the-official-chinese-government-...

your link is to chloroquine phosphate, which has a phosphate group and is only like 75% chloroquine by weight. So no, not less than half. Moreover, you are trying to compare a hydroxychloroquine dose with a chloroquine phosphate dose (active ingredient is chloroquine, not hydroxychloroquine), which is any one's guess if they even have the same mechanism of action here. Just because they both work against malaria, doesn't mean much about this virus. All in all, it is nearly useless to compare the chloroquine phosphate dose and outcomes to the hydroxychloroquine dose and outcomes.



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