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More Small Molecule Clinical Data Against Covid-19, As of April 16

There are several clinical trial updates for today – some that have reported data, and two that are apparently never going to report at all.

I refer to trials of Gilead’s remdesivir in China, one for moderate cases and one for severe ones, both of which were updated yesterday to “suspended” on That took people by surprise, and Gilead’s stock dropped in response. Both trials have the notice: “The epidemic of COVID-19 has been controlled well at present, no eligible patients can be recruited”. Now that’s interesting, and the first thing to note is that these were not trials that had been initiated by Gilead themselves. Here’s the company’s list of remdesivir trials, and these are the ones shown as initiated by Chinese health authorities, the ones coordinated by the China-Japan Friendship Hospital. For their part in these, Gilead contributed remdesivir at no cost and advised on trial design (both were randomized, double-blinded, and placebo-controlled).

But that means that these same authorities were responsible for suspending the trials, so what are we to understand from that? Many analysts have speculated that if the data were better for the drug that this wouldn’t have happened, and we can’t rule that out. But I also wonder about the explanation that no eligible patients can be recruited. Has the epidemic really receded that totally in Hubei? Or are patients just unwilling, for one reason or another (perhaps it’s the placebo control), to join these trials?

Update: I’m told that one big issue was the stringent inclusion criteria for the trials – apparently patients had to have no previous therapy with any other experimental agent to enroll, and that eliminates a *lot* of people.

According to the listings, the severe-patient trial had been enrolling patients since the first week of February and shows an Actual Primary Completion Date (the date on which the last patient received a trial intervention) of March 30, and an Actual Study Completion Date (the date on which the last patient had data collected) of April 10. So it would seem, at least from way over here, as if they had collected a fair amount of data (I have seen a figure of 237 enrollments out of a target of 300 patients) which makes you think that the speculation about lackluster effects might not be completely off the mark. Could they have unblinded right after that last data collection and decided that there was nothing to go on with? That seems like a quick decision, if so, but these are strange days. At any rate, given that remdesivir has not shown any particularly compelling data so far, I would say that people who have their hopes up for it should update to a new posterior probability, as the Bayesians say.

And while we’re on the topic of updating one’s expectations, there are more studies of hydroxychloroquine to review. This one (a multicenter effort from China) is randomized and has a control group, although it’s open-label. 75 patients received standard-of-care, while another 75 received that plus a loading dose of 1200 mg HCQ/day for the first three days, followed by 800 mg qd for two weeks (or three weeks in severe cases). Patients were 18 and over, were checked by upper respiratory swab (RT-PCR assay) for viral RNA on admission to the trial, and again at days 4, 7, 10, 14, 21 and 28. The primary endpoint was the rate of negative swab tests at day 28, and the secondary endpoints were negative tests at the earlier time points, improvement rate of clinical symptoms within the 28 days, and normalization of C-reactive protein (CRP) and lymphocyte count within that same period.

That primary endpoint was not met: the number of negative tests at the 28-day mark was statistically indistinguishable between the two groups at the 28-day mark (both in the mid-80% range). Post hoc analysis did not identify any subgroups that showed a difference, either (age, gender, obesity, pre-existing conditions, severity of disease, etc.) As for the secondary end points, (1) the rates of negative conversion at all the earlier time points were indistinguishable as well, (2) the rates of alleviation of symptoms between the two groups were likewise indistinguishable at 28 days – a post hoc analysis controlling for dosing of other anti-viral agents suggested more improvement in the HCQ group, but this did not reach statistical significance, (3) reduction in CRP and lymphocyte values seems to have been slightly more rapid in the HCQ-treated group (the two diverged a bit around day 8, although the two groups became were back to indistinguishable by day 14). In other words: no significant differences were seen with hydroxychloroquine treatment. There were no significant adverse events during the trial, but nothing that was apparently helpful, either. I have to congratulate the team that got this study working under what were very difficult conditions and their ability to coordinate so many testing centers. I’m sure that they would have wanted more exciting results, but the data are the data, and they’ve done valuable work by collecting it.

The second study is from France. It’s a retrospective one, not an intentional clinical trial, so keep that in mind. The team went back through the recent records across four French medical centers to compare 181 total coronavirus patients who were receiving oxygen as part of their therapy. 84 of these received hydroxychloroquine (600mg qd) and the other 97 did not; standard of care of the two groups was otherwise similar, as was their severity of disease. The composite primary endpoint was transfer to an ICU within 7 days or death from any cause, and a secondary endpoint was the development of acute respiratory distress syndrome (ARDS).

There were no statistical differences between the two groups in that primary endpoint, unfortunately, nor in the rate of developing ARDS. Meanwhile, 8 of the HCQ-treated patients had electrocardiogram changes that required them to be taken off the drug. The authors conclude that these results “do not support the use of HCQ in patients hospitalised for a documented SARS-CoV-2 pneumonia”.

Next up is another retrospective study from Guangzhou and Hong Kong, examining the records for 284 consecutive patients admitted in Guangzhou. 89% of them cleared viral RNA by day 21 overall, but there was no effect seen when examining any subgroup of antiviral treatment: oseltamivir (which one would not expect to work, a priori), arbidol (which to my knowledge has never shown activity under any controlled conditions, to the point that its Russian manufacturer seems to have actively avoiding such studies), the lopinavir/ritonavir combination (which has since failed at least two controlled coronavirus trials). . .and chloroquine. No effect. 43% of the patients received none of these drugs, while the others had them singly or in various combinations, but nothing differed from the supportive-treatment-only group.

Now, there are many more trials underway, and I very much look forward to their readouts. But when you look over the actual controlled data that we have so far for hydroxychloroquine, those previous links plus what we have today, the case for the drug is not encouraging at all. There is one small trial (from China) that showed some positive results, and data from China, Brazil, and France that show no benefit for either hydroxychloroquine or chloroquine itself and (in some cases) evidence of actual harm. The trials that are yet to report are going to have to start showing some strong positive effects if this story is going to have a good ending.

I get plenty of email and Twitter static to the effect that I’m favoring on-patent compounds like remdesivir over cheap generics like hydroxychloroquine, so let me reiterate the point I made earlier in this post: remdesivir isn’t looking very impressive, either. There is as yet no reason to recommend its use in the Covid-19 epidemic, either, as far as I’m concerned, and its ongoing trials are going to have to really look different from what’s come before, too. Honestly, at the moment, I don’t see any small molecule antiviral therapies that have much to recommend them based on the evidence in hand. Let’s hope that changes; there are quite a few being evaluated, and we really could use some encouraging data.

And while we’re mentioned email and Twitter static, the number of people who are telling me that I need to believe Dr. Raoult and the Marseilles group and that we need to immediately give everyone hydroxychloroquine, well. . .they’re beyond counting. But here’s how it works: if you come across an interesting, unusual, or potentially useful result, you then have to subject it to more and more stringent tests under different conditions. Something real will be able to pass some of these. You’ll get information and guidance from seeing when the signal is there and when it isn’t. But there are huge numbers of flickering, fluttering, hazy results that just seem to evaporate when you put the magnifying glass on them, though. Every time you zoom in, every time you give them the tiniest hurdle to jump over, they vanish. That is generally the sign of something that just wasn’t real to begin with, and the more different conditions that something fails to rise to, the more times it fails to show up, the greater the chances that it was a mistake or an illusion all along. This happens all the time in science, and in biomedical research in particular. You get used to it as a researcher. If you take every result at face value (particularly every startling result) and run with it before seeing how robust it is, you will spend your career chasing shadows. And boy howdy, are there ever a lot of shadows.

So to the people who keep insisting that one therapy or another is clearly, obviously working and why isn’t everyone using it, what’s wrong with all you people. . .well, the problem is that not many folks who practice medicine or who do medical research actually think that anything is clearly working yet at all. The data detailed in this post today are why they think that.

106 comments on “More Small Molecule Clinical Data Against Covid-19, As of April 16”

  1. Anon says:

    Thank you for continuing to be a voice of reason in these times of hyperbole and disinformation. Keep up the good work!

  2. Gianni's Zaxarioudakis says:

    Remdesivir seems to work decently in rhesus monkeys infected with SARS2.

    1. Anon the 2° says:

      Great. I’m glad that we’re all monkeys, right? But if we were mice it would be better since a lots of medicationsndid actually worked on then.

    2. loupgarous says:

      And restonvirus cuts through crab-eating monkeys like a scythe, spreading as easily as Covid-19 does, but doesn’t do much to people, despite looking just very much like Ebola under electron microscopes and in ELISA assays.

      Animal models like transgenic mice created to simulate human disease processes have shown all sorts of positive results for compounds which failed miserably in human clinical testing.

      1. Giannis says:

        Virus tropism has nothing to do with a drug being effective or not. Time and time again virologists make the claim that giving the antiviral drugs as soon as possible increases their effectiveness. In our attempt to save the most vulnerable (people in ICUs) we forget simple biological facts about how antivirals work. Hopefully there are pre or post exposure prophylaxis trials with remdesivir. I will be very surprised if it doesn’t perform very well in these cases.

        1. David Young MD says:

          I have the same sentiments. For the life of me, I don’t know why the NIH or Gilead has not offered a trial of Remdesivir in patients who have just become infected. Those who are not yet ill enough to be hospitalized. Like other antivirals, you would think that Remdesivir would have its best chance in early disease. I recognize that there would be some issues. One, is that infected individuals would have to come into a clinic daily and break their quarantine at home (since these patients are not yet sick enough to require hospitalization) to get the intravenous Remdesivir. Along with this, an outpatient clinic or infusion center would have to set aside an area, or the whole clinic to accommodate these contagious patients, and other patient who normally use that infusion center (for iron infusions or chemotherapy) would have to go elsewhere. And you would have to look for motivated patients who would come in despite not (yet) being very ill. You would have to employ nursing staff who are brave enough to wear extreme protective covering to start the iv’s and infuse Remdesivir. You might also explore other drugs, such as Favipiravir. And you might consider having an arm of the trial have a combination of Remdesivir and Favipiravir, even if the dose of Remdesivir was a little less in the combination arm. If you had a four armed study, with one being placebo, people might be more inclined to volunteer to participate. (The idea of combining drugs like this, in my opinion and experience, is an extremely foreign one to the NIH and the FDA, but it makes perfect sense to me). I think such a study can be done, and if it were opened at 150 sites could accrue 800 patients in a week, if done right. This study should have been started 5 weeks ago, but like so many things in this epidemic, everyone is late to the party (so to speak).

          1. loupgarous says:

            Seen this yet? “Early peek at data on Gilead coronavirus drug suggests patients are responding to treatment” By ADAM FEUERSTEIN @adamfeuerstein and MATTHEW HERPER @matthewherper APRIL 16, 2020

            “A Chicago hospital treating severe Covid-19 patients with Gilead Sciences’ antiviral medicine remdesivir in a closely watched clinical trial is seeing rapid recoveries in fever and respiratory symptoms, with nearly all patients discharged in less than a week, STAT has learned… .The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir. “The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.”

  3. Brian says:

    And this folks, is why we do clinical trials. Hopefully something good comes out of future trials, but so far we’ve got nothing.

  4. pol_pry says:

    Thanks for the informative post, Derek.
    I wonder if we’re in for another mudwrestling match in the commentary section, as seems to happen every time the ‘quine is mentioned.

    1. Derek Lowe says:

      Of that I have no doubt whatsoever.

    2. eub says:

      These comments sometimes have discussions about: why don’t we drop this Phase 3 efficacy barrier — it filters out so much, surely there are good drugs in there — and have the FDA certify for safety only, let prescribing MDs make their own informed decisions like for off-label.

      Current circumstances are surely a data point of some kind, though I’m sure complete consensus shall not be reached on just what kind.

  5. Chris Swain says:

    The problem is people will continue to pour money into trials that offer no significant benefit.

    1. The guy says:

      That’s all we ever do. It’s how we learn. What’s your point?

    2. loupgarous says:

      Negative results are still results, and still pay a benefit to those who are casting about frantically for cures to a deadly disease. Too many people want to dispense with the trials and conduct grisly experiments with drugs you can only justify giving to others if they can help the patient who gets them.

      After 100 people died after taking a poisoned antibiotic syrup sold in the late 1930s, Congress passed the Food, Drug and Cosmetic Act to require drug manufacturers to test their wares for safety. It took 24 more years for the Kefauver-Harris amendment to the FD&C Act to require drug makers to show their drugs actually worked – to treat a disease or restore lost health.

      Too many people don’t see the need for all that.

    3. Wilhelm Cody says:

      Yes. Perhaps next up will be testing these drugs on Alzheimer’s patients: that should work, right?

      1. Charles H. says:

        Well, to be fair, since there is no believable model about how Alzheimer’s works, that isn’t unreasonable in an of itself. It’s just horribly expensive, extremely time consuming, and there’s no particular reason to believe it would work. But given the results so far from attacking the plaques, it might have just as good a chance.

        In the case of Alzheimer’s I think the only reasonable thing to study is “how does it work?”. And the mouse models appear worthless.

        OTOH, I’m a programmer, not a biochemist, so take my opinions with a large tablespoon of salt.

    4. Hap says:

      Sometimes, you have to try and see – only then do you actually know (if you’ve powered the study enough). Occasionally, trials are made to deal with things that people think are cures that may or may not be – and the trials will only be effective will if they get good data and if the trials’ targets aren’t immune to data (a disease which seems to have no cure). If everyone knew what would work, it wouldn’t be research.

  6. Jeong Yeob Kim says:

    Sobering to say the least. Coupled with the US antibody testing setback and the general lack of testing (or even a national US plan) has convinced of one thing: my home will continue to be my ark until I see an olive leaf. Thank you for your work, Derek!

  7. Eric says:

    I’m a little surprised by your take on Remdesivir. In earlier posts you were encouraged by the in vitro and preclinical in vivo data. The compassionate use data came out and was difficult, if not impossible, to interpret without a control group. I certainly didn’t view it negatively. To me it looks like it has potential and we need a RCT to know if it works. How has that changed from before the compassionate use trial was published?

    1. Derek Lowe says:

      We have RCTs coming, and I’m very glad of it. But I think that some folks can already start adjusting their estimate of the effect size from what we’ve seen.

      1. Eric says:

        Fair enough. I don’t think most of us in industry ever thought it would be a massive effect size. That may not be true for the general public. I’m still optimistic it will have some benefit. As always, I keep my fingers crossed when projects get to the clinic.

  8. loupgarous says:

    The replies I’ve had in Twitter this morning where I talk about the need to find whether chloroquine and/or hydroxychloroquine even work remind me of the aftermath of World War Three in Walter Miller’s A Canticle for Leibowitz:

    “Simpletons! Yes, yes! I’m a simpleton! Are you a simpleton? We’ll build a town and we’ll name it Simple Town, because by then all the smart bastards that caused all this, they’ll be dead! Simpletons! Let’s go! This ought to show ’em! Anybody here not a simpleton? Get the bastard, if there is!”

    Clinical trials, the things that keep unscrupulous snake-oil peddlers from hawking killer miracle cures made with sulfanilamide and propylene glycol are being demonized along with those of us who speak up for them.
    Another quote from A Canticle for Leibowitz comes to mind, no particular politician in mind, this shoe fits a legion of feet:

    “Ignorance is king. Many would not profit by his abdication. Many enrich themselves by means of his dark monarchy. They are his Court, and in his name they defraud and govern, enrich themselves and perpetuate their power.”

    1. Derek Lowe says:

      That is a terrific book – I remembered the first quote, but had forgotten the second one.

      1. loupgarous says:

        Tthe second quote is part of Thon Taddeo’s speech at the festive dinner at the Abbey. It’s not a sympathetic speech, being aimed obliquely at Dom Paulo and the brothers of St. Leibowitz, and foreshadows the murderous expansion into the Southwest of Taddeo’s cousin the Mayor of Texarkana (and Grand Vaquero of the Plains) Hannegan. Dom Paulo reminds Thon Taddeo, afterward, that Hannegan signs his proclamations with an “X”.

    2. Shazbot says:

      I think a good angle to help make peace is to repeat how broad testing involves giving lots of people the substance. It’s not hiding it, it’s providing advocates of the drug their best ammunition for responding to skeptics. It’s not burying it where nobody will see it, it’s putting it on an elevated stage where it’s front and centre, right in plain view.

      If it works, it will work in public, and all the conditions that go into a trial are also ways to prevent people who don’t like the drug from fudging the numbers. Control groups give something to compare to, randomization and blindness prevents people from picking favorites and sinking the project.

      The clinical trial is an extremely useful tool for people who think a drug will work, not just those who are more skeptical.

      So work with those. You think someone’s playing games with the data? Well, prevent that from happening by having the people who deliver it not know the information necessary to game the data.

    3. eub says:

      Man, I haven’t read that book since I was… many ages younger. To be frank I think it was in the teen libertarian stage. Checked out the ebook to read it again; I expect it will be stepping in a very different river.

      1. Teve says:

        I remember those years well. As long as there are young healthy white males with little understanding of economics or history, there will always be libertarians! 😀

  9. Grateful says:

    This blog is so important right now and I want to thank Derek and all intelligent contributors in the comments for your hard work. Derek has clearly came to the table ready with data and analysis. This is a great resource. We all appreciate it!

  10. steve says:

    If you look at the history of antivirals (e.g., Tamiflu) they are only useful early on in an infection. The damaging sequelae are due to an over-exuberant inflammatory response, not so much from viral replication. Anti-IL-6 drugs like Actemra, Bruton’s kinase inhibitors like Calquence, etc are going to be more helpful later on. They may need to be paired with an antiviral to prevent reactivation of viral replication due to immune suppression but the antivirals are unlikely to be very useful for patients in ICU where it’s the cytokine storm that’s killing them.

  11. steve says:

    BTW, you might be interested in how Calquence is being given in the ICU. Since it is normally a capsule AZ had to figure out how to deliver it to patients who are intubated. Their solution? Dissolve it in CocaCola. You heard me. That’s the first time I’ve ever seen that particular formulation used.

    1. Inquiring Minds says:

      The solution is a solution, then. But why CocaCola, specifically? Wouldn’t any other fizzy drink perform just as well?

      1. Some idiot says:

        Probably a pH effect. My understanding is that Coca Cola is a lot more acidic than most other soft drinks, but I have no data on it…

        1. steve says:

          That’s actually the explanation AZ gave in the PR I read

          1. Some idiot says:

            Ah… Thanks! 🙂

    2. Robert R. Fenichel says:

      I don’t know of another example of Coca-Cola as a vehicle, but when N-acetylcysteine was developed as a treatment of acetaminophen poisoning, it was mixed with Fresca to make it more palatable, and mixtures with Fresca became (and may still be) the standard home-brew formulation administered to patients.

    3. Pp says:

      Yes… i also heard that using Pepsi led to lower bioavailability… 😱

  12. loupgarous says:

    You could try Schweppe’s Tonic Water and get some quinine in there, too.

    1. Some idiot says:

      And with that one, you win today’s comments prize…! (-:

    2. mymagoogle says:

      winner winner chicken dinner!

    3. Rich Stern says:

      Very nicely played!

    4. Covidiot19 says:

      Do other, generic versions of tonic work as well?

  13. Rock says:

    Derek won’t say it to keep his Twitter static from escalating, but it is our ignorant president and his sycophants who are peddling “intuition – based” treatments. For the good of the country, these briefings should not be televised.

  14. Sharkbite says:

    This all sounds familiar – “I knew that there was no real evidence that anything we had to offer had any effect on tuberculosis, and I was afraid that I shortened the lives of some of my friends by unnecessary intervention.” Archie Cochrane, the father of evidence based medicine

  15. JasonP says:

    I’ll start the mud wrestling…

    YOU SEE! Those studies are all flawed because EVERYONE KNOWS that HCQ alone is not the cure! HCQ has to be paired with Zinc, since EVERYONE KNOWS that HCQ’s mode of action is an ionaphore and without sufficient Zinc, replication can not be stymied in the cell. Go back and do the studies again! We’ll wait for the studies that “were done right” with HCQ and Zinc.

    Oh WAIT! Maybe we need the French scientist’s cocktail too? Where is the Z-Pak?


    Appreciate the clarity provided by this post and can only hope that others can appreciate it and learn from it too. Learning requires asking questions, not postulating “known facts” and opinions. When the student is ready the teacher will appear. Hmmmm.

    1. deoWER says:

      Can you please point me to any sources which explain why the “zinc ionophore” theory is not legitimate? I’ve been asking people this for the past week or two in the comments, yet no one seems to have any responses.

      1. rosie says:

        Hi deoWER, I couldn’t find zinc data for hydroxychloroquine, but I could find some for chloroquine. Here’s the paper:

        “A2780 cells were treated with 100–300 µM chloroquine in the presence of increased concentrations of zinc chloride for 1 hour…… However, when chloroquine was added to the culture medium intracellular zinc levels were dramatically enhanced (Figure 2A), indicating that chloroquine acts as a zinc ionophore.”

        I could only see chloroquine levels as low as 10 uM in this reference. I believe hydroxychloroquine plasma levels from historical treatment data are between 0.1 – 1.0 uM. Perhaps this is one of the sources of skepticism. If you can find hydroxychloroquine data please post it, thanks.

        1. deoWER says:

          In this paper “Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture” ( they used pyrithione as the Zn ionophore instead of a chloroquine compound. They saw inhibition of the viral polymerase at 2 micromolar.

          I’ve also posted a separate comment on this page with more links, including current clinical trials exploring the zinc+HCQ treatment.

          1. rosie says:

            thanks, that is interesting. I believe what is lacking is data that demonstrates hydroxychloroquine is indeed a zinc ionophore at typical plasma concentrations (0.1 – 1 uM). The reference I found only gives data down to 10 uM, and for chloroquine, not hydroxychloroquine.

            Based on this, I don’t see how hydroxychloroquine would be useful to import zinc (did the authors not report data on concentrations < 10 uM because they saw no effect?). Your pyrithione data seems more useful.

      2. Henk says:

        It is a bit strange to be promoted miracle cure A. And when tested, it doesn’t work. Oh, but you were doing it wrong, it is A+B, obviously. And when that trial is over it will be A+B+C, obviously!
        Point is that one can come up with ever so many new points of misinformation.
        And for this kind of talk I’d expect in-vitro proof first.

        1. deoWER says:

          There are links to in vitro studies in my comment directly above yours.
          And no, I had never said that hydroxychloroquine was the miracule cure. I (and a number of others here) have been saying all along that its mechanism of action might involve zinc, and thus that’s why the data from the “only hydroxychloroquine” studies might be so variable.

    2. x says:

      What’s interesting to me is that the “HQ WORKS!”, the “BUT ZINC!”, the “BUT AZ!”, and the “BUT DOSE EARLY IN THE COURSE!” people all have some rather limited overlap on an imaginary Venn diagram – meaning that many of them are giving different, and somewhat contradictory, excuses for why multiple studies are showing no real beneficial effect from HQ. If they were really on to something, they ought to have the same explanation.

      Perhaps, like many religious folk throughout history, they’ll just start synthesizing all the excuses into one common superexcuse. I wonder how long it will be before they insist that it needs to be given by a doctor standing on one leg while the patient recites the Lord’s Prayer twice.

      Meanwhile we’ve got people claiming that they take quercetin regularly, and they’ve never gotten COVID, or drop bears either.

      These comment sections over the past couple of weeks have been a grim illustration of why we have controlled trials and the scientific method, and how poorly both of those are understood by a population that reads a pharma chemist’s blog. I can only imagine it’s even worse in the general population, half of which seems to think that science itself is a political hoax.

      1. deoWER says:

        Absolutely not. I (and many others here) have been saying for a while that the reason HCQ by itself is so variable in its results is because its mechanism of action might involve zinc. This is supported by in vitro studies, for example, like this one: “Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture” (

        (please do a ctrl+F search for my other comments on this page, which contain more links to sources).

        I’d love to be proven wrong on this hypothesis. I have no personal stake in zinc. I have been asking numerous people to explain clearly why they think the “zinc ionophore” theory might be flawed, and have heard no response from them.

    3. Arnaud Tarantola says:

      A lot of stuff works in vitro or in animal models which doesn’t pan out in clinical studies in human patients. There is no extrapolability there, and in vitro results are only a first step and just substantiate theories or don’t.
      That is why research in the clinical setting has to be rigorous (and ethical of course). I’m very embarrassed by some of the work done in France recently and especially by the way it was adamantly defended.
      Maybe HCQ works, with or without zn, with or without azithromycin, with or without … The issue is simply that we don’t have sufficient evidence.
      Except for some politicians’ expert medical opinion, of course.

  16. deoWER says:

    Where’s your writeup on why the “hydroxychloroquine as a zinc ionophore” theory is not valid? Many people have been discussing this theory but it hasn’t been talked about or experimented on much so far. That’s what I and many others would interested in reading about.

    For those who are not aware, hydroxychloroquine (and other similar compounds) have been found to be zinc ionophores, thus helping facilitate zinc intake into cells. Zinc has been shown to inhibit the viral enzyme RNA-dependent RNA polymerase, and thus helps to slow down the proliferation of the virus before it gets to levels that overwhelm the immune system. Commenter JP Leonard has written an article on this with more information and sources: (Look up “Think Zinc: From Game-Changer to Game-Winner against Coronavirus” on Medium. I am not posting links because it seems my comments are getting blocked because of too many links)

    So with this in mind, it seems rational that administering hydroxychloroquine by itself probably isn’t going to deliver that great of results.

    A group in Turkey is doing a clinical trial on using HCQ+zinc as a prophylactic: (Look up “Chloroquine, Zinc Tested to Block COVID Infection” by WebMD)

    And a clinical trial sponsored by ProgenaBiome is looking at the same thing: (Look up “A Study of Hydroxychloroquine, Vitamin C, Vitamin D, and Zinc for the Prevention of COVID-19 Infection” on the website)

    There might be other trials which are also looking at this combination therapy. Once we start getting data from these trials, we can finally decide once and for all whether this theory is accurate or not.

    1. franko says:

      I agree, I have to say I am disappointed. Greater clarity might have been achieved by writing, for example, “In other words: no significant differences were seen with hydroxychloroquine treatment alone.” instead of “In other words: no significant differences were seen with hydroxychloroquine treatment.”

      Just to show an awareness and acknowledgement of the issue, if for no other reason.
      My old boss used to say, when shown a negative result, “You’re not repeating what works.” Meaning, the person did an experiment trying to build on an earlier finding, without including a repeat of the earlier finding that showed the positive result. Its seemingly an obvious point, and yet it is so often overlooked and it is frustrating. When someone reports a negative result, it is meaningless, unless they have repeated the conditions of the original positive finding alongside of their new tests. Because, your new findings may have failed for any number of trivial reasons. You can only be sure your test has not failed for trivial reasons, if you have repeated the conditions of the previous positive findings alongside, so you know that things are working.

      *sigh* Well, the hydroxychloroquine test along with zinc and azithromycin will eventually be performed, but don’t hold your breath. There seems to be a determined resistance to repeating the test under those conditions.

      Once you have repeated the original conditions of the test (hydroxychloroquine test along with zinc and azithromycin), then, if it works, sure, go ahead and repeat it along with an arm with each component alone, and with the components in pairwise combination. Knock yourself out. But be sure to repeat the original conditions each time. Or, to say it again: any negative results will be meaningless.

      Some people are arguing to me it is due to a conspiracy to avoid finding a cure too soon. Personally, I believe it is just stubbornness.

      1. Paul says:

        President Macron has been rather clear to the Marseille group, saying effectively “hold scientifically valid trials or STFU”. He was more diplomatic than that but the message was very clear.

  17. adam says:

    I wonder how much of the trouble recruiting patients in the Chinese remdesivir trials is related to the Chinese government’s insistence that they’ve conquered the epidemic? Between that and the requirement that patients haven’t taken any other experimental drugs, they’re really scraping the bottom of the barrel.

    I suspect they’ll run into the same problem in certain parts of the US, too, if they haven’t already enrolled enough patients.

  18. Daniel Barkalow says:

    My choice of cynical guesses for the remdesivir study is that, whether or not the epidemic has really receded that much in Hubei, the people who were conducting the study have to say it has for political and economic reasons. I’m inclined to say that the reason they gave is the real reason, even if it’s not actually true.

  19. drsnowboard says:

    @JasonP Congratulations, you beat the zinc posse by at least 12 minutes….
    To be honest, someone should do the HCQ+zinc trial because it has more going for it than some of the Alzheimers trials that have crashed and burned over the last 3 years.

    1. deoWER says:

      As I said in my previous comment, people are in fact starting clinical trials to explore this now.

      But, as I’ve been saying in the comments for some time now, why is the “zinc ionophore” theory not legitimate? I’ve seen so many people scoffing at it without giving an ounce of reasoning to back up their opinions. Since zinc has been shown to inhibit the RNA-dependent RNA polymerase enzymes of viruses, does it not make sense that getting higher levels of zinc into cells via ionophores can help slow down the exponential growth of viruses during an infection, and thus prevent the immune system from getting overwhelmed? This is a legitimate theory in my opinion. Why dismiss it? Please, I’d like to hear all the reasoning and logic there is against this theory. The problem is, no one has been able to provide this to me yet here.

      1. David Young MD says:

        Seems like a legitimate idea. Do you have a reference to a laboratory cell culture experiment on Coronavirus infecting cells, and how that differs with the presence of nothing, the presence of Hydroxychloroquine, the presence of hydroxychloroquine and added zinc and added zinc alone. If such a study was done and demonstrated a marked improvement in viral kill with the combination….. well then, you would have something there. Data that would call for a clinical study…. as long as the concentrations of zinc and HydroxyC were within obtainable levels with oral treatment

        1. deoWER says:

          Yes, please search for another comment that I posted on this page. It has several links to current clinical trials exploring this along with a short summary paper on the zinc theory.

        2. deoWER says:

          Here’s another one:
          “Zn2+ Inhibits Coronavirus and Arterivirus RNA Polymerase Activity In Vitro and Zinc Ionophores Block the Replication of These Viruses in Cell Culture” (, they used pyrithione as the Zn ionophore instead of a chloroquine compound.

        3. R. Toffey says:

          There is prior research in 2010 that shows that the Zinc 2+ ion prevents the replication of coronavirus in vitro.

          It is also known, however, that in actuality Zinc cannot traverse the cell wall boundary.
          It needs to “ride on” a vehicle to penetrate through the cell wall. That vehicle is called an ionophore. It is known that HydroChloroquine is an ionophore for Zinc. It is the Trojan horse that will carry the Greek soldiers into Troy. By itself, hydrochloroquine is not a cure. It’s value is only as a Trojan horse for Zinc.
          In the French experiment, it is possible that the people of Marseilles already had high Zinc levels in their blood due to eating oysters and mussels. The fact that the French experiment used Hydrochloroquine threw everyone including President Trump for a loop, causing them to believe that Hydrochloroquine is the cure. It is not. It is merely the Trojan horse for zinc to get inside the cell.
          The appropriate study today should be Remdesivir VS Zinc, since the former claims to do what the latter does.

    2. JasonP says:

      @drsnowboard…..funny you should mention crashed ALZ trials as, while I am inhaling Clove Bud Essential Oil (eugenol ) dispersed on my mask, I have been reading with much interest, these stories about research in the field.

      I recall a point being made that even failed trials have something to offer and deeper analysis is often where the learning commences. Looks like an OLE may show that AB antibodies might have cognitive benefit over a longer time frame. ( A disease that builds over 10s of years apparently takes more than a one-time treatment by a silver bullet to fix. Seems similar to what have we seen as to the “mean recovery time” of brains “healing” from chronic Opioid addiction? Certainly not “cured” in the standard 1-2 week detox period.) But alas, an OLE won’t be enough to get drug approval, another gold standard test will be needed.

      Of note, the secondary biomarker improvements they sure look like the biology is being effected. So a drug trial is only as good as its end points indicate? So AB antibodies failed to have cognitive benefit. Why then did these people waste their time digging deeper into the data? Gold standard failed – NEXT! {this approach is why it is hard for many to understand and accept “the process” methinks?}

      But that third paper points in an interesting direction. Is it possible the “cure” is more than one drug? Clear out the garbage, slow the inflammation storm and (the horror) boost Neurogenesis and help the brain recover from a long disease state?

      Hopefully the DIAN group will get around to multi-therapies sooner that later. er, SARS-CoV2/COVID-19 permitting.

      Time to switch over to the Hinoki Cypress Essential Oil, followed by a good Sauna bath and 8-hrs of sleep!


      Let’s not tire of efforts to educate/teach. What was that an old teacher said about patience?

      1. James Carlson says:

        Interesting you mention Hinoki Cypress Oil, it looks like the extract, Hinokitiol, is being explored by the “Dr ZinX” brand as a potential anti-viral oral spray with Zinc.

  20. Michael Wall, MD says:

    Anything new on Leronlimab?

  21. Calvin says:

    Worth noting that there has been much made of Remdesivir’s failure in Ebola. I think what people have to remember is that study was against SOC (ZMapp). The endpoint was mortality, so as brutal and endpoint as you can get. Remdesivir was pretty much on a par with ZMapp but not as good as the two other antibodies. Mortality in the Remdesivir arm was about 50%. The only problem is that mortality in Ebola is pretty broad (20-90%) so there is a chance that none of these compounds worked. But I think the general consensus is that mortality, on average, in a resource poor setting is generally in the 70% range.

    What was surprising is that Remdesivir was absolutely stellar in the preclinical models, including primates but in the clinic wasn’t as good. That surprised a lot of people.

    An earlier commentator pointed out that anti-virals tends to be best early in infection rather than later once the immune system gets over excited. I think that is correct in acute(!) viral infections (HIV, HCV are different). So I still think it will work in moderate disease but is going to be less effective in severe disease. If this is anything like RSV or flu, a one log reduction in peak viral load is all you need to see a better clinical outcome. I’d be surprised if we did not see some efficacy from Remdesivir. But it’s not going to be a perfect hit. 30%-50% efficacy in moderate disease is all we might see. I’d take that. And if it could prevent moderate disease progressing to severe it will be a really big deal.

    The trial withdrawals in China don’t change much as we still don’t know what the results are and it does seem that new cases in China have really gone down. Or it could be a Chinese state plot to make it look like things are better. Depending on your levels or paranoia.

    I remain highly skeptical of all the immune modulatory approaches. Likewise I think host targets are an appealing fantasy; a mirage in the desert if you like.

    1. Charles H. says:

      It’s not unreasonable to assume that China is starting to refuse to talk to anyone outside while it’s being assailed by people looking for scapegoats. That’s perfectly normal behavior among people, and even more among bureaucracies.

      Unfortunately, this isn’t very helpful. In fact my first thought when I say that the trials had been canceled was that “O, China’s upset that people are calling it names.”. This may not be correct, but it’s certainly plausible.

      As a result I can’t draw ANY conclusion from those cancelled trials, including that the results weren’t spectacularly good.

  22. emba says:

    ‘. . .well, the problem is that not many folks who practice medicine or who do medical research actually think that anything is clearly working yet at all. The data detailed in this post today are why they think that.’

    I think this should be stated more carefully. There *do* seem to be folks who practice medicine (I’ve had to educate two) who *do* think these are working. Credible evidence:

    This is a failure of the institution of medicine. I can’t tell if it is catastrophic, but it is very troubling.

    ‘In the end, the hype over these drugs and particularly the rush by doctors on the flimsiest of evidence to make hydroxychloroquine, in essence, a standard of care, have shown just how weak most doctors’ allegiance to evidence-based medicine is and represent one of the most massive failures of EBM that I can recall.’

  23. nobody says:

    My apologies, this isn’t a particularly related comment, but I’m wondering what the general feeling is on the likely timeline for a COVID-19 treatment vs. a vaccine. Is it reasonably probable that improved treatments will be widely available substantively before a vaccine is ready for mass deployment or will the timelines be generally similar i.e. around two years?

    1. Henk says:

      I suppose there may be found “something” that takes some sharp edges off the disease. By bending the immune response around perhaps, making the bad cases similar to the average case.
      Antivirals seem to be Hard To Get Working. I wouldn’t count on those.
      OTOH, vaccines are a proven way of working. And even if they might not fully prevent the disease, they may change its course, make is less infective or both.

    2. Sb says:

      believe me finding drugs is just difficult, very difficult if you wish they really work and much more difficult than most people realize……even if you are rich, stubborn, happy, cooperative, narcissist, power player or whatsoever: it remains difficult and downsizing intelligent multidisciplinary research sites by Big Pharma does not help either to find efficacious drugs. I really hope Pfizer, Gilead, J&J etc have still multidisciplinary teams understanding small molecule drug discovery for SARS-Cov molecular targets. Of course everybody hopes for a lucky shot repurposing an existing drug or combinations, but is there a lab on the world where 100 Medicinal chemists, 100 Virologists and 100 supportive scientists work as a multidisciplinary team on a new molecule that really works against SARS-Cov2. If there is not too much administration would take a couple of years and 100M dollars (which strange enough would be considered very costly, because it is so risky!?) for a clinical candidate and subsequently still the clinical trials………brrrrr

  24. Tom Boyer says:

    Thanks again for terrific explanation and perspective. I’ve learned a lot from this blog. If HCQ turns out not to have an effect, it’s fascinating how many patients were fooled into believing they turned the corner after they got what they thought was an effective drug. Did it help them psychologically?

    I think about all the really sick people who are having to battle this thing at home with no approved treatment at all. It can’t be good for them psychologically for the doctor or hospital to tell them — we have no approved treatment for you, you’ll either get better on your own or you’ll come to ICU and probably die here. If the government could advise something innocuous like zinc and low-dose aspirin, would it save lives through psychological benefit alone?

    1. JP Leonard says:

      HCQ and high dose zinc is innocuous enough and the doctors using it claim a 100% cure rate. (More innocuous in fact than NSAID’s according to some doctors who say they are contraindicated for this virus.)
      We can’t seem to get confirmation of this therapy altho this news is 3 weeks old on Fox. However, consider these practicing MDs would lose their license if they were making this up! So why would they talk through their hats?
      One doctor from Maine posted on this blog that he’s being investigated by the licensure board just for talking about zinc for coronavirus! With it being practically illegal to disagree with the CDC on anything what doctor would risk his livelihood going full quack on this?

      1. Arnaud Tarantola says:

        JP Leonard: Because you can be a well-educated MD, but also full of yourself and more generously desperate to help your patients. I should know: I’m a MD, did clinical work a long time ago and now am an epidemiologist.
        As you have some idea of what happens in your patient cohort (most recover) but little idea of what goes on everywhere, you don’t spend a lot of time comparing data with the knowledge of what’s out there.

    2. loupgarous says:

      This is why we run randomized and double-blinded drug studies – because the placebo effect’s powerful, and has confounded clinical trials before.

    1. Another Guy says:

      From the STAT article: “Her comments were made this week during a video discussion about the trial results with other University of Chicago faculty members. The discussion was recorded and STAT obtained a copy of the video.”

      Oh boy …. in the pre-COVID era, a leak like that could be grounds to invalidate the trial.

      Most likely in our current situation, all will be forgiven, as we need the drug .. if it indeed works., which I hope it does.

      1. WantToLearn says:

        Huh? No control arm on the Remdesivir studies?

        From the Stat article:

        >>>Gilead’s severe Covid-19 study includes 2,400 participants from 152 different clinical trial sites all over the world. Its moderate Covid-19 study includes 1,600 patients in 169 different centers, also all over the world.

        The trial is investigating five- and 10-day treatment courses of remdesivir. The primary goal is a statistical comparison of patient improvement between the two treatment arms. Improvement is measured using a seven-point numerical scale that encompasses death (at worst) and discharge from hospital (best outcome), with various degrees of supplemental oxygen and intubation in between.

        The lack of a control arm in the study could make interpreting the results more challenging. <<<

        How does a comparison like this work? Is this another type of study that is valid?

        1. Curious says:

          So why don’t they include a control group from the beginning? It seems like everyone is wasting time by running less ideal experiments.

      2. loupgarous says:

        In the good old days, study sponsors were 483’d for leaks like this.

        Covid-19 didn’t change this, either. The whole history of Sarepta’s exon-skipping drugs for Duchenne’s Muscular Dystrophy has been a litany of leaks, naked emotional appeals, and even at one point, the head of CDER mentioning Sarepta’s stock price while explaining why she overrode an ADCOM to approve eteplirsen.

  25. Ian Malone says:

    A pity for favipiravir/avigan studies too if Chinese trials are now having difficulty recruiting. There were a couple of decent sized studies registered that had an arm with that (one in Hubei I think). There was an early glimmer of an effect (also off patent I think, which right now is probably less relevant than manufacturing cost).

    1. David Young MD says:

      Japan opened a study on Favirpiravir about a week ago. Kind of late, but hopefully it will conducted well and hopefully it will show some benefit.

  26. Frank Schaper says:

    Hi Derek,
    I’m an inorganic chemist, thus completely ignorant of all this messy biochemistry. Thus I am **highly** grateful for your recent posts and recommended your blog to colleagues and students. As we all know: somebody else reading & summarizing the literature for you is absolutely invaluable!

  27. loupgarous says:

    Derek, great column as usual – while reading Reason I saw a story with today’s dateline:

    “Antiviral Is Reportedly Effective in Treating Severe Cases of COVID-19” with the subhead “STAT reports leaked comments of University of Chicago researcher”

    This is the STAT News article in question – covering 125 people recruited into Gilead’s two Phase 3 clinical trials.
    A quote from STAT News:

    “Chicago hospital treating severe Covid-19 patients with Gilead Sciences’ antiviral medicine remdesivir in a closely watched clinical trial is seeing rapid recoveries in fever and respiratory symptoms, with nearly all patients discharged in less than a week, STAT has learned… The entire world has been waiting for results from Gilead’s clinical trials, and positive results would likely lead to fast approvals by the Food and Drug Administration and other regulatory agencies. If safe and effective, it could become the first approved treatment against the disease. The University of Chicago Medicine recruited 125 people with Covid-19 into Gilead’s two Phase 3 clinical trials. Of those people, 113 had severe disease. All the patients have been treated with daily infusions of remdesivir. “The best news is that most of our patients have already been discharged, which is great. We’ve only had two patients perish,” said Kathleen Mullane, the University of Chicago infectious disease specialist overseeing the remdesivir studies for the hospital.”

    Have you seen it yet?

  28. Rick w says:

    I really appreciate your blog Derek.
    1. I find it puzzling that 1st the severe trial shut down and then several days later the moderate trial was cancelled in China.
    2. On feb 12 a Chinese company called something like ‘bright gene’ announced they had synthesized remdesivir, then were forced to retract it the next day. I apologize for my overactive imagination but I wonder if the Chinese gave remdesivir to anyone with a positive test and that’s how they really got rid of it in Wuhan
    3. A preprint came out about 3 weeks ago describing 12 us travelers in Wuhan that returned to quarantine at u Nebraska. 9 got better on their own but 3 received remdesivir since their o2 dropped and those 3 improved. Yes it’s anecdotal and no controls but what was interesting was that their viral levels in blood and stool dropped to zero while those that got better without drug continued to shed virus.
    4. And now this report from Chicago. Investigators are not supposed to talk.

  29. Kaleberg says:

    One of the great joys of pessimism is that, now and then, one is favorably surprised. Here’s hoping for a favorable surprise.

    1. cynical1 says:


  30. Philip De Groot says:

    A few weeks ago a paper was published in Cell about human recombinant soluble ACE2 protein as an inhibitor of SARS-CoV-2. It looked very promising. I checked to see if it was undergoing trials and found that a group in China had registered a trial which they had subsequently stopped. This was rather discouraging because everyone assumed that the trial was stopped because it was obvious that the treatment did not work. I have no way of knowing why the trial was cancelled but a few days later the University of British Columbia announced that, along with many partners, was initiating trials of hrsACE2.

  31. Britboy says:

    Wow…..what a piece of trash……I’m on my 4th postdoc ” experience ” in the USA and I still can’t see how these idiots take themselves seriously.

  32. Stanislav Radl says:


    And what about favipiravir?
    Regarding the hydroxychloroquine trials, I have read somewhere that a study including hydroxychloroquine + a zinc supplement arm was designed. Do you know something about the results?

    Thanks for your posts

  33. Lambchops says:

    There is now a large scale adaptive trial starting in the UK –

    Protocol is here –

    They are initially looking at arms of no treatment, lopinavir-ritonavir, low dose corticosteroids, hydroxychloroquine monotherapy and azithromycin monotherapy (doesn’t look like they are looking at the combination initially, but more arms can be added to the trial).

    1. Lambchops says:

      There’s also a frontline trial where GPs are trying to intervene earlier, currently with hydroxychloroquine, with azithromycin to be added later (I presume as monotherapy).

  34. JL says:


  35. NJBiologist says:

    “But there are huge numbers of flickering, fluttering, hazy results that just seem to evaporate when you put the magnifying glass on them, though.”

    That muffled shouting… could that be the ghost of Irving Langmuir, excitedly shouting “Yes, this, a thousand times this!!!”?

  36. Steve says:

    Maybe there’s not enough money in Zinc to warrant a reply…

  37. KwadGuy says:

    “And while we’re mentioned email and Twitter static, the number of people who are telling me that I need to believe Dr. Raoult and the Marseilles group and that we need to immediately give everyone hydroxychloroquine, well. . .they’re beyond counting. But here’s how it works: if you come across an interesting, unusual, or potentially useful result, you then have to subject it to more and more stringent tests under different conditions. Something real will be able to pass some of these.”

    Sadly, we have exactly the same thing on the other side, with regard to how bad Coronavirus might be. We have people willing to hang on every bad model projection, and unable and unwilling to consider that we don’t have sufficient data on mortality RATE or infection RATE to use those models. And we won’t until we have broad-based random population testing. (We should be watching Sweden with interest, though. It’s the closest thing we have to a control study).

    People on both sides are dug in here with religious fervor.

  38. Lawrence S. Mayer, MD, MS, PhD says:

    Thank you Derek. You are amazingly up to date on the data. I remind you that we have a Facebook group of over 2000 physicians, epidemiologists and biological science researchers devoted to keeping frontline docs (we have over 500) up to the minute on clinical epidemiology and science. The largest (if not only) such group. We would love for you to join us

    Covid 19 Clinical Epidemiology Discussion Group


    1. Derek Lowe says:

      Unfortunately, I’m not on Facebook any more, but it sounds like a good group!

  39. JP Leonard says:

    Tonight at 9 pm ET I will be interviewed on an Internet radio website about the HCQ+Zinc treatment. I also posted some thoughts note about the difficulty of getting people to look at it here

    1. TheMagpie says:

      In your Medium ‘article’ you used this phrase: “Maybe the gray eminences of the NWO are right to cull the herd?” – unironically as far as I can tell.

      I think your shiny metal hat is too tight… but your theories are eminently suited to the dumpster fire that is noliesradio (no lies? HAH!)

  40. Henk says:

    Dutch hospitals just started to test Valsartan to prevent lung problems, with a goal of ten to fifteen hospitals participating. 325 will get valsartan, and the name number on placebo.

  41. Lane says:

    Why are studies done with hydroxychloroquine alone? I would not expect it to work without zinc. The report of success from Dr. Vladimir Zelenko included azithromycin and zinc sulfate.

    Why don’t you point out the fact the studies do not ask the question?

  42. Here is another idea for a small-molecule approach to Covid-19. I post it here because this forum seems to have become a repository of therapeutic ideas (yes, they are blueberries in the mud-wrestling dough).
    The idea was triggered by an article in the New York Times (; the author (an emergency physician) reports that Covid-19 patients are often severely hypoxic, but asymptomatic, because they are not hypercapnic, and their pulmonary infiltrates, sometimes impressive on xrays, are somehow not triggering their pulmonary stretch receptors enough to make them dyspneic.
    Some of this description would apply to healthy people at high altitude. For example, typical oxygen saturation at 6000 meters is in the low 70s, but most climbers at that altitude are comfortable at rest. Even so, some of them thereafter decompensate more-or-less abruptly into life-threatening pulmonary or cerebral edema.
    Good trials have shown that these calamities of high altitude are less frequent in people who are taking acetazolamide, a carbonic-anhydrase inhibitor.
    I wonder if a proper trial of acetazolamide might be worthwhile in selected Covid-19 patients.
    Please don’t reply to say that the idea is so good that everyone should start using it right away, especially with zinc.

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