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Clinical Trials


OK, we have some more to think about this morning. The large SOLIDARITY trial from the WHO has reported more interim data on its investigation into repurposed drugs for the coronavirus pandemic. And some of this we already knew, but some of it’s a real surprise.

One drug reported on is hydroxychloroquine. This showed no apparent benefit along with a statistical possibility of increased hazard, although the latter was also not proven. This is consistent, as the paper points out, with the results of 27 other trials, and for God’s sake, enough said. Another was the lopinavir/ritonavir combination, and no benefit was found for that, either, which is consistent with two other reported trials. A third intervention was interferon-beta1, with and without lopinavir, but this also showed no evidence of benefit. The statistics on it do not rule out a small useful effect, but do rule out anything moderately beneficial or above, and it’s worth noting that they don’t rule out small amounts of harm, either. This was either subcutaneous or i.v. administration – there has been a report that administering it to the lungs via a nebulizer could be effective, but that only had 100 patients. There is also another trial underway with s.c. dosing, but after these results it’s hard to be optimistic about that one.

Now we get to remdesivir. In contrast to the report that just came out from the ACTT-1 trial in NEJM, the SOLIDARITY trial found no benefit at all. No benefit in ventilation, in time to recovery, nor in overall mortality. Combining the data from these two reports (and two other smaller controlled Remdesivir trials, the authors conclude:

This absolutely excludes the suggestion that Remdesivir can prevent a substantial fraction of all deaths. The confidence interval is comfortably compatible with prevention of a small fraction of all deaths, but is also comfortably compatible with prevention of no deaths.

Recall that the ACTT-1 trial showed some benefit, but not a dramatic one. These two results are probably not as incompatible as they seem, particularly (as the current paper notes) when you adjust for the fact that in ACTT-1 the randomization put slightly fewer patients on high-flow oxygen or ventilation into its treatment group. So in the same way that I noted that the ACTT-1 data came from a larger set of patients than the earlier remdesivir trials, we have to also deal with the fact that the SOLIDARITY data set is larger still. The authors again:

The unpromising overall findings from the regimens tested suffice to refute early hopes, based on smaller or non-randomized studies, that any will substantially reduce inpatient mortality, initiation of ventilation or hospitalisation duration. Narrower confidence intervals would be helpful (particularly for Remdesivir), but the main need is for better treatments.

I think that’s the major take-home. It looks like there is no case at all to be made for some of these therapies, and for remdesivir, it looks like the argument now is “Does it help a bit or just not at all?” The only thing that I’ve seen that really seems to be making a big difference now is dexamethasone, and we may soon (I hope) be adding the monoclonal antibodies to that list. The SOLIDARITY enrollment is still moving along at 2000 patients/month, and will be looking at these and other newer ideas as it continues. And that means abandoning the older ideas, because – as we’re finding out – they’re not much help. It’s time to move on.

161 comments on “The SOLIDARITY Data”

  1. Ezra Abrams says:

    Maybe I am totally missing something, As I understand drug development, one has to look through a very large # of chemicals (>> 10,000) to find one that is safe and effective
    And this usually requires a whole lot of tinkering with each hydrogen and methyl group to get things just right

    So wouldn’t your prior have been something on the order of

    “it is a bloody miracle of repurposing” works ?

    1. M says:

      It’s not quite as long odds as you might think.

      A lot of the tinkering is to control things like PK, so if that is “solved” it stays solved regardless of the disease. Same with toxicity (mostly.).

      Efficacy is trickier, but if you are hitting a human target it (or a related one) could have an impact on multiple diseases–this is so common it’s not “repurposing” unless the biology that drives it is a surprise. And for non-human targets, if they are related (proteases, polymerases, etc.) could certainly show activity.

      All that said, yeah, it’s rare for it to work. It gets talked about a lot because the candidates for repurposing are easily accessible to academics and AI companies so you can quickly from experiment to pre-print or press release.

      1. Patrick says:

        Also it’s spectacularly easy to try in comparison to new development. Properly done it can take as little as a few months to go from “maybe we could try” to completion of high quality trials.

        That’s just insane vs the cost and *time* for new stuff. So we try even if the chance is small.

    2. Mister B. says:

      Feel free to read this entry from this very blog:

      It gives you a very clear explanation of why it does or doesn’t work.

      Enjoy !

      1. Robert Clark says:

        I think that gives an unnecessarily restricted idea of repurposed drugs. It should simply be a drug used for one purpose, now used for another.

        Probably, HCQ is the most famous instance of this. It was originally used for malaria. Then it was found to be very useful for rheumatic disease as an anti-inflammatory.

        And now because HCQ is a highly effective anti-inflammatory it should be effective for the lung inflammation seen in COVID-19. Several different anti-inflammatories have shown effectiveness for patients on invasive ventilation such as steroids. It is very likely then that HCQ does as well.

        Robert Clark

        1. zero says:

          “Should be” and “Is” are not the same thing. The difference is testing, and the testing has been done. We didn’t get the answer we wanted. Our responses to this outcome are illuminating.

          1. theasdgamer says:

            Your philosophy of science sucks and therefore so does your science. You need to improve your understanding,

          2. Derek Lowe says:

            Calm it down. You’re getting closer to the sort of stuff that can get deleted here.

          3. theasdgamer says:


            Zero said that testing has been done.

            He fails to understand that there are different kinds of testing and that RCTs aren’t useful when testing antivirals if they are given too late. Results from such studies are meaningless. I’ve posted about this philosophy of science issue a couple of times.

            Retrospectives where antivirals are given within the treatment window are more useful than RCTs where antivirals are given outside the treatment window.

    3. AVS-600 says:

      You’re right that it often takes thousands of molecules to find a new therapy, and that any given repurposed drug is going to be a long-shot. Repurposing an existing drug cuts a lot of the normal failure rate out (in theory) because you avoid:
      – Compounds with bad physicochemical properties, for instance ones that are metabolized/eliminated too quickly to have any effect (those don’t become drugs in the first place)
      – Drugs that have high tox liabilities (you just don’t screen those compounds unless the trade-offs are worth it in the context of the disease).

      So the failures from repurposing are going to come from other categories, the most significant of which is that you aren’t choosing from a set of molecules that are optimized to affect your target of interest. I’m not sure whether the absolute numbers are better than creating a new therapy from scratch, but they aren’t directly comparable. Remdesivir in particular wasn’t a crazy hypothesis, since it operates on viral machinery that COVID should still have (though apparently not well enough to have a huge impact).

      Another note here is that the most successful “repurposed” drug is one we have isn’t really repurposed at all: dexamethasone is essentially doing what it’s always been prescribed for, which is to reduce inflammation.

      1. Robert Clark says:

        When the history of this pandemic is written about by future historians of science all of them en masse will be scratching their heads trying to figure out one thing. What is that?

        Well, if you were to ask an expert in infectious disease now, what is THE most key fact about using an antiviral medicine. What is THE most important thing???

        They will tell you that you have to use it EARLY. This is well known for HIV and it’s well known for Influenza.


        Time again antivirals are found effective in vitro for COVID-19. Then who do they use it for during human trials? On patients already on the brink of death in hospital beds!!!


        How could EXPERTS in infectious disease forget to use it EARLY! It’s THE most important thing!! It’s like a physicist forgetting about the existence of gravity! How could they forget that?!? It absolutely makes no sense.

        Robert Clark

        1. Not that easy says:

          How do you expect to do that? It’s a major pandemic that is already overwhelming testing capabilities in many geographic locations. How on earth are you going to catch patients early enough to test your hypothesis? You’d have to something like a challenge trial, which is not morally ethical.

          1. theasdgamer says:

            Here’s how you do the trial…

            You have a partner who is not ethically bound to give a med. His patients are the control.

            You obtain a provisional clinical diagnosis of covid before you do PCR testing.

            You do the PCR test.

            You exclude patients who fail to meet the safety requirements (qt prolongation).

            You begin treatment with med/placebo.

            When PCR results come back, you either retest or exclude people who are negative. (38% false negative PCR rate for early testing).


          2. Robert Clark says:

            Key is you do it even before the testing comes back positive. You prescribe the medications on the first signs of symptoms. Make that your overall national policy, not waiting till they need to be hospitalized with severe symptoms.


            In the Asian countries with death rates 1/100th that of the West that is the approach they take.

            And you have now many choices for the physicians using their own clinical experience, knowledge and judgement of which antivirals to use. With this as a national approach across the country would find out within days which ones are most effective at preventing the disease from progressing to serious illness needing hospitalization.

            Some patients tests will turn out to be negative, but you will catch the positive ones at early stages of the illness.

            Robert Clark

          3. Richard A Crane says:

            How to catch patients early. Give them the antiviral on the day their PCR test comes back positive.

        2. Walther White says:

          No, real experts wouldn’t say such nonsense. The first thought would be: is there an effective treatment for that disease? In the case of COVID-19, the answer is no. Hence the great emphasis on prevention, which is being ignored or mocked by demagogues and petty tyrants.

          Bear in mind that patients with COVID-19 may be asymptomatic, or the symptoms may not appear until at least Day 5 after exposure. So there is no way you can take a drug “early.”

          1. theasdgamer says:

            The petty tyrants are doing the lockdowns and demeaning effective treatements.

          2. theasdgamer says:

            Twelve studies on high risk patients say you’re wrong. Harvey Risch has done a meta analysis.

            “Early” means within five days after symptom onset. The earlier the better.

            You need to read more about the course of covid and viral clearance.

    4. emba says:

      Understanding how remdesivir got pushed into trials so quickly and the costs of that selection bias is something that is important to understand and can’t be hand waived away.

  2. Simon Auclair the Great and Terrible says:

    Thanks for addressing that.

    Almost looks like an eua is the kiss of death for any therapy…

  3. Matthew says:

    Seems all the HCQ kooks are now grasping onto a scabies drug that they claim is a miracle cure (no convincing data).

  4. cynical1 says:

    So it turns out HIV Protease inhibitors don’t work on SARs-CoV-2. Go figure. Whoever thought that one up should be voted off the team as the Weakest Link. (Right after the one who wanted to inject disinfectant.)

    Personally, I like those Coronavirus 3CL-Protease inhibitors that Pfizer just published and was mentioned here the other day more than any of this repurposed stuff including Remdesivir.

    1. Patrick says:

      Given it has pretty much the same protease, it’s not a bad idea *at all*. To suggest it was a bad idea based on what we knew at the time seems really arrogant.

      1. Bryan says:

        HIV protease an the SARS-CoV-2 proteases are nothing alike. HIV protease is an aspartyl protease that uses aspartate residues to activate and position water molecules for hydrolysis of the peptide bond. In contrast, the SARS-CoV-2 proteases are cysteine proteases that use the thiol moiety of a cysteine residue as the nucleophile for cleaving the peptide bond of its substrate. The enzymes use completely different mechanisms of action, so it’s no surprise that the HIV protease inhibitors do not work against SARS-CoV-2.

        1. Patrick says:

          Hm, interesting, ok.

          Then the in vitro data is *still* enough to make *trying it* a good idea:
          “ Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro.”

          I don’t think this has been disputed.

          I mean, look: chloroquine *obviously* doesn’t work in vivo and it seems likely Remdesivir does little or no good either.

          But given what we knew, there was nothing stupid at all about *checking to see what they did* in vivo. To suggest it was obviously futile in advance seems really arrogant.

          1. Albert says:

            In vitro wise, i bet bleach is much more effective than any of them.

          2. Robert Clark says:

            “I mean, look: chloroquine *obviously* doesn’t work in vivo and it seems likely Remdesivir does little or no good either.”

            I don’t agree it doesn’t work in vivo. Multiple studies have shown that it does. However, it has to be understood its mode of effect to see its effect. HCQ and CQ have both antiviral and anti-inflammatory effects. So they reduce the progression of the disease when used early to prevent hospitalization being needed.

            But in the case of hospitalization, when lung inflammation has taken root, they can reduce the degree of inflammation. This is especially important for patients on invasive mechanical ventilation, where lung inflammation is severe.

            Robert Clark

        2. luysii says:

          Excellent ! ! It’s time a chemist spoke up.

  5. Robert Elkjns says:

    HCQ would work with tamoxifen. but alas it is too cheap and easy after all the fuss

    1. Seebs says:

      Oooh, I like that, totally out of left field, no mechanism offered, but could be tested at great expense and risk to patients. Next up, I propose a theory that HCQ works only on Tuesdays and Thursdays, because that will make clinical trial scheduling more complex, and then we can blame shift workers for the lack of visible responses.

      1. Miles says:

        How about with curcurmin…nope….okay, I will have it with a bottle of single malt, i can at least enjoy the experience

        1. BF says:

          That would be a new kind of trial:)

          1. Skeptical says:

            I volunteer as tribute!

    2. Another Guy says:

      kindly See my comment from Oct 9:

      It is well-proven now that there is no need to include hydroxychloroquine in any experimental regimen to treat COVID-19, it simply doesn’t work and nothing will enhance, improve, tweak or otherwise resurrect it from the drug-repurposing grave. It is dead-weight at best, and possibly causes harm in some patients.

      1. Robert Clark says:

        “It is well-proven now that there is no need to include hydroxychloroquine in any experimental regimen to treat COVID-19, it simply doesn’t work and nothing will enhance, improve, tweak or otherwise resurrect it from the drug-repurposing grave. It is dead-weight at best, and possibly causes harm in some patients.”

        Except in the cases where it does:

        Research Paper
        Published: 15 May 2020
        Low dose of hydroxychloroquine reduces fatality of critically ill patients with COVID-19
        Bo Yu, Chenze Li, Peng Chen, Ning Zhou, Luyun Wang, Jia Li, Hualiang Jiang & Dao-Wen Wang
        Science China Life Sciences volume 63, pages1515–1521(2020)

        “These data demonstrate that addition of HCQ on top of the basic treatments is highly effective in reducing the fatality of critically ill patients of COVID-19 through attenuation of inflammatory cytokine storm. Therefore, HCQ should be prescribed as a part of treatment for critically ill COVID-19 patients, with possible outcome of saving lives.”
        hydroxychloroquine, IL-6, mortalities, COVID-19

        Robert Clark

        1. David says:

          Robert Clark: “Except in the cases where it does: … Research Paper … Low dose of hydroxychloroquine reduces fatality ”

          You are quoting a retrospective review, in which a total of 48 subjects were treated with HCQ. It’s not at all clear from the review how those were selected for treatment, or whether they were matched to appropriate controls from the non-treated group.

          In other words, that study is totally worthless, and shouldn’t be brought up when there are now several large prospective, randomized trials showing the exact opposite.

          1. theasdgamer says:

            Got any RCTs where HC is administered early to large groups including many high risk patients?

            Didn’t think so. Meanwhile, Risch has done a meta analysis of 12 small retrospective studies where HC was administered early to high risk patients. Small studies of high risk patients can show significance. And they do.

          2. Robert Clark says:

            Unfortunately, on either side, whether or not a study is called worthless is dependent on whether or not it supports their view on the topic.

            There have been many positive studies some including thousands or patients. In point of fact there have been far more positive studies than negative ones.

            That is a fact the public in general has not been made aware of.

            See the collection of studies:

            Robert Clark

  6. Hopeful Layman says:

    Some time ago, there was some optimistic noise about LAM-002A.,CoV%2D2%20virus%20in%20cells.
    Anyone know whether this is still be studied, and if so, what the status is?

  7. Me says:

    Derek Typo:

    ‘it’s worth nothing that they don’t rule out small amounts of harm, either’

  8. Rob says:

    Is there anything new on MRK-4482? It looked promising. Also, Gilead had a compound much more effective than remdesivir in vitro, same mechanism, though I don’t think they ever took into trials.

    1. David E. Young, MD says:

      You mean MK 4482. Well, it has an official name now: Molnupiravir

      Studies are underway but Merck says that they will done in…… wait for it…… April.

      Kind of a long time, don’t you think? I wish that they would have a 100 hospital outpatient program, recruiting 10 people a week at each location for a randomized trial, but I guess not.

  9. Klaus Witte says:

    PharmaMar announced today, that plitidepsin (Aplidin) was found to reduce viral load in Covid-19 patients. In the study, three dose levels were tested, that were lower than the one used in earlier studies for multiple myeloma (5 mg/sqm). If these findings are confirmed in a phase 3 study, to be discussed with regulatory agencies “in the next few days”, plitidepsin may become a positive example of drug repurposing.

    1. David E. Young, MD says:

      Curious. Using a very complicated drug from a sea animal to treat Covid. Do you have any idea of how complex a molecule Plitidepsin is? Check it out.

      This one would be very difficult to make available to the world to treat Covid19!! Makes Remdesivir look easy to make!

      1. Some idiot says:

        Not really, actually… It is actually a fairly simple structure, since it is basically a peptide chain which has cyclised almost all the way back.

        Looks messy at first, but when you zoom in on it, you can fairly easily step your way through the peptide chain. Almost exclusively natural amino acids as well. The cyclic part is formed via ester formation between the C-terminus and a threonine not far from the N-terminus.

        I wouldn’t want to have to deliver 1 kg tomorrow, but give me a couple of months and I reckon we could deliver…!


      2. Skeptical says:

        The EMA didn’t think it was safe enough to be a *cancer* therapy:
        At the time of the initial review, the CHMP was concerned that the data from the main study showed only a modest increase of around one month in the time patients given Aplidin lived without their disease getting worse, compared with those treated with dexamethasone alone. In addition, improvement in overall survival (how long patients lived overall) was not sufficiently demonstrated. Regarding safety, severe side effects were reported more frequently with the combination of Aplidin and dexamethasone than with dexamethasone alone. Based on the above, the CHMP was of the opinion that the benefits of Aplidin did not outweigh its risks and recommended that it be refused marketing authorisation.

  10. Harvey 6'3.5" says:

    I think the problem for these studies on remdesivir and interferon are the timing of administration. Based on mechanistic logic, if these drugs work, they would work best very early in infection by reducing the infectious dose. By the time a patient was in the hospital, it is probably too late to expect much. And looking at the WHO study, 8% were on ventilators and the rest were sick enough to be hospitalized.

    And because remdesivir requires IV administration and interferon was subcutaneous (or IV), these aren’t the sort of drugs that could be made widely available to patients who just tested positive on a rapid test. So even if my logic above is right, and they were much more effective immediately after a positive test rather than waiting until hospitalization, there is no practical way to administer the drugs at that timepoint, particularly since you aren’t certain which patients will actually have serious morbidity.

    1. David E. Young, MD says:

      A good point. I have been pushing, cajoling, begging for a study of Remdesivir in early Covid, having been arguing this point for the past 6 months. What I would like to see is a study of Remdesivir IV for two days for early covid followed by 6 more days of an oral antiviral, such as Favipiravir or Molnupiravir. Hasn’t happened. Not likely to happen. It’s a shame.

      1. John Wayne says:

        I agree that this could be interesting. If you could get access to patients with probable exposures and dose them with psuedoprofilactic remdesivir (with a placebo treatment control) that could be something. Opens up a new market as well.

      2. theasdgamer says:

        So studying remdesevir in early stages is relevant but studying HC in early stages is not?

        Derek keeps thinking that late treatment with an antiviral is somehow ever going to be meaningful.

        Several studies have shown that the virus is dead by day 8-10 post symptom onset in practically everybody. So giving an antiviral late in hospitals is…a little ridiculous, maybe?

        27 studies where an antiviral was administered after the virus was dead…

        27 x 0 = …….. 0!

        1. Zambo says:

          This is from mid-July: “Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19”
          Randomized trial showed no statistically significant reduction in hospitalizations/symptoms.

          1. theasdgamer says:

            Skipper showed 50% reduction in hospitalizations when treated with HC for a young study group when treatment was delayed from 70-140 hours. I’d call that a provisional win for HC.

            You have to get down in the weeds on occasion.

            Young study groups tend to not show much significance for antiviral treatment for covid. Shock!

            Risch, by contrast, looked at high risk groups.

          2. Chris Phillips says:


            Regarding the hospitalisation data in Skipper’s paper, that is (i) not the primary endpoint of the study and (ii) not a statistically significant difference anyway.

            When people put this kind of meaningless stuff forward as evidence, it only confirms the impression that there is no meaningful evidence.

          3. theasdgamer says:

            Mr. Phillips,

            You should work on following the conversational thread.

            Zambo brought up Skipper’s hospitalizations in reply to my comment about looking at preventing hospitalizations via early treatment with antivirals. I merely pointed out that Skipper actually showed some benefit which perhaps was kept marginally insignificant because the treatment was actually administered fairly late.

            The population was mostly young and not likely to show a significant benefit to the original primary outcome.

            Why didn’t you just say that Skipper was meaningless to the conversation?

          4. Chris Phillips says:



            Zambo brought it up as a study on non-hospitalised cases, which showed no significant results either for hospitalisation or symptoms.

            Of course it’s relevant – but as negative evidence, not a “provisional win” as you tried to claim!

            As I said, posting nonsense in support of hydroxychloroquine only weakens its case.

          5. Tony M says:

            i posted yesterday on another older article this link to an open letter published on three studies, including this Skipper study, signed by statisticians, medical researchers, clinicians and other quantitative researchers.concluded:

            “Due to the importance of clinical trials in COVID-19 public decision making, we believe it is fundamental that these three studies correct their conclusions and publicize these corrections.”

            I think it worth posting on a more recent article as I think it is worth a read if you have not read it!



          6. theasdgamer says:

            Mr. Phillips,

            I don’t think that Skipper means what you think it means. Tony M posted an article after your last article that shows what Skipper actually means.

            I should add that Skipper’s aims were solid, but it was underpowered and didn’t have a solid plan to ensure that dosing began early enough. Besides that, we have only recently gained solid evidence of what “early enough” means. It turns out that Zelenko’s definition of “early enough” was good enough for treatment to work.

          7. WST says:

            A question from a layman, isn’t following limitation of the Skipper trial worrying :
            Only 58% of participants received SARS-CoV-2 testing because of severe U.S. testing shortages.”

            Even when only symptomatic subjects were tested (early days in US and Western Europe), there were under 20% positive covid cases.
            It would not be surprising if there were false positive cases in the not tested 42% of participants. There is some discussion of these effects but IMHO its just opinions. But these cases obviously contributed to the statistical significance.
            Would a trial of a cancer drug with 42% of the patients without clinical diagnosis be acceptable?

    2. Ogamol says:

      “Immediately after a positive test”: In some places, a positive (or negative) test result takes 7 days to determine. In these cases, administering to the hospitalized makes sense. (My state is now in the “5 days to determine” category. It was in the “7 days to determine” category.)

  11. SteveM says:

    Perhaps Derek and others may want to comment on Favipirivir, (Avifavir, Avigan):

    Especially because if it works, you can’t be the price.

    1. ILikeMike says:

      I thought Stanford was conducting a trial of this drug. Unclear when results will be disclosed.

      1. David E. Young, MD says:

        Stanford has a puny trial, aiming for 120 outpatients, “by invitation only”. Boston has 4 hospitals with 4 outside of Boston that have had a trial in place for 5 months, aiming for 60 enrollees. After 5 months, 8 hospitals, it is still recruiting. No, they are not seriously looking at Favipiravir, and I think it is a shame. (rumors of a study of the drug in nursing homes to treat those exposed has been started, or nearly started). The problem with Favi is that it is thought to be teratogenic, and would likely need a REMS in the US (Other countries don’t care: Russia, India, etc.). And a REMS scares any prospective sponsor. I think that it is a shame that Favi is ignored. Inexpensive to manufacture and off patent.

        1. Adrian says:

          So this might be political correctness killing thousands of people?

          The easiest way to mitigate teratogenic effects would be to exclude women under 60 from the initial approval.

          The irony is that the practical effects of such an exclusion would be small in a disease where old people and men are main risk groups.

        2. confused says:

          Given that COVID risk is *overwhelmingly* concentrated at post-reproductive age, why would teratogenicity matter much?

          1. David E. Young, MD says:

            It is still a huge issue, given that some young woman who does not have covid could get ahold of the drug from a family member and then take it “to prevent” their getting covid

            Almost every case of myeloma occurs in individuals older than child bearing age. But the FDA has a very strict REMS for Thalidomide and Lenolidomide. It is just the issue of the drug getting into the wrong hands. There has not been a case of child birth defects in the US from Revlimid, but rumor has it that it has happened in South America, for that very reason.

          2. confused says:

            But … I mean… we’re in a pretty significant pandemic. Should the vague possibility that someone somewhere could take medicine they’re not supposed to be given any weight?

            1 birth defect somewhere seems like a much smaller issue, given that even a marginal effect from a cheap drug could save hundreds or even thousands of lives.

            IE – the FDA’s rules may not be well suited to the current situation.

          3. David Young, MD says:

            I agree with you. It should not matter. But understanding how the FDA looks at this,… well, to them it matters… at lot. The FDA does not want its name tarnished by approving a drug and then finding out that in 14 months there is a bit new article about 11 malformed babies due to young, pregnant women taking a drug that they thought would treat their common cold. All it has to happen is 11 times and there you have it, and embarrassed FDA with news hounds with microphones asking them why this was allowed to happen. Lenolidomide is a commonly used drug for myeloma in the US and is super teratogenic. But we haven’t had any bad babies because of it… probably because we have a REMS in place. I’ve heard rumors that there are bad babies in South American from Lenolidomide, but those could be false rumors……

            I have been emailing the NIH for the past 6 months begging then to sponsor a large study of Favipiravir for ambulatory, early Covid19. I have also asked Gilead to consider an outpatient study for early Covid where 200 mg of Remdesivir is given IV on days 1 and 2 followed by 5 to 6 days or oral Favi. My requests are falling on deaf ears.

            I am suppose to get an email from someone involved in Favi research but have not heard back yet. Hopefully in the next day or two I will get someone else’s perspective on it.

  12. SteveM says:

    FYI: Gilead Disputes WHO Data Confirming COVID-19 Drug Remdesivir Is A “Flop”

  13. Eric says:

    The Solidarity study does not meet any of the necessary criteria for reducing researcher error, including pre-specification of statistical endpoints for making adaptations, stopping, starting, and determining appropriate power:

    1. the US FDA regulations (

    “In general, as with any clinical trial, it is expected that the details of the adaptive design are completely specified prior to initiation of the trial and documented accordingly (section VIII.B.). Prospective planning should include prespecification of the anticipated number and timing of interim analyses, the type of adaptation, the statistical inferential methods to be used, and the specific algorithm governing the adaptation decision. Complete prespecification is important for a variety of reasons. First, for many types of adaptations, if aspects of the adaptive decisionmaking are not planned, appropriate statistical methods to control the chance of erroneous conclusions and to produce reliable estimates may not be feasible once data have been collected. Second, complete prespecification helps increase confidence that adaptation decisions were not based on accumulating knowledge in an unplanned way. For example, consider a trial with planned sample size re-estimation based on pooled, non-comparative interim estimates of the variance (section IV.) in which personnel involved in the adaptive decision- making (e.g., a monitoring committee) have access to comparative interim results. Prespecification that includes the exact rule for modifying the sample size reduces concern that the adaptation could have been influenced by knowledge of comparative results and precludes the use of a statistical adjustment to account for modifications based on comparative interim results (section V.B.). Finally, complete prespecification can motivate careful planning at the design stage, eliminate unnecessary sponsor access to comparative interim data, and help ensure that the DMC, if involved in implementing the adaptive design, effectively focuses on its primary responsibilities of maintaining patient safety and trial integrity (section VII.).”

    2. The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design, BMJ 2020; 369 doi: (Published 17 June 2020);

    ACE item 3b (new): Type of adaptive design used, with details of the pre-planned adaptations and the statistical information informing the adaptations
    Explanation—A description of the type of AD indicates the underlying design concepts and the applicable adaptive statistical methods. Although there is an inconsistent use of nomenclature to classify ADs, together with growing related methodology, some currently used types of ADs are presented in table 1. A clear description will also improve the indexing of AD methods and for easy identification during literature reviews.

    Specification of pre-planned opportunities for adaptations and their scope is essential to preserve the integrity of AD randomised trials and for regulatory assessments, regardless of whether they were triggered during the trial. Details of pre-planned adaptations enable readers to assess the appropriateness of statistical methods used to evaluate operating characteristics of the AD (item 7a) and for performing statistical inference (item 12b). Unfortunately, pre-planned adaptations are commonly insufficiently described.

    Details of pre-planned adaptations with rationale should be documented in accessible study documents for readers to be able to evaluate what was planned and unplanned (such as protocol, interim and final SAP or dedicated trial document). Of note, any pre-planned adaptation that modifies eligibility criteria (such as in population enrichment ADs) should be clearly described.

    ACE item 7a (modification): How sample size and operating characteristics were determined

    Explanation—Operating characteristics, which relate to the statistical behaviour of a design, should be tailored to address trial objectives and hypotheses, factoring in logistical, ethical, and clinical considerations. These may encompass the maximum sample size, expected sample sizes under certain scenarios, probabilities of identifying beneficial treatments if they exist, and probabilities of making false positive claims of evidence. Specifically, the predetermined sample size for ADs is influenced, among other things, by:
    Type and scope of adaptations considered (item 3b);
    Decision-making criteria used to inform adaptations (item 7b);
    Criteria for claiming overall evidence (such as based on the probability of the treatment effect being above a certain value, targeted treatment effect of interest, and threshold for statistical significance);
    Timing and frequency of the adaptations (item 7b);
    Type of primary outcome(s) (item 6a) and nuisance parameters (such as outcome variance);
    Method for claiming evidence on multiple key hypotheses (part of item 12b);
    Desired operating characteristics (see box 2), such as statistical power and an acceptable level of making a false positive claim of benefit;
    Adaptive statistical methods used for analysis (item 12b);
    Statistical framework (frequentist or Bayesian) used to design and analyse the trial….

    ACE item 14c (new): Specify what trial adaptation decisions were made in light of the pre-planned decision-making criteria and observed accrued data
    Explanation—ADs depend on adherence to pre-planned decision rules to inform adaptations. Thus, it is vital for research consumers to be able to assess whether the adaptation rules were adhered to as pre-specified in the decision-making criteria given the observed accrued data at the interim analyses. Failure to adhere to pre-planned decision rules may undermine the integrity of the results and validity of the design by affecting the operating characteristics (see item 7b for details on binding and non-binding decision rules).

    3. Adaptive designs in clinical trials in critically ill patients: principles, advantages and pitfalls, Intensive Care Medicine volume 45, pages678–682(2019) (

    Importantly, adaptive trials do not provide a free ticket for trial adaptations: adaptations are based on the analyses of accumulating data with adaptation rules being pre-specified in the study protocol.

    4. Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis, BMC Medical Ethics volume 16, Article number: 27 (2015) (

    All stakeholders agreed that adaptations need to be prespecified, and that having a clear understanding of what is being changed or “adapted” is prerequisite for conducting a valid, and hence ethical, ACT.

    5. Adaptive Designs for Clinical Trials: Application to Healthcare Epidemiology Research, Clin Infect Dis. 2018 Apr 1; 66(7): 1140–1146 (

    “To accomplish this goal, an adaptive trial uses data that accumulates during the study to modify study elements in a prespecified manner. The nature of the change is driven by the accumulating data, but the plan for the change is specified in advance and by design.”

    The WHO protocol has no pre-specified statistical points defined for superiority, inferiority, stopping or alteration of the methods. They are simply aggregating a huge amount of data and p-hacking it to death with ad hoc interim analyses that they perform whenever they feel like it.

    I can’t believe the scientific community has been silent (and supportive!) of this study for so long. The standards of science should be higher in the face of a global pandemic, not lower. As the statistician Douglas Altman said, “To maximise the benefit to society, you need to not just do research but do it well”

  14. mallam says:

    And as a reminder, not unfamiliar to those who have been engaged in this business for a while, after thousands of compounds tested (and over a few years), even having some with promising in vitro activity / potency, nothing emerges that can be an actual useful medicine in humans. Why? Poor PK, unwanted metabolites, toxicity, and (god forbid) nothing that’s been evaluated to date simply not work in the disease in real life humans.

  15. Steve Scott says:

    This version of the story by AP, very carefully worded, does not negate the earlier study. In fact, it says it was “more rigorous.”

    GENEVA (AP) — GENEVA (AP) — A large study led by the World Health Organization suggests that the antiviral drug remdesivir did not help hospitalized COVID-19 patients, in contrast to an earlier study that made the medicine a standard of care in the United States and many other countries.

    The results announced Friday do not negate the previous ones, and the WHO study was not as rigorous as the earlier one led by the U.S. National Institutes of Health. But they add to concerns about how much value the pricey drug gives because none of the studies have found it can improve survival.

  16. Daniel Barkalow says:

    Has there been more of a study of famotidine? Last I heard, it seemed like a reasonable thing to try, but didn’t seem to get any attention. It also seems like something that would be safe in COVID patients and cheap and common enough to use (following OTC instructions) without particularly good justification. Have there been negative results that didn’t get attention because it never got much traction, or no results?

    1. John Hasler says:

      I’d also like to see some discussion of fexofenadine which seems more likely to be useful than famotidine, especially in light of this:

  17. Adrian says:

    I sometimes wonder whether the business model of Gilead is to have some easy and cheap to produce and expensive to sell medications ready, and when the next pandemic comes they are quick to have someone present a study showing one of their products has some barely statistically relevant benefits. By they time it is confirmed whether or not their drug actually has benefits their bank accounts are already full.

    You can tell a similar story if you replace “COVID-19” with “swine flu”, “Remdesivir” with “Tamiflu” and “Gilead” with “Gilead”.

    Not saying any outright fraud is involved, but Gilead is definitely good at generating profits by creating a huge hype around products that offer no or small benefits.

    1. confused says:

      So Tamiflu ended up to not do very much for 2009 swine flu? Hmmm.

      I know when I got H1N1 swine flu in college, it was comforting to think something was available (though as it turned out the doctor just said, ‘you’re fine, we’re not going to give you tamiflu just drink a lot of fluids’).

      1. Adrian says:

        Whether Tamiflu has any statistically significant benefits for influenza at all was already a disputed topic years before the 2009 swine flu.

        Undisputed for both Tamiflu/flu and Remdesivir/COVID-19 is that any positive effects are not huge. Even studies supporting Tamiflu never observed huge effects, observed benefits are more in the ballpark of reducing symptoms by a day but no change in mortality.

        People often wrongly think that “statistically significant benefits” would be complete solutions.
        “Tamiflu for swine flu”, “Remdesivir for COVID-19” or “cloth face mask for COVID-19” are all in the “likely better than nothing” ballpark.
        If you were practicing risky behaviour in college because the availability of Tamiflu did comfort you to not practice social distancing, then this “likely better than nothing” might have had a net negative effect for you.

        1. Marko says:

          “People often wrongly think that “statistically significant benefits” would be complete solutions.”

          So true. With a large enough trial , you could demonstrate a 5% reduction in snot output with statistical significance.

        2. confused says:

          OK, makes sense.

          >>If you were practicing risky behaviour in college because the availability of Tamiflu did comfort you to not practice social distancing, then this “likely better than nothing” might have had a net negative effect for you.

          Oh, no, no one I knew was doing social distancing in 2009. The university provided hand sanitizer everywhere, and I used it.. but I’d already read the risk of death was like 1/5,000 or 1/10,000 or something, so I wasn’t real concerned.

    2. Nigel Dennis says:

      Desolate yet all undaunted, on this desert land enchanted—
      On this home by Horror haunted—tell me truly, I implore—
      Is there—is there balm in Gilead?—tell me—tell me, I implore!”
      Quoth the Raven “Nevermore.”

  18. RAHUL MALHOTRA says:

    The Solidarity trial was not placebo controlled. It is compared against “standard of care” in disparate global locations. That’s one thing. The other is that it’s not clear who got corticosteroids and who didn’t, and based on what. Notice that steroids are not part of this trial. Honestly, I expected a deeper analysis from Derek Lowe.

    1. David says:

      Rahul: “The Solidarity trial was not placebo controlled. It is compared against “standard of care” in disparate global locations.”

      well, it’s an open-label trial, so there’s no point in giving placebo in addition to standard of care. That said, it being open-label would be expected to generate false positive, rather than false-negative, results. If a drug can’t succeed in an open-label trial, it’s a failure.

      Rahul: “not clear who got corticosteroids and who didn’t, and based on what”

      From the study (page 6): “Absolute treatment vs control differences in use of corticosteroids and other non-study treatments were small (Table S2).” So, not a complete answer, but a reassurance that outcome differences between groups were unlikely due to imbalance in steroid use. We’ll have to wait for the full publication along with supplemental tables, to be sure of that.

      1. RAHUL MALHOTRA says:

        Open label means that there is no guarantee that everyone received the same standard of care. It can just as well happen that doctors directed more SOC resources to patients who they knew were not receiving any of the trial drugs to “balance” things out. This could be especially true as many centers in the trial are in places that may have limited experience running clinical trials.

        Regarding corticosteroids, it is true the paper says differences are “small” but we don’t know exactly how because the referenced tables are missing in the preprint.

        Another factor is that standard of care may well aggregate differently in the SOC group and the treatment groups. This is because randomization is not necessarily balanced in each center separately between treatment and SOC. Given multiple countries involved, this could be quite a mess.

  19. rhodium says:

    I have not seen much comment that when DJT got sick he got vitamin D, famotadine, then the antibodies, remdesivir and steroid. But one drug is missing (or two If you count azithromycin) although he may have gotten some zinc, too. I guess his doctors really wanted him to get well.

    1. Marko says:

      “…he may have gotten some zinc, too”

      Yes , he did :

      “Trump Takes Zinc. Maybe You Should Too”

  20. steve says:

    It all comes down to mechanism. The original HCQ in vitro study was flawed as it used Vero cells without TMPRSS. Once you transfect in TRMPRSS it did nothing in either Vero cells or in human lung organoids. The simple reason is that there are two entry methods for SARS-CoV-2 – receptor mediated and endocytotic. HCQ can block endocytosis but does squat in cells with receptor-mediated entry (which involves proteolytic activity of TMPRSS). For Remdesivir, the mechanism appears to be chain termination through competition with ATP. While this may be true for SARS-CoV-2 in vitro, it may just not achieve high enough concentration in vivo at non-toxic doses to successfully compete.

    1. theasdgamer says:

      There are three different methods of antiviral activity postulated for HCQ…alkalinization of endosomes, blocking of ACE2 receptors, and ferrying zinc into endosomes.

      Can HCQ enter endosomes mediated by TMPRSS receptors? Can HCQ ferry zinc into endosomes mediated by TMPRSS receptors?

      The virus replicates in various cells, including alveolar cells, but does its major damage through microemboli.

      So even reducing viral replication in non-alveolar cells produces some benefit.

      1. steve says:

        It makes no sense to hypothesize mechanisms for a drug that doesn’t work. The only validated mechanism for HCQ is acidification of lysosomes and that doesn’t work for SARS-CoV-2. The rest is speculative nonsense that wasted huge amounts of time, resources and money.

        1. theasdgamer says:

          Au contraire, there are 12 early treatment retrospective studies that show benefit from HC.

          Acidification of lysozomes is something only you are talking about.

          Maybe you should take up crocheting. I don’t think that medicine is your thing, lol.

          1. Steve says:

            Au contraire, restrospective studies are bullshit, only prospective randomized ones count and those all show it’s useless. Try doing science, not philosophy.

      2. Riah says:

        zinc has other benefits that are not connected to HCQ – I’m not sure it has to even get inside cells to reduce bradykinin production (by inhibiting the protease enzyme Kallikrein that is required to convert kininogens to bradykinin). I think that happens in the blood. As bradykinin is thought to be responsible for much of the unusual pathology seen in severe Covid (Derek has covered that in a previous post), it might help to add zinc to vitamin D. Vitamin D, as covered before, breaks down des-Arg9- bradykinin, the active form of bradykinin, modulates cytokynes, activates and regulates T-cells, drives antiviral (cathelicidin and defensins) production, tightens cell junctions, modulates B cells, up regulate many immune cells etc etc. It is a steroid hormone that epigenetically controls at least 300 genes involved in immunity . Another few good vitamin studies I think cements vitamin D deficiency as being a, or probably the major causal factor in covid and severe covid – not a merely contributory one:

        Beb-Gurion Uni
        Boston Uni

        I think I will forget the drugs and stick to 8,000 IU vitamin D (in coconut oil carrier, not tablet as its fat soluble), 100 micrograms K2, 400 mg magnesium (needed for both carrying/binding and activating/hydroxylating vitamin D ) and maybe zinc (but maybe not as I eat a zinc rich diet). Most people are severely deficient in both magnesium and vitamin D as its very difficult to get enough from food (no D from sun in winter).

  21. SteveM says:

    I don’t know what the real number is, but say 10,000 people a week are admitted the hospital for Covid and Remdesivir is the default standard of in-patient care. At $3,000 a pop, that’s $30,000,000 a week to Gilead. That’s a lot of Green.

    I have all kinds of respect for Dr. Fauci. But like it or not, benefit / cost has to be considered even in medicine. Fauci fronting for a high cost treatment that provides marginal if any benefit knocks him down a notch. Especially if he does not amend his endorsement of Remdesivir now given the updated information of its apparent real clinical value.

    1. Marko says:

      According to an average of these CDC estimates ( new hosp./day ), it’s probably more like ~30,000 hosp/wk , so nearly a $100 mil./ wk to Gilead if all were treated. Not too shabby , for a placebo :

  22. Digibom says:

    thanks for this good article

  23. Fraud Guy says:

    Just passing this on:

  24. drsnowboard says:

    I wouldn’t hold out much hope for Favipravir, it is a dog against flu, only approved in Japan not UK or US. Broad spectrum teratogenic antivirals have been used in the past ( ribavirin for HCV for example) but were blown out of the water by something that actually worked ie direct acting antivirals. OK, if all you want is 50% efficacy (as interferon – ribavirin was) in a pandemic, then go ahead.

  25. Philip says:

    The Solidarity trial is just another WHAT, as in Worthless Hopeless Antiviral Trial. This study, like just about all other studies to date, does not start antiviral therapies until a patient is hospitalized. That is too late in the course of SARS-CoV-2 infection to do much if any good.

    The good news from Solidarity is that if remdesivir is given late it does no harm. The bad news is we may never get results from a truly informative antiviral trial.

    1. SteveM says:

      Re: “The good news from Solidarity is that if remdesivir is given late it does no harm.”

      Except for the $3 Grand flushed down the toilet for every patient treated with remdesivir. Is Dr. Fauci going to amend his endorsement of remdesivir to save the health care system (excepting Gilead) some money?

      1. Philip says:

        SteveM, every patient treated late with remdesivir is money flushed down the toilet. That has been suspected for a long time. We do not know if remdesivir given soon after infection is effective or not. That is an answer we should have had months ago. We need trials that will answer the question of which if any antiviral therapies work if given soon after infection. Once we answer that question we still have a lot of work to do. We need to have frequent enough testing and much better tracing to catch patients early in infection. Once we can catch people early in infection we still have the problem of who to treat. For at least a hint of who to treat go back to the September 28 In The Pipeline and read about auto-antibodies to endogenous interferons.

        Please keep in mind that am not saying that any antiviral therapy works. I am saying we do not know which if any antiviral therapy works and that the Solidarity study does not answer that question.

        If $3,000 saves a life, I am all for it.

  26. PDINV says:

    Re remdesivir, I do not want to be this kind of guy, but I have to in this case 🙂

    It was clear that remdesivir is practically useless since

    1. It is an “anti-viral” that has never demonstrated reduction of viral loads in humans with any virus in any clinical trial.
    2. It is a clear NTP competitor that has shown vastly reduced potency in the lab when concentrations of ATP greater than 10 uM where used in the relevant biochemical assays
    3. It has never shown any benefit apart from rather modest “reduced hospital stay” that was mostly seen in younger adults with no complications
    4. In previous studies, higher or more doses of rwmdesivir actually resulted in more deaths than placebo
    5. First “positive” data that came out of the UK studies where communicated in a highly unethical manner that should have resulted in the study being halted. By the way, the same study changed primary and secondary endpoints several times in a clear attempt of data dredging
    6. In the previous trial that you talked about the “killer” for me was that in both the abstract and the conclusions “reduced infection” was prominently mentioned. Looking at the data, in a supppementary table there is a datapoint that says “pneumonia viral”. Basically in the same dataset in which healthier people got better “faster” there were reduced signs of pneumonia. And that is the data showing remdesivir “reducing infection” (LOL).
    7. All the above reduces dramatically the confidence that whatever weak effects they published in some of the studies are actually real. And all this for a very expensive drug that requires daily visits to the hospital for a 30 min IV administration.

    I had to say this, both as a scientist who is quiting science by my own decision starting next year (this sh1t isn’t for me and took me too long to realise) and as a member of the public who is concerned about the quality of medical information that we are flooded with the past 8 months. Not personal.

  27. theasdgamer says:

    Giving antivirals late as a “study” was always a straw man aimed at poisoning the well against RCTs of early administration of antivirals.

    Ask yourself why anyone who supposedly was competent would publish late studies of antivirals.

    1. sPh says:

      Help me understand how experimental drugs are going to be administered early in the course of COVID-19? At least in our region most people’s experience of COVID is a serious illness that takes a few sine-wave bounces up and down in effect. For the first 1 or 2 cycles the advice it to isolate at home, self-treat, and keep your primary care physician appraised of your symptoms. It is only the n% for whom the symptoms diverge upward in a cycle that are advised to go to the hospital and treated per protocol. Are you advocating prescribing drugs with potential significant side-effects off-label to persons who are still in the pedialyte, chicken soup, and acetaminophen stage of the illness? What is your estimate of the n% in your region?

      1. Marko says:

        You can do an outpatient trial on a limited , high-risk cohort first , then if it works you can trial lower-risk cohorts to see if the benefit is generalized.

        Direct antivirals , and perhaps immune modulators as well , should be prescribed in trials as early as possible , ideally on the day of confirmed PCR positivity , or within a few days thereafter , whether symptomatic or not. Plenty of people get a PCR+ test while having mild or no symptoms these days , compared to early in the pandemic , what with expanded testing , contact tracing , etc.

        A simple high-risk screen would be age , say > 65. Another would be multiple co-morbidities. Or some combination of age and co-morbidities. You can be sure that a decent fraction of these cohorts in the placebo group will eventually be hospitalized , so the sample size requirements to demonstrate efficacy in the drug will not be prohibitive. Of course , for direct antivirals , you could do sequential viral load determinations in the early days as an additional endpoint to symptom severity , hospitalization and death.

      2. theasdgamer says:

        You ask some excellent and perceptive questions.

        It’s possible that a RCT could be done in the context of an outpatient clinic. Not sure how enrollment would occur or blindness would be applied.

        Antivirals have best effect if administered as soon as symptoms occur. A family med physician would have to make a preliminary dx and begin treatment right away. How do you enroll people before that? How does a family med physician justify not treating with the tx he thinks is best in the context of a RCT? How do you solve the problem of getting a control group? Do you have to have two physicians as part of a RCT study–one who gives an antiviral and the other who thinks that giving no antiviral is best?

        And what if people are dilatory about seeing their PCP? Do you exclude people who can’t begin tx within 5 days of symptom onset?

        How do you determine primary outcomes? I favor hospitalization myself because it is well-defined and mortality reduction can be inferred from it. There would have to be exclusions for trauma, poisoning, and other obviously non-covid-related hospitalizations. Maybe you run a viral culture trial after symptoms disappear as a cutoff so that unrelated hospitalizations are excluded. Is this sufficient to decide that someone is recovered? Do you also have to look at other labs like IL-6 and neutrophil levels?

        I think that it might be helpful if Derek did a post about how to conduct an outpatient RCT for a novel infectious viral disease as a starting point for discussion.

        Do you select out the most vulnerable like black men 80+ y.o. or do you include people who represent a slice of the population? Maybe you limit your study to nursing home patients?

      3. theasdgamer says:

        Using drugs off label whose risk factors have been studied isn’t a problem in outpatient settings. Of course, that’s going to be a problem for drugs whose risk factors haven’t been studied.

        How do you test antivirals in a hospital setting, which typically is late and after viruses have been killed already?

        This is kind of like the Heisenberg Uncertainty Principle, where you can know mass or velocity, but not both. You can apply controls or you can treat with antivirals, but not both. At least medical science hasn’t figured out how.

      4. Philip says:

        Rapid Antigen Tests (RATs) in high risk environments for high risk individuals given daily. Prisoners, older faculty and staff at schools, older workers at meat packing plants and older health care workers would be a good start.

        After we know what works and when it needs to be used, we can work on how to make it happen. If we keep running Worthless, Hopeless Antiviral Studies we will never know what to do.

        1. theasdgamer says:

          We already have post hoc studies showing 80% reduction in hospitalization from Scholz and from Heras. Any RATs would be for purposes of confirmation. (Interesting idea, btw.)

        2. theasdgamer says:

          Well, am I not surprised to discover that Harvey Risch has done a meta analysis in the American Journal of Epidemiology of 12 small retrospective studies of high risk patients including the two I referenced!

  28. Robert Clark says:

    About the quoted passage from the report:

    “This absolutely excludes the suggestion that Remdesivir can prevent a substantial fraction of all deaths. The confidence interval is comfortably compatible with prevention of a small fraction of all deaths, but is also comfortably compatible with prevention of no deaths.“

    I don’t know if it works or not, but this blanket statement is over broad. Remdesivir is an antiviral. It’s well known antivirals work best early, before severe disease sets in.

    It is even still possible that Remdesivir could prevent all deaths when given in the proper window early on in the infection.

    It’s mystifying why antivirals continue to be tested under severe disease condition and NOT tested when they are well known to be most effective, early on in the disease process.

    Robert Clark

  29. Robert Clark says:

    A key comparison was left out of the report, the effect of HCQ on patients specifically under invasive mechanical ventilation. This is a key category beyond just being “ventilated”. This is when the lung inflammation is so severe the patients have to be intubated, i.e., given a breathing tube inserted down the throat.

    HCQ is a highly effective anti-inflammatory. Then it would be this case where it would be most effective for hospitalized patients. Note that the study was primarily focused on these drugs anti-viral effects. HCQ is the only one of them that also has an anti-inflammatory effect. Indeed it may be the only drug among all those being considered for COVID-19 that has both characteristics.

    Note that in the RECOVERY trial it was specifically for THIS type of ventilation that the steroid dexamethasone was found to cut mortality, via its anti-inflammatory effect.

    But in Table S1 of the Supplementary file to this SOLIDARITY report it states the “ventilation” discussed includes both invasive and non-invasive types.

    The authors need to add to the report the effect of HCQ specifically for patients under invasive mechanical ventilation.

    BTW, the report does show the result of Remdesivir on invasive mechanical ventilation patients in Fig. 3 of the report itself, showing null effect. But this was not a useful set of data anyway because Remdesivir does not have an anti-inflammatory effect.

    The more important and relevant case of HCQ was not shown.

    Robert Clark

    1. Marko says:

      The half-life of Hcq in the cells and tissues is upwards of 40 days. If Hcq is acting as an immunomodulator , it makes sense that using it early , before the immune dysregulation is established , would work best. Dex is a strong immunosuppressant , and is somewhat effective if used relatively late in disease , but not in the intubation stage.

      The best way to save intubated patients is to make sure they never get intubated in the first place.

      A trial of Hcq used on intubated patients sounds to me like another designed-to-fail trial. If that’s the goal , don’t forget to use the toxic doses.

      1. Marko says:

        Sorry , dex WAS somewhat effective when used on intubated patients. This doesn’t impact my point , however. Preventing the immune dysregulation early – before the inflammatory cascade destroys tissues , causes clotting , etc. – makes more sense than rescue therapies later.

        Hcq , interferons , and perhaps even lower-dose corticosteroids , could have the potential help prevent the inflammatory cascade that seems to become established during the transition from innate to adaptive immune response. The trick is to dampen the hyper-response without overly inhibiting a normal immune response.

        1. theasdgamer says:

          My understanding of covid is that it kills via microemboli that set off ARDS and/or kill organs via hypoxemia. This would mean that clotting would precede ARDS, not the other way around.

          1. Marko says:

            It may be a chicken/egg phenomenon , but this paper suggests to me that the immune dysregulation probably precedes the clotting problem. Admittedly, there’s more to learn about this :

            “Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome”


            “….Our findings support that the rapid release of NETs in COVID-19 contributes to their maladaptive potential and that NETs may be responsible for propagation of thrombi in the vasculature, leading to ARDS and multiorgan failure similar to other systemic inflammatory syndromes.11,34,35

            The potential involvement of NETs in COVID-19 is further supported by the well-described recruitment of neutrophils in the progression of SARS-CoV-2 pulmonary infection. Neutrophils, the effector cell for NET production, increase dramatically with COVID-19 severity and ARDS.36,37 In addition, NET cytokine signatures have been demonstrated following SARS-CoV-2 infection in patient lungs (eg, IL-1, tumor necrosis factor)38 and serum (eg, IL-6). “

          2. theasdgamer says:


            Have you seen “Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications”?


            Looks like covid produces complement-activated TMA rather than DIC.

          3. Marko says:

            No , I hadn’t , but that’s another good one. I like their take on therapeutic interventions :

            “….interventions would include anticoagulation and antiviral treatment (as would be used for DIC), as well as complement inhibition or more broad-spectrum immune suppression, plasma exchange and/or IVIG. Whether one or all of these approaches should be considered for all patients with COVID-19 and clinical laboratory evidence of TMA before severe hypoxia develops or progression to a cytokine storm is unknown; however, to ignore these options could be unwise.”

            I agree that we shouldn’t ignore these options in early treatment , especially when we have options to try that are known to be safe.

            It’s also intriguing that they report that many Covid-19 patients are positive for lupus anticoagulant , which hints at a connection between the known thrombosis prevention effect provided by Hcq in lupus patients and the potential for a similar such benefit in Covid-19.

  30. John Hasler says:

    What does HCQ do that dex doesn’t do better?

    1. Robert Clark says:

      An advantage of HCQ is that it has both antiviral and anti-inflammatory effects. Indeed it may be the only treatment that has both characteristics.
      So HCQ can be used as a treatment both in the early stage and also later when lung inflammation has taken root, the famous “cytokine storm” phase. Note that the RECOVERY trial because of the side effects of DEX, like all steroids, they actually recommended against using it in early phases of the disease.

      When the disease progression has become severe though all organs of the body become damaged and simply reducing lung inflammation can’t correct all the other damage done to the organs of the body and death can still result.

      What’s dismaying though is that this reduction in lung inflammation by HCQ and other anti-inflammatories can be seen in real-time by CAT scan imaging of the lungs. So doctors don’t have to wait for months for RCT’s to be completed or weeks later to find out if the patient dies or not, they can see within days on this key measure THEMSELVES if the medication is working or not.

      What’s dismaying is that this extremely important fact has not been communicated to doctors actually treating patients. This is not just true for HCQ but the several other anti-inflammatories shown to have a positive effect in treating COVID-19.

      Robert Clark

      1. Tom says:

        Oh goodness, you’re back with the HCQ supporting bandwagon… and I had started to think you’d disappeared from these comment sections!

        I’ll bite.

        Even if previous very small scale trials and retrospective studies may have shown any positive effect of HCQ, the overwhelming majority of data collected since shows that in fact is not the case. It is quite easy for a statistician/mathematician such as yourself to extrapolate forward the positive effect you want to see from a dataset based on the early results, I get it, but you cannot keep making the argument you want to make when the larger datasets refute your case.. this is what surprises me about you continuing to put forward the points you try to make, you should know better.

        You are not a physician or someone trained in the field of pharmaceutical/medicinal sciences. Yes scientists within their respective fields will not always agree with one another, but when the overwhelming scientific consensus from the majority these trained experts is that HCQ does not work we should trust that to be the case. A lot of these experts are working hard to fight this pandemic, and they should be trusted to do so, without the noise of opinion makers like yourself trying to make this any harder.

        Just. Leave. This. Alone.

        1. theasdgamer says:

          Evidence against HCQ is from fantasyland…late treatment…manufactured data…you have 80 studies against HCQ whose sum total of value is zero.

          Therefore there is an illusion that the bulk of evidence is against HCQ.’

          People who lack an adequate philosophy of science are prone to falling for illusions.

          1. Tom says:

            I’ll bite again.

            I’m quite secure in my belief that I have an ‘adequate philosophy of science’ considering that I do in fact have my PhD in Chemistry. That may not be sufficient for you, but it makes me feel comfortable that I have not fallen for any ‘illusion’ in my views against HCQ as a suitable Covid-19 therapy.

          2. theasdgamer says:

            Having an advanced degree in Science is no guarantee that your philosophy of science is adequate. Chemistry is a science. Philosophy of Science is an art. Philosophy of Science studies Science.

            “Science advances one funeral at a time.” Testimony to the inadequacy of Philosophy of Science among scientists.

            Until you have read Feyerabend or Kuhn, you won’t understand how much of science is irrational.

        2. Robert Clark says:

          “Oh goodness, you’re back with the HCQ supporting bandwagon… and I had started to think you’d disappeared from these comment sections!”

          The point was not just about HCQ but about the multiple anti-inflammatories shown effective against COVID-19. Doctors who are actually treating patients don’t have to wait months for a RCT to complete, and they don’t have to wait weeks to see if their patients die or not. The effect of these anti-inflammatories on lung infection can be actually SEEN on CAT scans in real time.

          Doctors treating patients can determine themselves which of these anti-inflammatories is most effective and can make that determination within days.

          A new perspective: Virtual reality shows exactly how COVID-19 can damage the lungs.
          by HEATHER GRAF, WJLAMonday, March 23rd 2020

          Robert Clark

  31. sgcox says:

    It is actually quite amusing to watch the whole HCQ saga propagates relentlessly for months and months regardless of the events in the real life..

    If President Trump ever had a curious mind, he would certainly giggle reading comments over here…

    “Throwing pebbles into the water, look at the ripples they form on the surface. Otherwise this activity will be an empty amusement.”

    1. Skeptical says:

      The only good thing to come out of the last four years, and especially, the last 10 months, is the provision of vast amounts of data for the psychologists, sociologists, and political scientists who study conspiracy theories and their adherents.

  32. LL says:

    What I am missing in the Solidarity Data (only browsed) is the stratification based on stage of infection / severity of the disease status in general:

    If I am not mistaken antivirals such as remdesivir only have an impact if they are applied during the early stage of the infection where most patients typically don’t display the severe symptoms triggering ventilation etc. When remdesivir is applied at this later stage – where the inflammation and cytokines wrack havoc, but the actual infection has either calmed down or has progressed to a point where antivirals can’t do much – then the drug can’t provide significant benefits anymore.

    If the solidarity study either focuses on the late-stage, severe patients and doesn’t discriminate application of the drug at an early stage of the infection, or it lumps everything together, then the results are not really meaningful and the conclusion is misleading.

    Doesn’t the Solidarity data squarely contradict the NEJM report indicating a significant albeit small benefit when applied early after an infection?

    1. Skeptical says:

      “If I am not mistaken antivirals such as remdesivir only have an impact if they are applied during the early stage of the infection…”

      It depends on how good the antiviral is. Every anti-infective is probably better early in the disease. But drugs for HIV and hepatitis C are very effective with established infections. Drugs for hepatitis B are effective for established infections, but are less active than those for HIV and hepatitis C. Drugs for herpes viruses, like herpes simplex or varicella zoster are mostly palliative, but they are somewhat active for established infections.

      So the notion that you can dismiss all the evidence against efficacy for hydroxychloroquine and remdesivir with “Well of COURSE it didn’t work! You didn’t give it early enough!” is disingenuous or misguided at best. What we have is good evidence that they aren’t strongly efficacious. We lack conclusive evidence that they aren’t efficacious at all (especially for remdesivir), but that isn’t saying much.

  33. Daniel says:


    Wondering if you could take a look to Aplidin. It is an anticancer compound approved in Australia which apparently is showing promising activity against coronavirus. A phase II study has concluded recently, it is all over the news here at Spain (the compound was discovered and is marketed by a small spanish pharma company)


    1. David E. Young, MD says:

      Aplidin is an extremely complex molecule made by a sea animal. This drug is not going to be manufactured from scratch (unless you are one of those university professors who take up the challenge to do so like some people climb El Capitan). It must not be a simple matter to purify Aplidin either. My guess is that manufacturing enough to treat thousands of Covid19 patients would be nearly impossible. That’s my hunch. I do applaud PharmaMar for sticking to their goal of search the sea for anti-cancer compounds. They found Yondelis, which is super, super potent on a weight basis (2.4 mg and your white count goes down to zero.). My hunch is that Aplidin is not too different. Potent, toxic and not likey a suitable drug for Covid19.

      1. Some idiot says:

        It’s actually not as complex as it first looks. It is basically a hexapeptide with a few other units thrown in for good measure. Yes, some challenges involved, but I would be far happier given the job to make a large (>50 kg) delivery of this rather than Remdesivir.

        Btw, I am a process chemist, and making API for phase 2-3 (plus delivering a process to production) is my job…! 🙂

      2. Marko says:

        “…Chemically, it is a cyclic depsipeptide originally isolated from the marine tunicate Aplidium albicans and currently obtained by total synthesis.”

        1. David Young, MD says:

          My mistake

          1. Skeptical says:

            I looked at the abstracts for some synthesis papers, and it still looked pretty involved, especially given the non-standard amino acids. However, given that it’s apparently toxic at nanomolar concentrations, the therapeutic dose, if any, would have to be small.

  34. Hólmsteinn Jónasson says:

    Ivermectin, Doxicycline and Zink works !

  35. theasdgamer says:

    This comment is about signal and noise. In the context of antivirals, late treatment studies of antivirals are all noise. n x 0 is always going to be 0, no matter how large n is. Only early treatment studies can detect signal and the signal may rise to the confidence level looked for because not enough of the vulnerable population was studied. If the vast bulk of your population is young in the case of covid, you probably won’t have significance from any signal.

    RCT’s CANNOT be anything but noise if antivirals are given after viral clearance has already occurred. Hospital studies of antivirals are worthless, for the most part.

    Otoh, underpowered studies of antivirals have the potential to provide evidence either for or against the null hypothesis if a meta analysis can combine them to establish significance. Retrospective studies of early treatment with antivirals can be used to either confirm or disconfirm the null hypothesis.

    Massive quantities of RCT’s of hospitalized patients who were given antivirals are no evidence against the null hypothesis. They are merely noise.

    Several underpowered studies of antivirals lacking significant effectiveness are not evidence against the null hypothesis either.

    Meta analyses of underpowered studies have the potential to either confirm or disconfirm the null hypothesis.

    You have to have an effective way to test the null hypothesis. That way can be either RCTs or retrospective studies, although retrospectives have more of a burden to provide significance because of confounders. A RCT might be able to provide a 90% CL of a 10% benefit while a retrospective might need to show an 80% reduction in negative outcomes to generate a 90% CL.

    The key, therefore, is to discover an effective way to test the null hypothesis.

    1. Marko says:

      “The key, therefore, is to discover an effective way to test the null hypothesis.

      Indeed. There’s a Catch-22 in play here : We have to start treatment of high-risk patients on the day of , or within a few days of , PCR-positivity , but there’s no RCT design available to do that.

      That’s not the fault of the drugs or their mechanism of action , it’s the fault of the constipated people that design and interpret what they consider to be “proper” RCTs.

      1. theasdgamer says:

        I think that PCR positivity is only useful for confirmation of the initial dx. Treatment has to occur at least the same day of the swab test and before test results are reported.

        I don’t think that the problem has to do with anal-retentive personality, but with how things have always been done which have worked well for discovering treatments for chronic, non-time-critical problems.

        The problem is really one of critical thinking about anti-viral treatments and understanding of philosophy of science.

        I’m still a little agnostic about antivirals, but I’m more concerned that science has failed to develop adequate tests of the null hypothesis. It’s not a huge deal for covid, but it might become important if a very infectious and deadly viral disease goes pandemic.
        If you want to use PCR positivity effectively, you have to do viral cultures like Raoult did.

        1. theasdgamer says:

          Treatment has to _begin_ the day that the swab is done and only patients who have begun treatment within 3 days of symptom onset should be included in the study.

          1. J N says:

            RT-PCR doesn’t record false positives, absent lab or technique error.

            That NYT article was really not helpful.

            RT-PCR is a diagnostic test. If you have a positive PCR for COVID, you either have COVID or have had COVID recently, period. It says nothing about whether you are infectious or shedding live virus.

            The various antigen tests have lower sensitivity. It’s possible that this lower sensitivity might better reflect “contagious,” but there’s no particular reason to expect that, until we know more about what makes COVID patients contagious.

            An ideal screening test would determine rapidly whether a patient is infectious or not. We don’t have such a thing. As RT-PCR can detect very low levels of viral DNA, and can’t determine whether detected virus is viable, and it’s (relatively) slow and (relatively) expensive, it’s not an ideal screening test.

            Antigen tests are of variable and not consistently great accuracy and again they don’t answer the question: “Is this person infectious?”. Instead, they answer the question “Does this person have a pretty significant load of viral antigen?” which is a reasonable surrogate for “Is this person likely infectious?”, but not the same. Antigen tests might also fail to catch many infectious subjects depending on situation.

            But the main take-away here is that PCR does not create false positives. It’s just very sensitive, which is ideal for a diagnostic test.

          2. Marko says:

            This thread describes some real world data from Australia showing the negligible false-positivity rate with PCR :


          3. theasdgamer says:


            I can’t access your twitter link. Do you have another link?

          4. Marko says:

            You can try this :


            Scroll down his twitter posts and you’ll find the discussion from ~11hrs. ago.

          5. Marko says:

            You do know you don’t have to be signed up for twitter to read twitter , right ?

            I can’t imagine why that link wouldn’t work for you.

          6. theasdgamer says:


            Any time I try to access twitter, I get a data protocol violation error.

          7. Marko says:

            Can you access this image ? :


            The relevant commentary was as follows :

            “Worth noting that this represents 607,559 COVID-19 tests with 226 positives, giving a positive rate of 0.0372%. Even if EVERY TEST was a false positive, that gives a specificity of ~99.96%.

            But, because positive people are almost always retested here we can actually examine this question more robustly. Of the 226 positive results, one was later retested and found to be a false positive!

            To calculate test specificity, we take TN/(TN+FP) = 607333/(607333+1) = 99.99984%. To put it another way, very roughly 1 false positive test per million tests done. “

          8. theasdgamer says:


            I still don’t understand how you test the test. How do you know if a result is a false positive or an asymptomatic real case. Are the tests specific for SARS-COV2 or are there other coronaviruses that will give a positive result?

          9. Marko says:

            No the PCR doesn’t react to the other coronavirus strains in any meaningful way. If it did , those results from Australia would undoubtedly have picked up many positives by that route. Besides , in developing the assay , the first thing developers look for is specificity , and the other coronavirus strains are the first thing they examine , to rule out cross-reactivity.

            There’s a legit concern with “false positives” by PCR , which Raoult and others recognize : If you want to follow active , replicating viral load throughout the course of disease , PCR can be misleading , because it will respond to viral RNA fragments even after the immune system ( or a therapeutic ) has defeated the virus. This is not an issue for the initial diagnosis or for viral load prior to the initiation of the immune clearance process – or about the first week or so after infection.

            You’re much too susceptible to stuff you read on the net. Most of it is undiluted sewage. Verify everything yourself before you incorporate it into your worldview.

          10. theasdgamer says:


            I have less faith than you in the development of PCR covid tests, especially since they were rushed. I have seen articles by nurses saying that they sent in blank swabs to test labs and the results were positive.

            Do you have any links to articles that discuss how pcr tests don’t show cross-reactivity with various coronaviruses?

          11. Marko says:

            One of the earliest ( and most rushed ? ) PCR assays – no cross-reactivity :


            Believe whatever you want. I played my tape.

          12. theasdgamer says:


            Have you seen the following paper which is cited 89 times?


          13. Marko says:

            So now we’re talking about false negatives ? This is a known and accepted characteristic of PCR , usually related to sample handling issues :

            “…In our study, we found a potentially high false negative rate of RT‐PCR testing for SARS‐CoV‐2 in hospitalized patients in Wuhan clinically diagnosed with COVID‐19. Furthermore, the RT‐PCR results showed a fluctuating trend. These may be caused by insufficient viral material in the specimen, laboratory error during sampling, or restrictions on sample transportation.”

          14. theasdgamer says:


            The PCR results were labile. You should never get positive, negative, positive within a few weeks.

        2. Marko says:

          PCR turnaround is only a couple of hours with point-of-care testing , which should be a requirement in the main recruiting sites. The big central labs are worthless for rapid PCR turnaround. One of the newer rapid molecular tests could also be used for a presumptive positive to allow start of treatment , with a follow-up PCR.

          It seems to me that it should be possible to capture some number of patients even before symptoms are present , especially if you focus on congregate settings where testing is frequent when a positive is detected , like care homes , or among contact-tracing networks.

          1. theasdgamer says:

            PCR records a large number of false positives because of over-cycling. If you’re gonna use PCR preemptively, you have to do virus culturing. But that’s dilatory.

          2. Marko says:

            Nonsense. You’re running the trial , you can set the Ct threshold at any level you like to weed out false-positives. Viral culture is only of use to distinguish false positives a week or more after infection , when sub-genomic RNA becomes problematic because of immune clearance of intact virus. By then , you’ve missed your window for early treatment and an antiviral would not be of much use in those patients anyway as they’ve passed the viral stage. Your screening has to capture people early after infection , when the virus is still replicating.

            As to viral culture , that might be useful if you’re going to carefully track viral load throughout the length of the trial. However , hospitalization or disease severity and/or death are going to be the endpoints of most interest.

          3. theasdgamer says:

            I didn’t know that labs would let you set the Ct.

            Lab cultures might let you discover false positives so that you could exclude those patients from your study. We’d have more confidence in results if trouble were taken to exclude false positives and we’d likely have more significance.

  36. Marko says:

    FDA approves Tamiflu for Covid-19. No , wait , make that remdesivir for Covid-19.

    Next in line for approval , sugar pills :

    The important thing is , the stock market will be happy.

    1. miles says:

      And the FDA bosses get to keep their jobs a little longer…

    2. Nurse Ratchet says:

      Well any anti-viral is best used early on mild to moderate patents to be “Key”, using any medications in a study on very critically ill patients you will never have decent outcomes unless your throwing a “Hail Mary” and use a steroid or IL-6 medication. Other ongoing studies show using this early on it works much better, most of the hospital and our hospital have much better success with it, if we give it once patient comes in with mild/moderate symptoms and then they go on the Covid floor, more severe patients go to the ICU.. We give supplemental humidified oxygen and we are thinking about “MATH” protocol as well.. If the Inhaled version of Remdesivir comes out, this will be more of an outpatient setting which hopefully will be more beneficial.

  37. Marko says:

    ” Some Covid Survivors Have Antibodies That Attack the Body, not Virus : New research found ‘autoantibodies’ similar to those in lupus and rheumatoid arthritis patients. But patients may also benefit from treatments for those autoimmune diseases.”

    MOA of Hcq in Covid-19 ? Not as direct antiviral , but immune-modulating , just as it is in RA and lupus treatment ?

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