Many Doctors Weigh in: Hydroxychloroquine (HCQ), Zinc and Azithromycin Should be Greenlighted for COVID-19

_{Barry Arrington

April 14, 2020

Intelligent Design}

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It’s important to note that HCQ, zinc, and azithromycin are very well understood drugs with clear safety profiles; they are widely available, generic, inexpensive, and can be scaled rapidly, including to the developing world…

Our primary strategic objective must be to prevent ICU overwhelm, which on our current course is imminent in most states. It is an axiom of infectious diseases that treatment in earlier stages is more effective than treating advanced stages. Early COVID-19 treatment is more likely to prevent disease progression to critical status, radically lowering hospitalizations and CFR than inaction.

Current clinical drug trials are mostly focused on treating late stages of disease, when immunologic damage is a dominant threat. We believe that trials should focus on earlier stage infection to prevent progression to advanced disease.

Some health authorities have given the typical caution against early treatment until large, peer-reviewed, randomized controlled trials (RCTs) provide conclusive data. We fully support the continued effort to investigate existing and novel pharmaceuticals to determine the best intervention through blinded and controlled trials. Weighing the urgency of this unprecedented situation combined with the effects of inaction, plus the relative safety of the drugs, and the preponderance of data showing effective early treatment significantly decreases the percentage of cases that progress to needing hospitalization, we believe that the proposed recommendation is not only adequately founded but ethically obligate[d]…

Early clinical reports suggest it’s best to treat within 5 days of symptom onset. Waiting until a patient is hospitalized or critically ill is unwarranted and unwise.

Comments

To break a lance for Bob O'H and in reply to the "parachute" trial: bornagain77 wrote: "I wonder if Bob O’H will volunteer for the following randomised controlled trial? Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials" Non randomized/blinded trial **can** have conclusions, if the effect size is big enough: We know from a long history of clinical trials that - The placebo effect: It is real and can effect the outcome with up to 30%. I. e., some patients in a trial **always** get better, just because they believe on being treated. Thus a non-blinded trial on the patient side **always** yields slightly better results than standard of care. - Evaluation bias: Humans **want** to see a positive effect. Thus if the evaluator is not blinded towards whether the patient was dosed, the results are always slightly better. - Selection bias: If the researcher decides which patients to include and which to exclude in his results (as Raoul did) we **know** that he will unconsciously bias the results, even if he tries to be objective. All these three points are unimportant in a "parachute study" with a large effect size. If we chuck two people out of an airplane and both of them survive, we can conclude that parachutes are effective, because there is a really big difference between 100% survival and the 0% survival which is reported from standard care (= no parachute). In such a trial, a control group without parachute would be unethical, since we know that these patients would die. However if two people wearing parachutes cross a street and survive, we cannot conclude that parachute are effective against traffic accidents, since 9999 out of 10 000 people survive crossing streets. To see such small effects, we need blinded, randomized trials of big groups. It is not unethical to not provide a parachute, since we do not know if a parachute actually helps. It might even increase the risk (begin bulky and such). Clincal trials on terminal cancer patients are airplane-parachute studies and done without any control group. COVID-19 is a street-crossing parachute study. Look at Raoult's reported results: only 10 out of 2500 people treated died. That's 0.4% and looks good compared to the 3% we see floating around. However, the real mortality rate is **not** known. It is likely to be around 1%, but might be 0.1%. Or 5%. Add to this, that his 0.4% where affected by the placebo effect. And add to this that Raoult selected which patients to include in the study. I cannot stress enough how **useless** this makes this study. We know, for example, that mortality rate is higher in social classes with less income (for a variety of reasons). Thus simply the effect that you might have to pay to receive the treatment, that patients drove from outside the area to participate or other factors would induce a selection bias which would be easily large enough to explain his results. Even statistical error makes this difficult to distinguish from the 1%. All this does not mean that HCQ does not work. And do not forget: doctors **are** authorized to use it. We just do not **know** right now if it works. And we know that Dr. Raoult knows all this and decided to do it anyway. And for that reason I call him a quack.Ernst Reim_{April 20, 2020
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Jerry @ 64 - as kf notes, the problem is size. We'd need larger sample sizes to be sure the patterns aren't just noise. They also only accepted patients who had a mild case, i.e. the patients who are less likely to die. What I take from this study is that it's worth doing larger studies.Bob O'H_{April 17, 2020
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kf @ 59 -
You also know that informed opinion is studies on the grand scale you envision would come in at best a year from now.
Err, no, the UK's trial, which is just starting, is saying they expect results by June.
You also continue to duck the summary certificate on Raoult’s study, now at the 2500 level.
The summary certificate doesn't mitigate the glaringly obvious methodological problems with the "study".Bob O'H_{April 17, 2020
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Jerry, they object to size. It seems a 100,000 trial is now starting up. Wec await the new objections. KFkairosfocus_{April 16, 2020
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Hey, there has be a controlled double blind test done in China.
Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial But for TTCR, the body temperature recovery time and the cough remission time were significantly shortened in the HCQ treatment group. Besides, a larger proportion of patients with improved pneumonia in the HCQ treatment group (80.6%, 25 of 31) compared with the control group (54.8%, 17 of 31). Notably, all 4 patients progressed to severe illness that occurred in the control group. However, there were 2 patients with mild adverse reactions in the HCQ treatment group. Significance: Among patients with COVID-19, the use of HCQ could significantly shorten TTCR and promote the absorption of pneumonia. Reactions to HCQ - one patient developed a rash and one patient experienced a headache when they compared CT changes seen on day six as compared to day zero
https://www.medrxiv.org/content/10.1101/2020.03.22.20040758v3 Let's here if from the nitpickers. They are in the comments section which I am sure our nitpickers will reinforce.jerry_{April 16, 2020
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I wonder if Bob O'H will volunteer for the following randomised controlled trial?
Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials Excerpt: We were unable to identify any randomised controlled trials of parachute intervention. Conclusions As with many interventions intended to prevent ill health, the effectiveness of parachutes has not been subjected to rigorous evaluation by using randomised controlled trials. Advocates of evidence based medicine have criticised the adoption of interventions evaluated by using only observational data. We think that everyone might benefit if the most radical protagonists of evidence based medicine organised and participated in a double blind, randomised, placebo controlled, crossover trial of the parachute. https://www.bmj.com/content/327/7429/1459
bornagain77_{April 16, 2020
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Because no sick patients were refused treatment as a control, an inhuman action by any standard, critics argue that the results were worthless. Those critics are in fact people who do not have the coronavirus. The truth is that the entire infected world of people who were not given this drug were the control. Their lengthy recovery times are the data.

Hydroxychloroquine is a pleiotropic drug, a fancy way of saying it works in many mysterious ways. One primary action is that it increases the pH of lysosomes inside cells from around 4 to 6. This inhibits acidic proteases and decreases intracellular processing, glycosylation, and protein secretions. In antigen-presenting cells, this leads to a decrease in inflammatory activities. Perhaps more importantly, in other cells infected with the coronavirus, this leads to a decrease in viral loads.

Hydroxychloroquine also binds to specific zinc transporters, or zinc ionophores, and keeps them open. If excess zinc is available, this presumably lets more zinc enter the cell. Zinc appears to alter the membrane permeability of lysosomes,7 but it has another important function. It can block the unique RNA-dependent RNA polymerase (RdRP) of the coronavirus.8 Although the literature calls hydroxychloroquine itself an ionophore, it only binds to the real zinc ionophores in the cell. This term is at best awkward and at worst misapplied.
There is a lot more. From one of the inference references posted: https://inference-review.com/report/therapeutic-options-for-covid-19jerry_{April 16, 2020
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BO'H, and in the face of a fast acting killer plague, what is a sugar pill, again? As in "an i ____ t___. " See what dismissing evidence in hand leads to? KFkairosfocus_{April 16, 2020
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@58 BobO'H
so we can be confident we are not going to kill patients by giving them ineffective treatments.
Where in 'nature' is it written that we shall not kill? Is killing objectively wrong?Truthfreedom_{April 16, 2020
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BO'H: you know just what you wrote and just who it was meant to dismiss directly [Zelenko et al] and indirectly [Raoult et al]. I quote you from 56 above, again: "OK, so no trial results yet." KF PS: You also know that informed opinion is studies on the grand scale you envision would come in at best a year from now. Too late for the pandemic we deal with. You also continue to duck the summary certificate on Raoult's study, now at the 2500 level. And more.kairosfocus_{April 16, 2020
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kf @ 57 -
Why are you still in denial of the fact of multiple, global in vivo trials?
Huh? When have I denied that trials are taking place?
I suggest to you that it is thus manifestly improper for you to dismiss Professor Raoult’s work as not being “proper trials.”
I can dismiss it because I have the expertise to understand the problems with his work - no control groups, no randomisation (for example).
And, double-blind, placebo control studies will necessarily expose a significant fraction of patients to a disease capable of killing and/or of — emerging — major organ damage — within 2 weeks or less [much less] of onset. Such poses double ethical dilemmas in the face of the equivalent of a world war.
I agree. So everyone should be trying to reduce the time to get enough results. This means doing the studies rigorously, so we can be confident we are not going to kill patients by giving them ineffective treatments.
Those informal reports are increasingly backed by Raoult’s work and other studies.
What other studies? I know there's a small one from China from a few weeks ago that suggested an effect in mild cases, but even the document in the OP says "According to ClinicalTrials.gov, there are 47 CQ/HCQ & COVID-19 trials with only 1 complete and results not yet published. There are two small RCTs from China available in pre-publication."Bob O'H_{April 16, 2020
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BO'H:
OK, so no trial results yet
Why are you still in denial of the fact of multiple, global in vivo trials? And notice, again, this regarding Professor Raoult's work, per Google Translate . . . and as again appears at 54 above:
Research protocol approved by the ANSM and the Île-de-France CPP in progress at the IHU Méditerranée Infection: Treatment of respiratory infections with Coronavirus SARS-Cov2 by hydroxychloroquine Acronym: SARS-CoV2quine.”
I suggest to you that it is thus manifestly improper for you to dismiss Professor Raoult's work as not being "proper trials." You are in the position of demanding a type of study that as the NIH reports, at best will deliver results a year from now (similar to the likely outcome on vaccines, though local news just had Cuba claiming to have an oral/nasal delivery vaccine in trials). The real-world, non Ivory Tower strategic and ethical decision problem here is, we have a disease capable of killing 100's of thousands to tens of millions over the next several months. And, double-blind, placebo control studies will necessarily expose a significant fraction of patients to a disease capable of killing and/or of -- emerging -- major organ damage -- within 2 weeks or less [much less] of onset. Such poses double ethical dilemmas in the face of the equivalent of a world war. In that context, we have a natural contrast of types of treatments and outcomes, with literally thousands of professionally recorded cases showing a strong pattern of clearing viruses in about 5 - 7 days, with some cases taking more than that. Significant numbers of patients report impact within 24 hours, consistent with the 4th power law on fluid flow with constrictions, i.e. relatively small changes in cross section have significant impact. In this context, it is unsurprising that, as Raoult further reports, there is a global wave of [emergency use] approvals, including that India has specifically approved for prophylaxis. All of this has been headlined here at UD with source-links, so there is no good reason for you to have written as above, in a way that is all too reminiscent of the "there's no evidence . . ." claim we have seen so often over the years here. A claim, that exposes selective hyperskepticism, a fallacy that ill-advisedly tries to promote targetted skepticism as a virtue in place of prudence. Where, too, I again point out the Inference Review article BA77 brought to our attention yesterday:
Antimalarial Drugs as COVID-19 Therapy J. Scott Turner J. Scott Turner is Professor of Biology at the State University of New York College of Environmental Science and Forestry, and a Fellow of the Stellenbosch Institute for Advanced Study. Section Special Reports Published April 10, 2020 Chloroquine (CQ) and hydroxychloroquine (HCQ) are showing promise as therapeutic treatments for COVID-19 infections. These drugs are widely used for the treatment of malaria, and their use against COVID-19 was a source of some controversy in the early stages of the current pandemic. Nevertheless, the FDA has recently given emergency approval to what had long been a common off-[label] use application for treatment of viral infections. This approval was granted in light of a long history of using CQ and HCQ as antiviral drugs, including during past coronavirus epidemics. Furthermore, informal reports [--> in fact, see Raoult et al, as well as studies across the world, it is not just Zelenko et al] coming from emergency and critical care clinics indicate they are effective against COVID-19, particularly when combined with antiviral agents and antibiotics.”
Those informal reports are increasingly backed by Raoult's work and other studies. The fundamental challenge is to strike the balance of adequate warrant to base responsible action in the face of a global pandemic with life and health on the line. That forces us to balance accessible degree of empirical warrant with urgency, given the quasi infinite value of life on the line. In that context, fair comment: it is ill-advised or worse to suggest in the teeth of evidence on the table that "OK, so no trial results yet . . . " KFkairosfocus_{April 16, 2020
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OK, so no trial results yet. In vitro results don't support treatment straight away - humans are not Petri dishes, and it's axiomatic in drug development that most drugs that show promise in vitro or even in animals won't be clinically effective - there are just too may other variables involved. That's why we have clinical trials - to test that they are effective, and to work out what dose to use (the Brazilian study that had to stop showed that their high dose was too high, for example). By not doing proper trials, Raoult is helping to delay the possible deployment of HCQ. And if it's ineffective, he's helping to extend the use of an ineffective and possibly dangerous treatment.Bob O'H_{April 16, 2020
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Hydroxychloroquine in the management of critically ill patients with COVID-19: the need for an evidence base https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(20)30172-7/fulltext Fourth, the search for effective new drugs requires appropriate and valid trials—ie, prospective, randomised, placebo-controlled clinical studies. Although many drugs have in-vitro activity against the virus, the proposal that such drugs might provide more benefit than harm is inappropriate in the face of no clinical evidence supporting efficacy and safety in patients with COVID-19. International multicentre studies, such as the Discovery study (NCT04315948) and the Solidarity study (EudraCT Number 2020-000982-18), will randomise patients with COVID-19 to receive different antiviral drugs, including hydroxychloroquine, in an adaptive study design. These initiatives will provide important data to guide the management of patients with COVID-19 and help to improve understanding of the effects of antiviral therapies in critically ill patients.rhampton7_{April 15, 2020
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Jerry & BO'H: trials, in both science [including med] and statistics are subject to ethical controls; that automatically means, there's more than one way to skin a catfish. In this context, I already put up the control on Raoult's work, per Google Translate: "Research protocol approved by the ANSM and the Île-de-France CPP in progress at the IHU Méditerranée Infection: Treatment of respiratory infections with Coronavirus SARS-Cov2 by hydroxychloroquine Acronym: SARS-CoV2quine". As BO'H knows or knows he should know, there are other results on the ground. Ideologically loaded selective hyperskepticism and no true Sassenach in the face of a fast moving pandemic where 1 1/2 weeks can be time from onset to demise, with demise effectively irreversible in too many cases once cytokine storm fully sets in, cannot be justified ethically. Not when such trials are announced in terms like: "NIH scientists said urgent clinical evidence is needed. Even so, the study is not estimated to be completed until July 2021. " In vitro studies showed broad chemical effectiveness since 2005, as published. Case investigations and other studies have shown a growing pattern of evidence of effectiveness. We are dealing with known quantity drugs, and as BA77 linked earlier today,
"the FDA has recently given emergency approval to what had long been a common off-use application for treatment of viral infections. This approval was granted in light of a long history of using CQ and HCQ as antiviral drugs, including during past coronavirus epidemics. Furthermore, informal reports coming from emergency and critical care clinics indicate they are effective against COVID-19, particularly when combined with antiviral agents and antibiotics."
In short, there is evidently a track record here, reflected in clinical results. Which, is what Prof Raoult and Dr Zelenko have further put on the table. Where, the case study method is a longstanding, recognised method of investigation AND per phil of sci, despite the school "method," there is no one size fits all and only conventionally labelled sciences. Moreover, logic and epistemology are actually aspects of core philosophy, so, yes, worldviews issues and ideology are pivotal. This point is of course directly relevant to longstanding major issues at UD and to the ongoing civilisational, cultural civil war. Which, in the USA, is at low end 4th gen civil war level. KFkairosfocus_{April 15, 2020
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It’s funny seeing evos, who obviously don’t care about science, talk of scientific trials.
Bob O’H believes in ID. Have you ever seen him present an argument that undermines it?jerry_{April 15, 2020
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What science? Does he have scientific trials to back up his claims
You are making a fundamental mistake. Science and scientific trials are not the same thing. As someone just pointed out Darwinian processes are not science. There can never be a scientific trial to prove Darwin’s ideas. And you know it!!!!!jerry_{April 15, 2020
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It's funny seeing evos, who obviously don't care about science, talk of scientific trials.ET_{April 15, 2020
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@49 Bob O'H
Does he have scientific trials to back up his claims?
Did Darwin have any scientific trial to back up his claim that 'natural' selection has designing capabilities? How can you scientifically test such an abstract concept? Because fairy-tales (I can imagine this process went this way blah blah blah add some fairy dust...) ARE NOT science.Truthfreedom_{April 15, 2020
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I prefer Zelenko since his protocol is simple, logical, backed by science and extremely inexpensive.
What science? Does he have scientific trials to back up his claims?Bob O'H_{April 15, 2020
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Jerry, the key person is Didier Raoult
He certainly is getting the most press. What is interesting is that the polarization going on for treating this disease mirrors the debate on politics. It also seems to mirror the debate on evolution. I have always emphasized the most fascinating thing about the evolution debate is human behavior towards it. It has nothing to do with science or reason or logic. It is all emotional. It seems this same human behavior shows up in lots of areas and the debate over HCQ and CQ is just another canary in the mine to the inner soul of individuals. I come here not to debate evolution anymore since it is so obvious what is known and not known. But I find that the pro ID people provide the best insights into science in general and I have learned more about the virus through links here than anywhere else. Which I said, I find interesting as a general assessment of human behavior. All this means is that there seems to be some broad underlying world view which determines how one reacts to facts. Which I said is the most fascinating part of these debates. I prefer Zelenko since his protocol is simple, logical, backed by science and extremely inexpensive. But the knives are out for Raoult by the obvious people which says to me he must be onto something. PS - most of the objectors come from the left of the political spectrum. They fail to recognize that the Jacobins turned on Robespierre and sent him to the guilotine. They should look up the Montagnards and Girondins. Eventually the left always turns on its own and destroys them.jerry_{April 15, 2020
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Jerry, the key person is Didier Raoult. KFkairosfocus_{April 15, 2020
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BA77 sent several links to articles on the virus in a science journal. I read the first one on the history of CQ and HCQ and it is also a brief history of malaria and how these drugs might work. Gets very technical at end but first part is fascinating history. https://inference-review.com/report/antimalarial-drugs-as-covid-19-therapyjerry_{April 15, 2020
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What verification do we have for Zelenko’s claims at this time?
The New York Times verified his results. By the "dog barking in the night" verification process. They did a hit piece on him but said nothing about his results being invalid. Can you imagine if his results were misrepresented that the Times would not have reported it.jerry_{April 15, 2020
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What verification do we have for Zelenko's claims at this time?Seversky_{April 15, 2020
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None of the studies is comparable. That is the problem.
Probably could be said about anything in life. But three times the daily dosage as Zelenko, who claims near 100% success, seems like it should be pointed out. And also for twice as long. It leaves a false impression which was not warranted. Especially when some of the doctors using see a distinct change for the better within 12 hours.jerry_{April 15, 2020
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F/N: A reminder for those who need to clarify the timeline on crisis management: https://uncommondescent.com/medicine/tracking-covid-19-apr-3-are-we-peaking-for-this-wave/#comment-697652 KFkairosfocus_{April 15, 2020
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PS: My first linked begins:
Immediate Treatment for Early Stage SARS-CoV-2 Infections Recommended To Be Supported Nationally Starting Now A strategic principle and practical approach to rapid response to novel pandemics Authored by Ben Kaplan Singer, M.D.; Daniel Stickler, M.D.; Avery J. Knapp Jr., M.D.; with many contributing doctors. BOTTOM LINE: Our primary strategic objective must be to prevent ICU overwhelm, which on our current course is imminent in most states. It is an axiom of infectious diseases that treatment in earlier stages is more effective than treating advanced stages. Early COVID-19 treatment is more likely to prevent disease progression to critical status, radically lowering hospitalizations and CFR than inaction. Current clinical drug trials are mostly focused on treating late stages of disease, when immunologic damage is a dominant threat. We believe that trials should focus on earlier stage infection to prevent progression to advanced disease. Given the suggestion of efficacy of hydroxychloroquine (HCQ), and the imperative to treat disease before it progresses to cytokine storm, we believe that the current data are sufficient to recommend FDA provisional approval for early outpatient treatment of COVID-19 with HCQ plus zinc and azithromycin. This triple combination treatment can be modified where needed in patients with prolonged QTc or other contraindications at the physicians’ discretion Following this same rationale, we recommend that other clinical trials involving drugs that have already been approved for non-COVID-19 diseases, and for which the safety profile is well understood and reasonably acceptable, should begin clinical trials on patients in early stages of COVID-19 disease, alongside patients with more advanced disease.
kairosfocus_{April 15, 2020
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Folks, again, look here; where of course the map in my OP here from Prof Raoult speaks for itself on what the verdict on HCQ is in many significant countries, including Brazil, the US. Russia, India, China, Italy and South Korea. Instapundit is interesting, in:cluding this comment:
Narniaman • 3 days ago As most know, the media/Democrat politicians/FDA want the use of the hydroxychloroquine/azithromycin/zinc combination to be restricted until late in the course of the infection, when the patient's infection is well-advanced. As a physician, this baffles me. I can't think of a single infectious condition -- bacterial, fungal, or viral -- where the best medical treatment is to delay the use of a anti-bacterial, anti-fungal, or anti-viral until the infection is far advanced.
It would be interesting to see a cogent answer. KFkairosfocus_{April 15, 2020
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None of the studies is comparable.
Ed doesn't know that.ET_{April 14, 2020
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