New NIH Clinical Trial May Cause Pulmonary Damages and Deaths

This article reviews the clinical trial protocol announced this May 14 by the National Institutes of Health in the US, to study the effectiveness of hydroxychloroquine / azithromycin as a treatment for COVID-19. While this research may look like a good idea at first glance, the analysis here suggests it’s crippled with flaws and is unlikely to be of any usefulness. It also suggests that, with an anticipated 1000 patients being, by design, denied the very early treatment it is deemed to study, the research may lead to pulmonary damages and deaths. 

The analysis presented here focuses on three aspects: the absence of zinc from the treatment protocol, while zinc is now widely understood to be a key in any early therapies; the use of large numbers of placebo patients and the deep ethical issues associated with denying treatment to them; and the bias of Dr Fauci and NIH, which have fast tracked the competing redemsivir drug, despite no evidence it reduces mortality.

In the concluding remarks, it is argued that the large clinical trials, touted by WHO and many governments as a solution to find therapies for COVID-19, seem to have mostly failed. Rather, the therapeutic advances to treat COVID-19 occurred thanks to clinical excellence, know-how, creative thinking, good medicine, by individual doctors or small teams of doctors and researchers, around the world. This was done in a very short amount of time, under intense pressure to do what’s best for patients and to save lives.

This May 14, the US National Institutes of Health (NIH) announced a major clinical trial “to evaluate whether the malaria drug hydroxychloroquine, given together with the antibiotic azithromycin, can prevent hospitalization and death from coronavirus disease 2019 (COVID-19).”

This is a major trial, involving a range of institutions throughout the US: Alabama CRS; UCSD Antiviral Research Center CRS; Rush University CRS;  Greensboro CRS; Cincinnati Clinical Research Site; Ohio State University CRS; University of Pittsburgh CRS; Dallas Trinity Health and Wellness Center CRS; University of Washington AIDS CRS. All these sites are now recruiting volunteer patients.

The trial intends to recruit 2000 volunteer patients, half of them to be given placebo. Patients will be at least 18 year old, will have tested positive for COVID-19, and will have at least one of these symptoms: fever, cough or shortness of breath.

To participate, all volunteer patients have to agree not to obtain any medications outside the study, even if such medication could very well save their life …

Don’t hold your breath for results any time soon. The estimated primary completion date is October 9, 2020, while the estimated study completion date is March 5, 2021 – a timing that is disconnected from the 7 days duration of the tested treatment and the two weeks follow-up period.

All the existing research about hydroxychloroquine and azithromycin, including the 1061 patients study completed in Marseille, by the world’s #1 expert in infectious diseases Professor Didier Raoult, is presented as “anecdotal” by NIH. 

Dr Anthony Fauci – who by the way ranks much lower on the world’s ranking of experts in infectious diseases by Expertscape, declared: “Although there is anecdotal evidence that hydroxychloroquine and azithromycin may benefit people with COVID-19, we need solid data from a large randomized, controlled clinical trial.”

While this randomized controlled trial is just starting, it is not without major flaws. We examine three of them in this article.

Sub-Optimal Treatment

The most obvious flaw of the NIH research is about Zinc. As we already reported on April 6, well before the NIH research was submitted to clinicaltrials.gov, there were clear indications that Zinc was emerging as a key element for hydroxychloroquine-based treatments. 

Several researchers had already provided scientific explanations about the role of Zinc in controlling the spread of the disease. And a NY-based medical doctor, who pioneered the use of Zinc with his outpatients, also emphasized its role. The role of Zinc was also stressed by Dr Anthony Cardillo, who treats COVID-19 patients in the Los Angeles area.

This is pretty old news, and various other treatment protocols now include Zinc in their formulation. An example is the research conducted in Sao Paulo, Brazil, where hydroxychloroquine, azithromycin given in combination with Zinc, enabled to considerably reduce the need for hospitalization. All of this is not new and could have easily been integrated into the research protocol.

And then of course came the NYU study, “Hydroxychloroquine and azithromycin plus zinc vs hydroxychloroquine and azithromycin alone: outcomes in hospitalized COVID-19 patients” by by Philip M. Carlucci, Tania Ahuja, Christopher Petrilli, Harish Rajagopalan, Simon Jones and Joseph Rahimian. The study shows the considerable role of Zinc in reducing mortality for those patients hospitalized but not in ICU. 

The study was commented by Chris Masterson, PhD, who announced that, as far as he was concerned, he was going to want a treatment with Zinc plus Hydroxychloroquine plus Azithromycin, in case he would catch the disease.

Threat to the Placebo Patients Lives

The clinical trial proudly announced by NIH could actually be responsible for the death of dozens of patients. Why? There are two equal groups, those with treatment, and those with placebo. For those with treatment, we have already analyzed that treatment is sub-optimal, as lacking Zinc. In the NYU study analyzed above, the mortality rate was statistically significantly higher without the Zinc. 

The group the most at risk is obviously the placebo controlled group, made of up to 1,000 volunteer patients, who will have given their “consent” – a document that is not publicly available but which probably repeats the WHO refrain that there is no proven cure for COVID-19 – and agreed with the Fauci doctrine, that hydroxychloroquine-based treatments are anecdotal. These patients will receive the “standard of care” and be denied any form of effective treatment.

As is now known since the first study by Raoult’s team, dated March 20, and was actually known before by the Chinese, the key with this disease is to catch it early. The reason is pretty simple. It’s a viral infection and the viral load is reduced through early treatment. This March 20 study already showed how the combination hydroxychloroquine with azithromycin was the most effective in reducing the viral load. 

Already at the time, these researchers decided it was not appropriate, on an ethical basis, to have a randomized controlled trial, yet there was a control group made of individuals who did not want to get the treatment.

Now what will happen in this NIH randomized controlled trial? Half of the patients will not get treatment, at the crucial time treatment is effective and can essentially stop the disease in its tracks. Half of these well intended volunteer patients will not receive the hydroxychloroquine azithromycin combination. We are talking here about 1000 people. This means that their likelihood of later mortality from the disease, and also the likelihood of lasting pulmonary damage if they survive, will be much higher. 

How many will die in the control group? Professor Didier Raoult, in his landmark research on 1061 patients, achieved a 91.7% success rate in curing patients within 10 days.  Some patients needed longer care, yet the study indicates 98.7% of patients were cured. Some patients died (8 – aged 74 to 95, corresponding to 0.75% of the treated patients), and the outcome for a few patients was still uncertain by April 18, when the latest evaluation of the data was carried out. The actual case fatality rate among treated patients withing the study is not known, but is comprised between 0.75% and 1.3%.

What will be the case fatality rate for the placebo patients receiving the “standard of care,” i.e. no treatment? In the US, presently, the case fatality rate is around 5.9%. If one takes this number, one would expect about 59 deaths in the placebo group. In the treatment group, if the Raoult’s outcomes are reproduced, one can estimate to between 7 and 13 the number of deaths in the treatment group. Therefore one can make a very indicative forecast that approximately 40 to 50 deaths may be caused by the non-provision of early treatment with hydroxychloroquine and azithromycin to the placebo control group.

It’s important to note that it’s absolutely not necessary to have such a large study with so many patients. It’s very likely that after a few dozens of patients, the difference between treatment and placebo would become clear. And as already alluded to, the difference between treatment and placebo would even be starker if Zinc was part of the protocol. For further analysis about this issue of sample size and other pitfalls of randomized trials, see our previous analysis “COVID-19 Treatment Research: Time to Indict the Randomized Trials.”

The conventional wisdom is that randomized controlled trials are the gold standard when it comes to clinical research. But reality is that, in these pandemic times, those are not conducted according to the proper ethical standards. 

As previously analyzed in this blog, for many years, there have been internationally recognized ethical principles for clinical trials. These principles can be found in the Helsinki Declaration, first approved in 1964, not long after WWII and its medical research atrocities.

The Helsinki Declaration recognizes the need for research for medical progress, yet emphasizes: 

“It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.”

The use of placebo is covered in some detail in the Helsinki Declaration, which emphasizes that the benefits, risks, harms, and effectiveness of a new intervention should be tested and compared to those of the best existing proven interventions / treatments.

There are some limited exceptions to this general principle, yet patients receiving placebo “will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.”

Clearly, this NIH trial, as well as so many trials for COVID-19 treatments, seems to be in blatant breach of these ethical principles. Many innocents may lose their life because they will be denied treatment. 

This fundamental ethical issue is why Professor Raoult and his team refused to proceed with randomized controlled trials for their own research. They also emphasized that participating in such trials is contrary to the Hippocratic Oath that medical doctors have to take.

NIH / Fauci Bias

Dr Fauci has been leading the way in discrediting hydroxychloroquine, repeatedly stating it’s unproven. Despite the well-established safety profile of the drug, NIH developed recommendations against its use, after FDA had provided emergency approval for using the drug for COVID-19. 

Dr Fauci, who incidentally had daily calls with CNN Chris Cuomo who followed a novel “corona protocol” that includes an hydroxychloroquine analog, has been very keen in touting another medication, remdesivir, even if there is no scientific evidence that the drug, that is very expensive, has well established toxicity and side-effects and requires hospitalization for the intra-venous treatment, has any efficacy in reducing mortality.

On April 29, on the same day The Lancet published a peer reviewed article showing remdesivir to be ineffective for COVID-19, Dr Fauci at a press briefing in the White House Oval Office, referred to preliminary, non-published, non-peer reviewed, findings of a study about remdesivir and sponsored by his own NIH institute. He was soon to declare the drug to be very promising and, days later, to got it approved by the FDA on an emergency basis as the new standard of care in the US – an episode that will likely make the history books and that we previously covered in some detail. 

Against that background, how could any research sponsored by NIH about hydroxychloroquine / azithromycin be taken seriously? And it’s not only because Fauci’s obvious preference for Remdesivir. It’s well known that one of the contemplated goals of Dr Fauci is large scale and maybe even compulsory vaccination. Early treatment with the extremely cheap generic hydroxychloroquine and azithromycin drugs, as recommended by Professor Didier Raoult, is not only a vital threat to remdesivir but also to vaccination.

Concluding Remarks

Even if it could easily yield results rapidly, on a much smaller sample of patients, the time frame announced by NIH will make the study of little use. This alone should shed doubts about it. But there is much more. Because the protocol is so outdated, the results won’t be of much help either, when they will emerge. So maybe this is not the helpful research exercise that one could naïvely think it is. Maybe this research is more kind of a political tactic to attempt addressing the criticisms that have emerged vis-à-vis NIH and Dr Fauci, following the April 29 oval office media event.

It’s not only in the US that research efforts are being somewhat manipulated for political ends. In France, lots of research efforts were launched just to “validate” the work of Prof. Raoult. This occurred in particular under the auspices of the European DISCOVERY programme.  What happened is that, as reported in the French media, clinical trials have an increasingly hard time recruiting volunteer patients. One of the researchers responsible for the European DISCOVERY programme told the media that they had just been able to recruit a single patient outside France, in Luxembourg. That’s a bit short, knowing that there are now 27 countries in the European Union!

In France, one of the reasons why volunteers cannot be found for the clinical trials is that many people don’t want to eat a placebo as they know it won’t cure them from COVID-19. Professor Raoult is well known and popular in France, and polls conducted by IFOP indicated that a majority of the French population believed in his treatment. In addition, with the declining epidemic, like in other initially hard hit countries such as Italy and Spain, recruiting volunteer patients for clinical trials is increasingly hard. Actually, all these countries have to varying extents official treatment guidelines that embrace hydroxychloroquine and azithromycin, and there is now a better understanding in the medical profession about how to treat COVID-19, including through early treatment and outpatient care.

The UK RECOVERY programme, thanks probably to a high incidence of the epidemic in the UK, coupled with a suspicious consensus between the UK government and the UK media that there is no cure whatsoever for COVID-19, was able to recruit thousands of volunteer patients. The problem with that programme is that it’s also not testing the right treatments. We covered this a long time ago in this blog There there is an arm with hydroxychloroquine alone, and another with azithromycin  alone. Zinc is not on the radar screen. In the mean time, hydroxychloroquine-based treatments are being denied to the population, with an epidemic still raging and large case fatality rates in the country, especially in the elderly homes. 

All of this points to a failure of the large scale WHO instigated research programmes that were supposed to generate the solutions for treating COVID-19 patients. There have been, however, major advances for the clinical treatment of COVID-19. How did they occur?

It was largely work done in countries such as China and South Korea initially, on which Professor Raoult and his team relied upon. The therapeutic advances to treat COVID-19 seem to have occurred instead thanks to clinical excellence, know-how, creative thinking, good medicine, by individual doctors or small teams of doctors and researchers, around the world. This was done in a very short amount of time, under intense pressure to do what’s best for patients and to save lives. 

It’s too early to write the history of these therapeutic efforts that made a difference, but some names and initiatives can already be mentioned. NY-based Dr Vladimir Zelenko, who first used in March the combination of hydroxychloroquine with azithromycin and zinc for treating his patients, is a prime example of foresight. Those general practitioners in France, who started treating early with azithromycin and zinc, as the government was not giving them access to hydroxychloroquine, need also to be mentioned.

The East Virginia Medical Group initiative, with Professor Paul E. Marik, having developed comprehensive protocols covering prophylaxis, early treatment and later treatment, is also to be highlighted. The NYU retrospective study analyzing the effects of adding zinc to hydroxychloroquine / azithromycin treatment is another example of highly helpful work.

All these initiatives, and others that we did not cover here but exist in countries such as Spain, Italy, Germany, South Korea, etc. have brought, in a short amount of time, a much better understanding of the disease and how to best treat it. Real doctors, having the health of their patients at heart, may have done much more to advance therapeutic treatments for COVID-19 than grandiose research efforts, several of them falling apart, others being way too slow, and most of them yielding no useful results for those on the front lines, for saving lives.

In that context, it may be useful for all the researchers involved in this new NIH study, which is not asking the right questions, is way too large, and will arrive way too late, to reconsider their protocols, to make them more helpful and timely. And most importantly, they may want to reconsider giving placebos to innocent volunteer patients, which will likely cause, for many of them, severe lifelong pulmonary damage, and may send several of them to their death.

The author, Jean-Pierre Kiekens is an independent policy analyst, a former Lecturer at the Université Libre de Bruxelles, and a Graduate from the Universities of Brussels and Oxford. This is a blog article, presenting a reasonably informed opinion on this matter. It’s food for thought for those who want to understand what’s going on.

© 2020 Jean-Pierre Kiekens. All Rights Reserved.