April 29 2020
Dr. Fauci announced today on live TV that preliminary results from double-blind, randomized, placebo-controlled multi-center trial of Remdesivir titled Adaptive COVID-19 Treatment Trial (ACTT, ClinicalTrials.gov Identifier: NCT04280705) involving 1063 patients demonstrated that Remdesivir shortened time to clinical improvement from 15 to 11 days with p<0.001.
There was no difference in mortality between groups. The press-release was published at the National Institute of Allergy and Infectious Diseases (NIAID) web site.
Dr. Fauci proceeded to say that from now on Remdesivir is a new “standard of care” for patients with COVID-19. Markets rallied on the news.
Great news? Not so fast!
Coincidentally, The Lancet published today Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial of 237 patients titled A Trial of Remdesivir in Adults With Severe COVID-19 (ClinicalTrials.gov Identifier: NCT04257656) conducted earlier this year in China with participation of the researchers from the UK (Oxford, Cambridge, Lancaster), and the US (from the University of Virginia School of Medicine). Contrary to the NIH results, this trial did not demonstrated difference in time to clinical improvement, although there was a “signal” that such improvement is possible. There was no difference in mortality with 15% and 13% of patients dying by day 28.
Why did these trials produce different results? The short answer - we do not know yet, because results of the NIH trial are yet to be finalized, made available to the public, and published in a peer-reviewed journal. The comparison of preliminary results of NIH trial and published peer-reviewed Chinese trial is difficult, if not impossible.
There are some clues, although, which can be obtained from comparing these trials based on Clinicaltrials.gov descriptions and The Lancet article.
First and foremost, NIH trial enrolled x 4 times more patients, although the number of patients in the NIH treatment group must be confirmed. The Chinese study had 158 patients in the treatment group.
Second, Chinese trial randomized patients 2:1 vs. NIH 1:1;
Third, Chinese trial enrolled patients with severe disease with 100% of the treated patients requiring supplemental oxygen vs. 95% in placebo group, while NIH allowed patients with disease of moderate severity, although careful review of the Chinese study reveals that only <10% required ventilation;
Forth, Chinese trial was conducted on hospitalized patients, while NIH trial also followed patients who were discharged from hospital. This implies that such patients had less severe disease;
Fifth, comparison of the eligibility criteria reveals:
Chinese trial required both laboratory (RT-PCR) confirmation of COVID-19 AND lung involvement confirmed by chest imaging;
NIH trial also required laboratory (RT-PCR) confirmation of COVID-19 and at least one of the following:
Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
SpO2 < / = 94% on room air, OR
Requiring supplemental oxygen, OR
Requiring mechanical ventilation.
This begs the question: were radiographic changes confirmed in all patients, or not? If not, what is the basis for the diagnosis of viral pneumonia?
Chinese trial enrolled patients with < or = 12 days after illness onset vs. NIH trial allowed enrollment of patients with illness of any duration. This means that some NIH patients might have been enrolled at the time when they were already improving anyway.
6. Six, Chinese trial allowed concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. We do not know yet, if NIH patients were permitted to receive other treatments.
Dr. Why: Dr. Fauci’s announcement that preliminary data warrant change of the standard of care sounded premature. This reminds me the situation with Hydroxychloroquine when preliminary data indicated possible benefit, only to be crushed by more diligent research. I must say that it was clear without any research that the latter would not work. One only needed to do a literature review to demonstrate that 60 years of attempts to use Hydroxychloroquine for treatment of more than 50 viral diseases failed (refer to the post from March 21st "Can Chloroquine Work for COVID-19?"). The situation is different with Remdesivir, because it is an antiviral with well documented mechanism of action.
Another important reminder we must derive from NIH trial that even if final analysis will confirm preliminary findings, use of medications may only shorten the time to improvement by approximately 30%, hence we are not talking about cure, although less time to recovery is still important. Interestingly, use of Tamiflu to treat influenza resulted in similar outcome: shortening of the time to improvement by 30% from 5 to 3.5 days. The Tamiflu also shown to prevent the disease, if used prophylactically after exposure to the virus. It will be very interesting to see, if the same will be true for Remdesivir. If yes, this will be a major positive by itself.
Dr. Fauci made another mistake: he changed the standard of care by (political) decree, which goes contrary to all established conventions when such change requires serious peer-reviewed research and agreement between experts, societies and the government. This is reminiscent of his “decree” changing the way cause of death is determined (see blog posts: from April 8th "Cause of Death", and "Liberal Approach to Mortality?", as well as from April 22nd "Inconvenient Truth" ). Both mistakes are bad precedents and must be reversed and explained to the public and future generations of physicians.
The announcement reached one goal - rally the financial market. It also serves political goals of the current administration by demonstrating that something good may be happening and there might be a light at the end of the tunnel. I will pray and hope that this is not just a wishful thinking.