Weekly COVID-19 Research Update
May 6, 2020
During the COVID-19 pandemic, it is vital to make objective and informed decisions that affect your family and loved ones. As part of Princeton Longevity Center’s strategic partnership with PinnacleCare, we are excited to bring you their Pandemic Response Research updates as a complimentary resource through the remainder of this crisis. These updates will bring you factual, objective, scientific information to help make safe decisions for you, your family and your community. Updates, while scientifically based, are easy to understand and will include both resources and references for a more clinical insight.
What is FDA Emergency Use Approval (EUA)?
The FDA process for approving diagnostic and screening tests is a complicated process even during times without a health emergency. The FDA status of COVID-19 tests has been very confusing, in part due to imprecise wording used in the media, but also due to unclear messages from federal officials.
There is an FDA provision for providing access to a test or drug during emergency situations, like a pandemic, is called an Emergency Use Authorization, or EUA. This provision allows the FDA Commissioner “to allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life- threatening diseases or conditions when there are no adequate, approved, and available alternatives.”
Several studies on the antiviral drug remdesivir were released. One of the trials, called the Adaptive COVID-19 Treatment Trial, or ACTT, was organized in part by the National Institutes of Health, and an interim analysis of the results was made available (NIH, 2020). The results did not have the large positive benefit expected based on cell culture experiments and investigations in animal models. The researchers found that there was a reduction in the median time to recovery from 13 days to 11 days in hospitalized patients with severe symptoms from COVID-19. This corresponds to a 31% faster time to recovery with the drug. There was no statistically significant difference in the mortality rate between the two groups (8% for those receiving the drug and 11.6% for those who did not). An associated trial, called the SIMPLE trial, was announced on the same day by Gilead, the company that manufactures remdesivir (Gilead, 2020). One important point learned from the SIMPLE trial was that a five-day dosing period worked similarly to a ten-day dosing period, which would conserve the medication while achieving the same results.
There was also news of a trial performed in China using remdesivir (Silverman et al., 2020 and Gilead, 2020). The results from the trial were accidently published on the WHO website before they were supposed to be released. The trial had been terminated before its expected end date due to an insufficient number of participants, but the results from those who completed the trial were analyzed. The results of the study were officially published a few days later in The Lancet (Wang et al., 2020). The authors of the paper state that remdesivir use was not associated with statistically significant clinical benefits. As with the NIH trial, there was no statistically significant difference in the mortality rate between participants who had been treated with remdesivir (13.9%) and those who did not receive the treatment (12.8%). The researchers found that there was a reduction in the time to clinical improvement in those treated earlier, but suggest that because the trial was small it was not possible to determine if this was a statistically significant difference. The WHO commentary on the results stated that in the study of “hospitalized adult patients with severe COVID-19 that was terminated prematurely, remdesivir was not associated with clinical or virological benefits.”
Drug Studies to Reverse the Immune Response to COVID-19
There is evidence that the severe symptoms observed in some hospitalized individuals with COVID-19 result from an extremely intense reaction from their own immune system. This phenomenon, called a cytokine storm, involves an overresponse from a protein called a cytokine that is used as a messenger to recruit immune system components to the site of an infection or injury. The main cytokine that has been identified as contributing to this scenario is called IL-6. IL-6 has also been identified as contributing to autoimmune diseases such as rheumatoid arthritis, and there are drugs that have been developed to reduce the effect of IL-6 for these diseases. Clinical trials to determine if the drugs have an effect on the cytokine storm associated with COVID-19 have been organized, and two recently released preliminary results.
In one study, researchers evaluated the effects of a drug called Kevzara (Herper, 2020). The trial included two groups, those with severe symptoms and those with very severe symptoms, referred to as the critical group. When all the participants were evaluated as one group, there was no benefit from the use of Kevzara. However, when the individuals in the critical group were analyzed separately, there was a small benefit where an extra 1 in 10 patients who received high-dose Kevzara was discharged from the hospital compared to those who received placebo. A similar study in China, using another version of the drug from a different manufacturer called Actemra, showed similar results and was halted early due to a lack of effect.
Another study in France is investigating the effect of tocilizumab, an antibody treatment that reduces the effect of IL-6 (APHP, 2020). The details of the study have not yet been published, but the results were announced by the hospital where the trial occurred. Participants in the study had been hospitalized for moderate or severe COVID-19. There were a total of 129 participants, and 65 received tocilizumab in addition to standard of care while 64 received standard care alone. Fewer participants in the group receiving tocilizumab died or needed ventilation during the 14 days they were monitored.
There has been increased discussion about antibody testing to better define the course of the outbreak and to determine if so called “herd immunity” is being approached. In its current state, antibody testing has a high false-negative rate that prevents it from defining immunity on an individual level. For example, one of the tests that has been granted an EUA by the FDA is made by Cellex, and the company reports that the test has a 95% sensitivity and 95% specificity (Dall, 2020). This level of accuracy would mean that testing conducted in a million people would correctly detect 47,500 cases, 2,500 false-negatives, and 47,500 false-positives.
With this accuracy, if 5 % of a population was infected, the number of true-positives and false positives would be the same, or in other words there is a 1 in 2 chance it is not the real result. Informing 47,500 people that they had had the virus when they had not could vastly increase their risk of actually getting COVID-19 because of the potential relaxation of infection prevention measures. A group that big could also start a sizable infection cluster that would promote transmission of the outbreak.
Even if the potential false positives associated with the recently released antibody surveys in California, New York, and Florida do not end up contributing significantly to the results, the level of potential immunity in the population is still well below that needed to stop transmission of the virus. The level of immunity required can range from 60% to 90% depending on how contagious the virus is, and it is estimated that 70% would be necessary in the case of COVID-19 (Dowdy and D’Souza, 2020 and Dean and Rivers, 2020). Experts are concerned by the erroneous narrative emerging after the release of these reports, which suggests that the fatality rate is much lower than originally predicted and that shutdowns of communities were an over- reaction. While the number of people who die from COVID-19 may be less than originally estimated, the rapid spread of the virus has revealed that the number of cases at one time can quickly overwhelm the healthcare systems of even potentially well-equipped regions, like Italy. If the levels of infection reported in the surveys (ranging from 2.5% to 4% in Santa Clara County, CA; 3% to 6% in Los Angeles County, CA; 6% in Miami-Dade County, FL; and 14% across New York state) do correspond to the number of people who are now immune, which has not been determined, lifting restrictions at this time would still lead to transmission rates at levels similar to those observed at the start of the outbreak.
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Assistance Publique-Hôpitaux de Paris. Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID-19 pneumonia. Published April 27, 2020. Accessed on May 3, 2020 at https://www.aphp.fr/contenu/tocilizumab-improves-significantly-clinical- outcomes-patients-moderate-or-severe-covid-19
Dall C. Antibody tests may hold clues to COVID-19 exposure, immunity —but it’s complicated. CIDRAP News. Published April 15, 2020. Accessed on April 21, 2020 at https://www.printfriendly.com/p/g/aygumU
Dean NA, Rivers C. Antibody tests show we’re nowhere near herd immunity. The New York Times. Published April 29, 2020. Accessed on May 3, 2020 at https://www.washingtonpost.com/outlook/2020/04/29/antibody-test-coronavirus-fatality- immunity/
Dowdy D, D’Sousa G. Early Herd Immunity against COVID-19: A Dangerous Misconception. Johns Hopkins Coronavirus Resource Center. Published May, 2020. Accessed May 3, 2020 at https://coronavirus.jhu.edu/from-our-experts/early-herd-immunity-against-covid-19-a-dangerous- misconception
Gilead. Gilead Sciences Statement on Data From Remdesivir Study in Patients With Severe COVID-19 in China. Published April 23, 2020. Accessed on May 4, 2020 at https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on- data-from-remdesivir-study-in-patients-with-severe-covid-19-in-china
Gilead. Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients With Severe COVID-19. Published April 29, 2020. Accessed on May 3, 2020 at https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces- results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19
Herper M. Closely watched arthritis drug disappoints as a Covid-19 treatment, studies show. STAT News. Published April 27, 2020. Accessed May 3, 2020 at https://www.statnews.com/2020/04/27/arthritis-drug-kevzara-disappoints-as-coronavirus- treatment/
NIH. NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19. Published April 29, 2020. Accessed on May 3, 2020 at https://www.niaid.nih.gov/news- events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19
Silverman E, Feuerstein A, Herper M. New data on Gilead’s remdesivir, released by accident, show no benefit for coronavirus patients. Company still sees reason for hope. STAT News.
Published April 23, 2020. Accessed on May 4, 2020 at https://www.statnews.com/2020/04/23/data-on-gileads-remdesivir-released-by-accident-show- no-benefit-for-coronavirus-patients
Wang Y et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. Published April 29, 2020. Accessed May 3, 2020 at https://www.thelancet.com/journals/lancet/onlinefirst