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    6 Comments for this article
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    COVID-19: Remdesivir failure; Or "Standard Care" Success?
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Thank you for your study. I am sorry that your 'double-blind' methodology ended up being open-label. Although this might seem to represent one in a series of 'failures' supporting the use of remdesivir in the treatment of COVID-19, I would like to look at it the other way around. I believe that your study shows the success of "standard care" of serious cases of COVID-19. "Standard care" included use of steroids, HCQ, lopinavir-ritonavir, tocilizumab, and azithromycin. Although the control group received these medications, (making it an unworthy control group) yours is a successful study group with an effectiveness equivalent to that of remdesivir. This may support the use of the "standard care" until the administration of vaccine. Thank you and stay safe.
    CONFLICT OF INTEREST: None Reported
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    Clinical Efficacy at Best Uncertain
    Jean-Francois Grenier |
    The authors duly mention several limitations of this open-label study. One point though that does not seem to be sufficiently discussed is the discrepancy observed between the statistically significant difference of the 5-day remdesivir (RMD) course vs standard care (SC) and the lack of significance of the 10-day RMD course vs SC taking into consideration that the actual median treatment length was 5 vs 6 days! So, with one additional day of treatment length, statistical significance is lost. This observation alone should lead us to seriously question the meaningfulness of the statistical significance observed in the 5-day RMD treatment group. />
    Therefore, I beg to disagree with the statement made in the joining editorial comment "Some of the RCT findings suggest remdesivir could improve recovery for many millions of individuals around the world who may be hospitalized with COVID-19."

    I'd rather say that, at this time, we do not have any convincing evidence that RMD could improve recovery of patients hospitalized with COVID-19.
    CONFLICT OF INTEREST: None Reported
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    Why Was This Study not Double-blinded and Placebo-controlled?
    David Keller, MS, MD | Internal Medicine Physician
    In an open-label clinical trial such as this, every participant and physician was potentially aware of whether placebo or remdesivir (the medication under investigation), was being administered in each case. Therefore, the results of this trial are not placebo-controlled, nor controlled for other expectation effects.

    Furthermore, the impact of expectation effects is magnified in this trial by the small or absent differences in clinical outcomes between the three groups of subjects, and the reliance on statistical analysis to detect these differences.

    Therefore, the placebo effect cannot be ruled out as falsely contributing
    some or all of the putative benefits of treatment. Contrariwise, the nocebo effect could have falsely detracted from the magnitude of treatment benefit.

    Given the greater accuracy of double-blinded placebo-controlled trials compared with open-label trials for measuring treatment effects, it is important to discuss why the investigators chose not to invest whatever additional resources would have been required to have provided a double-blinded placebo control.

    The authors state: "Treatment was open label because the sponsor had an insufficient number of placebo-containing vials to support this trial."

    But surely the cost of providing vials of saline placebo would have to be utterly miniscule to the sponsor of this trial, Gilead Sciences, a large, well-capitalized pharmaceutical company which owns the patent on remdesivir (brand-named "Veklury"). For the trivial price of a few hundred empty vials with Veklury labels, Gilead Sciences sacrificed the more accurate results that could have been obtained from a placebo-controlled trial, and the resulting clinical benefits to their customers' patients, and potential profits to their company's shareholders.
    CONFLICT OF INTEREST: None Reported
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    Five Day and Ten Day Remdesivir Study Devolved into a Different Study.
    Craig Fink, Rocket Scientist (BSAE) |
    Thank you for your study.

    So, the "double blind" devolved into an "open-label" clinical study. It also devolved in another way, the 10-day remdesivir (RMD) treatment group devolved into what is essentially the 5-day RMD treatment followed by an extra 5-days of "standard care". So, the three treatment groups are essentially.

    1) 5-day RMD treatment with discharge from "standard care" on day 6
    2) 6-day RMD treatment with discharge from "standard care" on day 11
    3) "Standard care" treatment.

    The major difference for the RMD treatment groups being the additional 5 days of "standard care"
    where the patients recovery from 5.5 days of RMD treatment declined the longer they received "standard care"

    I'd rather say that, at this time, it's fairly convincing evidence that RMD, even though it was used improperly, works. But, it is the "Standard Care" that is problematic as the extra 5 days of "standard care" showed a significant decline in metrics of the study.
    CONFLICT OF INTEREST: None Reported
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    Remdesivir doesn't seem to be fulfilling expectations for increased effectiveness over standard care
    Steven Brenner, MD | Saint Louis University (retired)
    While there is some difference between standard care at the 5 day level, 10 day level seems to go the other way, which intuitively doesn't make much sense.

    With those kind of results, one would be led to believe that after five days of treatment, stop because additional treatment makes things worse, and that could be a legitimate result, since there may be other effects besides just arresting viral replication.

    The borderline improvement over standard care raises the issue of whether it should have designation as emergency authorization due to no other approved medication for COVID-19.


    Just this afternoon, there was emergency authorization for convalescent plasma, which may have benefit, although cellular response may be the most important for long term immunity if there is success with a vaccine.

    Should there be emergency authorization for other treatments, such as hydroxychloroquine, which had US emergency authorization which was then withdrawn? And more recently, there appears to be some benefit from dexamethasone.

    Likely, multiple medications or a drug cocktail will be necessary, with the benefits of each drug hopefully outweighing drawbacks.

    With the large number of patients now in the world, in the millions rather than thousands, statistical analysis is losing its applicability. Statistics is utilized to obtain a representative sample from a large population and then extrapolate to larger numbers, however numbers of patients treated now is numbering in the millions so tabulating basic results from gross numbers will likely be more important in determining real world treatment results than statistical sampling in research institutions.

    There have been some problems obtaining different results from different studies. This could relate to different medical systems in different countries being including in sampling, and may even reflect changes in the pathogenicity of different strains of SARS-CoV-2, since it was thought the virus in Europe was losing pathogenicity.

    Comparing results among countries with different approaches to treatment may provide more information than isolated sampling.
    CONFLICT OF INTEREST: None Reported
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    Remdesivir Paradox
    Erdem Cantekin, PhD | None
    This article reports that remdesivir treatment for patients with moderate COVID-19 provides some benefit, but the "difference was of uncertain clinical importance" [1].  Those conclusions do not support findings from a previous NIH-funded "preliminary" randomized trial [2].  In fact, it supplements the findings of a different report [3]. Regardless, in late August 2020 FDA approved use of remdesivir for the treatment of all hospitalized COVID patients [4].

    The conclusions of the NIH clinical trial were not supported by that incomplete data presented in the article (2). After three months, we are still waiting for a final report from
    the NIH while thousands are treated with remdesivir. The primary data of the NIH trial should be available to qualified parties.

    References:

    1. Spinner et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients with Moderate COVID-19A Randomized Clinical Trial JAMA. Published online August 21, 2020. doi:10.1001/jama.2020.16349 

    2. Beigel et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report N Engl J Med. May 22, 2020 DOI: 10.1056/NEJMoa2007764.

    3. Wang et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;395:1569-1578.

    4. FDA News Release: COVID-19 Update: FDA Broadens Emergency Use Authorization for Veklury (remdesivir) to Include All Hospitalized Patients for Treatment of COVID-19 For Immediate Release: August 28, 2020.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    August 21, 2020

    Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

    Author Affiliations
    • 1Technical University of Munich, School of Medicine, University Hospital Rechts der Isar, Munich, Germany
    • 2Baylor University Medical Center, Dallas, Texas
    • 3Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
    • 4Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
    • 5Azienda Ospedaliera di Padova, Padova, Italy
    • 6Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain
    • 7Yale School of Medicine, New Haven, Connecticut
    • 8North Shore University Hospital, Manhasset, New York
    • 9University of Chicago, Chicago, Illinois
    • 10IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
    • 11National University Health System, Singapore
    • 12Leiden University Medical Center, Leiden, the Netherlands
    • 13Princess Margaret Hospital, Hong Kong, China
    • 14Ente Ospedaliero Cantonale, Bellinzona, Switzerland
    • 15University of Nantes, Nantes, France
    • 16National Taiwan University Hospital, Taipei, Taiwan
    • 17Gilead Sciences, Foster City, California
    • 18King’s College, London, England
    • 19Royal Free Hospital, London, England
    • 20Seoul Medical Center, Seoul, South Korea
    • 21Virginia Commonwealth University, Richmond
    • 22Cook County Health, Chicago, Illinois
    • 23Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
    JAMA. 2020;324(11):1048-1057. doi:10.1001/jama.2020.16349
    Visual Abstract. Remdesivir vs Standard Care and Clinical Outcomes in Patients With Moderate COVID-19
    Remdesivir vs Standard Care and Clinical Outcomes in Patients With Moderate COVID-19
    Key Points

    Question  Does remdesivir provide a benefit on clinical status for patients hospitalized with moderate coronavirus disease 2019 (COVID-19) pneumonia?

    Findings  In this randomized, open-label, phase 3 trial that included 584 patients with moderate COVID-19, the day 11 clinical status distribution measured on a 7-point ordinal scale was significantly better for those randomized to a 5-day course of remdesivir (median length of treatment, 5 days) compared with those randomized to standard care. The difference for those randomized to a 10-day course (median length of treatment, 6 days) compared with standard care was not significantly different.

    Meaning  Hospitalized patients with moderate COVID-19 randomized to a 5-day course of remdesivir had a statistically significantly better clinical status compared with those randomized to standard care at 11 days after initiation of treatment, but the difference was of uncertain clinical importance.

    Abstract

    Importance  Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.

    Objective  To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.

    Design, Setting, and Participants  Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.

    Interventions  Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.

    Main Outcomes and Measures  The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.

    Results  Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.

    Conclusions and Relevance  Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

    Trial Registration  ClinicalTrials.gov Identifier: NCT04292730

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