Snce the first cases were reported in December 2019, infection with the severe acute respiratory coronavirus 2 (SARS-CoV-2) has become a worldwide pandemic.1,2 Cov id-19 — the illness caused by SARS-CoV-2 — is over-whelming health care systems globally.3,4 The symptoms of SARS-CoV-2 infection vary widely, from asymptomatic disease to pneumonia and life-threatening complications, including acute respiratory distress syndrome, multisystem organ failure, and ultimately, death.5-7 Older patients and those with preexisting respiratory or cardio-vascular conditions appear to be at the greatest risk for severe complications.6,7 In the absence of a proven effective therapy, current management consists of supportive care, including invasive and noninvasive oxygen support and treatment with antibiotics.8,9 In addition, many patients have received off-label or compassionate-use therapies, including antiretrovirals, antiparasitic agents, antiinf lammatory compounds, and convalescent plasma.10-13Remdesivir is a prodrug of a nucleoside ana-logue that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral RNA polymerases. Remdesivir has broad-spectrum activity against members of several virus families, including filoviruses (e.g., Ebola) and coronaviruses (e.g., SARS-CoV and Middle East respiratory syndrome coronavirus [MERS-CoV]) and has shown prophylactic and therapeu-tic efficacy in nonclinical models of these coro-naviruses.14-17 In vitro testing has also shown that remdesivir has activity against SARS-CoV-2. Remdesivir appears to have a favorable clinical safety profile, as reported on the basis of expe-rience in approximately 500 persons, including healthy volunteers and patients treated for acute Ebola virus infection,18,19 and supported by our data (on file and shared with the World Health Organization [WHO]). In this report, we describe outcomes in a cohort of patients hospitalized for severe Covid-19 who were treated with remdesivir on a compassionate-use basis
and disease-status information about their pa-tient (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Approval of requests was reserved for hospitalized patients who had SARS-CoV-2 infection confirmed by reverse-transcriptase–polymerase-chain-reac-tion assay and either an oxygen saturation of 94% or less while the patient was breathing ambient air or a need for oxygen support. In addition, patients were required to have a creatinine clear-ance above 30 ml per minute and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than five times the upper limit of the normal range, and they had to agree not to use other investigational agents for Cov id-19.In approved cases, the planned treatment was a 10-day course of remdesivir, consisting of a loading dose of 200 mg intravenously on day 1, plus 100 mg daily for the following 9 days. Sup-portive therapy was to be provided at the discre-tion of the clinicians. Follow-up was to continue through at least 28 days after the beginning of treatment with remdesivir or until discharge or death. Data that were collected through March 30, 2020, are reported here. This open-label program did not have a predetermined number of patients, number of sites, or duration. Data for some pa-tients included in this analysis have been re-ported previously.20-22 Details of the study design and conduct can be seen in the protocol (available at NEJM.org)
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Patients
Gilead Sciences began accepting requests from clinicians for compassionate use of remdesivir on January 25, 2020. To submit a request, clinicians completed an assessment form with demographic the hospital, a decrease of at least 2 points from baseline on a modified ordinal scale (as recommended by the WHO R&D Blueprint Group), or both. The six-point scale consists of the following categories: 1, not hospitalized; 2, hospitalized, not requiring supplemental oxygen; 3, hospitalized, requiring supplemental oxygen; 4, hospitalized, requiring nasal high-f low oxy-gen therapy, noninvasive mechanical ventila-tion, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death.
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Program Oversight
Regulatory and institutional review board or inde-pendent ethics committee approval was obtained for each patient treated with remdesivir, and con-sent was obtained for all patients in accordance with local regulations. The program was designed and conducted by the sponsor (Gilead Sciences), in accordance with the protocol. The sponsor col-lected the data, monitored conduct of the pro-gram, and performed the statistical analyses. All authors had access to the data and assume re-sponsibility for the integrity and completeness of the reported data. The initial draft of the manu-script was prepared by a writer employed by Gilead Sciences along with one of the authors, with input from all the authors
.Statistical Methods
No sample-size calculations were performed. The analysis population included all patients who re-ceived their first dose of remdesivir on or before March 7, 2020, and for whom clinical data for at least 1 subsequent day were available. Clinical im-provement and mortality in the remdesivir com-passionate-use cohort were described with the use of Kaplan–Meier analysis. Associations be-tween pretreatment characteristics and these out-comes were evaluated with Cox proportional hazards regression. Because the analysis did not include a provision for correcting for multiple comparisons in tests for association between baseline variables and outcomes, results are re-ported as point estimates and 95% confidence intervals. The widths of the confidence intervals have not been adjusted for multiple comparisons, so the intervals should not be used to infer de-finitive associations with outcomes. All analyses were conducted with SAS software, version 9.4 (SAS Institute).
Patient Randomization
In total, 61 patients received at least one dose of remdesivir on or before March 7, 2020; 8 of these patients were excluded because of missing post-baseline information (7 patients) and an erroneous remdesivir start date (1 patient) (Fig. S1 in the Supplementary Appendix). Of the 53 remaining patients included in this analysis, 40 (75%) re-ceived the full 10-day course of remdesivir, 10 (19%) received 5 to 9 days of treatment, and 3 (6%) fewer than 5 days of treatment.
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Unfortunately, our compassionate-use program did not collect viral load data to confirm the anti-viral effects of remdesivir or any association be-tween baseline viral load and viral suppression, if any, and clinical response. Moreover, the duration of remdesivir therapy was not entirely uniform in our study, largely because clinical improvement enabled discharge from the hospital. The effective-ness of a shorter duration of therapy (e.g., 5 days, as compared with 10 days), which would allow the treatment of more patients during the pan-demic, is being assessed in ongoing randomized trials of this therapy.No new safety signals were detected during short-term remdesivir therapy in this compas-sionate-use cohort. Nonclinical toxicology stud-ies have shown renal abnormalities, but no clear evidence of nephrotoxicity due to remdesivir thera-py was observed. As reported in studies in healthy volunteers and patients infected with Ebola virus, mild-to-moderate elevations in ALT, AST, or both were observed in this cohort of patients with se-vere Cov id-19.18,19 However, considering the fre-quency of liver dysfunction in patients with Covid-19, attribution of hepatotoxicity to either remdesivir or the underlying disease is challeng-ing.29 Nevertheless, the safety and side-effect pro-file of remdesivir in patients with Covid-19 require proper assessment in placebo-controlled trials.Interpretation of the results of this study is limited by the small size of the cohort, the rela-tively short duration of follow-up, potential miss-ing data owing to the nature of the program, the lack of information on 8 of the patients initially treated, and the lack of a randomized control group. Although the latter precludes definitive conclusions, comparisons with contemporaneous cohorts from the literature, in whom general care is expected to be consistent with that of our co-hort, suggest that remdesivir may have clinical benefit in patients with severe Covid-19. Never-theless, other factors may have contributed to dif-ferences in outcomes, including the type of sup-portive care (e.g., concomitant medications or variations in ventilatory practices) and differ-ences in institutional treatment protocols and thresholds for hospitalization. Moreover, the use of invasive ventilation as a proxy for disease se-verity may be inf luenced by the availability of ventilators in a given location. The findings from these uncontrolled data will be informed by the ongoing randomized, placebo-controlled trials of remdesivir therapy for Covid-19.
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