By: The New England Journal of Medicine (https://www.nejm.org/)

Abstract

BACKGROUND

Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2.

METHODS

We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day.

RESULTS

Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation.

CONCLUSIONS

In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.)

Since 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 Covid-19 — the illness caused by SARS-CoV-2 — is overwhelming 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 cardiovascular 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, antiinflammatory compounds, and convalescent plasma.10-13

Remdesivir is a prodrug of a nucleotide analogue 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 therapeutic efficacy in nonclinical models of these coronaviruses.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 experience 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.

Methods

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 and disease-status information about their patient (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-reaction 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 clearance 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 Covid-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. Supportive therapy was to be provided at the discretion 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 patients included in this analysis have been reported previously.20-22 Details of the study design and conduct can be seen in the protocol (available at NEJM.org).

STUDY ASSESSMENTS

Data on patients’ oxygen-support requirements, adverse events, and laboratory values, including serum creatinine, ALT, and AST, were to be reported daily, from day 1 through day 10, and additional follow-up information was solicited through day 28. Although there were no prespecified end points for this program, we quantified the incidence of key clinical events, including changes in oxygen-support requirements (ambient air, low-flow oxygen, nasal high-flow oxygen, noninvasive positive pressure ventilation [NIPPV], invasive mechanical ventilation, and extracorporeal membrane oxygenation [ECMO]), hospital discharge, and reported adverse events, including those leading to discontinuation of treatment, serious adverse events, and death. In addition, we evaluated the proportion of patients with clinical improvement, as defined by live discharge from 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-flow oxygen therapy, noninvasive mechanical ventilation, or both; 5, hospitalized, requiring invasive mechanical ventilation, ECMO, or both; and 6, death.

PROGRAM OVERSIGHT

Regulatory and institutional review board or independent ethics committee approval was obtained for each patient treated with remdesivir, and consent 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 collected the data, monitored conduct of the program, and performed the statistical analyses. All authors had access to the data and assume responsibility for the integrity and completeness of the reported data. The initial draft of the manuscript was prepared by a writer employed by Gilead Sciences along with one of the authors, with input from all the authors.

STATISTICAL ANALYSIS

No sample-size calculations were performed. The analysis population included all patients who received 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 improvement and mortality in the remdesivir compassionate-use cohort were described with the use of Kaplan–Meier analysis. Associations between pretreatment characteristics and these outcomes 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 reported 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 definitive associations with outcomes. All analyses were conducted with SAS software, version 9.4 (SAS Institute).

Results

PATIENTS

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 postbaseline 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%) received 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.

Read more: https://www.nejm.org/doi/full/10.1056/NEJMoa2007016