Compassionate Use of Remdesivir for Patients with Severe Covid-19

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).

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.

Baseline Characteristics of the Patients

Table 1 shows baseline demographic and clinical characteristics of the 53 patients in the compassionate-use cohort. Patients were enrolled in the United States (22 patients), Japan (9), Italy (12), Austria (1), France (4), Germany (2), Netherlands (1), Spain (1), and Canada (1). A total of 40 patients (75%) were men, the age range was 23 to 82 years, and the median age was 64 years (interquartile range, 48 to 71). At baseline, the majority of patients (34 [64%]) were receiving invasive ventilation, including 30 (57%) receiving mechanical ventilation and 4 (8%) receiving ECMO. The median duration of invasive mechanical ventilation before the initiation of remdesivir treatment was 2 days (interquartile range, 1 to 8). As compared with patients who were receiving noninvasive oxygen support at baseline, those receiving invasive ventilation tended to be older (median age, 67 years, vs. 53 years), were more likely to be male (79%, vs. 68%), had higher median serum ALT (48 U per liter, vs. 27) and creatinine (0.90 mg per deciliter, vs. 0.79 [79.6 μmol per liter, vs. 69.8]), and a higher prevalence of coexisting conditions, including hypertension (26%, vs. 21%), diabetes (24%, vs. 5%), hyperlipidemia (18%, vs. 0%), and asthma (15%, vs. 5%). The median duration of symptoms before the initiation of remdesivir treatment was 12 days (interquartile range, 9 to 15) and did not differ substantially between patients receiving invasive ventilation and those receiving noninvasive ventilation (Table 1).

Clinical Improvement during Remdesivir Treatment

Over a median follow-up of 18 days (interquartile range, 13 to 23) after receiving the first dose of remdesivir, 36 of 53 patients (68%) showed an improvement in the category of oxygen support, whereas 8 of 53 patients (15%) showed worsening (Figure 1). Improvement was observed in all 12 patients who were breathing ambient air or receiving low-flow supplemental oxygen and in 5 of 7 patients (71%) who were receiving noninvasive oxygen support (NIPPV or high-flow supplemental oxygen). It is notable that 17 of 30 patients (57%) who were receiving invasive mechanical ventilation were extubated, and 3 of 4 patients (75%) receiving ECMO stopped receiving it; all were alive at last follow-up. Individual patients’ changes in the category of oxygen support are shown in Figure 2. By the date of the most recent follow-up, 25 of 53 patients (47%) had been discharged (24% receiving invasive ventilation [8 of 34 patients] and 89% [17 of 19 patients] receiving noninvasive oxygen support).

By 28 days of follow-up, the cumulative incidence of clinical improvement, as defined by either a decrease of 2 points or more on the six-point ordinal scale or live discharge, was 84% (95% confidence interval [CI], 70 to 99) by Kaplan–Meier analysis (Figure 3A). Clinical improvement was less frequent among patients receiving invasive ventilation than among those receiving noninvasive ventilation (hazard ratio for improvement, 0.33; 95% CI, 0.16 to 0.68) (Figure 3B) and among patients 70 years of age or older (hazard ratio as compared with patients younger than 50 years, 0.29; 95% CI, 0.11 to 0.74) (Figure 3C). Sex, region of enrollment, coexisting conditions, and duration of symptoms before remdesivir treatment was initiated were not significantly associated with clinical improvement (Table S1).

Mortality

Seven of the 53 patients (13%) died after the completion of remdesivir treatment, including 6 of 34 patients (18%) who were receiving invasive ventilation and 1 of 19 (5%) who were receiving noninvasive oxygen support (see the Supplementary Appendix for case narratives). The median interval between remdesivir initiation and death was 15 days (interquartile range, 9 to 17). Overall mortality from the date of admission was 0.56 per 100 hospitalization days (95% CI, 0.14 to 0.97) and did not differ substantially among patients receiving invasive ventilation (0.57 per 100 hospitalization days; 95% CI, 0 to 1.2]) as compared with those receiving noninvasive ventilation (0.51 per 100 hospitalization days; 95% CI, 0.07 to 1.1]). Risk of death was greater among patients who were 70 years of age or older (hazard ratio as compared with patients younger than 70 years, 11.34; 95% CI, 1.36 to 94.17) and among those with higher serum creatinine at baseline (hazard ratio per milligram per deciliter, 1.91; 95% CI, 1.22 to 2.99). The hazard ratio for patients receiving invasive ventilation as compared with those receiving noninvasive oxygen support was 2.78 (95% CI, 0.33 to 23.19) (Table S2).

Safety

A total of 32 patients (60%) reported adverse events during follow-up (Table 2). The most common adverse events were increased hepatic enzymes, diarrhea, rash, renal impairment, and hypotension. In general, adverse events were more common in patients receiving invasive ventilation. A total of 12 patients (23%) had serious adverse events. The most common serious adverse events — multiple-organ-dysfunction syndrome, septic shock, acute kidney injury, and hypotension — were reported in patients who were receiving invasive ventilation at baseline.

Four patients (8%) discontinued remdesivir treatment prematurely: one because of worsening of preexisting renal failure, one because of multiple organ failure, and two because of elevated aminotransferases, including one patient with a maculopapular rash.

Laboratory Data

Given the nature of this compassionate-use program, data on a limited number of laboratory measures were collected. Median serum ALT, AST, and creatinine fluctuated during follow-up (Fig. S2).