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. Table 1. Baseline Demographic and Clinical 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

Figure 1. Figure 1. Oxygen-Support Status at Baseline and after Treatment. For each oxygen-support category, percentages were calculated with the number of patients at baseline as the denominator. Improvement (blue cells), no change (beige) and worsening (gray) in oxygen-support status are shown. Invasive ventilation includes invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), or both. Noninvasive ventilation includes nasal high-flow oxygen therapy, noninvasive positive pressure ventilation (NIPPV), or both.

Figure 2. Figure 2. Changes in Oxygen-Support Status from Baseline in Individual Patients. Baseline (day 0) was the day on which treatment with remdesivir (RDV) was initiated. Final oxygen support statuses shown are based on the most recent reported data. For each patient, the colors in the line represent the oxygen-support status of the patient over time. The colored circles to the left of each line indicate the patient’s overall change in status from baseline. A patient’s status “improved” if the oxygen-support status improved before the last follow-up or the patient was discharged. The vertical black marks show the last day of treatment with RDV. The gray dashed lines represent missing data between the patient’s most recent reported oxygen status and an event (death or discharge) or the last dose of RDV. A solid square at the end of a line indicates that the patient died; an open diamond indicates that the patient was discharged from the hospital. If there is neither a square nor a diamond at the end of a line, neither death nor discharge had occurred. Patient 2 was breathing ambient air through day 36. Patients 19 and 31 were discharged on day 44.

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).

Figure 3. Figure 3. Cumulative Incidence of Clinical Improvement from Baseline to Day 36. Clinical improvement is shown in the full cohort, in the cohort stratified according to ventilation status at baseline, and in the cohort stratified by age.

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

Table 2. Table 2. Summary of Adverse Events.

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).