Objective. To assess the efficacy, safety, and clinical benefit of remdesivir in hospitalized adults with confirmed pneumonia due to severe SARS-CoV-2 infection.
Design. Randomized, investigator-initiated, placebo-controlled, double-blind, multicenter trial.
Setting and participants. The trial took place between February 6, 2020 and March 12, 2020, at 10 hospitals in Wuhan, China. Study participants included adult patients (aged ≥ 18 years) admitted to hospital who tested positive for SARS-CoV-2 by reverse transcription polymerase chain reaction assay and had the following clinical characteristics: radiographic evidence of pneumonia; hypoxia with oxygen saturation ≤ 94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg; and symptom onset to enrollment ≤ 12 days. Some of the exclusion criteria for participation in the study were pregnancy or breast feeding, liver cirrhosis, abnormal liver enzymes ≥ 5 times the upper limit of normal, severe renal impairment or receipt of renal replacement therapy, plan for transfer to a non-study hospital, and enrollment in a trial for COVID-19 within the previous month.
Intervention. Participants were randomized in a 2:1 ratio to the remdesivir group or the placebo group and were administered either intravenous infusions of remdesivir (200 mg on day 1 followed by 100 mg daily on days 2-10) or the same volume of placebo for 10 days. Clinical and safety data assessed included laboratory testing, electrocardiogram, and medication adverse effects. Testing of oropharyngeal and nasopharyngeal swab samples, anal swab samples, sputum, and stool was performed for viral RNA detection and quantification on days 1, 3, 5, 7, 10, 14, 21, and 28.
Main outcome measures. The primary endpoint of this study was time to clinical improvement within 28 days after randomization. Clinical improvement was defined as a 2-point reduction in participants’ admission status on a 6-point ordinal scale (1 = discharged or clinical recovery, 6 = death) or live discharge from hospital, whichever came first. Secondary outcomes included all-cause mortality at day 28 and duration of hospital admission, oxygen support, and invasive mechanical ventilation. Virological measures and safety outcomes ascertained included treatment-emergent adverse events, serious adverse events, and premature discontinuation of remdesivir.
The sample size estimate for the original study design was a total of 453 patients (302 in the remdesivir group and 151 in the placebo group). This sample size would provide 80% power, assuming a hazard ratio (HR) of 1.4 comparing remdesivir to placebo, and corresponding to a change in time to clinical improvement of 6 days. The analysis of primary outcome was performed on an intention-to-treat basis. Time to clinical improvement within 28 days was assessed with Kaplan-Meier plots.
Main results. A total of 255 patients were screened, of whom 237 were enrolled and randomized to remdesivir (158) or placebo (79) group. Of the participants in the remdesivir group, 155 started study treatment and 150 completed treatment per protocol. For the participants in the placebo group, 78 started study treatment and 76 completed treatment per-protocol. Study enrollment was terminated after March 12, 2020, before attaining the prespecified sample size, because no additional patients met study eligibility criteria due to various public health measures implemented in Wuhan. The median age of participants was 65 years (IQR, 56-71), the majority were men (56% in remdesivir group vs 65% in placebo group), and the most common comorbidities included hypertension, diabetes, and coronary artery disease. Median time from symptom onset to study enrollment was 10 days (IQR, 9-12). The time to clinical improvement between treatments (21 days for remdesivir group vs 23 days for placebo group) was not significantly different (HR, 1.23; 95% confidence interval [CI], 0.87-1.75). In addition, in participants who received treatment within 10 days of symptom onset, those who were administered remdesivir had a nonsignificant (HR, 1.52; 95% CI, 0.95-2.43) but faster time (18 days) to clinical improvement, compared to those administered placebo (23 days). Moreover, treatment with remdesivir versus placebo did not lead to differences in secondary outcomes (eg, 28-day mortality and duration of hospital stay, oxygen support, and invasive mechanical ventilation), changes in viral load over time, or adverse events between the groups.