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Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

Our take —

Remdesivir did not appear to change outcomes in this underpowered study when used later in the disease course (median of 10 days). In addition, remdesivir did not appear to affect viral replication. This study does not support the clinical use of remdesivir later in the course of COVID-19 disease. However, conclusions should be made cautiously given the lack of statistical power for examining the study hypotheses.

Study design

Randomized Controlled Trial

Study population and setting

This was a randomized, double-blinded, placebo-controlled, multi-center clinical trial of a 10-day course of daily remdesivir versus placebo among inpatient participants who mostly required supplemental oxygen and had laboratory-confirmed SARS-CoV-2 infection.

Summary of Main Findings

In this 2:1 placebo-controlled RCT, 237 patients were enrolled from 10 hospitals in China; 158 participants were assigned remdesivir, 78 were assigned to placebo. This was lower enrollment than planned due to a lack of further SARS-CoV-2 patients identified in the province. Eligible adults (18+ years) were SARS-CoV-2 positive, had <12 days of symptoms, and had pneumonia on imaging. Patients in the remdesivir arm received 10 days of IV-administered drug. Other antivirals were permitted, and their use was balanced between the remdesivir and placebo groups at baseline; while under study more placebo arm participants received inhaled interferon-alpha than remdesivir arm participants (38% vs. 29%). In addition, there was prevalent use of antibiotics (>90% in both arms) and corticosteroids (>65% in both arms). Upon enrollment, 96% of participants required supplemental oxygen. There was a higher proportion of men in the remdesivir arm, 65%, compared to placebo, 56%. Other characteristics of participants were roughly matched, with a median age in the remdesivir arm of 66 years, and in the placebo arm of 64 years. Comorbidities were found in approximately 70% of participants in both arms. The median interval between symptom onset and randomization was 10 days (11 for remdesivir and 10 for placebo).

The primary endpoint was time to clinical improvement, defined as a decrease in two stages on a 6-stage scale. There were no differences in the time to clinical improvement, which was on average 23 and 21 days in the remdesivir and placebo arms, respectively. There was also no difference in mortality between the arms, nor in the number of people requiring mechanical ventilation. Nucleic acid amplification data showed high-level replication in the upper and lower respiratory tracts at baseline. The kinetics of viral decline did not appear different by arm; both declined to low levels 28 days after enrollment. Adverse events were recorded in both remdesivir (66%) and placebo (64%) arms, and consisted of lab abnormalities (e.g., low albumin, low potassium, anemia, low platelets), rash, and gastrointestinal complaints. Serious adverse events were found less frequently in the remdesivir arm (18%) than in the placebo arm (26%). More people in the remdesivir arm (12%) discontinued the drug than in the placebo arm (5%). None of the deaths that occurred during the study were determined to be related to remdesivir or placebo.

Study Strengths

This is a placebo-controlled RCT examining remdesivir efficacy and safety in a clinical cohort of people with SARS-CoV-2 infection. The study was completed with minimal drop-out and excellent ascertainment of study endpoints.

Limitations

The study was terminated early because of failure to fully enroll. This affects the overall power of the study. In addition, the study protocol enrolled people within up to 12 days of symptom onset, with a median time since symptom onset of 10 days. There was an imbalance in duration of symptoms prior to study entry: 54% of the remdesivir arm and 40% of placebo arm had >10 days of symptoms. In acute viral infections such as influenza, treatment needs to be early to improve clinical outcomes; the late initiation of treatment in this trial may have affected the efficacy outcome. The lack of difference in viral nucleic acid clearance during serial RNA assays raises some questions as to the antiviral effect and the biological plausibility of antiviral activity. Use of these PCR assays rather than viral culture is an additional limitation as the correlation between PCR positivity and viral replication and infectious virion is unclear at this time. One non-significant finding was more rapid clinical improvement in those receiving remdesivir when compared to placebo among the subgroup enrolling within 10 days of symptoms. Given that this was a subgroup analysis of an already underpowered study, no conclusions should be drawn from this observation.

Value added

This was a well-conducted RCT that suggested the safety of remdesivir use in treating COVID-19 and found no benefit when remdesivir is used later in the disease course.