Remdesivir for COVID-19: Remain sceptical

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Remdesivir has been shown to reduce the duration of illness in patients with severe COVID-19. But what about patients with moderate disease? This EBM Focus article, from the DynaMed editorial team, provides a concise summary of clinical trials most likely to inform clinical practice.

The United States Food and Drug Administration (FDA) authorised emergency use of remdesivir in hospitalised patients with severe COVID-19 in May 2020. The authorisation occurred after publication of the ACTT-1 trial, which was reviewed in a previous DynaMed EBM Focus article earlier this year. The ACTT-1 study population was quite sick: about 25% were intubated or on extracorporeal membrane oxygenation (ECMO), and 90% required oxygen. Data from those 1,059 patients indicated a shorter time to recovery with remdesivir (11 vs. 15 days) but no significant difference in mortality; however, the possibility of benefit could not be excluded.

A subsequent NIH guideline on treatment of COVID-19 recommended 10 days of remdesivir in patients requiring high-flow oxygen, BiPAP, mechanical ventilation, or ECMO, with five days for all other patients on supplemental oxygen.

In September, an open-label trial sponsored by Gilead was published in JAMA evaluating remdesivir for hospitalised patients less ill than those in the ACTT-1 trial. This trial was followed by an expanded FDA authorisation of remdesivir for any patient hospitalised with COVID-19. In this trial, 596 patients at least 12 years of age (median age 57 years, 61% male) hospitalised with laboratory-confirmed COVID-19 and moderate pneumonia (pulmonary infiltrates and room air oxygen saturation over 94%) were randomised to one of three groups: standard care alone, or standard care plus either five or 10 days of remdesivir (200 mg IV on day one followed by 100 mg IV daily for either four or nine days).

Outcomes were evaluated on a seven-point ordinal scale of morbidity where death was one and discharge was seven, with improvement defined as an increase of at least two points on this seven-point scale. Median length of treatment was five days in the five-day remdesivir group and six days in the 10-day remdesivir group. At day 11, at least two points of improvement were observed in 65% of the 10-day remdesivir group, 70% of the five-day remdesivir group, and 61% of the standard-care-only group. The only significant difference was between five days of remdesivir and standard care alone. There were no significant differences in mortality, time to recovery, duration of oxygen therapy, or length of hospitalisation amongst the three groups.

This trial suggests remdesivir may help patients improve a little faster, consistent with the ACTT-1 trial. There are, however, numerous concerns with the data.

First, seeing benefit in the five-day but not the 10-day remdesivir group seems peculiar, and raises the possibility that this is a chance finding. It could also suggest that there is some harm associated with prolonged treatment, but that seems less likely given that the median duration of treatment in the 10-day group was only six days.

Second, since the scale used is ordinal and not cardinal, improving by two points means different things depending on where on the scale you start. For example, getting off a ventilator is more meaningful than decreasing the level of oxygen support, so an outcome capturing the percent of patients who are improving by two points may miss subtle differences in the group.

Third, the dichotomous outcome reporting treats patients who worsened and those who do not get better as one group.

Finally, the lack of benefit for any specific outcome such as mortality or length of hospital stay supports the impression that while remdesivir may have a benefit, it is a modest one at best. This scepticism is reflected in the Infectious Diseases Society of America’s (IDSA) recommendation for five days of remdesivir only in hospitalised patients sick enough to require supplemental oxygen, with longer use reserved for those on mechanical ventilation or ECMO.

For more information, see the COVID-19 (Novel Coronavirus) topic in DynaMed.