Early remdesivir to prevent progression to severe COVID-19 in outpatients
Gottlieb RL, Vaca CE, Paredes R, et al. N Engl J Med. 2022;386(4):305-315.
SUMMARY:
Remdesivir is a direct-acting nucleotide prodrug inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, which the virus uses to replicate itself. Tests of remdesivir have indicated some positive results among hospitalized patients.
The active form of remdesivir is incorporated into nascent RNA and subsequently blocks viral replication by either halting RNA synthesis or resulting in generation of defective RNA.
This therapeutic option may be promising, but when a patient presents with symptoms and full cytokine inflammation, would stopping further viral replication have any value, or has the damage already been done?
This randomized, double-blind, placebo-controlled trial examined the efficacy and safety of remdesivir among high-risk outpatients with confirmed COVID-19, who were seen within 1 week after symptom onset.
High-risk conditions included age >60 years, hypertension, cardiovascular disease, diabetes, obesity, chronic lung disease, and chronic liver disease.
The study was a multinational effort from 64 sites in the U.S., Spain, Denmark, and the U.K.
Patients were randomized to receive IV remdesivir or placebo for 3 days (mostly administered at infusion centers).
The primary outcome was a composite of COVID-19-related hospitalization (disease specific) or death by any cause within 28 days. The primary safety outcome was any adverse event.
According to a power calculation, the authors estimated a need to enroll 1,264 patients, but the sponsor stopped the trial early because of waning infections, ethical concerns in giving only placebo when monoclonal antibodies were available, and increased vaccination rates.
Data are reported for 562 patients with a mean age of 50 years, 47.9% of whom were women, and 41.8% of whom were Hispanic or Latinx. The most common coexisting conditions were diabetes (61.6%), obesity (55.2%), and hypertension (47.7%). One-third of the patients were older than 60 years, and the median duration from the time of the first symptom to the first infusion was 5 days.
No deaths occurred in either group, but the hospitalization rate was lower in the remdesivir group (0.7% vs 5.3%), which showed a relative decrease of 87%.
Symptom resolution was higher at 14 days in the remdesivir group (34.8% vs 25%).
Adverse events were mild but were more frequent in the remdesivir group (12.2% vs 8.8%).
The authors suggest that remdesivir, although not superior in efficacy to monoclonal antibody therapy, may be more likely to maintain efficacy against emerging variants because of its mechanism of action.
The major limitations of this trial are that (like many trials to date) it excluded vaccinated patients, and it was stopped early for administrative reasons.
EDITOR’S COMMENTARY: In this multinational blinded RCT, the authors found that a 3-day course of remdesivir decreased hospitalization among unvaccinated high-risk outpatients with COVID-19. Although remdesivir may be more readily available than monoclonal antibodies, it might be more difficult to organize and administer, because it requires 3 separate infusions. We should be aware of all the new options for patients with COVID-19 who are being discharged, and this one actually has FDA approval (not just emergency-use authorization) for this purpose in adults.
EMA 2022 MayFull episode audio for MD edition211:27 min - 212 MB - M4AEMA 2022 May - Abstract PDF954 KB - PDFEMA 2022 May - MP3s285 MB - ZIPTime to Talk a Little Nerdy: Peer Review222 KB - PDF
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