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Remdesivir

Last Update: September 16, 2020

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject.

Overview 

Remdesivir is the first drug found to have a beneficial effect on hospitalized patients with COVID-19. Remdesivir is an intravenous nucleotide prodrug of an adenosine analog that was initially developed during the 2013 Ebola epidemic (Weston, March 2020; Brown, September 2019).  When metabolized to its active form, remdesivir interferes with RNA polymerase and is thought to lead to premature termination of RNA transcription. It is also able to evade viral exonuclease proofreading.  

Early in the pandemic, remdesivir was found to have antiviral effects against SARS-CoV-2 in both in-vitro studies and in-vivo studies with rhesus macaques (Wang, February 2020; Williamson, June 2020). On May 1, 2020, FDA approved an Emergency Use Authorization for remdesivir in adults and children hospitalized with severe COVID-19 disease. 

Guidelines 

IDSA guidelines recommend the use of remdesivir in SARS-CoV-2 infection among hospitalized patients with severe COVID-19 disease (defined as patients with SpO2 ≤94% on room air, or patients who require supplemental oxygen, mechanical ventilation or extracorporeal mechanical oxygenation). 

  • Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, the IDSA panel suggests treatment with five days of remdesivir rather than 10 days of remdesivir
  • Among patients with severe COVID-19 on supplemental oxygen but not on mechanical ventilation or ECMO, IDSA suggests treatment with five days of remdesivir rather than 10 days of remdesivir.

Key Literature 

Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial (Spinner, Aug 2020)

Study population

  • 584 patients at 105 hospitals in the United States, Europe, and Asia, hospitalized with moderate COVID-19 (defined as pulmonary infiltrates and room-air oxygen saturation >94%)
  • Patients were randomized to either a 5 day course of Remdesivir, a 10 day course, or standard of care
  • The median age was 57 (IQR 46-66) and 227 (39%) women
  • 56% had cardiovascular disease, 42% had hypertension, and 40% had diabetes
  • Patients were enrolled if they had a positive SARS-CoV-2 PCR within 4 days of randomization

Primary endpoint:

  • Day 11 clinical status based on a 7-point ordinal scale; category 1 was death, category 7 was discharged

Key findings:

  • 533 (91%) of the participants completed the trial, including 76% of the 5 day remdesivir group and 38% of the 10 day group.
  • Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group.
  • On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; P = .02).
  • The clinical status distribution on day 11 between the 10-day Remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test).
  • There was no difference in 28 day all-cause mortality

Limitations:

  • Open-label design, which could have lead to selection bias
  • No virologic data was collected
  • An important number of patients did not complete their assigned treatment duration, primarily due to hospital discharge; the occurred more frequently in the 10 day group, and could have affected the results
  • The median duration of symptoms prior to randomization over a week in all groups. Thi could have affected the study results
  • The initial endpoint was proportion of patients discharged by day 14; this was changed the day study enrollment began
  • Other therapies used for SARS-CoV-2 as part of local standard of care were initially allowed
  • The 10 day group actually received a median of 6 days of Remdesivir; the effect of 5 days of treatment compared to 10 days of treatment is not adequately answered in this study
  • All participants had moderate disease with low risk of mortality or clinical progression. It is unclear whether differences in outcomes would be observed by duration of remdesivir treatment with a population that was more ill

Overall, in this open-label randomized controlled trial, 5 days of Remdesivir was associated with a higher odds of a better clinical status distribution than those receiving standard care. The clinical significance of this finding is unclear.

 

Adaptive COVID-19 Treatment TrialAn NIH-sponsored randomized, double-blind, placebo-controlled adaptive trial (Beigel, May 2020). 

Study population:  

  • Preliminary 14-day outcomes for 1,063 hospitalized adult patients with COVID-19. 
  • Median 9 days from symptom onset to starting remdesivir 

Primary endpoint:  

  • Time to clinical recovery (defined as discharge from the hospital or hospitalization for infection control purposes only).   

Key findings: 

  • Patients who received remdesivir had a 31% faster time to recovery versus patients who received placebo (median 11 days vs. 15 days; p<0.001).   
  • There was also a non-statistically significant trend toward a survival benefit, with a 14-day mortality rate of 7.1% for the remdesivir arm versus 11.9% for placebo. 

Limitations:  

  • The original primary endpoint was ordinal endpoint after 14 days, but this was changed to a time-to-recovery endpoint based on researchers’ realization that the clinical course of COVID-19 could be longer than initially thought. 

Overall, the strongest evidence of clinical benefit from starting remdesivir may be in those requiring supplemental oxygen. Administration early in disease may also be important.  

 

SIMPLE-Severe Trial: Gilead-sponsored multinational, open-label trial of remdesivir in patients with severe COVID-19 (Goldman, May 2020).   

Study population:  

  • Patients in this study had either SpO2 ≤94% on room air or were receiving supplemental oxygen.   
  • 397 patients received remdesivir for 5 days; 197 received remdesivir for 10 days. 

Primary endpoint 

  • Clinical status at day 14.  

Key findings: 

  • After adjusting for imbalances in the baseline clinical status, the day 14 distribution in clinical status on the ordinal scale was similar in the 5-day and 10-day groups (p=0.14).   

Overall, in hospitalized patients with COVID-19 who are not on mechanical ventilation or extracorporeal mechanical oxygenation, 5 days of remdesivir shows similar clinical benefit to 10 days. 

 

A multicenter, double-blind, randomized, placebo-controlled trial evaluated patients with severe COVID-19 in China (Wang, May 2020).   

Study population: 

  • 237 patients received IV remdesivir for 10 days; concomitant use of lopinavir/ritonavir, corticosteroids and interferons was permitted.   
  • The median time from symptom onset to starting remdesivir was 10 days.   

Primary endpoint 

  • Time to clinical improvement, defined as improvement on an ordinal scale or discharged alive from the hospital, whichever came first.  

Key findings: 

  • There was no difference in the time to clinical improvement between the groups (median 21 days vs. 23 days).   
  • For those who started remdesivir within 10 days of symptom onset, a faster time to clinical improvement was seen in the remdesivir arm (median 18 days vs. 23 days); this was not statistically significant.   
  • There was no mortality benefit at 28 days. 

Limitations: 

  • Due to under-enrollment, the trial was stopped early and was likely under-powered.   

Overall, in this under-powered study, remdesivir did not show a benefit in time to clinical improvement, 28-day mortality or rate of viral clearance in patients with severe COVID-19 compared to placebo.  

 

Safety 

Although the understanding of remdesivir’s safety profile remains incomplete, notable considerations include:  

Hepatotoxicity 

  • Remdesivir should not be used in combination with other hepatotoxic drugs, and clinicians should monitor hepatic function throughout treatment (FDA EUA, July 2020).  

Nephrotoxicity 

  • Clinicians should monitor kidney function of all patients on remdesivir, particularly those with pre-existing renal impairments and those receiving other nephrotoxins.  
  • Avoid use for patients with eGFR <30 ML/min or full-term neonates with SCr >1 mg/dL (FDA EUA, July 2020). 

 

Resources 

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