This medication is recommended in the context of enrollment in a clinical trial, prescribing under Emergency Use Authorization (EUA), or an individual compassionate use request for adults or pediatric patients hospitalized with confirmed COVID-19 and disease classified as severe.

Clinical Circumstances

Inpatient use only, with moderate to severe disease (defined as patients with evidence of pneumonia on chest imaging, or an oxygen saturation (SpO2) ≤94% on room air, or requiring supplemental oxygen, or mechanical ventilation, and/or extracorporeal membrane oxygenation).

Can be considered in consultation with ID. Extremely limited medication supply also necessitates restriction, currently managed by an unbiased triage team.

Medication Specific Considerations

Drug monitoring: AST/ALT, signs and symptoms of liver dysfunction, eGFR

Supply and procurement consideration:

• ACTT study enrollment: patients who meet the criteria and consent to be enrolled in the ACTT clinical trial can be enrolled and potentially receive remdesivir.

• Use under EUA is not yet available at any M Health Fairview site. The US government will coordinate the donation and distribution of remdesivir to hospitals in cities most heavily impacted by COVID-19. It has not yet been announced which hospitals will receive any drug supply.

Use in special populations: There is minimal data regarding the use of remdesivir in patients who are <18 years old, pregnant, or immunosuppressed. For recommendations in renal and/or hepatic dysfunction, see Table 1.

Major peer-reviewed studies:

1. Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;9(2):e00221-18. Published 2018 Mar 6. doi:10.1128/mBio.00221-18

   • In vitro study (SARS-CoV-1)

   • https://www.ncbi.nlm.nih.gov/pubmed/29511076

2. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020;13:1922083117.

   • In vivo study (MERS)

   • https://www.ncbi.nlm.nih.gov/pubmed/32054787

3. Gordon CJ, Tchesnokov EP, Feng JY, et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol Chem 2020;24:013056.

   • In vitro study (MERS)

   • https://www.ncbi.nlm.nih.gov/pubmed/32094225

4. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017;9.

   • In vitro study (SARS-CoV-1, MERS)

   • https://www.ncbi.nlm.nih.gov/pubmed/28659436

5. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro: Cell Res. Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4.; 2020.

   • In vitro study (SARS-CoV-2)

   • https://www.ncbi.nlm.nih.gov/pubmed/32020029/

6. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. NEJM. 2020. DOI: 10.1056/NEJMoa2007016

   • Observational study (SARS-CoV-2)

   • https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

7. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020. https://doi.org/10.1016/S0140-6736(20)31022-9

   • Randomized controlled trial (SARS-CoV-2)

   • https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext

8. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report [published online ahead of print, 2020 May 22]. N Engl J Med. 2020;NEJMoa2007764. doi:10.1056/NEJMoa2007764

9. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 [published online ahead of print, 2020 May 27]. N Engl J Med. 2020;10.1056/NEJMoa2015301. doi:10.1056/NEJMoa2015301

Extended Review

• Remdesivir is a novel antiviral drug in the class of nucleotide analogs. Remdesivir incorporates into viral RNA chains causing their premature termination. It was developed by Gilead Sciences as a treatment for viral hemorrhagic fever, though it subsequently was found to show antiviral activity against other single-stranded RNA viruses, including coronaviruses.

• Preliminary reports using remdesivir were very promising and it was used throughout 2018-2019 until RCT data was published in August 2019

• RCTs identified that remdesivir was significantly less efficacious than mAb114 and REGN-EB3 and its use was discontinued.

• SARS-CoV-1: Remdesivir has never been tested in SARS-CoV-1

• MERS-CoV

  • In vivo primates

    • De Wit et al. identified significantly reduced viral load and lung histology score in primates infected with the MERS-CoV virus treated with therapeutic remdesivir. It was more effective in this model as a prophylactic medication

• COVID-19

  • In vitro

    • Wang et al. identified that remdesivir was efficacious in Vero E6 cells infected with SARS-CoV-2

    • https://www.nature.com/articles/s41422-020-0282-0/figures/1

• Clinical studies

  • Grein et al described outcomes from compassionate use of remdesivir in a group of 53 patients with no control group.

    • The median age was 64 years (interquartile range, 48 to 71), and at baseline, 64% of the patients were receiving invasive ventilation, including 4 people (8%) on ECMO.

    • Over a median of 18 days after receiving the first dose of remdesivir, 68% showed an improvement in their need for oxygen support, and 15% showed worsening.

    • The mortality rate after 28 days was 13% overall and 18% within the group which required invasive ventilation prior to enrollment

    • 60% of the patients reported any adverse events during follow-up and 23% had serious adverse events, although it could not be determined whether the cause of these events was the study medication or the underlying disease process.

• • Wang et al described outcomes from a randomized, controlled, double-blinded, multi-center trial in China

    • Included 237 hospitalized adults with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrollment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia

    • Randomized 2:1 to IV remdesivir (200 mg on day 1, then 100 mg daily on days 2–10) or placebo. Use of lopinavir–ritonavir, interferons, and corticosteroids was allowed

    • Primary endpoint: time to clinical improvement up to day 28, defined as days from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first

    • n=158 received remdesivir and 79 received placebo; study was terminated prior to meeting power based on the termination criteria prespecified in the protocol

    • No difference in primary outcome: hazard ratio 1·23 [95% CI 0·87–1·75]

    • Remdesivir was associated with a numerically faster time to clinical improvement among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]), but this was not statistically significant

    • AEs were reported in 66% of remdesivir recipients vs 64% of placebo recipients. The AEs reported in multiple patients from remdesivir > placebo were: rash, thrombocytopenia, increased T bili, increased neutrophils, nausea

  • The Adaptive COVID-19 Treatment Trial (ACTT) was a double-blind, randomized, placebo-controlled trial with the primary endpoint of time to recovery (defined as hospital discharge or hospitalization for infection control purposes only).

    • This study enrolled 1,063 patients with COVID-19 and evidence of lower respiratory tract infection. The participants in both the remdesivir and placebo groups were similar at baseline.

    • Patients treated with remdesivir had a 31% faster median time to recovery than placebo (11 days versus 15 days, RR for recovery 1.32, 95% CI 1.12-1.55, p<0.001).

    • The subgroup of patients receiving mechanical ventilation or ECMO at enrollment had a rate ratio for recovery of 0.95 (95% CI 0.64-1.42), thus the investigators did not observe faster recovery compared to placebo in this group.

    • Mortality was numerically lower in the remdesivir group but was not statistically significant (8.0% versus 11.6%, p=0.059)

    • This study was stopped early due to the finding of superiority of remdesivir for the primary outcome and the result were published prior to all participants completing follow-up.

  • Goldman et al describes a randomized, open-label, phase 3 trial completed in hospitalized patients with COVID-19, radiologic evidence of pneumonia, and an oxygen saturation of 94% or less on ambient air.

    • N=397 patients were randomized to receive remdesivir for either 5 days or 10 days. The authors estimated that a sample size of 400 patients would provide at least 85% power to detect clinically significant improvement.

    • The primary outcome was clinical improvement by at last 2 points on an ordinal scale.

    • After adjusting for baseline clinical status, the primary outcome was not different between the 5-day and 10-day groups (P=0.14).