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Remdesivir

Last Updated: June 11, 2020

Recommendations for Hospitalized Patients with Severe COVID-19

  • The COVID-19 Treatment Guidelines Panel (the Panel) recommends the investigational antiviral agent remdesivir for treatment of COVID-19 in hospitalized patients with SpO2 ≤94% on ambient air (at sea level) or those who require supplemental oxygen (AI).
  • The Panel recommends remdesivir for treatment of COVID-19 in patients who are on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) (BI).

Rationale

Data from a multinational, randomized, placebo-controlled trial (the Adaptive COVID-19 Treatment Trial [ACTT]) of hospitalized patients with COVID-19 showed that patients with severe disease who were randomized to receive remdesivir had a shorter time to clinical recovery than those who received placebo.1 The benefit of remdesivir on reducing time to recovery was clearest in the subgroup of hospitalized patients with severe disease who were not intubated but who required supplemental oxygen. In the preliminary analysis of ACTT, there was no observed improvement in the time to recovery among those who were mechanically ventilated, but the follow-up period may have been too short to have shown a difference.

Recommendation for Duration of Therapy in Patients with Severe COVID-19 Who Are Not Intubated

  • The Panel recommends that hospitalized patients with severe COVID-19 who are not intubated receive 5 days of remdesivir (AI).

Rationale

Data from a multinational, open-label trial of hospitalized patients with severe COVID-19 showed that remdesivir treatment for 5 or 10 days had similar clinical benefit in patients who were not on mechanical ventilation or ECMO.2

Recommendation for Duration of Therapy for Mechanically Ventilated Patients, Patients on ECMO, or Patients Who Have Not Shown Adequate Improvement After 5 Days of Therapy

  • There are insufficient data on the optimal duration of therapy for mechanically ventilated patients, patients on ECMO, or patients who have not shown adequate improvement after 5 days of therapy. In these groups, some experts extend the total remdesivir treatment duration to up to 10 days (CIII).

Rationale

Because the trial that compared 5 days to 10 days of remdesivir excluded people who were mechanically ventilated or on ECMO, the optimal duration of therapy in this population is not known. Similarly, the optimal duration of therapy for people who do not improve after 5 days of receiving remdesivir is unclear. In the absence of data, some experts may consider extending the total treatment duration of remdesivir for up to 10 days in people who are on mechanical ventilation or ECMO and in those who do not improve after 5 days of remdesivir.3

Recommendation for Patients with Mild or Moderate COVID-19

  • There are insufficient data for the Panel to recommend for or against remdesivir for the treatment of patients with mild or moderate COVID-19.

Rationale

In the preliminary analysis of ACTT, there was no observed benefit for remdesivir in people with mild or moderate COVID-19; however, the number of people in this category was relatively small. Remdesivir is being evaluated in another clinical trial for the treatment of patients with moderate COVID-19; complete data from this trial are expected soon. The Food and Drug Administration (FDA) emergency use authorization (EUA) for remdesivir limits its use to people with severe COVID-19.

Proposed Mechanism of Action and Rationale for Use in Patients with COVID-19

Remdesivir is an intravenous (IV) investigational nucleotide prodrug of an adenosine analog. It has demonstrated in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),4 and in vitro and in vivo activity (based on animal studies) against SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV).5-7 Remdesivir binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through premature termination of RNA transcription.

Preclinical studies show that remdesivir improves disease outcomes and reduces levels of SARS-CoV in mice.5 When given as prophylaxis or therapy, remdesivir also reduces MERS-CoV levels and lung injury in mice. In a rhesus macaque model of MERS-CoV infection, prophylactic remdesivir prevented MERS-CoV clinical disease.7 When given to rhesus macaques 12 hours after inoculation with MERS-CoV, remdesivir reduced viral replication and the severity of lung disease in treated animals compared to control animals. In a rhesus macaque model of SARS-CoV-2 infection, remdesivir treatment was started soon after inoculation in six of 12 monkeys. The remdesivir-treated animals had lower lung virus levels and less lung damage than the control animals.8

Clinical Data to Date

Multinational Randomized Controlled Trial of Remdesivir Versus Placebo in Hospitalized Patients

Study Design

ACTT is a National Institutes of Health-sponsored, multinational, randomized, double-blind, placebo-controlled trial in hospitalized adults with COVID-19.1 Participants were randomized 1:1 to receive IV remdesivir or placebo for 10 days. The primary study endpoint was time to clinical recovery, which was defined as either discharge from the hospital or hospitalization for infection control purposes only. Severity of illness at baseline and at Day 15 was assessed using an ordinal scale:

  1. Not hospitalized, no limitations
  2. Not hospitalized, with limitations
  3. Hospitalized, no active medical problems
  4. Hospitalized, not on oxygen
  5. Hospitalized, on oxygen
  6. Hospitalized, on high-flow oxygen or noninvasive mechanical ventilation
  7. Hospitalized, on mechanical ventilation or ECMO
  8. Death

Study Population

The study population consisted of hospitalized patients aged ≥18 years with laboratory-confirmed SARS-CoV-2 infection. Patients were enrolled if they met at least one of the following conditions:

  • The patient had pulmonary infiltrates, as determined by radiographic imaging;
  • SpO2 was ≤94% on ambient air;
  • The patient required supplemental oxygen;
  • The patient was on mechanical ventilation; or
  • The patient was on ECMO.

The study excluded individuals who had alanine aminotransaminase (ALT) or aspartate aminotransaminase (AST) levels >5 times the upper limit of normal (ULN), those who had an estimated glomerular filtration rate (eGFR) <30 mL/min, and those who were pregnant or breastfeeding.

Preliminary Results

Participant Characteristics:
  • Of 1,063 enrolled participants, 1,059 had preliminary results available for analysis (n = 538 for the remdesivir group; n = 521 for the placebo group).
  • The mean age was 58.9 years; 64.3% of participants were male, 53.2% were white, and 79.8% were enrolled in North America.
  • 52.1% of participants had two or more co-morbidities; 37% were obese (mean body mass index 30.6 kg/m2).
  • The median time from symptom onset to randomization was 9 days (interquartile range [IQR] 6–12 days).
Follow-Up:
  • At the time of the preliminary analysis, 391 remdesivir recipients and 340 placebo recipients had completed the study through Day 29, recovered, or died.
  • Eight remdesivir recipients and nine placebo recipients terminated the study prior to Day 29.
  • 132 remdesivir recipients and 169 placebo recipients had not recovered and had not completed the Day 29 follow-up visit at the time of this analysis.
Study Endpoint Analyses:
  • Remdesivir significantly reduced time to recovery compared to placebo (median time to recovery 11 days vs. 15 days, respectively; recovery rate ratio 1.32; 95% confidence interval [CI], 1.12–1.55; P < 0.001).
  • Clinical improvement based on the ordinal scale outlined above was significantly higher in patients who received remdesivir than in those who received placebo at Day 15 (odds ratio 1.50; 95% CI, 1.18–1.91; P < 0.001).
  • The benefit of remdesivir on reducing time to recovery was clearest in the subgroup of hospitalized patients who required supplemental oxygenation at study enrollment (ordinal scale 5; n = 421).
  • Among patients who were on mechanical ventilation or ECMO at enrollment (ordinal scale 7; n = 272), there was no observed difference between the remdesivir and placebo groups in time to recovery (recovery rate ratio 0.95; 95% CI, 0.64–1.42).
  • Among patients who were classified as having mild to moderate disease at enrollment, there was no difference in the median time to recovery between the remdesivir and placebo groups (recovery rate ratio 1.09; 95% CI, 0.73–1.62; n = 119). Mild to moderate disease was defined as SpO2 >94% on ambient air and respiratory rate <24 bpm without supplemental oxygen.
  • The mortality estimate by Day 14 was lower in the remdesivir arm than in the placebo arm (7.1% vs. 11.9%, respectively), but the difference was not statistically significant (hazard ratio [HR] 0.70; 95% CI, 0.47–1.04).
  • The use of remdesivir was associated with a shorter time to recovery regardless of the duration of symptoms prior to randomization (≤10 days vs. >10 days).
  • The percentages of participants who experienced serious adverse events (AEs) were similar in the remdesivir and placebo groups (21.1% vs. 27.0%, respectively).
  • Transaminase elevations occurred in 4.1% of remdesivir recipients and 5.9% of placebo recipients.

Limitations

  • At the time of publication, the full dataset was not available for analysis.

Interpretation

In patients with severe COVID-19, remdesivir reduced the time to clinical recovery. The benefit of remdesivir was most apparent in hospitalized patients who were not intubated but who required supplemental oxygen. There was no observed benefit of remdesivir in those who were mechanically ventilated, but the follow-up period may have been too short to see a difference between the remdesivir and placebo groups. There was no observed benefit of remdesivir in patients with mild or moderate COVID-19, but the number of participants in these categories was relatively small.

Multinational Randomized Trial of Different Durations of Remdesivir Treatment in Hospitalized Patients

Study Design

This was a manufacturer-sponsored, multinational, randomized, open-label trial in hospitalized adolescents and adults with COVID-19. Participants were randomized 1:1 to receive either 5 days or 10 days of IV remdesivir. The primary study endpoint was clinical status at Day 14, which was assessed using a seven-point ordinal scale:2

  1. Death
  2. Hospitalized, on invasive mechanical ventilation or ECMO
  3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices
  4. Hospitalized, requiring low-flow supplemental oxygen
  5. Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care for COVID-19 or for other reasons
  6. Hospitalized, not requiring supplemental oxygen or ongoing medical care (other than the care that was specified in the protocol for remdesivir administration)
  7. Not hospitalized

Study Population

The study enrolled hospitalized patients aged ≥12 years with reverse transcription polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection and radiographic evidence of pulmonary infiltrates. Patients in this study had either SpO2 ≤94% on ambient air or were receiving supplemental oxygen. The study excluded patients who were receiving mechanical ventilation or ECMO or who had multiorgan failure, ALT or AST levels >5 times ULN, or an estimated creatinine clearance of <50 mL/min. Patients were also excluded if they had received an agent with putative anti-SARS-CoV-2 activity within 24 hours of starting treatment in the trial.

Results

Participant Characteristics:
  • Of 402 randomized participants, 397 began 5 days (n = 200) or 10 days (n = 197) of remdesivir treatment.
  • In the 5-day group, the median age was 61 years; 60% of participants were male, and 71% were white. In the 10-day group, the median age was 62 years; 68% of participants were male, and 70% were white. The frequency of coexisting conditions was similar in both groups.
  • The median time from symptom onset to the first dose of remdesivir was 8 days in the 5-day group and 9 days in the 10-day group. The median duration of hospitalization before the first remdesivir dose was 2 days in both groups.
  • At baseline, patients in the 10-day group had worse clinical status (based on the ordinal scale distribution outlined above) than those in the 5-day group (P = 0.02).
  • A few patients were on mechanical ventilation: four (2%) were assigned to the 5-day group, and nine (5%) were assigned to the 10-day group. Although mechanical ventilation was an exclusion criterion for enrollment, some patients were intubated between screening and treatment initiation; others were protocol deviations.
  • 172 participants (86%) in the 5-day group completed a median of 5 days of treatment, and 86 (44%) in the 10-day group completed a median of 9 days of treatment.
Study Endpoint Analyses:
  • 65% of patients in the 5-day group and 54% of those in the 10-day group had a two-point improvement in clinical status on the ordinal scale.
  • 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).
  • The time to clinical improvement of at least two levels on the ordinal scale (median day of 50% cumulative incidence) was similar in the 5-day and 10-day groups (10 days vs. 11 days, respectively).
  • The median durations of hospitalization among patients who were discharged on or before Day 14 were similar in the 5-day group (7 days; IQR 6–10 days) and the 10-day group (8 days; IQR 5–10 days).
  • By Day 14, 120 patients (60%) in the 5-day group had been discharged and 16 (8%) had died; in the 10-day group, 103 patients (52%) had been discharged and 21 (11%) had died.
  • Serious AEs were more common in the 10-day group (35%) than in the 5-day group (21%). Four percent of patients in the 5-day group and 10% of patients in the 10-day group stopped treatment because of AEs.

Limitations

  • This was an open-label trial without a placebo control group, so the clinical benefit of remdesivir could not be assessed.
  • There were baseline imbalances in the clinical statuses of participants in the 5-day and 10-day groups. At the start of the study, more patients in the 10-day group than in the 5-day group were receiving noninvasive ventilation or high-flow oxygen (30% vs. 24%, respectively), and fewer patients in the 10-day group than in the 5-day group were not receiving supplemental oxygen (11% vs. 17%, respectively).

Interpretation

In hospitalized patients with COVID-19 who were not on mechanical ventilation or ECMO, remdesivir treatment for 5 or 10 days had similar clinical benefit. Because this trial only evaluated a few patients who were on mechanical ventilation, the appropriate duration of remdesivir treatment for critically ill patients is still unclear.

Randomized Controlled Trial of Remdesivir Versus Placebo for Severe COVID-19 in China

Study Design

This was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated patients with severe COVID-19 in China.9 Patients were randomized 2:1 to receive IV remdesivir or normal saline placebo for 10 days. Concomitant use of lopinavir/ritonavir, corticosteroids, and interferons were allowed. The primary study endpoint was time to clinical improvement, defined as improvement on an ordinal scale or discharged alive from the hospital, whichever came first. The planned sample size was 453 patients.

Participant Population

This study enrolled hospitalized adults with laboratory-confirmed COVID-19 whose time from symptom onset to randomization was <12 days, whose O2 saturation was ≤94% on ambient air or whose PaO2/FiO2 was <300 mm Hg, and who had radiographically confirmed pneumonia.

Results

  • 237 hospitalized patients were enrolled and randomized to treatment from February 6, 2020, to March 12, 2020; 158 patients were randomized to receive remdesivir and 79 patients were randomized to receive placebo. The study was stopped before the target enrollment was reached due to control of the COVID-19 outbreak in China.
  • The median age of the participants was 65 years; 56% of the participants in the remdesivir arm and 65% of the participants in the placebo arm were male.
  • There were more patients with hypertension, diabetes, or coronary artery disease in the remdesivir arm than in the placebo arm.
  • At Day 1, 83% of the participants required supplemental oxygen by nasal cannula or mask; only one participant required mechanical ventilation or ECMO.
  • The median time from symptom onset to randomization was 9 days in the remdesivir group and 10 days in the placebo group.
  • 65% of the participants in the remdesivir group and 68% of the participants in the placebo group received corticosteroids.
  • 28% of the participants in the remdesivir group and 29% of the participants in the placebo group received lopinavir/ritonavir.
  • 29% of the participants in the remdesivir arm and 38% of the participants in the placebo arm received interferon alfa-2b.

Study Endpoints

  • There was no difference in the time to clinical improvement between the remdesivir and placebo groups (a median of 21 days vs. 23 days, respectively; HR 1.23; 95% CI, 0.87–1.75).
  • For patients who started the study drug within 10 days of symptom onset, faster time to clinical improvement was seen in the remdesivir arm than in the placebo arm (a median of 18.0 days vs. 23.0 days, respectively; HR 1.52, 95% CI, 0.95–2.43); however, this was not statistically significant.
  • The 28-day mortality rate was similar for the two study arms (14% and 13% of participants in the remdesivir arm and placebo arm, respectively).
  • There was no difference between the groups in SARS-CoV-2 viral load at baseline, and the rate of decline over time was similar between the two groups.
  • The number of participants who experienced AEs was similar in the two groups (66% and 64% of participants in the remdesivir and placebo groups, respectively).
  • More participants in the remdesivir arm than in the placebo arm discontinued therapy due to AEs (12% vs. 5% of participants in the remdesivir and placebo groups, respectively).

Limitations

  • The study was terminated early; as a result, the sample size did not have sufficient power to detect differences in clinical outcomes.
  • The use of concomitant medications (corticosteroids, lopinavir/ritonavir, interferon) may have obscured the effects of remdesivir.

Interpretation

There was no difference in time to clinical improvement, 28-day mortality, or rate of viral clearance between the remdesivir-treated patients and the placebo-treated patients.

Uncontrolled Case Series from Remdesivir Compassionate Use Program

In an uncontrolled case series of 53 hospitalized people with COVID-19, most patients needed less oxygen support after receiving compassionate use remdesivir. There was no comparison group, however, so it is not possible to assess whether the improvement was the result of using remdesivir.10

Clinical Trials

Multiple clinical trials are currently underway or in development. Please check ClinicalTrials.gov for the latest information.

Monitoring, Adverse Effects, and Drug-Drug Interactions

Remdesivir can cause gastrointestinal symptoms (e.g., nausea, vomiting), elevated transaminase levels, and prothrombin time elevation (without change in international normalized ratio). In vitro, remdesivir is a cytochrome P450 (CYP) 3A4, CYP2C8, and CYP2D6 substrate. Coadministering remdesivir with inhibitors of these enzymes is not expected to have a significant impact on remdesivir concentrations. Remdesivir concentration may be affected by strong CYP inducers, but the interaction is not expected to be clinically significant.11

Because the remdesivir formulation contains renally cleared sulfobutylether-beta-cyclodextrin sodium, patients with an eGFR <50 mL/min are excluded from some clinical trials (some trials have a cutoff of eGFR <30 mL/min).

Considerations in Pregnancy

  • Use remdesivir in pregnant patients only when the potential benefit justifies the potential risk to the mother and the fetus.3
  • The safety and effectiveness of remdesivir for COVID-19 treatment have not been evaluated in pregnant patients. Remdesivir should not be withheld from pregnant patients if it is otherwise indicated.
  • Remdesivir is available through the FDA EUA for adults and children and through a compassionate use program for pregnant women with COVID-19.
  • In a randomized controlled Ebola treatment trial of therapies that included remdesivir, among 98 female participants who received remdesivir, six had a positive pregnancy test. The obstetric and neonatal outcomes were not reported in the study.12

Considerations in Children

  • The safety and effectiveness of remdesivir for COVID-19 treatment have not been evaluated in pediatric patients.
  • Remdesivir is available through an FDA EUA for adults and children and through a compassionate use program for patients aged <18 years with COVID-19.
  • In the same randomized controlled trial for the treatment of Ebola virus infection, 41 pediatric patients aged <7 days to <18 years received remdesivir.12 The safety and clinical outcomes in children were not reported separately in the published results for the trial.

References

  1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19—preliminary report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.
  2. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32459919.
  3. Food and Drug Administration. Fact sheet for health care providers emergency use authorization (EUA) of remdesivir (GS-5734™). 2020. Available at: https://www.fda.gov/media/137566/download. Accessed May 8, 2020.
  4. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020;30(3):269-271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32020029.
  5. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017;9(396). Available at: https://www.ncbi.nlm.nih.gov/pubmed/28659436
  6. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020;11(1):222. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31924756.
  7. 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;117(12):6771-6776. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32054787.
  8. Williamson BN, Feldmann F, Benjamin Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv. 2020;[Preprint]. Available at: https://www.biorxiv.org/content/10.1101/2020.04.15.043166v2.full.pdf.
  9. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet. 2020. Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext#seccestitle10.
  10. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe COVID-19. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32275812.
  11. Gilead Sciences. Remdesivir (GS-5734) investigator’s brochure. Edition 5. February 21, 2020.
  12. Mulangu S, Dodd LE, Davey RT, Jr., et al. A randomized, controlled trial of ebola virus disease therapeutics. N Engl J Med. 2019;381(24):2293-2303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31774950.