Remdesivir: Selected Clinical Data
Last Updated: November 3, 2020
Remdesivir is approved by the Food and Drug Administration for the treatment of COVID-19 in hospitalized adult and pediatric patients (aged ≥12 years and weighing ≥40 kg).1
The information presented in this section may include data from preprints or articles that have not been peer reviewed. This section will be updated as new information becomes available. Please see ClinicalTrials.gov for more information on clinical trials that are evaluating remdesivir.
Multinational Randomized Controlled Trial of Remdesivir Versus Placebo in Hospitalized Patients
The Adaptive COVID-19 Treatment Trial (ACTT-1) is a National Institutes of Health-sponsored, multinational, randomized, double-blind, placebo-controlled trial.2 Patients received either placebo for 10 days or intravenous (IV) remdesivir at a dose of 200 mg on Day 1 and then 100 mg daily for up to 9 more days. The primary study endpoint was time to clinical recovery. Severity of illness at baseline and at Day 15 was assessed using an eight-point ordinal scale:
- Not hospitalized, no limitations
- Not hospitalized, with limitations
- Hospitalized, no active medical problems
- Hospitalized, not on oxygen
- Hospitalized, on oxygen
- Hospitalized, on high-flow oxygen or noninvasive mechanical ventilation
- Hospitalized, on mechanical ventilation or extracorporeal membrane oxygenation (ECMO)
The study population consisted of hospitalized patients aged ≥18 years with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (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 room 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 transaminase (ALT) or aspartate transaminase (AST) levels >5 times the upper limit of normal (ULN), those who had an estimated glomerular filtration rate <30 mL/minute, and those who were pregnant or breastfeeding.
- 1,062 participants were enrolled.
- The median time from symptom onset to randomization was 9 days (IQR 6–12 days).
- Remdesivir significantly reduced the time to recovery compared to placebo (median time to recovery was 10 days vs. 15 days; recovery rate ratio 1.29; 95% CI, 1.12–1.49; P < 0.001).
- Clinical improvement based on the ordinal scale outlined above was significantly higher at Day 15 in patients who received remdesivir than in those who received placebo (OR 1.5; 95% CI, 1.2–1.9, P < 0.001).
- The benefit of remdesivir for reducing time to recovery was clearest in the subgroup of hospitalized patients who required supplemental oxygenation at study enrollment (ordinal scale 5, n = 435; recovery rate ratio 1.45; 95% CI, 1.18–1.79). In a post hoc analysis of deaths by Day 15, remdesivir appeared to confer a survival benefit in this subgroup (HR for death 0.28; 95% CI, 0.12–0.66).
- In patients who required high-flow oxygen or noninvasive ventilation at study enrollment (ordinal scale 6, n = 193), there was no observed difference in time to recovery between the remdesivir and placebo groups (recovery rate ratio 1.09, 95% CI, 0.76–1.57). In a post hoc analysis of deaths by Day 15, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 0.82; 95% CI, 0.40–1.69).
- Among the patients who were on mechanical ventilation or ECMO at study enrollment (ordinal scale 7, n = 285), there was no observed difference in time to recovery between the remdesivir and placebo groups (recovery rate ratio 0.98; 95% CI, 0.70–1.36). In a post hoc analysis of deaths by Day 15, there was no evidence that remdesivir had an impact on the mortality rate in this subgroup (HR 0.76; 95% CI, 0.39–1.50).
- 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. Mild to moderate disease was defined as SpO2 >94% on room air and a respiratory rate of <24 breaths/minute without supplemental oxygen.
- There was no statistically significant difference in mortality by Day 29 between the remdesivir (11.4%) and placebo (15.2%) arms (HR 0.73; 95% CI, 0.52-1.03; P = 0.07).
- Mortality rates by Day 29 differed between groups according to baseline severity, with the greatest difference observed in ordinal scale 5 (HR 0.30; 95% CI, 0.14-0.64), compared to ordinal scale 6 (HR 1.02; 95% CI, 0.54-1.91) and ordinal scale 7 (HR 1.13; 95% CI, 0.67-1.89).
- The benefit of remdesivir was greater in participants who were randomized during the first 10 days after symptom onset.
- The percentages of participants with serious adverse effects (AEs) were similar in the remdesivir and placebo groups (25% vs. 32%).
- Transaminase elevations occurred in 6% of remdesivir recipients and 10.7% of placebo recipients.
- The study was conducted in patients with a wide range of disease severity. The study was not powered to detect differences within subgroups.
- The study was powered to detect differences in clinical improvement, not mortality.
- No data were collected on longer-term morbidity.
In patients with severe COVID-19, remdesivir reduced the time to clinical recovery. The benefit of remdesivir was most apparent in hospitalized patients who only required supplemental oxygen. There was no observed benefit of remdesivir in those who were on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO, but the study was not powered to detect differences within subgroups. 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.
Randomized Controlled Trial of Remdesivir Versus Placebo for Severe COVID-19 in China
This was a multicenter, double-blind, randomized, placebo-controlled trial that evaluated patients with severe COVID-19 in China. Patients were randomized 2:1 to receive IV remdesivir (200 mg on Day 1, followed by 100 mg daily) or normal saline placebo for 10 days. 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.3
This study enrolled hospitalized adults with laboratory-confirmed SARS-CoV-2 infection whose time from symptom onset to randomization was <12 days. These patients had SpO2 ≤94% on room air or PaO2/FiO2 <300 mm Hg and radiographically confirmed pneumonia.
- In this study, 237 patients were randomized to receive remdesivir (n = 158) or placebo (n = 79). The study was stopped before target enrollment was reached due to control of the COVID-19 outbreak in China.
- The median time from symptom onset to randomization was 9 days for the remdesivir group and 10 days for the placebo group.
- Sixty-five percent of the participants in the remdesivir group and 68% of the participants in the placebo group received corticosteroids.
- Twenty-eight percent of the participants in the remdesivir group and 29% of the participants in the placebo group received lopinavir/ritonavir.
- Twenty-nine percent of the participants in the remdesivir arm and 38% of the participants in the placebo arm received interferon alfa-2b.
- There was no difference in the time to clinical improvement between the remdesivir and placebo groups (median time to clinical improvement was 21 days vs. 23 days; HR 1.23; 95% CI, 0.87–1.75).
- For patients who started remdesivir or placebo within 10 days of symptom onset, a faster time to clinical improvement was seen in the remdesivir arm than in the placebo arm (median of 18 days vs. 23 days; HR 1.52; 95% CI, 0.95–2.43); however, this was not statistically significant.
- The 28-day mortality was similar for the two study arms (14% of participants in the remdesivir arm vs. 13% in the placebo arm).
- 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 between the two groups (66% of participants in the remdesivir arm vs. 64% in the placebo arm).
- More participants in the remdesivir arm discontinued therapy due to AEs (12% of participants in the remdesivir arm vs. 5% in the placebo arm).
- The study was terminated early because it did not reach its target enrollment; as a result, the sample size did not have sufficient power to detect differences in clinical outcomes.
- The use of concomitant medications (i.e., corticosteroids, lopinavir/ritonavir, interferons) may have obscured the effects of remdesivir.
There was no difference in time to clinical improvement, 28-day mortality, or rate of SARS-CoV-2 clearance between remdesivir-treated and placebo-treated patients; however, the study was underpowered to detect differences in these outcomes between the two groups.
Remdesivir Versus Standard Care in Hospitalized Patients with Moderate COVID-19
This open-label, randomized trial compared the use of 10 days of remdesivir (n = 197) or 5 days of remdesivir (n = 199) to “standard care” (n = 200) in hospitalized patients.4 Remdesivir was administered intravenously at a dose of 200 mg on Day 1 and then 100 mg daily.
The study enrolled patients with laboratory-confirmed SARS-CoV-2 infection and moderate pneumonia, which was defined as radiographic evidence of pulmonary infiltrates and SpO2>94% on room air at sea level.
- Demographic characteristics and baseline disease characteristics were similar across the three study groups.
- Patients who received 5 days of remdesivir had significantly higher odds of having a better clinical status distribution on Day 11 than those who received standard care (OR 1.65; 95% CI, 1.09–2.48; P = 0.02).
- The clinical status distribution on Day 11 was not significantly different between the patients who received 10 days of remdesivir and those who received standard care (P = 0.18).
- By Day 28, there were more hospital discharges among the patients who received remdesivir (89% in the 5-day group and 90% in the 10-day group) than among those who received standard care (83% of patients).
- Mortality was low in all groups (1% to 2%).
- Several AEs occurred more frequently among patients who were treated with remdesivir than among those who received standard care: nausea (10% of patients vs. 3% of patients), hypokalemia (6% vs. 2%), and headache (5% vs. 3%).
- The open-label design of this study may have affected decisions related to concomitant medication use and hospital discharge.
- Compared with the remdesivir groups, a greater proportion of participants in the standard care group received hydroxychloroquine, lopinavir/ritonavir, or azithromycin, which may cause AEs and which have not been shown to have a clinical benefit in hospitalized patients with COVID-19.
- The study did not collect data on the time to return to activity for patients who were discharged from the hospital.
Hospitalized patients with moderate COVID-19 who received 5 days of remdesivir had better outcomes than those who received standard care; however, the difference between the groups was of uncertain clinical importance.
Multinational, Randomized Trial of Different Durations of Remdesivir Treatment in Hospitalized Patients
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 (200 mg on Day 1, followed by 100 mg daily). The primary study endpoint was clinical status at Day 14, which was assessed using a seven-point ordinal scale:5
- Hospitalized, on invasive mechanical ventilation or ECMO
- Hospitalized, on noninvasive ventilation or high-flow oxygen devices
- Hospitalized, requiring low-flow supplemental oxygen
- Hospitalized, not requiring supplemental oxygen, but requiring ongoing medical care for COVID-19 or for other reasons
- Hospitalized, not requiring supplemental oxygen or ongoing medical care (other than the care that was specified in the protocol for remdesivir administration)
- Not hospitalized
The study enrolled hospitalized patients aged ≥12 years with confirmed SARS-CoV-2 infection and radiographic evidence of pulmonary infiltrates.
Patients in this study had either SpO2 ≤94% on room air or were receiving supplemental oxygen. The study excluded patients who were receiving mechanical ventilation or ECMO or who had multiorgan failure, an ALT or AST level >5 times ULN, or an estimated creatinine clearance <50 mL/minute.
- Out of 402 randomized participants, 397 began 5 days (n = 200) or 10 days (n = 197) of remdesivir treatment.
- At baseline, participants in the 10-day group had worse clinical status (based on ordinal scale distribution) than those in the 5-day group (P = 0.02).
- 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 achieve a 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).
- 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 10-day group (8 days; IQR 5–10 days).
- 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.
- 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 status of participants in the 5-day and 10-day groups.
In hospitalized patients with severe COVID-19 who were not on mechanical ventilation or ECMO, remdesivir treatment for 5 or 10 days had similar clinical benefit.
Other Reviewed Studies
The clinical trials described in this section do not represent all of the trials that the Panel reviewed while developing the recommendations for remdesivir. The studies summarized above are those that have had the greatest impact on the Panel’s recommendations.
- Remdesivir (VEKLURY) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf. Accessed: October 25, 2020.
- Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19 - Final Report. N Engl J Med. 2020. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32445440.
- 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;395(10236):1569-1578. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32423584.
- Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324(11):1048-1057. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32821939.
- 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.