Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial

Abstract

Importance: Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.

Objective: To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.

Design, setting, and participants: Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.

Interventions: Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.

Main outcomes and measures: The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.

Results: Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. 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; 95% CI, 1.09-2.48; 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). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.

Conclusions and relevance: Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.

Trial registration: ClinicalTrials.gov Identifier: NCT04292730.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Spinner reported receipt of personal fees from AbbVie and grants and personal fees from Janssen-Cilag, Merck Sharp & Dohme, and ViiV Healthcare/GlaxoSmithKline. Dr Gottlieb reported receipt of nonfinancial support from Gilead Sciences outside the current work. Dr Arribas López reported receipt of honoraria from Gilead for participating in an advisory board, and his institution has received grants from Gilead for an unrelated project; he also reported receipt of grants and personal fees from ViiV and personal fees from Janssen, Merck Sharp & Dohme, Teva, and Aelix. Dr Soriano Viladomiu reported receipt of honoraria as speaker or advisor from Pfizer, Merck Sharp & Dohme, Angelini, Menarini, and Shionogi. Dr Ogbuagu reported receipt of advisory board honoraria from Gilead and ViiV and speakers fees from Gilead. Dr Chai reported receipt of grant support from and advisership/consultancy for Pfizer, Gilead, Astellas, and Merck Sharp & Dohme. Dr Bernasconi reported that his institution has received fees for his participation in advisory boards and travel grants from Gilead, Merck Sharp & Dohme, ViiV, Pfizer, AbbVie, and Sandoz. Dr Bhagani reported receipt of research support and honoraria for lectures and advisory boards from Gilead Sciences and grants and personal fees from AbbVie, Merck Sharp & Dohme, Roche, and ViiV. Dr Sanyal reported being employed at Sanyal Bio; receiving royalties from Elseiver and UpToDate; holding stock in Exhalenz, Akarna, Genfit, Hemoshear, Durect, and Tozoama; receiving grants from Galectin and Bristol-Myers; consulting for Conatus, Gilead, Pfizer, Boehringer Ingelheim, Merck, Hemoshear, Lilly, Novo Nordisk, Ardelyx, Terns, ENYO, Birdrock, Albireo, Sanofi, Janssen, Takeda, Zydus, AMRA, Poxel, Servier, Second Genome, and General Electric; receiving grants and consulting for Mallinckrodt, Salix, Novartis, and Nimbus; being principal investigator of an ongoing trial for Genfit; receiving grants and being principal investigator of an ongoing trial for Immuron; receiving grants, consulting for, and being principal investigator of ongoing trials for Echosens-Sandill and Sequana; providing advice but receiving no personal remuneration for Intercept, Galectin, Fractyl, Durect, Indalo, Allergan, Chemomab, Affimmune, Teva, BASF, Perspectum, and 89bio; and being the inventor for a patent held jointly by OWL and Virginia Commonwealth University. Dr Huhn reported that his institution received grants from Gilead, GlaxoSmithKline/ViiV, Janssen, Bristol-Meyers Squibb, Proteus, Lilly, and the National Institute of Allergy and Infectious Diseases and that he received consulting fees from Gilead, ViiV, Janssen, and Theratechnologies. Dr Marty reported receipt of grants from Ansun, Chimerix, Gilead, and Merck and personal fees from AlloVir, Janssen, Kyorin, Merck, ReViral, and Symbio. Drs SenGupta, Hyland, Osinusi, Cao, Blair, Wang, Gaggar, and Brainard are employees of and own stock in Gilead Sciences. No other disclosures were reported.

Figures

Figure 1.. Participant Flow in a Randomized Clinical Trial of Remdesivir vs Standard Care in Patients With Moderate Coronavirus Disease 2019

aBoth patients met the eligibility criteria for creatinine clearance at screening but not on the day of randomization. bPatient tested negative for severe acute respiratory syndrome coronavirus 2. cPatient’s oxygen saturation was less than 94% on the day of randomization. dThree patients improved enough for discharge in the judgment of the investigator; 1 patient discontinued because of episodes of hypotension. eOne patient discontinued because of use of a prohibited medication and 1 patient was found to have been enrolled in error (creatinine clearance <50 mL/min). fPersistent difficulty with intravenous access led investigator to decide to stop treatment in this patient.

Figure 2.. Clinical Status on a 7-Point Ordinal Scale on Study Days 11, 14, and 28 by Treatment Group

COVID-19 indicates coronavirus disease 2019; ECMO, extracorporeal membrane oxygenation. All percentage values in each point category are provided in eTables 5 and 6 in Supplement 3. At day 11, P = .18 for comparison of the distribution of the 10-day remdesivir group vs standard care and P = .02 for 5-day remdesivir vs standard care (Table 2). At day 14, P = .03 for comparisons of both the 5-day and 10-day remdesivir groups vs standard care (eTable 5 in Supplement 3). At day 28, P = .03 for comparison of the 10-day remdesivir group vs standard care and P = .08 for 5-day remdesivir vs standard care (eTable 6 in Supplement 3). P values were calculated with the Wilcoxon rank sum test comparing the distribution of the groups.