Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV)

Abstract

Background: Uncertainty over the therapeutic benefit of parenteral remdesivir in coronavirus disease 2019 (COVID-19) has resulted in varying treatment guidelines.

Methods: In a multicenter open-label, controlled, adaptive, pharmacometric platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to 1 of 8 treatment arms including intravenous remdesivir (200 mg followed by 100 mg daily for 5 days) or no study drug. The primary outcome was the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population. This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907).

Results: The 2 study arms enrolled 131 patients (remdesivir n = 67, no study drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated viral clearance by 42% (95% credible interval, 18%-73%).

Conclusions: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the method described can determine in vivo clinical antiviral efficacy rapidly and efficiently.

Keywords: COVID-19; SARS-CoV-2; antiviral efficacy; pharmacometrics; remdesivir.

Figure 1.

Consolidated Standards for Reporting Trials diagram of the PLATCOV phase 2 open-label, randomized, controlled adaptive platform trial for remdesivir in Thailand and Brazil. Enrollment ended 10 June 2022. Abbreviations: ATK, antigen test kit; BMI, body mass index; ECG, electrocardiogram; mITT, modified intention-to-treat; PCR, polymerase chain reaction.

Figure 2.

Effect of parenteral remdesivir on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral clearance. Left: Median SARS-CoV-2 oropharyngeal virus clearance profiles following remdesivir (darker/grey) and no study drug (lighter/green). Right: estimated treatment effects under the linear model (light with circle) and nonlinear model (dark with triangle). The thick lines show the 80% credible interval (CrI); the thin lines show the 95% CrI.

Figure 3.

Individual estimate of the viral clearance half-lives with point estimates (squares) and 80% credible intervals (lines). The vertical dashed lines show the median population viral clearance half-lives by treatment arm (lower: no study drug; upper: remdesivir). The median estimated viral clearance half-lives under the linear model were 12.8 (range, 4.8–50.0) hours in the remdesivir arm and 18.0 (range, 3.6–46.7) hours in the contemporaneous control arm.