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. 2023 Apr;12(4):1189-1203.
doi: 10.1007/s40121-023-00789-y. Epub 2023 Apr 19.

Consistent Effects of Early Remdesivir on Symptoms and Disease Progression Across At-Risk Outpatient Subgroups: Treatment Effect Heterogeneity in PINETREE Study

Samuel M Brown  1 , Morgan J Katz  2 , Adit A Ginde  3 , Kavita Juneja  4 , Monica Ramchandani  4 , Joshua T Schiffer  5 , Carlos Vaca  6 , Robert L Gottlieb  7 , Yuan Tian  4 , Emon Elboudwarej  4 , Joshua A Hill  5 , Richard Gilson  8 , Lauren Rodriguez  4 , Charlotte Hedskog  4 , Shuguang Chen  4 , Jairo M Montezuma-Rusca  4 , Anu Osinusi  4 , Roger Paredes  9
Affiliations

Consistent Effects of Early Remdesivir on Symptoms and Disease Progression Across At-Risk Outpatient Subgroups: Treatment Effect Heterogeneity in PINETREE Study

Samuel M Brown et al. Infect Dis Ther. 2023 Apr.

Abstract

Introduction: In the PINETREE study, early remdesivir treatment reduced risk of coronavirus disease 2019 (COVID-19)-related hospitalizations or all-cause death versus placebo by 87% by day 28 in high-risk, non-hospitalized patients. Here we report results of assessment of heterogeneity of treatment effect (HTE) of early outpatient remdesivir, focusing on time from symptom onset and number of baseline risk factors (RFs).

Methods: PINETREE was a double-blind, placebo-controlled trial of non-hospitalized patients with COVID-19 who were randomized within 7 days of symptom onset and had ≥ 1 RF for disease progression (age ≥ 60 years, obesity [body mass index ≥ 30], or certain coexisting medical conditions). Patients received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) or placebo.

Results: In this subgroup analysis, HTE of remdesivir by time from symptom onset at treatment initiation and number of baseline RFs was not detected. Treatment with remdesivir reduced COVID-19-related hospitalizations independent of stratification by time from symptom onset to randomization. Of patients enrolled ≤ 5 days from symptom onset, 1/201 (0.5%) receiving remdesivir and 9/194 (4.6%) receiving placebo were hospitalized (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01-0.82). Of those enrolled at > 5 days from symptom onset, 1/78 (1.3%) receiving remdesivir and 6/89 (6.7%) receiving placebo were hospitalized (HR 0.19; 95% CI 0.02-1.61). Remdesivir was also effective in reducing COVID-19-related hospitalizations when stratified by number of baseline RFs for severe disease. Of patients with ≤ 2 RFs, 0/159 (0.0%) receiving remdesivir and 4/164 (2.4%) receiving placebo were hospitalized; of those with ≥ 3 RFs, 2/120 (1.7%) receiving remdesivir and 11/119 (9.2%) receiving placebo were hospitalized (HR 0.16; 95% CI 0.04-0.73).

Conclusions: In the outpatient setting, benefit of remdesivir initiated within 7 days of symptoms appeared to be consistent across patients with RFs. Therefore, it may be reasonable to broadly treat patients with remdesivir regardless of comorbidities.

Trial registration: ClinicalTrials.gov number NCT04501952.

Keywords: Antiviral; COVID-19; Coronavirus; Outpatients; Remdesivir; SARS-CoV-2.

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Conflict of interest statement

Monica Ramchandani, Yuan Tian, Emon Elboudwarej, Shuguang Chen, Jairo M. Montezuma-Rusca, Anu Osinusi, Lauren Rodriguez, and Charlotte Hedskog are employees and stockholders of Gilead Sciences. Samuel M. Brown received funding for COVID-19 research from NIH, Department of Defense (DoD), and CDC outside the present study and chairs a Data and Safety Monitoring Board for Hamilton Ventilators, outside the present study. Morgan J. Katz received research funding from CDC and the Agency for Healthcare and Research Quality and consulting fees from Artis Health Systems and Skinflique outside the present study. Adit A. Ginde received funding for COVID-19 research from NIH, DoD, CDC, Faron Pharmaceuticals, and AbbVie outside the present study. Kavita Juneja was an employee of Gilead Sciences at the time this work was done and is now an employee of Corcept Therapeutics. Joshua T. Schiffer was an investigator for the PINETREE study; he assisted Gilead in designing the clinical trial but was not compensated for this work. Dr. Schiffer declares no additional personal interests. Carlos Vaca declares no personal interests. Robert L. Gottlieb has been a consultant for AbbVie, Gilead Sciences, Johnson & Johnson, Roivant Pharmaceuticals, Roche Pharmaceuticals, GSK, and Eli Lilly. Dr. Gottlieb is also a national coordinating principal investigator for Johnson & Johnson, served on an academic steering committee for Roivant Pharmaceuticals, and received a gift-in-kind to Baylor Scott and White Research Institute to facilitate NCT03383419 from Gilead Sciences. Dr. Gottlieb owns de minimis stock in AbCellera Biologics and has served as a speaker for Pfizer outside of the scope of COVID-19. Joshua A. Hill received research funding from Gilead Sciences related to the current work; research funding from Takeda, Allovir, Karius, Merck, and Deverra outside the current work; and consulting fees from Amplyx, Allovir, Allogene, Takeda, and CRISPR outside the current work. Richard Gilson was an investigator for the PINETREE study; he has no other interests to declare. Roger Paredes received funding for COVID-19 research from NIH, Gilead, Lilly, and PharmaMar outside the present study, and has participated in COVID-19-related advisory boards for Gilead, MSD, Lilly, Roche, Atea, GSK, and Pfizer.

Figures

Fig. 1
Fig. 1
COVID-19-related hospitalization stratified by time from symptom onset to infusion. Patients with a ≤ 5 days and b > 5 days between symptom onset and infusion. COVID-19 coronavirus disease 2019, RDV remdesivir, PBO placebo, HR hazard ratio, CI confidence interval
Fig. 2
Fig. 2
COVID-19-related hospitalization stratified by risk factors. Patients with a 1–2 risk factors and b ≥ 3 risk factors. COVID-19 coronavirus disease 2019, RDV remdesivir, PBO placebo, HR hazard ratio, N/A not applicable, CI confidence interval. aIncluding 1 subject without a risk factor
Fig. 3
Fig. 3
Symptom alleviation stratified by time from symptom onset to infusion. Patients with a ≤ 5 days and b > 5 days between symptom onset and infusion. RDV remdesivir, PBO placebo, RR rate ratio, CI confidence interval
Fig. 4
Fig. 4
Symptom alleviation stratified by risk factors. Patients with a 1–2 risk factors and b ≥ 3 risk factors. RDV remdesivir, PBO placebo, HR hazard ratio, CI confidence interval. aIncluding 1 subject without a risk factor
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