Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia

Abstract

ImportanceImmune dysregulation contributes to poorer outcomes in COVID-19.ObjectiveTo investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.Design, Setting, and ParticipantsRandomized, double-masked, placebo-controlled clinical trial using a master protocol to investigate immunomodulators added to standard care for treatment of participants hospitalized with COVID-19 pneumonia. The results of 3 substudies are reported from 95 hospitals at 85 clinical research sites in the US and Latin America. Hospitalized patients 18 years or older with confirmed SARS-CoV-2 infection within 14 days and evidence of pulmonary involvement underwent randomization between October 2020 and December 2021.InterventionsSingle infusion of abatacept (10 mg/kg; maximum dose, 1000 mg) or infliximab (5 mg/kg) or a 28-day oral course of cenicriviroc (300-mg loading dose followed by 150 mg twice per day).Main Outcomes and MeasuresThe primary outcome was time to recovery by day 28 evaluated using an 8-point ordinal scale (higher scores indicate better health). Recovery was defined as the first day the participant scored at least 6 on the ordinal scale.ResultsOf the 1971 participants randomized across the 3 substudies, the mean (SD) age was 54.8 (14.6) years and 1218 (61.8%) were men. The primary end point of time to recovery from COVID-19 pneumonia was not significantly different for abatacept (recovery rate ratio [RRR], 1.12 [95% CI, 0.98-1.28]; P = .09), cenicriviroc (RRR, 1.01 [95% CI, 0.86-1.18]; P = .94), or infliximab (RRR, 1.12 [95% CI, 0.99-1.28]; P = .08) compared with placebo. All-cause 28-day mortality was 11.0% for abatacept vs 15.1% for placebo (odds ratio [OR], 0.62 [95% CI, 0.41-0.94]), 13.8% for cenicriviroc vs 11.9% for placebo (OR, 1.18 [95% CI 0.72-1.94]), and 10.1% for infliximab vs 14.5% for placebo (OR, 0.59 [95% CI, 0.39-0.90]). Safety outcomes were comparable between active treatment and placebo, including secondary infections, in all 3 substudies.Conclusions and RelevanceTime to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.Trial RegistrationClinicalTrials.gov Identifier: NCT04593940

Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19

“…This is a secondary analysis of abatacept pharmacokinetics and exposure-response data collected from the ACTIV-1 IM randomized clinical trial. The ACTIV-1 IM methods and full eligibility criteria were previously published . Briefly, the ACTIV-1 IM multinational trial was conducted between October 16, 2020, and December 31, 2021, using the ACTIV-1 IM master protocol (Supplement 1) that randomized adults hospitalized with moderate to severe COVID-19 to 1 of 3 immune modulators or placebo plus standard of care.…”

“…Abatacept (Orencia; Bristol Myers Squibb) is a recombinant fusion protein that inhibits T-cell activation, thereby reducing multiple inflammatory cytokines, including interleukin 6 and tumor necrosis factor α, that are part of the COVID-19 cytokine storm . In the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) multicenter randomized clinical trial, abatacept, combined with standard of care that often included remdesivir and corticosteroids, decreased mortality in patients hospitalized with moderate to severe COVID-19, but the primary end point of time to recovery was not met . However, the pharmacokinetics of abatacept and optimal dosing in this patient population are unknown.…”

Treatment of Adults Hospitalized With COVID-19 Pneumonia—Reply

“…In Reply We thank Drs Mathew and Feldmann for their comments on the results of ACTIV-1 . We agree that mortality is a very important clinical outcome, but designing a trial such as ACTIV-1 to have sufficient power to detect an effect on mortality was challenging in June 2020, when data on clinical outcomes of severe COVID-19 were in flux.…”

Treatment of Adults Hospitalized With COVID-19 Pneumonia

“…To the Editor We have several comments about the recent randomized clinical trial (ACTIV-1) that investigated the effect of abatacept, cenicriviroc, or infliximab on COVID-19 pneumonia.…”

“…Currently, a large phase 3 trial assessing infliximab and abatacept (inhibitor of T-cell activation), both highly effective in rheumatoid arthritis, has demonstrated the largest reduction in mortality reported to date at 60 days in severe and critical COVID-19 respiratory failure . Another cytokine inhibitor cenicriviroc, a CC chemokine receptor (CCR2/CCR5) inhibitor, effectively served as a negative control along with placebo.…”