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. 2023 Jul 25;330(4):328-339.
doi: 10.1001/jama.2023.11043.

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

Jane A O'Halloran  1 , Emily R Ko  2 , Kevin J Anstrom  3 , Eyal Kedar  4 , Matthew W McCarthy  5 , Reynold A Panettieri Jr  6 , Martin Maillo  7 , Patricia Segura Nunez  8 , Anne M Lachiewicz  3 , Cynthia Gonzalez  9 , P Brian Smith  10 , Sabina Mendivil-Tuchia de Tai  11 , Akram Khan  12 , Alfredo J Mena Lora  13 , Matthias Salathe  14 , Gerardo Capo  15 , Daniel Rodríguez Gonzalez  16 , Thomas F Patterson  17 , Christopher Palma  18 , Horacio Ariza  19 , Maria Patelli Lima  20 , John Blamoun  21 , Esteban C Nannini  22 , Eduardo Sprinz  23 , Analia Mykietiuk  24 , Radica Alicic  25 , Adriana M Rauseo  1 , Cameron R Wolfe  2 , Britta Witting  5 , Jennifer P Wang  26 , Luis Parra-Rodriguez  1 , Tatyana Der  2 , Kate Willsey  5 , Jun Wen  10 , Adam Silverstein  10 , Sean M O'Brien  10 , Hussein R Al-Khalidi  10 , Michael A Maldonado  27 , Richard Melsheimer  28 , William G Ferguson  29 , Steven E McNulty  10 , Pearl Zakroysky  10 , Susan Halabi  10 , Daniel K Benjamin Jr  10 , Sandra Butler  30 , Jane C Atkinson  9 , Stacey J Adam  31 , Soju Chang  9 , Lisa LaVange  3 , Michael Proschan  32 , Samuel A Bozzette  9 , William G Powderly  1 ; ACTIV-1 IM Study Group Members
Collaborators, Affiliations

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial

Jane A O'Halloran et al. JAMA. .

Abstract

Importance: Immune dysregulation contributes to poorer outcomes in COVID-19.

Objective: To investigate whether abatacept, cenicriviroc, or infliximab provides benefit when added to standard care for COVID-19 pneumonia.

Design, setting, and participants: Randomized, 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.

Interventions: Single 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 measures: The 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.

Results: Of 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 relevance: Time to recovery from COVID-19 pneumonia among hospitalized participants was not significantly different for abatacept, cenicriviroc, or infliximab vs placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT04593940.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr O’Halloran reported receiving grants from Janssen Scientific outside the submitted work. Dr Anstrom reported receiving grants from Merck, Bayer, NIH, and Pfizer during the conduct of the study. Dr Panettieri reported receiving grants from AstraZeneca, RIFM, TEVA, Medimmume, AgoMab, ACTIV-1, Janssen, and Vault Health; personal fees from Sanofi, Merck & Co, and AstraZeneca; and serving on an advisory beard for Genentech and RIFM outside the submitted work. Dr Maillo reported receiving institutional investigation fees from Technical Resources International, Inc during the conduct of the study. Dr Lachiewicz reported receiving funding for clinical trial participation from Duke Clinical Research Institute during the conduct of the study; clinical trial research support from Pfizer, Shionogi, Novartis, Cidara, and Contrafect outside the submitted work. Dr Smith reported receiving grants from BARDA during the conduct of the study and personal fees from UCB and Syneos Health outside the submitted work. Dr Mendivil-Tuchia de Tai reported receiving sponsorship for Technical Resource International during the conduct of the study. Dr Khan reported receiving grants from Roche, Dompe Pharmaceuticals, United Therapeutics, Baxter, Regeneron, and Johnson & Johnson and personal fees from Dompe Pharmaceutics outside the submitted work. Dr Mena Lora reported receiving grants from NIH during the conduct of the study. Dr Salathe reported receiving grants from NIH during the conduct of the study and personal fees from Arrowhead Pharmaceuticals; collaborations with Enterprise Therapeutics; and grants from NIH, FAMRI, and Cystic Fibrosis Foundation outside the submitted work. Dr Rodríguez Gonzalez reported receiving grants from Technical Resources International TRI during the conduct of the study and grants from Regeneron Pharmaceutical, Inc outside the submitted work. Dr Patterson reported receiving grants from Gilead to UT Health San Antonio outside the submitted work. Dr Ariza reported having a contract with Technical Resources International funded by BARDA during the conduct of the study. Dr Nannini reported receiving grants from Pfizer and Basilea and personal fees from GSK and MSD outside the submitted work. Dr Wolfe reported receiving personal fees from Gilead, Regeneron, and Adagio and serving on a board for Biogen, Adamis, and Atea outside the submitted work. Dr O’Brien reported receiving grants from Technical Resources International/Biomedical Advanced Research and Development Authority during the conduct of the study. Dr Maldonado reported receiving personal fees from Bristol Myers Squibb during the conduct of the study. Dr Melsheimer reported being an employee of and stockholder in Janssen Pharmaceuticals, a division of Johnson & Johnson, which commercializes one of the drugs, infliximab, evaluated in the ACTIV-1 study. Dr Ferguson reported being an employee of AbbVie during the conduct of the study. Dr Halabi reported being a member of a data and safety monitoring board for Sanofi, Aveo, Janssen, and Bristol Myers Squibb during the conduct of the study. Dr Benjamin reported providing consultancy for AbbVie consultancy, PPD, and Syneos Health outside the submitted work. Dr Butler reported contract from BARDA (NCATS Technical Lead) during the conduct of the study and contracts with NIH outside the submitted work. Dr Adam reported receiving US Government funding through OWS during the conduct of the study. Dr Bozzette reported receiving salary from NIH during the conduct of the study. Dr Powderly reported receiving grants from National Center for Advancing Translational Sciences and Technical Resources International Support for Role as ACTIV-1 PI during the conduct of the study and personal fees from Merck Laboratories outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Participants in a Master Protocol Assessing Use of Abatacept, Cenicriviroc, and Infliximab to Treat COVID-19 Pneumonia
aOne participant with estimated glomerular filtration rate <30 mL/min, known or suspected history of untreated tuberculosis, male or pregnant female <18 years at enrollment, neutropenia, no ongoing illness and radiographic infiltrates by imaging, oxygen saturation as measured by pulse oximetry ≤ 94% on room air, requiring supplemental oxygen, or requiring mechanical ventilation/extracorporeal membrane oxygenation. bEach participant was randomized (open label) with equal probability to one of the agents available at the time of enrollment after applying agent-specific safety exclusions. Then each participant was assigned in a masked manner to the test agent or its matching placebo in an n:1 ratio, where n equals the number of agents for which that the participant was eligible. Randomization was stratified by geographic location and disease severity. cOverall, 346 participants were eligible to receive all 3 interventions, 156 were eligible to receive abatacept and infliximab, 10 were eligible for cenicriviroc and infliximab, 4 were eligible for abatacept and cenicriviroc, 19 were eligible for abatacept, 3 were eligible for cenicriviroc, and 18 were eligible for only infliximab.
Figure 2.
Figure 2.. Cumulative Incidence of Time to Recovery (Primary Outcome) and Time to Death (Secondary Outcome)
Recovery was defined as the first day the participant scored ≥6 on the 8-point ordinal scale. The median (IQR) observation time for time to recovery and time to death for abatacept, cenicriviroc, and infliximab was 28 (28-28) days.
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