Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19

Abstract

Background: We investigated whether abatacept, a selective costimulation modulator, provides additional benefit when added to standard-of-care for patients hospitalized with Covid-19. Methods: We conducted a master protocol to investigate immunomodulators for potential benefit treating patients hospitalized with Covid-19 and report results for abatacept. Intravenous abatacept (one-time dose 10 mg/kg, maximum dose 1000 mg) plus standard of care (SOC) was compared with shared placebo plus SOC. Primary outcome was time-to-recovery by day 28. Key secondary endpoints included 28-day mortality. Results: Between October 16, 2020 and December 31, 2021, a total of 1019 participants received study treatment (509 abatacept; 510 shared placebo), constituting the modified intention-to-treat cohort. Participants had a mean age 54.8 (SD 14.6) years, 60.5% were male, 44.2% Hispanic/Latino and 13.7% Black. No statistically significant difference for the primary endpoint of time-to-recovery was found with a recovery-rate-ratio of 1.14 (95% CI 1.00-1.29; p=0.057) compared with placebo. We observed a substantial improvement in 28-day all-cause mortality with abatacept versus placebo (11.0% vs. 15.1%; odds ratio [OR] 0.62 [95% CI 0.41-0.94]), leading to 38% lower odds of dying. Improvement in mortality occurred for participants requiring oxygen/noninvasive ventilation at randomization. Subgroup analysis identified the strongest effect in those with baseline C-reactive protein >75mg/L. We found no statistically significant differences in adverse events, with safety composite index slightly favoring abatacept. Rates of secondary infections were similar (16.1% for abatacept; 14.3% for placebo). Conclusions: Addition of single-dose intravenous abatacept to standard-of-care demonstrated no statistically significant change in time-to-recovery, but improved 28-day mortality. Trial registration: ClinicalTrials.gov (NCT04593940).

Competing Interest Statement

This information is being collected.

Clinical Trial

NCT04593940

Funding Statement

This project has been funded with federal funds from the U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under contract number HHSO100201400002I/75A50120F33002. The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components. Bristol Myers Squibb provided abatacept for use in this trial but did not provide any financial support. Gilead Sciences provided remdesivir for use in this trial but did not provide any financial support. Employees of BMS and Gilead Sciences participated in discussions about protocol development and in weekly protocol team calls. The final trial protocol was developed by the protocol chair, Dr. William Powderly, the IND sponsor Dr. Daniel K. Benjamin, Jr, and a protocol development committee including representatives from the National Center for Advancing Translational Sciences (NCATS). NCATS had a collaborative role in the trial design, management, interpretation of the data and the preparation of the manuscript along with the protocol chair, the study statisticians and the study writing group. Infrastructure support and resources for research reported in this publication were provided in part by NCATS of the National Institutes of Health under award number(s):UL1TR002345 to Washington University in St. Louis; the Duke University-Vanderbilt University Medical Center Trial Innovation Center (U24TR001608) (NCATS, Trial Innovation Network).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All sites conducted the study under IRB/EC oversight. WCG IRB gave ethical approval for this work in the US for all sites with the exception of one site that received approval from the Mid-Michigan IRB of the MyMichigan Medical Center. The following ethics committees gave approval in Argentina-Fundacion Medica del Litoral (FUMELIT), Comite de etica en investigacion del sanatorio Britanico, CEDIMP-Comite de Etica Instituto Medico Platense, Comite de Etica en Investigacion del Hospital Gral de Agudos J. M. Ramos Mejia, Comite de etica e investigacion clinica (CEIC), Sanatorio Allende, Comite de Etica en Investigacion (CIEIS) del Nino y del Adulto, Comite de Etica en Investigacion con Seres Humanos del Hospital Interzonal General Dr. Jose Penna. The following ethics committees gave approval in Brazil-Comite de Etica em Pesquisa da Irmandade da Santa Casa de Misericordia de Porto Alegre, Comite de Etica da Associacao dos Funcionarios Publicos do RS-Hospital Ernesto Dornelles, Comite de Etica em Pesquisa do Hospital de Clinicas de Porto Alegre, Comite de Etica em Pesquisa em Seres Humanos da Pontificia Universidade Catolica de Campinas PUC Campinas, Comite de Etica em Pesquisa do Instituto DOr de Pesquisa e Ensino-IDOR, Comite de Etica em Pesquisa do Hospital Felicio Rocho, Comite de Etica em Pesquisa do Hospital 9 de Julho. The following ethics committees gave approval in Mexico-Nuevo Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Hospital Universitario Dr. Jose Eleuterio Gonzalez, Centro Medico Nacional Siglo XXI (Coordinacion de Investigacion en Salud), Hospital Civil de Guadalajara Fray Antonio Alcalde. The following ethic committees gave approval for all sites in Peru-Comite Nacional Transitorio de Etica e Investigacion (CNTEI).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

It is expected that a partial de-identified patient dataset will be made available via the ACTT Trial Database at NIAID (Access Clinical Data @ NIAID) beginning 6 months after publication of the primary results and for 5 years following article publication.

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