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

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.

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

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 ).

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

Background: Immune dysregulation contributes to poorer outcomes in severe Covid-19. Immunomodulators targeting various pathways have improved outcomes. We investigated whether infliximab provides benefit over standard of care. Methods: We conducted a master protocol investigating immunomodulators for potential benefit in treatment of participants hospitalized with Covid-19 pneumonia. We report results for infliximab (single dose infusion) versus shared placebo both with standard of care. Primary outcome was time to recovery by day 29 (28 days after randomization). Key secondary endpoints included 14-day clinical status and 28-day mortality. Results: A total of 1033 participants received study drug (517 infliximab, 516 placebo). Mean age was 54.8 years, 60.3% were male, 48.6% Hispanic or Latino, and 14% Black. No statistically significant difference in the primary endpoint was seen with infliximab compared with placebo (recovery rate ratio 1.13, 95% CI 0.99-1.29; p=0.063). Median (IQR) time to recovery was 8 days (7, 9) for infliximab and 9 days (8, 10) for placebo. Participants assigned to infliximab were more likely to have an improved clinical status at day 14 (OR 1.32, 95% CI 1.05-1.66). Twenty-eight-day mortality was 10.1% with infliximab versus 14.5% with placebo, with 41% lower odds of dying in those receiving infliximab (OR 0.59, 95% CI 0.39-0.90). No differences in risk of serious adverse events including secondary infections. Conclusions: Infliximab did not demonstrate statistically significant improvement in time to recovery. It was associated with improved 14-day clinical status and substantial reduction in 28- day mortality compared with standard of care. Trial registration: ClinicalTrials.gov ( NCT04593940 ).

[Cardiac compromise in patients recovered from COVID-19 without troponin elevation assessed by cardiac magnetic resonance imaging]. / Hallazgos en resonancia cardiaca post COVID-19 en pacientes sin elevación de troponinas.

Background: The disease caused by coronavirus (COVID-19) affects the cardiovascular system, whether by direct viral aggression or indirectly through systemic inflammation and multiple organ compromise. A widely used method to determine cardiac injury is troponin measurement. The aim of this study is to evaluate the prevalence of cardiac involvement (CINV) in a population recovered from COVID-19, referred to cardiac MRI (CMR), who did not present troponin elevation. Methods: There were 156 patients that recovered from COVID-19 and who did not present troponin elevation referred to CMR. CINV was considered to be the presence of: late gadolinium enhancement (LGE), edema, myocarditis, pericarditis, left ventricular systolic dysfunction (LVSD) and/or depressed right ventricular systolic dysfunction (RVSD). Results: Prevalence of CINV was 28.8%, being more frequent in men (p=0.002), in patients who required hospitalization (p=0.04) and in those who experienced non-mild cases of infection (p=0.007). RVSD (17.9%) and LVSD (13.4%) were the most frequent findings. The rate of myocarditis was 0.6%. LGE manifested in 7.1% of patients and its presence was related to less left ventricular ejection fraction (LVEF) (p=0.0001) and right ventricular ejection fraction (RVEF) (p=0.04). Conclusion: In patients who recovered from COVID-19, 28.8% of CINV was found. It was more frequent in men, in patients who required admission and in patients with cases of non-mild infection. The patients that presented LGE had less LVEF and RVSF.

Antecedentes: La enfermedad por coronavirus 2019 (COVID-19) afecta al sistema cardiovascular, ya sea mediante la agresión directa viral o indirectamente por medio de la inflamación sistémica y afectación multiorgánica. Las troponinas son ampliamente utilizadas para determinar lesión cardiaca. La finalidad de este estudio es evaluar la prevalencia de afectación cardiaca (ACARD) en una población recuperada de COVID-19, derivada a resonancia magnética cardiaca (RMC), sin elevación de troponinas al momento del estudio. Métodos: Ciento cincuenta y seis pacientes que se recuperaron de COVID-19 y que no presentaron elevación de troponinas fueron derivados a RMC. Se consideró ACARD a la presencia de: realce tardío de gadolinio (RTG), edema, miocarditis, pericarditis, deterioro de la función sistólica del ventrículo izquierdo (DFSVI) y/o depresión de la función sistólica del ventrículo derecho (DFSVD). Resultados: La prevalencia de ACARD fue del 28.8%, siendo más frecuente en hombres (p = 0.002), en pacientes que requirieron hospitalización (p = 0.04) y en aquellos que cursaron cuadro no leve de infección (p = 0.007). La DFSVD (17.9%) y la DFSVI (13.4%) fueron las hallazgos más frecuentes. La frecuencia de miocarditis fue del 0.6%. El RTG se manifestó en el 7.1% de los pacientes y se relacionó con menor fracción de eyección del ventrículo izquierdo (FEVI) (p = 0.0001) y derecho (FEVD) (p = 0.04). Conclusión: La prevalencia de ACARD fue del 28.8%. Esta es más frecuente en hombres, en pacientes que requirieron internación y que cursaron cuadros de infección no leve. La miocarditis presentó una prevalencia muy baja. Los pacientes que presentaron RTG tuvieron menor FEVI y FSVD.