Immunomodulators Flop for COVID-19 Pneumonia Outcomes

Immunomodulators abatacept (Orencia), cenicriviroc, and infliximab (Remicade) all failed to improve time to recovery for patients hospitalized with COVID-19 pneumonia in the randomized, double-masked ACTIV-1 platform trial.

Among nearly 2,000 hospitalized participants, the primary endpoint of recovery rate ratio (RRR) at day 28 was similar for abatacept (RRR 1.12, 95% CI 0.98-1.28), cenicriviroc (RRR 1.01, 95% CI 0.86-1.18), and infliximab (RRR 1.12, 95% CI 0.99-1.28) versus placebo.

The difference in 28-day all-cause mortality was not significant by the trial statistical plan for any of the three agents, William G. Powderly, MD, of the Washington University School of Medicine in St. Louis, Missouri, and co-authors reported in JAMA.

All-cause mortality at 28 days was nominally lower for abatacept than its placebo (11% vs 15.1%, OR 0.62, 95% CI 0.41-0.94) and for infliximab versus its placebo (10.1% vs 14.5%, OR 0.59, 95% CI 0.39-0.90), though not for cenicriviroc (13.8% vs 11.9% for OR 1.18, 95% CI 0.72-1.94).

Early clinical status was better with infliximab than placebo as well, with higher proportional odds of improvement at day 14 (OR 1.32, 95% CI 1.05-1.66).

For the abatacept and infliximab results, the primary and key secondary endpoints were all in the beneficial direction, “with the mortality benefit showing remarkable consistency across subgroups.” Notably, they wrote that “the consistent lack of benefit among all 3 outcomes for cenicriviroc within the same master protocol further supports the validity of the findings for abatacept and infliximab.”

But because the primary endpoint was negative, the researchers wrote, 28-day mortality and day 14 clinical status “cannot be considered statistically significant based on the predefined gatekeeping approach, despite nominally significant CIs, although these end points are clinically important.”

These findings do not put the immunomodulators in line for clinical use, Andre Kalil, MD, MPH, University of Nebraska Medical Center and colleagues wrote in a simultaneously published editorial comment.

“Unless these drugs comprising the current immunomodulation of standard care are unavailable, abatacept and infliximab should not be routinely used for patients hospitalized for COVID-19,” Kalil and co-authors wrote. “If a shortage of standard medications were to occur (as was the case during early 2022), abatacept and infliximab could be considered, especially given the known safety profile of these agents, even though their safety for use in COVID-19 remains limited.”

Since baricitinib (Olumiant) and tocilizumab (Actemra) immunomodulatory agents are recommended as secondary treatment to corticosteroids for treating respiratory failure and systemic inflammation, “the benefit of additional immunomodulators is particularly important in the setting of previous drug shortages within these categories during periods of the pandemic,” Powderly and colleagues added.

In the meantime, more study affirming the reduction in mortality and other benefits is “essential for abatacept or infliximab to have the potential to become part of standard care,” the editorialists concluded.

Importantly, Powderly and co-authors noted, “this study highlights a major challenge in the selection of a primary end point for this and other COVID-19 studies in the setting of a rapidly changing clinical arena.”

While a mortality primary end point is considered “definitive and free from subjectivity,” it can require large participant enrollment “potentially resulting in prolonged study recruitment with delayed results.” Moreover, it does not negate other patient-centered outcomes, such as time to recovery or clinical status. “As research moves forward for COVID-19, the selection of primary endpoints will be important to encompass evaluable patient-centered outcomes, but take steps to do so with lower enrollment targets.”

ACTIV-1 included 1,971 participants age 18 and older with COVID-19 pneumonia admitted to the hospital and enrolled between Oct. 16, 2020, and Dec. 31, 2021. The participants were randomized to abatacept (n=524) or placebo (525), cenicriviroc (360) or placebo (363), and infliximab (531) or placebo (530). Those taking abatacept and infliximab received it as a one-time infusion, while cenicriviroc was dosed orally twice daily for 28 days.

Composite safety endpoints and serious and grade 3 or 4 adverse events were similar across all groups. There were three serious infusion reactions for abatacept and one case of anaphylaxis. Number of infections was similar.

Study limitations included that it took place in the Omicron era, so results may not be relevant to current circulating variants. Further, vaccination status data was not gathered. Moreover, there were challenges with adherence for the twice-daily oral medication, cenicriviroc, which may have contributed to the negative results observed for this medication.

Moreover, the data and safety monitoring board recommended discontinuation of randomization to the cenicriviroc group due to futility in September 2021.