In a randomized, controlled trial of more than 1,000 adults hospitalized with COVID-19 pneumonia, treatment with the anti-inflammatory drug baricitinib resulted in faster recovery and a greater likelihood of clinical improvement, when combined with the antiviral drug remdesivir.
The results of the international ACTT-2 (Adaptive COVID-19 Treatment Trial), sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, were published Friday Dec. 11 in the New England Journal of Medicine.
Baricitinib was originally developed by Eli Lilly and Company for rheumatoid arthritis and was FDA-approved for that indication in 2017. The drug, part of a class of drugs that inhibits JAK enzymes, received an emergency use authorization for COVID-19 treatment in November 2020, based upon the ACTT-2 results.
The ACTT-2 study lasted from May until July, and included participants from 55 sites in the United States and 8 sites in Mexico, Europe and Asia. The lead author for ACTT-2 was Andre Kalil, MD at University of Nebraska Medical Center.
“This study provides evidence that baricitinib can speed recovery and provide clinical benefits that are relevant to patient care, such as less oxygen use and fewer days on a ventilator,” says Aneesh Mehta, MD, chief of infectious diseases at Emory University Hospital and one of the lead Emory investigators for the study. “The benefits of adding baricitinib to remdesivir were strongest in patients who required high-flow oxygen or non-invasive ventilation.”
Patients who received baricitinib plus remdesivir had a median recovery time of 7 days, as compared with 8 days among those who received remdesivir alone. Those requiring high-flow oxygen or non-invasive ventilation at the beginning of their hospitalization recovered 8 days faster (18 days versus 10).
Early in the pandemic, Emory/Atlanta Veterans Affairs Medical Center physicians led by Vincent Marconi, MD played a critical role in establishing the safety and potential efficacy of baricitinib in COVID-19, when given on a compassionate-use basis (see video).
“One of the encouraging findings from this study was the reduction of the overall COVID-19 mortality rate among participating hospitals around the world, even since ACTT-1,” says Marconi, who was a co-investigator on the ACTT-2 study. “Another is that despite concerns about how baricitinib might suppress immunity or lead to blood clots, the rate of adverse events was significantly less in the baricitinib group.”
Although the ACTT-2 study was not designed to assess mortality as a primary outcome, mortality by day 28 was about 35 percent less with baricitinib plus remdesivir compared to remdesivir (5.1 percent versus 7.8 percent). In addition, among ACTT-2 patients who were not already on a ventilator, the baricitinib plus remdesivir combination reduced the likelihood of progression to ventilation or death – at a level that was statistically significant (22.6 percent compared to 29.3 percent).
The Emory investigators say that evidence for barictinib’s efficacy is now strong enough to compare it against the anti-inflammatory steroid dexamethasone, which is used for many non-COVID-19 disorders. The NIAID-supported ACTT-4 study, a multi-center head-to-head comparison of baricitinib and dexamethasone in COVID-19, evaluating both drugs in combination with remdesivir, began in November. The trial is enrolling hospitalized adults COVID-19 who require supplemental oxygen.
Physicians have considerable experience with dexamethasone and its side effects, which can include fluid retention, hospital-acquired infections, GI bleeding and hyperglycemia. In ACTT-2, steroids such as dexamethasone were used optionally in about 20 percent of patients.
“A head-to-head study is necessary to determine at what level of severity patients are more likely to benefit from baricitinib or dexamethasone,” says Nadine Rouphael, MD, interim director of the Hope Clinic at Emory Vaccine Center and co-investigator on the ACTT-2 study. “Potent immunomodulators seem to be helpful in severe COVID-19 infections. Now, it is important for clinicians to understand which immune modulators to use in specific situations.”
The benefits of dexamethasone on COVID-19 mortality were demonstrated in the international RECOVERY study. However, RECOVERY was not a randomized double-blind study conducted in the same way as the ACTT series, and mortality in RECOVERY was more than three times higher than in ACTT-2, the Emory investigators say.
Emory and Grady Memorial Hospital sites were organized through the National Emerging Special Pathogens Training and Education Center (NETEC – U3REP150549, U3REP170552), comprised of faculty and staff from Emory University, University of Nebraska Medical Center/Nebraska Medicine and NYC Health + Hospitals/Bellevue. The ACTT clinical trials are supported by NIAID through the Infectious Diseases Clinical Research Consortium (IDCRC) (grants: UM1AI148576, UM1AI148684).
The IDCRC, consisting of the Vaccine Treatment and Evaluation Units (VTEUs) and the IDCRC Leadership Group, was formed in 2019 to support the planning and implementation of infectious diseases clinical research that efficiently addresses the scientific priorities of NIAID. The consortium includes infectious diseases leaders and clinical researchers from Emory University, University of Maryland School of Medicine, Baylor College of Medicine, Cincinnati Children’s Medical Center and University of Cincinnati, FHI360, Fred Hutchinson Cancer Research Center, Johns Hopkins University, Kaiser Permanente Washington Health Research Institute, New York University, Saint Louis University, Vanderbilt University Medical Center, University of Alabama at Birmingham, University of Rochester, University of Washington, and NIAID.