The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) has kicked off enrollment for the fourth iteration of the Adaptive COVID-19 Treatment Trial (ACTT-4). The study, involving hospitalized adult COVID-19 patients requiring supplemental oxygen, is expected to enroll as many as 1,500 patients at about 100 sites in the US as well as other countries.
According to investigators, patient participants will be assigned randomly to one of two treatment arms, both of equal size:
- The first will receive both dexamethasone (a corticosteroid available as a generic) and remdesivir, a broad-spectrum antiviral discovered, developed and offered by Gilead Sciences as Veklury. The treatment recently received US Food and Drug Administration (FDA) approval for treatment of hospitalized patients 12 and older.
- The second group will receive remdesivir and baricitinib (Eli Lilly brand name Olumiant), an FDA-approved inflammation modulator, indicated to treat certain adult patients with moderate to severe rheumatoid arthritis. In November, the FDA granted an emergency use authorization (EUA) for baricitinib in combination with remdesivir to treat suspected or laboratory confirmed COVID-19 in hospitalized patients aged 2 years and older who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation.
Investigators are blinding the trial for the dexamethasone and baricitinib components. Dexamethasone is administered via IV, and baricitinib is an oral tablet. All patients enrolled will receive intravenous remdesivir.
The first trial, ACTT-1, began in February and studied remdesivir compared to placebo in hospitalized adult COVID-19 patients. The interim results published in May indicated that remdesivir shortened the time to recovery.
Baricitinib was tested in combination with remdesivir in ACTT-2, which enrolled 1,033 adults hospitalized with COVID-19. The primary results of this study, announced by Lilly in September, indicated that the combination of baricitinib and remdesivir shortened the time to recovery relative to treatment with a placebo and remdesivir; the EUA of baricitinib was based in part on data from the ACTT-2 trial.
Dexamethasone was evaluated in the global Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial sponsored by the University of Oxford. The results showed patients receiving dexamethasone demonstrated a lower mortality rate compared with patients receiving usual care.
Dexamethasone and baricitinib are the only two therapies shown to date to reduce inflammation that have demonstrated efficacy for the treatment of hospitalized adults with COVID-19 in large, randomized clinical trials. However, differences in study populations, mortality rates and endpoint data collected in the trials make it challenging to form firm conclusions about the value of the interventions in various patient populations.
ACTT-4 aims to determine whether baricitinib or dexamethasone, when administered with remdesivir, is more effective at preventing hospitalized adults on supplemental oxygen from progressing to requiring mechanical ventilation or death, among other outcomes, or if they are similar.
Researchers reportedly will assess patients’ clinical status daily using an eight-point ordinal scale ranging from a return to baseline pre-COVID-19 status and not hospitalized, to death. If discharged from the hospital, clinical status data will be collected during outpatient visits on days 15, 22, 29 and 60.
The trial will evaluate the difference in the proportion of participants surviving without requiring invasive mechanical ventilation between the two treatment arms. A key secondary goal is to compare overall clinical status at day 15 in each group by comparing differences in the distribution of the eight-point ordinal scale in each group.
Investigators reportedly expect enrollment to take up to four months. Representatives from NIAID and NIH could not be reached for additional comment.
