NIH ends ACTT-4 enrollment: Difference 'unlikely' between baricitinib, dexamethasone
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The NIH has closed enrollment to the fourth iteration of the Adaptive COVID-19 Treatment Trial, indicating that neither treatment — baricitinib plus remdesivir or dexamethasone plus remdesivir — outperforms the other.
According to an NIH statement, an independent data and safety monitoring board on April 13 determined that it is “unlikely” that the study, commonly known as ACTT-4, will demonstrate a “significant difference between the two arms” even if allowed to continue to the planned full enrollment of 1,500 participants. The National Institute of Allergy and Infectious Diseases (NIAID), the trial’s sponsor, closed enrollment immediately that same day with just more than 1,000 participants.
However, as the data and safety monitoring board found no safety issues with either treatment regimen, the trial will remain blinded and researchers will continue to monitor and follow up with the participants currently in the study. The phase 3 study is expected to be completed by June 30.
Launched in November 2020, ACTT-4 primarily aims to examine the difference in the proportion of participants who survive without requiring invasive mechanical ventilation between the two treatment groups. In addition, the trial seeks to compare the overall clinical status at day 15 in each arm, based on differences in the distribution of an eight-point ordinal scale, ranging from a return to baseline pre-COVID-19 status and not hospitalized, to death, in each group.
Participants were randomly assigned to one of the two treatment groups. In the first arm, individuals received intravenous remdesivir (Veklury, Gilead Sciences), intravenous dexamethasone and oral placebo tablets to mimic baricitinib (Olumiant, Eli Lilly & Co.). Meanwhile, those in the second group received intravenous remdesivir, baricitinib tablets and intravenous placebo to mimic dexamethasone. The trial is double-blinded and featured researchers assessing participants’ clinical status daily using the eight-point ordinal scale.
Remdesivir is currently approved by the FDA to treat COVID-19 in hospitalized patients aged 12 years and older. The FDA has granted an emergency use authorization 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.
Meanwhile, the NIH Treatment Guidelines Panel has recommended dexamethasone for use in patients hospitalized with COVID-19 who require supplemental oxygen, based on evidence from clinical trials showing it can improve survival in this population.
The NIH plans to release a more detailed report on the trial results when they are available, according to the statement.
Perspective
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Leonard H. Calabrese, DO
The stopping of the ACTT-4 for futility suggests non–inferiority of baricitinib to dexamethasone in combination with remdesivir for patients in hospital on supplemental oxygen, but not on mechanical ventilation.
Without seeing the full data, I am encouraged that no safety signal was observed, which has been a concern when considering JAK inhibition in COVID-19, especially with regards to risks of infection and thrombosis. At the minimum, it tells us that JAKs are reasonable and likely preferred when glucocorticoids are high-risk (i.e. diabetes etc.). It does not, however, guide as to whether these drugs can be safely combined which is occurring in practice settings.
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