Baricitinib + SoC may reduce mortality in hospitalized COVID-19 patients

The oral selective Janus kinase 1/2 inhibitor baricitinib, when added to standard of care (SoC), reduced the risk of mortality among adults hospitalized with COVID-19. However, the primary outcome of disease progression was not met in the baricitinib group, results of the phase III COV-BARRIER study showed.

“In this study, baricitinib plus SoC (including dexamethasone) did not significantly reduce progression to increased oxygen support or death (the composite primary endpoint) when compared with placebo plus SoC,” the researchers said.

“However, the group of patients allocated to receive baricitinib did show absolute risk reductions of 5 percentage points in all-cause mortality at 28 days and 4.9 percentage points in all-cause mortality at 60 days, resulting in a number-needed-to-treat of 20 to yield one additional survivor at these two timepoints,” they pointed out.

This double-blind study conducted in 12 countries included 1,525 adults (mean age 57.6 years, 63.1 percent male) hospitalized with confirmed COVID-19, with pneumonia or active and symptomatic disease, and ≥1 elevated inflammatory marker. In addition to SoC (systemic corticosteroids and/or antivirals), they were randomized 1:1 to receive oral baricitinib (4 mg QD) or placebo for ≤14 days.

Two-thirds of patients were aged <65 years. Thirty-three percent had obesity and 48 percent hypertension. About 83 percent had symptoms for ≥7 days pre-enrolment. At baseline, 79.3 percent of patients were on systemic corticosteroids, 91.3 percent of whom were on dexamethasone, and 18.9 percent were on remdesivir, of whom 91.6 percent were also on corticosteroids.

At 28 days, the primary composite endpoint comprising progression to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death did not significantly differ between patients who received baricitinib or placebo (27.8 percent vs 30.5 percent; odds ratio [OR], 0.85, 95 percent confidence interval [CI], 0.67–1.08; p=0.18; absolute risk difference, -2.7 percentage points). [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00331-3]

The results were similar in a subpopulation comprising patients on oxygen supplementation who were not receiving corticosteroids at baseline (population 2; 28.9 percent vs 27.1 percent; OR, 1.12; p=0.73).

All-cause mortality by day 28 was reduced with baricitinib vs placebo (8 percent vs 13 percent; hazard ratio [HR], 0.57, 95 percent CI, 0.41–0.78; p_nominal=0.0018; absolute risk difference, -5.0 percentage points). This represented a 38.2 percent relative reduction in mortality with baricitinib, with one additional death prevented for every 20 patients treated with baricitinib.

The exploratory outcome of all-cause mortality at 60 days was also reduced in the baricitinib vs placebo group (10 percent vs 15 percent; HR, 0.62, 95 percent CI, 0.47–0.83; p=0.0050; absolute risk difference, -4.9 percentage points), a finding also noted with population 2 (5 percent vs 18 percent; HR, 0.27; p=0.0080).

Likelihood of overall improvement on the NIAID-OS* score was significantly greater with baricitinib vs placebo at days 7 and 14 (ORs, 1.25 and 1.28, respectively; p=0.017 for both). Median time to recovery did not significantly differ between groups, nor did duration of hospitalization, or number of ventilator-free days.

Treatment-emergent adverse events (AEs) occurred in 45 and 44 percent of baricitinib and placebo recipients, respectively. Serious AEs occurred at a comparable rate between baricitinib and placebo recipients (15 percent vs 18 percent), as did serious infections (9 percent vs 10 percent), venous thromboembolic events (3 percent in each group), and major adverse cardiovascular events (1 percent each). Serious infection rates among corticosteroid users were also similar between groups (10 percent vs 11 percent).

The incidence of death due to AEs was numerically lower among baricitinib than placebo recipients (2 percent vs 4 percent), as was AE-related discontinuations (7 percent vs 9 percent).

According to the researchers, a potential reason for the lack of significance pertaining to the primary outcome could be the rapid deterioration of COVID-19 disease. “Nearly 22 percent of COV-BARRIER participants progressed on the first day. It is unlikely that a treatment would act so quickly as to meaningfully reduce progression to higher oxygen needs within the first 24 hours of treatment.”

One step ahead in preventing mortality?

“Taken together, these findings suggest that baricitinib has synergistic effects with other SoC treatment modalities, including remdesivir and dexamethasone,” the researchers said.

“To our knowledge, baricitinib showed the largest effect size on mortality of any COVID-19 treatment reported in other randomized trials in hospitalized patients and showed a benefit in addition to the use of SoC (corticosteroids) alone,” they added.

“No other anti-COVID-19 therapy has shown such a profound reduction in mortality,” commented Professors Andre Kalil from the University of Nebraska Medical Center, Omaha, Nebraska, US, and Justin Stebbing from Imperial College London, London, UK, in an accompanying commentary. [Lancet Respir Med 2021;doi:10.1016/S2213-2600(21)00358-1]

They pointed out that the other immunomodulatory treatments that were associated with reduced mortality were dexamethasone and tocilizumab, which had relative reductions of 17 and 15 percent, respectively. [N Engl J Med 2021;384:693-704; Lancet 2021;397:1637-1645]

The study “also provides reassurance for the first time that the combination of baricitinib and steroids might be safe,” said Kalil and Stebbing, noting that the low cost and oral administration of both these drugs render themselves useful in low- and middle-income countries.

“[B]aricitinib is a potentially effective oral treatment option to decrease mortality in hospitalized patients with COVID-19,” the researchers concluded, suggesting that further research into the effects of baricitinib in COVID-19 assess higher doses or a greater loading dose.