A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2

Abstract

Background: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib.

Objective: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile.

Design: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579).

Setting: Sixty-seven trial sites in 8 countries.

Participants: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants).

Intervention: Baricitinib+remdesivir versus placebo+remdesivir.

Measurements: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories.

Results: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile.

Limitation: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants.

Conclusion: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19.

Primary funding source: National Institute of Allergy and Infectious Diseases.

Figure 1.

Effect of baricitinib+remdesivir compared with placebo+remdesivir in hospitalized patients with COVID-19 for the outcomes of death, IMV or death, and recovery within 28 days, by ACTT risk quartile. ACTT = Adaptive COVID-19 Treatment Trial; IMV = invasive mechanical ventilation; NA = not applicable. Top. Effect of baricitinib+remdesivir compared with placebo+remdesivir. Fine–Gray subdistribution hazard ratios and 95% CIs are shown. Bottom. Kaplan–Meier curves for the high-risk quartile.

Figure 2.

Changes in ALC, ANC, and platelet count after initiation of treatment with baricitinib+remdesivir vs. placebo+remdesivir in hospitalized patients with COVID-19. Panel A shows distributions of ALC, ANC, and platelet count at baseline (yellow) and at day 5 (blue) by risk quartile and treatment group. Panel B shows the distributions of ratio change in hematologic parameters from baseline to day 5 in the high-risk quartile and in the overall study population by treatment group. The center of the ratio change distribution is quantified by the geometric mean of the ratio change with the 95% CI. P values are from t tests on the log-transformed ratio changes. ALC = absolute lymphocyte count; ANC = absolute neutrophil count.

Figure 3.

Differences in the magnitude of change from baseline to day 5 for ALC, ANC, and platelet count in baricitinib+remdesivir recipients in the high-risk quartile. The figure shows changes in ALC (left), ANC (middle), and platelet count (right), expressed as a ratio of the value at day 5 to the baseline value, by ACTT risk quartile in the baricitinib + remdesivir treatment group. The center of the ratio change distribution is quantified by the geometric mean of the ratio change with the 95% CI. P values are from t tests on the log-transformed ratio changes. ACTT = Adaptive COVID-19 Treatment Trial; ALC = absolute lymphocyte count; ANC = absolute neutrophil count.