Prognostic and predictive biomarkers in patients with COVID-19 treated with tocilizumab in a randomised controlled trial

Tom, J.; Bao, M.; Tsai, L.; Qamra, A.; Summers, D.; Carrasco-Triguero, M.; McBride, J.; Rosenberger, C. M.; Lin, C. J. F.; Stubbings, W.; Blyth, K. G.; Carratala, J.; Francois, B.; Benfield, T.; Haslem, D.; Bonfanti, P.; van der Leest, C. H.; Rohatgi, N.; Wiese, L.; Luyt, C. E.; Kheradmand, F.; Rosas, I. O.; Cai, F.

Background Retrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti-IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia. Methods Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Findings Modelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo. Interpretation Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.