Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Abstract

Background: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19.

Methods: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464).

Findings: Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62-1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88-2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group.

Interpretation: Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation.

Funding: UK Medical Research Council, UK National Institute for Health Research Cambridge Biomedical Research Centre, Eli Lilly and Company, Alexion Pharmaceuticals, and Addenbrooke's Charitable Trust.

Figure 1

Trial profile

Figure 2

Cumulative incidence for the primary endpoint and discharge (A) Cumulative incidence of the composite primary endpoint: time to incidence (up to and including day 14) of the first event of death, IMV, ECMO, cardiovascular organ support, or renal failure. (B) Cumulative incidence of discharge without a primary endpoint event being reached (to day 14). (C) Cumulative incidence of death, a component of the composite primary endpoint (to day 14). (D) Cumulative incidence of IMV or ECMO, components of the composite primary endpoint (to day 14). There were no cases of renal failure and only two cases of cardiovascular organ support, and these components of the primary composite endpoint are not shown. The inset in each graph shows the conditional hazard ratio for the two investigational medicinal product study groups, each compared with standard of care, adjusting for site. cHR=conditional hazard ratio. ECMO=extracorporeal membrane oxygenation. IMV=invasive mechanical ventilation.

Figure 3

Serious adverse events in the ravulizumab and baricitinib treatment groups Proportions of each category of serious adverse events are reported for each group. RRs of each category of serious adverse event are shown for the ravulizumab and baricitinib groups. IMP=investigational medicinal product. RR=relative risk.