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
Frances Hall, Joseph Cheriyan, Andrew P. Cope, James Galloway, Ian B. Wilkinson, Simon Bond, Sam Norton, Edward Banham-Hall, Hannah Bayes, Michalis Kostapanos, Marianna Nodale, William Petchey, Thomas Sheeran, Jonathan Underwood, David Jayne, Frances Hall, Joseph Cheriyan, Andrew P. Cope, James Galloway, Ian B. Wilkinson, Simon Bond, Sam Norton, Edward Banham-Hall, Hannah Bayes, Michalis Kostapanos, Marianna Nodale, William Petchey, Thomas Sheeran, Jonathan Underwood, David Jayne, James Galloway, Deepak Nagra, Sam Norton, Georgina Bird, Jonathan Underwood, Rhys Davies, Dónall Forde, Clemency Nye, Andrea Balan, Sam Bird, Vianne Britten, Lauren Broad, Teriann Evans, Sharon Frayling, Laura J. Gray, Matthew Haynes, Catherine Oliver, Karen Rahilly, Gail Williams, Tanwir Ahmed, C E Bayliss, Natalie Byrne, Elena Hernan-Sancho, Mary Kasanicki, Louise Stockley, Heike Templin, Michalis Kostapanos, Joseph Cheriyan, Edward Banham-Hall, Marie Fisk, James Goodman, Johann Graggaber, Joanna Gray, Tania Gudu, Spoorthy Kulkarni, Ing Ni Lu, Peta Masters, Fraz Mir, Carmel B. Stober, Donna Abercrombie, Areti Bermperi, Stella Burns, Laura Canna, Jason Domingo, Kathy Hodges, Sherly Jose, Evgenia Kourampa, Anne Meadows, Vivien Mendoza, Thelma Mushapaizdi, Aileen Nacorda, Ciro Pasquale, Debbie Read, Jane Rowlands, Valentina Ruffulo, C. Soave, Lissamma Titti, Hugo Tordesillas, Samantha Wright, Hannah Bayes, Kathryn Scott, Varun Sharma, Susanne Cathcart, Dominic Rimmer, Gary Semple, Tom Sheeran, Laurence Phiri, Ann Plumbe, William Petchey, Shweta Bhagat
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.