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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., Competing Interests: Declaration of interests FCH has received contributions towards trial running costs from Alexion Pharmaceuticals and Eli Lilly and Company; towards randomisation and investigational medicinal product distribution from UK Research and Innovation (UKRI); and towards research infrastructure from the UK National Institute for Health and Care Research (NIHR). FCH reports payment for weekend shifts for Clinical Investigators from Addenbrooke's Charitable Trust. JC has received funding (via his institution) from Alexion and Lilly, as well as UKRI, for partial funding of the TACTIC-R trial, and funding from AstraZeneca and GSK for other clinical trial work. APC has received support for the current manuscript in the form of funding for drugs from Lilly and Alexion. JG has received payment for the delivery of an educational talk on rheumatoid arthritis from Eli Lilly and Company (manufacturer of baricitinib). IW has received payments (via his institution) from UKRI and NIHR. EB-H is employed by the UK National Health Service; however, 50% of his time is seconded to GSK. MK received a monthly consulting fee for the design and conduct of early-phase trials (not associated with this trial or COVID-19) and is an investigator for GSK (not including any therapeutic or vaccine trials for COVID-19). MK is also co-founder and 50% shareholder of Cambridge Early Phase Clinical Trials (which has not undertaken any work for the trial). WGP has received speaker honoraria from Novartis. JU holds a UK Medical Research Council grant investigating blood–brain barrier dysfunction following bloodstream infection and COVID-19, and has received honoraria from Gilead Sciences (manufacturer of remdesivir) for educational material and from Celltrion Healthcare for participation on an advisory board regarding regdanvimab, an antibody treatment for COVID-19 (unavailable in the UK). DRJ has received consulting fees from AstraZeneca, GSK, Roche, Takeda, UCB, and Vifor; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational services from UCB and Vifor; and holds stock or stock options in Aurinia. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)