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

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

A Practical Taxonomy of TAS-related Usecase Scenarios

This paper proposes a taxonomy of experimental usecase scenarios to facilitate research into trustworthy autonomous systems (TAS). Unable to identify an open-access repository of usecases to support our research, the project team embarked on development of an online library where fellow researchers would be able to find, share and recommend usecases to other practitioners in the field. To organise the library’s content, we needed a taxonomy and, informed by a commitment to responsible research and innovation (RRI), we prioritised stakeholder involvement to shape its development. Conflict arose, however, between the project team’s objective—a rigorous taxonomy focused on surfacing genuine “benchmarks” that can be used to test a multiplicity of variables in a range of domains under differing experimental conditions—and stakeholder expectation that the library would provide details of particular studies and results. How then can we reconcile project requirements with stakeholder preferences? A practical solution has to be found

Elements of Country: a First Nations-first approach to chemistry

Collectively, we have chosen to explore an Australian First Nations-first approach to understanding the chemical elements. We believe that engagement with cultural heritage, ongoing cultures, and the knowledges of this place—the lands on which we work, live, and study—will lead to new ways of understanding the elements and change the way we practice chemistry. The “First Nations first” phrase and approach comes from understanding the unique place that Aboriginal and Torres Strait Islander peoples have in the Australian context. In this paper we explore how a First Nations-first approach could take place in Sydney on Aboriginal lands. This approach is led by Aboriginal people, engages with culture, and is produced with local knowledge holders. So far, the work has entailed two years of meeting, conversing, and sharing space to determine appropriate ways of working together, interrogating the complexities of the ideas, and to refining our approach to the work. To appreciate the significant shift that a First Nations-first approach represents for chemistry, we consider the legacy of the Periodic Table. We share some reflections on how Indigenous knowledges can contribute to an expanded chemistry curriculum through the recognition of productive cultural tension