mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 – Repurposed Drugs (TACTIC-R)

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The COVID-19 pandemic, declared on 11th March 2020 by the World Health Organisation (WHO), is caused by a novel coronavirus (SARS-Cov-2). In the UK by 3rd May 2020, 185,599 cases had a laboratory-confirmed diagnosis and SARS-Cov-2 associated deaths totalled 28,446. The majority of individuals infected with SARS-Cov-2 have mild/moderate symptoms, but 15% have severe disease and there is 1% mortality. Several risk factors for adverse outcomes have been identified, although their interaction with the disease course is not understood. SARS-Cov-2 causes acute respiratory distress syndrome, which can lead to multi-organ failure and death. There are no vaccines and one drug therapy, remdesivir, that has just received regulatory approval. Severe organ damage is accompanied by a dysregulated inflammatory hyperactivation syndrome with high levels of IL-6, TNF-alpha, IL-1-beta, and influx of neutrophils and cytotoxic T cells. Activation of the coagulation and complement cascades results in amplification of the inflammatory response culminating in tissue cytotoxicity and, and micro thrombosis.
TACTIC addresses the hypothesis that immunomodulation of hospitalised patients at high risk of a severe diseasecourse will increase the time to mechanical ventilation, other vital organ failure or death. Eligible patients will be18 years or older with suspected SARS-Cov-2 infection who have been admitted to hospital and score at least 3 points in an 8 point risk score that includes radiologic, demographic and laboratory criteria.
Patients will be randomised 1:1:1 to open label ravulizumab (anti-complement C5 monoclonal antibody, Alexion),baricitinib (oral JAK inhibitor, Lilly) or standard of care alone. The treatment duration will be from entry to discharge, to 14 days or until the primary end-point is reached. Following hospital discharge, patients will have telephone follow-up at 28 and 90 days. Those receiving ravulizumab will require antibiotic prophylaxis and meningococcal vaccination after discharge.
Termination of treatment groups and addition of further interventions will follow recommendations by the Independent Data Monitoring Committee. A planned interim analysis will occur when approximately 125 patients/group have been recruited. Recruitment of potentially effective therapies will continue until 229-469 patients/group, based on a frequentist hypothesis. Bayesian posterior distributions will inform the advice of the IDMC.
A key sub-hypothesis is that predictive biomarkers for drug response can be identified, and a parallel biomarker program involving the NIHR bioresource has been developed.