mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 – Repurposed Drugs (TACTIC-R)
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
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Technical Summary
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.
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.
Publications
Gudu T
(2021)
Baricitinib set to join the Covid-19 therapeutic arsenal?
in Rheumatology (Oxford, England)
Description | mulTi-Arm Therapeutic study in pre-ICu patients admitted with Covid-19 - Repurposed Drugs (TACTIC-R) |
Amount | £699,710 (GBP) |
Funding ID | MC_PC_20006 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 04/2020 |
End | 04/2021 |
Description | TACTIC Consortium |
Organisation | Alexion Pharmaceuticals |
Country | United States |
Sector | Private |
PI Contribution | The TACTIC Consortium was formed in March 2020 by bringing together clinicians in Cambridge and London with expertise in multi system inflammatory disease (Dr Frances Hall (Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust) and Prof David Jayne (Professor of Clinical Autoimmunity, University of Cambridge), Prof Andrew Cope (Versus Arthritis Professor of Rheumatology, King's College London) and Dr James Galloway (Senior Lecturer and Hon Consultant in Rheumatology, King's College London)), with the Cambridge Clinical Trials Unit (Prof Ian Wilkinson (Professor of Therapeutics, University of Cambridge), Dr Joseph Cheriyan (Consultant Clinical Pharmacologist, Cambridge University Hospitals Trust)). Cambridge provided co-Chief Investigators (two due to the uncertainties of pandemic times) Dr Frances Hall and Prof David Jayne and the expertise and infrastructure of the Cambridge Clinical Trials Unit (CCTU). I chaired the Trial Management Group, which designed and oversaw the conduct of the trial, raised the funding, assembled the clinical investigators across 22 sites and performed the analysis. I also established collaborations with Lilly and Alexion. The CCTU provided the trial co-ordinator, and monitoring and the statisticians for design and analysis. The Cambridge members of the TMG recruited clinical and nursing staff to recruit and treat patients in Addenbrooke's. Prof Jayne participated in all TMG activities and provided a link between the TACTIC consortium and UKRI oversight of the high-priority COVID platform trials. Prof Wilkinson redeployed resources from CCTU and Clinical Pharmacology to set up and deliver the TACTIC-R trial under challenging, pandemic conditions. Dr Cheriyan participated in all TMG roles, organised redeployment of CCTU resources and delivery of the IMP to the participating centres. |
Collaborator Contribution | Lilly - provided Baricitinib and a contribution to trial running costs Alexion - provided Ravulizumab and a contribution to trial running costs Professor Andrew Cope provided input into the design and analysis of the trial and served as PI for GSST; he has also arranged further collaboration for biomarker studies at KCL, using samples from TACTIC-R Dr James Galloway provided input into the design and analysis of the trial and served as PI for KCH |
Impact | 2 Manuscipts published 1 Manuscript (reporting results from the trial) in preparation |
Start Year | 2020 |
Description | TACTIC Consortium |
Organisation | King's College London |
Department | NIHR Biomedical Research Centre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The TACTIC Consortium was formed in March 2020 by bringing together clinicians in Cambridge and London with expertise in multi system inflammatory disease (Dr Frances Hall (Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust) and Prof David Jayne (Professor of Clinical Autoimmunity, University of Cambridge), Prof Andrew Cope (Versus Arthritis Professor of Rheumatology, King's College London) and Dr James Galloway (Senior Lecturer and Hon Consultant in Rheumatology, King's College London)), with the Cambridge Clinical Trials Unit (Prof Ian Wilkinson (Professor of Therapeutics, University of Cambridge), Dr Joseph Cheriyan (Consultant Clinical Pharmacologist, Cambridge University Hospitals Trust)). Cambridge provided co-Chief Investigators (two due to the uncertainties of pandemic times) Dr Frances Hall and Prof David Jayne and the expertise and infrastructure of the Cambridge Clinical Trials Unit (CCTU). I chaired the Trial Management Group, which designed and oversaw the conduct of the trial, raised the funding, assembled the clinical investigators across 22 sites and performed the analysis. I also established collaborations with Lilly and Alexion. The CCTU provided the trial co-ordinator, and monitoring and the statisticians for design and analysis. The Cambridge members of the TMG recruited clinical and nursing staff to recruit and treat patients in Addenbrooke's. Prof Jayne participated in all TMG activities and provided a link between the TACTIC consortium and UKRI oversight of the high-priority COVID platform trials. Prof Wilkinson redeployed resources from CCTU and Clinical Pharmacology to set up and deliver the TACTIC-R trial under challenging, pandemic conditions. Dr Cheriyan participated in all TMG roles, organised redeployment of CCTU resources and delivery of the IMP to the participating centres. |
Collaborator Contribution | Lilly - provided Baricitinib and a contribution to trial running costs Alexion - provided Ravulizumab and a contribution to trial running costs Professor Andrew Cope provided input into the design and analysis of the trial and served as PI for GSST; he has also arranged further collaboration for biomarker studies at KCL, using samples from TACTIC-R Dr James Galloway provided input into the design and analysis of the trial and served as PI for KCH |
Impact | 2 Manuscipts published 1 Manuscript (reporting results from the trial) in preparation |
Start Year | 2020 |
Title | Evaluating the Efficacy of Inhibition of either JAK2 or Complement Activation in severe COVID-19 |
Description | Ravulizumab was shown to be ineffective in hospitalised patients with COVID-19 and will not be taken forward. Baricitinib was not shown to be effective in hospitalised patients with COVID-19 in TACTIC-R but this may relate to the short dosing period of baricitinib in over 50% of the patient randomised to this arm, due to discharge from hospital. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Late clinical evaluation |
Year Development Stage Completed | 2021 |
Development Status | Closed |
Clinical Trial? | Yes |
Impact | No further impacts. |
URL | https://www.camcovidtrials.net/trials/view,tacticr_1.htm |
Description | British Thoracic Society Winter Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Title: mulTi-Arm Therapeutic study in pre-Icu patients admitted with Covid -19 - Repurposed Drugs (TACTIC-R) Delivered a talk online to the BTS regarding the rationale for the trial, the set-up and progress up until Feb 2021. |
Year(s) Of Engagement Activity | 2021 |
Description | Cambridge Festival |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Prof Ian Wilkinson, Prof John Bradley (Cambridge BRC Director) and Dr Frances Hall were interviewed about TACTIC-R, and the challenges of running clinical trials in the pandemic, during a video podcast event as part of the Cambridge Festival 2021 |
Year(s) Of Engagement Activity | 2021 |
Description | ITN News |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Dr Frances Hall did an interview with ITN regarding the launch of the TACTIC-R trial. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.itv.com/news/2020-05-21/clinical-trial-treating-covid-19-coronavirus-icu-baricitinib-rav... |