PMID- 35106809 OWN - NLM STAT- MEDLINE DCOM- 20220615 LR - 20221207 IS - 1365-2125 (Electronic) IS - 0306-5251 (Print) IS - 0306-5251 (Linking) VI - 88 IP - 7 DP - 2022 Jul TI - Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies. PG - 3272-3287 LID - 10.1111/bcp.15253 [doi] AB - There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation. CI - (c) 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. FAU - van Haren, Frank M P AU - van Haren FMP AUID- ORCID: 0000-0001-8037-4229 AD - Australian National University, Canberra, Australia. AD - University of New South Wales, Sydney, Australia. AD - Intensive Care Unit, St George Hospital, Sydney, Australia. FAU - Laffey, John G AU - Laffey JG AUID- ORCID: 0000-0002-1246-9573 AD - Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CURAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland. AD - Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland. FAU - Artigas, Antonio AU - Artigas A AD - Critical Center, Corporacio Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain. FAU - Page, Clive AU - Page C AD - Sackler Institute of Pulmonary Pharmacology, King's College London, UK. FAU - Schultz, Marcus J AU - Schultz MJ AD - Department of Intensive Care, Amsterdam University Medical Centre, Amsterdam, the Netherlands. AD - Nuffield Department of Medicine, Oxford University, Oxford, UK. AD - Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand. FAU - Cosgrave, David AU - Cosgrave D AD - Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland. FAU - McNicholas, Bairbre AU - McNicholas B AD - Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland. FAU - Smoot, Thomas L AU - Smoot TL AUID- ORCID: 0000-0002-6188-2217 AD - Frederick Memorial Hospital, Frederick, Maryland, USA. FAU - Nunes, Quentin AU - Nunes Q AD - Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK. FAU - Richardson, Alice AU - Richardson A AD - Australian National University, Canberra, Australia. FAU - Yoon, Hwan-Jin AU - Yoon HJ AD - Australian National University, Canberra, Australia. FAU - van Loon, Lex M AU - van Loon LM AD - Australian National University, Canberra, Australia. FAU - Ghosh, Angajendra AU - Ghosh A AD - Intensive Care Unit, The Northern Hospital, Melbourne, Australia. FAU - Said, Simone AU - Said S AD - Intensive Care Unit, The Northern Hospital, Melbourne, Australia. FAU - Panwar, Rakshit AU - Panwar R AD - John Hunter Hospital, Newcastle, Australia. FAU - Smith, Roger AU - Smith R AD - Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia. FAU - Santamaria, John D AU - Santamaria JD AD - Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia. FAU - Dixon, Barry AU - Dixon B AD - Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia. CN - CHARTER Collaborative Research Group LA - eng PT - Clinical Trial Protocol PT - Journal Article DEP - 20220220 PL - England TA - Br J Clin Pharmacol JT - British journal of clinical pharmacology JID - 7503323 RN - 9005-49-6 (Heparin) SB - IM MH - Airway Extubation MH - Heparin MH - Humans MH - Lung MH - *Noninvasive Ventilation MH - Randomized Controlled Trials as Topic MH - *Respiratory Insufficiency/chemically induced MH - SARS-CoV-2 MH - Treatment Outcome MH - *COVID-19 Drug Treatment PMC - PMC9303761 OTO - NOTNLM OT - ARDS OT - COVID-19 OT - RCT OT - SARS OT - SARS-CoV-2 OT - meta-trial OT - nebulised heparin OT - pandemic OT - randomised study OT - respiratory failure OT - unfractionated heparin COIS- F.v.H., J.L., D.C., B.M., T.S., Q.N., E.G., A.G., S.S., R.P., R.S., J.S. and B.D. have nothing to declare. A.A. reports a research grant for preclinical research from Grifols and from Fisher&Paykel, and payment as Scientific Advisor for Grifols, outside the submitted work. C.P. reports receiving personal fees from Cipla, Immune Regulation, EpiEndo and Glycosynnovation, and has equity in Verona Pharma, outside of the submitted work. EDAT- 2022/02/03 06:00 MHDA- 2022/06/16 06:00 PMCR- 2022/02/20 CRDT- 2022/02/02 05:38 PHST- 2022/01/06 00:00 [revised] PHST- 2021/05/13 00:00 [received] PHST- 2022/01/22 00:00 [accepted] PHST- 2022/02/03 06:00 [pubmed] PHST- 2022/06/16 06:00 [medline] PHST- 2022/02/02 05:38 [entrez] PHST- 2022/02/20 00:00 [pmc-release] AID - BCP15253 [pii] AID - 10.1111/bcp.15253 [doi] PST - ppublish SO - Br J Clin Pharmacol. 2022 Jul;88(7):3272-3287. doi: 10.1111/bcp.15253. Epub 2022 Feb 20.