Frank M P van Haren1,2, Alice Richardson3, Hwan-Jin Yoon3, Antonio Artigas4, John G Laffey5,6, Barry Dixon7, Roger Smith7, Alicia B Vilaseca8, Ruben A Barbera8, Tarek I Ismail9, Rabab S Mahrous10, Mohamed Badr11, Gilberto De Nucci12,13, Carlos Sverdloff12, Lex M van Loon1, Marta Camprubi-Rimblas4, David W Cosgrave6, Thomas L Smoot14, Sabrina Staas14, Khine Sann14, Caitlin Sas14, Anusha Belani14, Christopher Hillman14, Janis Shute15, Mary Carroll16, Tom Wilkinson16, Miles Carroll17, Dave Singh18, Clive Page19. 1. Australian National University, College of Health and Medicine, Canberra, Australia. 2. Faculty of Health, University of Canberra, Canberra, Australia. 3. Statistical Consulting Unit, Australian National University, Canberra, Australia. 4. Critical Center, Corporació Universitaria Sanitaria Parc Tauli, CIBER Enfermedades Respiratorias, Autonomous University of Barcelona, Sabadell, Spain. 5. Anaesthesia and Intensive Care Medicine, School of Medicine, and Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, Biomedical Sciences Building, National University of Ireland Galway, Galway, Ireland. 6. Department of Anaesthesia, University Hospital Galway, Saolta Hospital Group, Ireland. 7. Department of Critical Care Medicine, St Vincent's Hospital, Melbourne, Australia. 8. Service of Haematology and Haemostasis, San Camilo Clinic, Buenos Aires, Argentina. 9. Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Helwan University, Cairo, Egypt. 10. Department of Anaesthesia and Surgical Intensive Care, Faculty of Medicine, Alexandria University, Alexandria, Egypt. 11. Department of Critical Care Medicine, Faculty of Medicine, Helwan University, Cairo, Egypt. 12. Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil. 13. Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, Brazil. 14. Frederick Memorial Hospital, Frederick, Maryland, USA. 15. School of Pharmacy and Biomedical Science, University of Portsmouth, Portsmouth, UK. 16. Department of Respiratory Medicine, University of Southampton, Southampton, UK. 17. National Infection Service, Public Health England, Porton Down, UK. 18. Medicines Evaluation Unit, University of Manchester, Manchester, UK. 19. Sackler Institute of Pulmonary Pharmacology, King's College London, UK.
Abstract
AIMS: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus' entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. METHODS: The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) metatrial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. ANALYSIS: We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. TRIAL REGISTRATION, ETHICS AND DISSEMINATION: The metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.
AIMS: Inhaled nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale that warrants urgent investigation of its therapeutic potential in patients with COVID-19. UFH has antiviral effects and prevents the SARS-CoV-2 virus' entry into mammalian cells. In addition, UFH has significant anti-inflammatory and anticoagulant properties, which limit progression of lung injury and vascular pulmonary thrombosis. METHODS: The INHALEd nebulised unfractionated HEParin for the treatment of hospitalised patients with COVID-19 (INHALE-HEP) metatrial is a prospective individual patient data analysis of on-going randomised controlled trials and early phase studies. Individual studies are being conducted in multiple countries. Participating studies randomise adult patients admitted to the hospital with confirmed SARS-CoV-2 infection, who do not require immediate mechanical ventilation, to inhaled nebulised UFH or standard care. All studies collect a minimum core dataset. The primary outcome for the metatrial is intubation (or death, for patients who died before intubation) at day 28. The secondary outcomes are oxygenation, clinical worsening and mortality, assessed in time-to-event analyses. Individual studies may have additional outcomes. ANALYSIS: We use a Bayesian approach to monitoring, followed by analysing individual patient data, outcomes and adverse events. All analyses will follow the intention-to-treat principle, considering all participants in the treatment group to which they were assigned, except for cases lost to follow-up or withdrawn. TRIAL REGISTRATION, ETHICS AND DISSEMINATION: The metatrial is registered at ClinicalTrials.gov ID NCT04635241. Each contributing study is individually registered and has received approval of the relevant ethics committee or institutional review board. Results of this study will be shared with the World Health Organisation, published in scientific journals and presented at scientific meetings.
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