PMID- 36990381 OWN - NLM STAT- MEDLINE DCOM- 20230524 LR - 20230616 IS - 1522-9629 (Electronic) IS - 1094-5539 (Print) IS - 1094-5539 (Linking) VI - 80 DP - 2023 Jun TI - Inhaled nebulised unfractionated heparin (UFH) for the treatment of hospitalised patients with COVID-19: A randomised controlled pilot study. PG - 102212 LID - S1094-5539(23)00024-X [pii] LID - 10.1016/j.pupt.2023.102212 [doi] AB - There is a strong scientific rationale to use nebulised unfractionated heparin (UFH) in treating patients with COVID-19. This pilot study investigated whether nebulised UFH was safe and had any impact on mortality, length of hospitalisation and clinical progression, in the treatment of hospitalised patients with COVID-19. This parallel group, open label, randomised trial included adult patients with confirmed SARS-CoV-2 infection admitted to two hospitals in Brazil. One hundred patients were planned to be randomised to either "standard of care" (SOC) or SOC plus nebulized UFH. The trial was stopped after randomisation of 75 patients due to falling COVID-19 hospitalisation rates. Significance tests were 1-sided test (10% significance level). The key analysis populations were intention to treat (ITT) and modified ITT (mITT) which excluded (from both arms) subjects admitted to ITU or who died within 24 h of randomisation. In the ITT population (n = 75), mortality was numerically lower for nebulised UFH (6 out of 38 patients; 15.8%) versus SOC (10 out of 37 patients; 27.0%), but not statistically significant; odds ratio (OR) 0.51, p = 0.24. However, in the mITT population, nebulised UFH reduced mortality (OR 0.2, p = 0.035). Length of hospital stay was similar between groups, but at day 29, there was a greater improvement in ordinal score following treatment with UFH in the ITT and mITT populations (p = 0.076 and p = 0.012 respectively), while mechanical ventilation rates were lower with UFH in the mITT population (OR 0.31; p = 0.08). Nebulised UFH did not cause any significant adverse events. In conclusion, nebulised UFH added to SOC in hospitalised patients with COVID-19 was well tolerated and showed clinical benefit, particularly in patients who received at least 6 doses of heparin. This trial was funded by The J.R. Moulton Charity Trust and registered under REBEC RBR-8r9hy8f (UTN code: U1111-1263-3136). CI - Copyright (c) 2023. Published by Elsevier Ltd. FAU - DeNucci, Gilberto AU - DeNucci G AD - Department of Pharmacology, University of Sao Paulo, Brazil; Department of Pharmacology, University of Campinas, Brazil. FAU - Wilkinson, Tom AU - Wilkinson T AD - Department of Respiratory Medicine, University of Southampton, UK. FAU - Sverdloff, Carlos AU - Sverdloff C AD - ATCGen, Brazil. Electronic address: carsver@atcgen.com.br. FAU - Babadopulos, Tainah AU - Babadopulos T AD - Department of Pharmacology, University of Campinas, Brazil. FAU - Woodcock, Ashley AU - Woodcock A AD - Manchester Academic Health Sciences Centre, Medicines Evaluation Unit, University of Manchester, UK. FAU - Shute, Jan AU - Shute J AD - School of Pharmacy and Biomedical Sciences, University of Portsmouth, UK. FAU - Renato Guazelli, Pedro AU - Renato Guazelli P AD - Sao Roque Hospital, Sao Paulo, Brazil. FAU - Gerbase, Luis Frederico AU - Gerbase LF AD - Santa Casa de Sorocaba Hospital, Sao Paulo, Brazil. FAU - Mourao, Paulo A S AU - Mourao PAS AD - Hospital Universitario Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Brazil. FAU - Singh, Dave AU - Singh D AD - Manchester Academic Health Sciences Centre, Medicines Evaluation Unit, University of Manchester, UK. FAU - van Haren, Frank M P AU - van Haren FMP AD - Australian National University, College of Health and Medicine, Canberra, Australia; Intensive Care Unit, St George Hospital, Sydney, Australia. FAU - Page, Clive AU - Page C AD - Sackler Institute of Pulmonary Pharmacology, King's College London, UK. LA - eng SI - ReBec/RBR-8r9hy8f PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230327 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 9005-49-6 (Heparin) SB - IM MH - Adult MH - Humans MH - *COVID-19 MH - Heparin/adverse effects MH - Pilot Projects MH - SARS-CoV-2 MH - Hospitalization MH - Treatment Outcome PMC - PMC10064078 OTO - NOTNLM OT - COVID-19 OT - Inhaled heparin OT - Nebulised heparin OT - Randomised controlled trial OT - Respiratory failure OT - SARS-CoV-2 OT - Unfractionated heparin COIS- Declaration of competing interest TW reports receiving fees and grant support from Synairgen, Bergenbio, AstraZeneca, Janssen, UCB and Valneva in the area of the submitted work, and from GSK, Boehringer-Ingelheim, AZ, and Roche outside the area of the submitted work. CP reports receiving personal fees and grant support from EpiEndo, Eurodrug, Recipharm and Glycosynnovation, and has equity in Verona Pharma, outside of the submitted work. AW reports receiving fees from Theravance in the area of work, and personal fees from Boehringer-Ingelheim, GSK and Novartis outside the submitted work. JS has equity in Ockham Biotech Ltd. who are developing inhaled heparin for the treatment of respiratory diseases. DS has received personal fees from Aerogen, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Epiendo, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Kinaset, Menarini, Novartis, Pulmatrix, Sanofi, Synairgen, Teva, Theravance and Verona. EDAT- 2023/03/30 06:00 MHDA- 2023/05/24 06:42 PMCR- 2023/03/27 CRDT- 2023/03/29 19:35 PHST- 2023/01/13 00:00 [received] PHST- 2023/03/07 00:00 [revised] PHST- 2023/03/19 00:00 [accepted] PHST- 2023/05/24 06:42 [medline] PHST- 2023/03/30 06:00 [pubmed] PHST- 2023/03/29 19:35 [entrez] PHST- 2023/03/27 00:00 [pmc-release] AID - S1094-5539(23)00024-X [pii] AID - 102212 [pii] AID - 10.1016/j.pupt.2023.102212 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2023 Jun;80:102212. doi: 10.1016/j.pupt.2023.102212. Epub 2023 Mar 27.