{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:58:10Z","timestamp":1765598290812,"version":"3.48.0"},"reference-count":26,"publisher":"BMJ","issue":"11","license":[{"start":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T00:00:00Z","timestamp":1701302400000},"content-version":"unspecified","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Belfast R&D office","award":["R&D office COM\/5612\/20"],"award-info":[{"award-number":["R&D office COM\/5612\/20"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,7,19]]},"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste\/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.<\/jats:p>\n                  <jats:p>These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>In this study, hypoxic patients with COVID-19 with symptom onset \u22647\u2009days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study has received the following approvals: West Midlands\u2013Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05407597\">NCT05407597<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2023-074726","type":"journal-article","created":{"date-parts":[[2023,11,30]],"date-time":"2023-11-30T19:30:13Z","timestamp":1701372613000},"page":"e074726","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS)"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct05407597","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05407597","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6300-0436","authenticated-orcid":false,"given":"Melanie","family":"Bailey","sequence":"first","affiliation":[{"name":"Mater Hospital, Belfast Health and Social Care Trust, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dermot","family":"Linden","sequence":"additional","affiliation":[{"name":"Mater Hospital, Belfast Health and Social Care Trust, Belfast, UK"},{"name":"Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivia","family":"Earley","sequence":"additional","affiliation":[{"name":"Mater Hospital, Belfast Health and Social Care Trust, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Guo Parke","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3283-1947","authenticated-orcid":false,"given":"Daniel Francis","family":"McAuley","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6265-0381","authenticated-orcid":false,"given":"Tunde","family":"Peto","sequence":"additional","affiliation":[{"name":"Mater Hospital, Belfast Health and Social Care Trust, Belfast, UK"},{"name":"Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cliff","family":"Taggart","sequence":"additional","affiliation":[{"name":"Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joe","family":"Kidney","sequence":"additional","affiliation":[{"name":"Mater Hospital, Belfast Health and Social Care Trust, Belfast, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2023,11,30]]},"reference":[{"key":"2025121219552059000_13.11.e074726.1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1570"},{"key":"2025121219552059000_13.11.e074726.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2179-y"},{"key":"2025121219552059000_13.11.e074726.3","doi-asserted-by":"crossref","DOI":"10.3390\/jcm10184218","article-title":"Continuous remote patient monitoring shows early cardiovascular changes in COVID-19 patients","volume":"10","author":"Eisenkraft","year":"2021","journal-title":"J Clin Med"},{"key":"2025121219552059000_13.11.e074726.4","doi-asserted-by":"crossref","DOI":"10.1111\/ijcp.14786","article-title":"Characteristics of hospitalised COVID-19 patients and parameters associated with severe pneumonia","volume":"75","author":"Turan","year":"2021","journal-title":"Int J Clin Pract"},{"key":"2025121219552059000_13.11.e074726.5","doi-asserted-by":"publisher","DOI":"10.1007\/s40620-021-00997-0"},{"key":"2025121219552059000_13.11.e074726.6","doi-asserted-by":"crossref","first-page":"12493","DOI":"10.18632\/aging.103579","article-title":"Epidemiological, Comorbidity factors with severity and prognosis of COVID-19: a systematic review and meta-analysis. aging (Albany NY)","volume":"12","author":"Fang","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"2025121219552059000_13.11.e074726.7","doi-asserted-by":"crossref","DOI":"10.1093\/jamiaopen\/ooad002","article-title":"Understanding Comorbidities and health disparities related to COVID-19: a comprehensive study of 776 936 cases and 1 362 545 controls in the state of Indiana, USA","volume":"6","author":"Zidan","year":"2023","journal-title":"JAMIA Open"},{"key":"2025121219552059000_13.11.e074726.8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.3947\/ic.2020.0136","article-title":"Comparison of Comorbidities in relation to critical conditions among Coronavirus disease 2019 patients: A network meta-analysis","volume":"53","author":"Hoang","year":"2021","journal-title":"Infect Chemother"},{"key":"2025121219552059000_13.11.e074726.9","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.26041"},{"key":"2025121219552059000_13.11.e074726.10","doi-asserted-by":"crossref","DOI":"10.1186\/s12890-020-01389-z","article-title":"Temporal changes of haematological and radiological findings of the COVID-19 infection-a review of literature","volume":"21","author":"Lim","year":"2021","journal-title":"BMC Pulm Med"},{"key":"2025121219552059000_13.11.e074726.11","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.25757"},{"key":"2025121219552059000_13.11.e074726.12","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.613422","article-title":"Interleukin-6 is a biomarker for the development of fatal severe acute respiratory syndrome Coronavirus 2 pneumonia","volume":"12","author":"Santa Cruz","year":"2021","journal-title":"Front Immunol"},{"key":"2025121219552059000_13.11.e074726.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.10.080"},{"key":"2025121219552059000_13.11.e074726.14","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2002-0040OC"},{"key":"2025121219552059000_13.11.e074726.15","doi-asserted-by":"publisher","DOI":"10.1001\/archinte.1992.00400200128023"},{"key":"2025121219552059000_13.11.e074726.16","doi-asserted-by":"publisher","DOI":"10.1038\/nm0796-814"},{"key":"2025121219552059000_13.11.e074726.17","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.299.6705.981"},{"key":"2025121219552059000_13.11.e074726.18","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1997.03540300050033"},{"key":"2025121219552059000_13.11.e074726.19","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1159\/000441060","article-title":"Icatibant for multiple hereditary angioedema attacks across the controlled and open-label extension phases of FAST-3","volume":"168","author":"Lumry","year":"2015","journal-title":"Int Arch Allergy Immunol"},{"key":"2025121219552059000_13.11.e074726.20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0906393"},{"key":"2025121219552059000_13.11.e074726.21","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2020.17708","article-title":"Outcomes associated with use of a kinin B2 receptor antagonist among patients with COVID-19","volume":"3","author":"van de Veerdonk","year":"2020","journal-title":"JAMA Netw Open"},{"key":"2025121219552059000_13.11.e074726.22","doi-asserted-by":"crossref","DOI":"10.3390\/v13020309","article-title":"Safety and outcomes associated with the pharmacological inhibition of the kinin-Kallikrein system in severe COVID-19","volume":"13","author":"Mansour","year":"2021","journal-title":"Viruses"},{"key":"2025121219552059000_13.11.e074726.23","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1093\/cid\/ciac984","article-title":"Three-day Icatibant on top of Standard care in patients with Coronavirus disease 2019 pneumonia: A randomized, open-label, phase 2, proof-of-concept trial","volume":"76","author":"Malchair","year":"2023","journal-title":"Clin Infect Dis"},{"key":"2025121219552059000_13.11.e074726.24","doi-asserted-by":"crossref","first-page":"101889","DOI":"10.1016\/j.eclinm.2023.101889","article-title":"Report of the first seven agents in the I-SPY COVID trial: a phase 2, open label, adaptive platform randomised controlled trial","volume":"58","author":"Files","year":"2023","journal-title":"eClinicalMedicine"},{"key":"2025121219552059000_13.11.e074726.25","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1056\/NEJMoa1312524","article-title":"A randomized trial of Icatibant in ACE-inhibitor-induced angioedema","volume":"372","author":"Ba\u015f","year":"2015","journal-title":"N Engl J Med"},{"key":"2025121219552059000_13.11.e074726.26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/cpdd.138","article-title":"Pharmacokinetics of single and repeat doses of Icatibant","volume":"4","author":"Leach","year":"2015","journal-title":"Clin Pharmacol Drug Dev"}],"container-title":["BMJ Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/bmjopen-2023-074726","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:55:28Z","timestamp":1765598128000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmjopen.bmj.com\/lookup\/doi\/10.1136\/bmjopen-2023-074726"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":26,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11,30]]},"published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1136\/bmjopen-2023-074726"],"URL":"https:\/\/doi.org\/10.1136\/bmjopen-2023-074726","relation":{},"ISSN":["2044-6055","2044-6055"],"issn-type":[{"type":"print","value":"2044-6055"},{"type":"electronic","value":"2044-6055"}],"subject":[],"published":{"date-parts":[[2023,11]]}}}