Fernando G. Zampieri , Glauco Adrieno Westphal , Maria Adelaide Dos Santos , Samara P.C. Gomes , Jackeline O. Gomes , Karina L. Negrelli , Renato H.N. Santos , Luciana M. Ishihara , Tamiris A. Miranda , Ligia N. Laranjeira , Nanci Valeis , Eliana Vieira Santucci , Vicente Cés de Souza Dantas , Otávio Gebara , Danny M. Cohn , Gustavo Buchele , Mariano Janiszewski , Flávio Geraldo de Freitas , Felipe Dal-Pizzol , Alexandre de Matos Soeiro , Alexandre B. Cavalcanti
{"title":"阻断 COVID-19 中 Kallikrein-kinin 通路的反义疗法:ASKCOV 随机对照试验。","authors":"Fernando G. Zampieri , Glauco Adrieno Westphal , Maria Adelaide Dos Santos , Samara P.C. Gomes , Jackeline O. Gomes , Karina L. Negrelli , Renato H.N. Santos , Luciana M. Ishihara , Tamiris A. Miranda , Ligia N. Laranjeira , Nanci Valeis , Eliana Vieira Santucci , Vicente Cés de Souza Dantas , Otávio Gebara , Danny M. Cohn , Gustavo Buchele , Mariano Janiszewski , Flávio Geraldo de Freitas , Felipe Dal-Pizzol , Alexandre de Matos Soeiro , Alexandre B. Cavalcanti","doi":"10.1016/j.jcrc.2024.154892","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><p>To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients.</p></div><div><h3>Material and methods</h3><p>Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life.</p></div><div><h3>Results</h3><p>From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference − 0.65, 95% confidence intervals from −2.95 to 1.36, <em>p</em> = 0.520).</p></div><div><h3>Conclusion</h3><p>Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020.</p></div><div><h3><span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> Identifier</h3><p><span><span>NCT04549922</span><svg><path></path></svg></span></p></div>","PeriodicalId":15451,"journal":{"name":"Journal of critical care","volume":"84 ","pages":"Article 154892"},"PeriodicalIF":3.2000,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0883944124003794/pdfft?md5=c02b91df4fc585eb826de481dd846f71&pid=1-s2.0-S0883944124003794-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial\",\"authors\":\"Fernando G. Zampieri , Glauco Adrieno Westphal , Maria Adelaide Dos Santos , Samara P.C. Gomes , Jackeline O. Gomes , Karina L. Negrelli , Renato H.N. Santos , Luciana M. Ishihara , Tamiris A. Miranda , Ligia N. Laranjeira , Nanci Valeis , Eliana Vieira Santucci , Vicente Cés de Souza Dantas , Otávio Gebara , Danny M. Cohn , Gustavo Buchele , Mariano Janiszewski , Flávio Geraldo de Freitas , Felipe Dal-Pizzol , Alexandre de Matos Soeiro , Alexandre B. Cavalcanti\",\"doi\":\"10.1016/j.jcrc.2024.154892\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><p>To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients.</p></div><div><h3>Material and methods</h3><p>Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life.</p></div><div><h3>Results</h3><p>From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference − 0.65, 95% confidence intervals from −2.95 to 1.36, <em>p</em> = 0.520).</p></div><div><h3>Conclusion</h3><p>Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020.</p></div><div><h3><span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> Identifier</h3><p><span><span>NCT04549922</span><svg><path></path></svg></span></p></div>\",\"PeriodicalId\":15451,\"journal\":{\"name\":\"Journal of critical care\",\"volume\":\"84 \",\"pages\":\"Article 154892\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2024-08-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S0883944124003794/pdfft?md5=c02b91df4fc585eb826de481dd846f71&pid=1-s2.0-S0883944124003794-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of critical care\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0883944124003794\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of critical care","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0883944124003794","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial
Purpose
To assess the effect of antisense therapy to block kallikrein-kinin pathway in COVID-19 patients.
Material and methods
Randomized, placebo-controlled, double blind, controlled trial enrolling hospitalized COVID-19 patients that required supplementary oxygen to sustain peripheral oxygen saturation. Key exclusion criteria included use of mechanical ventilation or vasopressors, and patients with more than 10 days since symptom onset or more than 48 h of oxygen use. Patients were randomized to either one subcutaneous dose of ISIS721744, an antisense that blocks prekallikrein, or placebo. The primary outcome was the number of days alive and free of oxygen support up to 15 days (DAFOR15). Secondary endpoints included organ failure score, need and duration of mechanical ventilation up to 15 days, and all-cause mortality at 30 days. Exploratory endpoints included physiological parameters, biomarkers, and quality of life.
Results
From October 10, 2020, to December 09, 2020, 111 patients were randomized at thirteen sites in Brazil (56 to treatment and 55 to control group). Average age was 57.5 years, and most patients were male (68.5%). There were no significant differences in DAFOR15 between groups (5.9 ± 5.2 days for the intervention arm and 7.7 ± 5.1 for the control group; mean difference − 0.65, 95% confidence intervals from −2.95 to 1.36, p = 0.520).
Conclusion
Antisense therapy designed to block the kallikrein-kinin pathway did not demonstrate clinical benefits in increasing days-alive without respiratory support at 15 days in patients with COVID-19 during the first wave in 2020.
期刊介绍:
The Journal of Critical Care, the official publication of the World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM), is a leading international, peer-reviewed journal providing original research, review articles, tutorials, and invited articles for physicians and allied health professionals involved in treating the critically ill. The Journal aims to improve patient care by furthering understanding of health systems research and its integration into clinical practice.
The Journal will include articles which discuss:
All aspects of health services research in critical care
System based practice in anesthesiology, perioperative and critical care medicine
The interface between anesthesiology, critical care medicine and pain
Integrating intraoperative management in preparation for postoperative critical care management and recovery
Optimizing patient management, i.e., exploring the interface between evidence-based principles or clinical insight into management and care of complex patients
The team approach in the OR and ICU
System-based research
Medical ethics
Technology in medicine
Seminars discussing current, state of the art, and sometimes controversial topics in anesthesiology, critical care medicine, and professional education
Residency Education.