Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial.

Autor: Zampieri FG; HCOR Research Institute, São Paulo, SP, Brazil; Department of Critical Care Medicine, University of Alberta, Edmonton, Canada. Electronic address: fzampier@ualberta.ca., Westphal GA; Centro Hospitalar Unimed, Joinville, SC., Santos MAD; Hospital Dona Helena, Joinville, SC, Brazil., Gomes SPC; HCOR Research Institute, São Paulo, SP, Brazil., Gomes JO; HCOR Research Institute, São Paulo, SP, Brazil., Negrelli KL; HCOR Research Institute, São Paulo, SP, Brazil., Santos RHN; HCOR Research Institute, São Paulo, SP, Brazil., Ishihara LM; HCOR Research Institute, São Paulo, SP, Brazil., Miranda TA; HCOR Research Institute, São Paulo, SP, Brazil., Laranjeira LN; HCOR Research Institute, São Paulo, SP, Brazil., Valeis N; HCOR Research Institute, São Paulo, SP, Brazil., Santucci EV; HCOR Research Institute, São Paulo, SP, Brazil., de Souza Dantas VC; Hospital Naval Marcílio Dias, Rio de Janeiro, RJ, Brazil., Gebara O; Hospital Santa Paula, São Paulo, SP, Brazil., Cohn DM; Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Amsterdam, Netherlands., Buchele G; Ionis Pharmaceuticals, California, USA., Janiszewski M; Ionis Pharmaceuticals, California, USA., de Freitas FG; Hospital Sepaco, São Paulo, SP, Brazil., Dal-Pizzol F; Hospital São José, Criciúma, SC, Brazil., de Matos Soeiro A; Instituto do Coração do Hospital das Clínicas da FMUSP, São Paulo, SP, Brazil., Berti IR; Hospital Tacchini, Bento Gonçalves, RS, Brazil., Germano A; Hospital Universitário Regional de Maringá, PR, Brazil., Schettini DA; Hospital da Luz, São Paulo, SP, Brazil., Rosa RG; Internal Medicine Department, Hospital Moinhos de vento, Porto Alegre (RS), Brazil., Falavigna M; Internal Medicine Department, Hospital Moinhos de vento, Porto Alegre (RS), Brazil., Veiga VC; BP - A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil., Azevedo LCP; Hospital Israelita Albert Einstein, São Paulo, SP, Brazil; Universidade Federal de São Paulo, São Paulo, SP, Brazil., Damiani LP; HCOR Research Institute, São Paulo, SP, Brazil., Machado FR; Universidade Federal de São Paulo, São Paulo, SP, Brazil., Cavalcanti AB; HCOR Research Institute, São Paulo, SP, Brazil.
Jazyk: angličtina
Zdroj: Journal of critical care [J Crit Care] 2024 Dec; Vol. 84, pp. 154892. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1016/j.jcrc.2024.154892
Abstrakt: 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.
Gov Identifier: NCT04549922.
Competing Interests: Declaration of competing interest None. This study was funded by Ionis Pharmaceutical, US, through a grant provided to HCor. The sponsor reviewed and agreed with the protocol, but had no role in any other aspect of the trial execution. MJ and GB were Ionis employees at the time this study was designed and provided relevant feedback on design of the trial and reviewed the final manuscript for intellectually relevant content. FGZ has received consulting fees from Baxter, unrelated to the scope of this manuscript.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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