Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial
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, Isabele Ribeiro Berti, Almir Germano, Daniel Almeida Schettini, Regis G Rosa, Maicon Falavigna, Viviane C Veiga, Luciano C P Azevedo, Lucas P Damiani, Flávia R Machado, Alexandre B Cavalcanti
Journal of Critical Care, doi:10.1016/j.jcrc.2024.154892
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).
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.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.jcrc.2024.154892.
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