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Antisense therapy to block the Kallikrein-kinin pathway in COVID-19: The ASKCOV randomized controlled trial
Fernando G Zampieri1, Glauco Adrieno Westphal2, Maria Adelaide Dos Santos3
1HCOR Research Institute, São Paulo, SP, Brazil; Department of Critical Care Medicine, University of Alberta, Edmonton, Canada.
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.
Insights
Antisense therapy targeting the kallikrein-kinin pathway did not improve outcomes for hospitalized COVID-19 patients. The study found no significant difference in days alive without oxygen support between treated and placebo groups.
Area of Science:
- Pharmacology
- Infectious Diseases
- Clinical Trials
Background:
- The kallikrein-kinin pathway plays a role in inflammation and vascular permeability, potentially contributing to COVID-19 severity.
- Antisense therapy offers a targeted approach to modulate specific biological pathways.
Purpose of the Study:
- To evaluate the efficacy of antisense therapy (ISIS721744) in blocking the kallikrein-kinin pathway in hospitalized COVID-19 patients.
- To determine if this intervention improves clinical outcomes, specifically days alive and free of oxygen support.
Main Methods:
- A randomized, double-blind, placebo-controlled trial involving 111 hospitalized COVID-19 patients requiring supplementary oxygen.
- Patients received a single subcutaneous dose of ISIS721744 or placebo.
- The primary outcome was days alive and free of oxygen support (DAFOR15).
Main Results:
- No significant difference in DAFOR15 was observed between the ISIS721744 group (5.9 days) and the placebo group (7.7 days).
- The mean difference was -0.65 days, with a p-value of 0.520, indicating no statistically significant benefit.
- Secondary and exploratory endpoints also did not show significant improvements.
Conclusions:
- Antisense therapy targeting the kallikrein-kinin pathway did not demonstrate clinical benefit in COVID-19 patients during the initial phase of the pandemic.
- Further research may be needed to explore other therapeutic targets or patient populations.
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