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BACKGROUND: Thrombo-inflammation is central to COVID-19-associated coagulopathy. TF (tissue factor), a driver disordered coagulation and inflammation in viral infections, may be a therapeutic target in COVID-19. The safety and efficacy of the novel TF inhibitor rNAPc2 (recombinant nematode anticoagulation protein c2) in COVID-19 are unknown. METHODS: ASPEN-COVID-19 was an international, randomized, open-label, active comparator clinical trial with blinded end point adjudication. Hospitalized patients with COVID-19 and elevated D-dimer levels were randomized 1:1:2 to lower or higher dose rNAPc2 on days 1, 3, and 5 followed by heparin on day 8 or to heparin per local standard of care. In comparisons of the pooled rNAPc2 versus heparin groups, the primary safety end point was major or nonmajor clinically relevant International Society of Thrombosis and Haemostasis bleeding through day 8. The primary efficacy end point was proportional change in D-dimer concentration from baseline to day 8, or discharge if before day 8. Patients were followed for 30 days. RESULTS: Among 160 randomized patients, median age was 54 years, 43.1% were female, and 38.8% had severe baseline COVID-19. There were no significant differences between rNAPc2 and heparin in bleeding or other safety events. Overall, median change in D-dimer was −16.8% (interquartile range, −45.7 to 36.8; P =0.41) with rNAPc2 treatment and −11.2% (−36.0 to 34.4; P =0.91) with heparin ( P intergroup =0.47). In prespecified analyses, in severely ill patients, D-dimer levels tended to increase more within the heparin (median, 29.0% [−14.9 to 145.2]; P =0.02) than the rNAPc2 group (median, 25.9% [−49.1 to 136.4]; P =0.14; P intergroup =0.96); in mildly ill patients, D-dimer levels were reduced within each group with a numerically greater reduction with rNAPc2 versus heparin (rNAPc2 median, −32.7% [−44.7 to 4.3]; P =0.007 and heparin median, −16.8% [−36.0 to 0.5]; P =0.008, P intergroup =0.34). CONCLUSIONS: rNAPc2 treatment in hospitalized patients with COVID-19 was well tolerated without excess bleeding or serious adverse events but did not significantly reduce D-dimer more than heparin at day 8. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04655586.

Background: Tissue factor contributes to thrombo-inflammation in viral infection and may be a target in COVID-19. Recombinant nematode anticoagulant protein c2 (rNAPc2), a tissue factor inhibitor with anticoagulant, anti-inflammatory, and antiviral properties, has not been studied in COVID-19. Methods: In Phase 2b of ASPEN-COVID-19 (NCT04655586), an open-label blinded endpoint study, COVID-19 inpatients with elevated D-dimer are randomized 1:1:2 to higher or lower dose rNAPc2 given subcutaneously up to 5 days or local standard of care heparin. Primary efficacy and safety endpoints are D-dimer change (to Day 8 or discharge if earlier) and ISTH major bleeding. Recovery time is an exploratory outcome. Results: 160 patients were randomized at 24 sites in 3 countries. The average age was 56 years, 43% were female, 19% were Hispanic, and 21% were black. Baseline comorbidities included hypertension (51%), diabetes (35%), and smoking (35%); 11% were critically ill. On average, randomization occurred 10 days after COVID-19 symptom onset, and qualifying D-dimers were elevated 3.7-fold above the upper limit of normal. Median recovery time was 6 days (aggregate distribution shown in Figure). Enrollment has completed, database lock is anticipated Q1 2022, and final results will be ready for presentation at Vascular Discovery. Conclusion: ASPEN tests the hypothesis that compared to heparin, rNAPc2 reduces D-dimer in COVID-19. Results may help to provide a novel therapy for thromboprophylaxis in virus-related coagulopathies.

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