Recombinant C1 inhibitor in the prevention of severe COVID-19: a randomized, open-label, multi-center phase IIa trial.

Background: Conestat alfa (ConA), a recombinant human C1 inhibitor, may prevent thromboinflammation.
Methods: We conducted a randomized, open-label, multi-national clinical trial in which hospitalized adults at risk for progression to severe COVID-19 were assigned in a 2:1 ratio to receive either 3 days of ConA plus standard of care (SOC) or SOC alone. Primary and secondary endpoints were day 7 disease severity on the WHO Ordinal Scale, time to clinical improvement within 14 days, and safety, respectively.
Results: The trial was prematurely terminated because of futility after randomization of 84 patients, 56 in the ConA and 28 in the control arm. At baseline, higher WHO Ordinal Scale scores were more frequently observed in the ConA than in the control arm. On day 7, no relevant differences in the primary outcome were noted between the two arms ( p = 0.11). The median time to defervescence was 3 days, and the median time to clinical improvement was 7 days in both arms ( p = 0.22 and 0.56, respectively). Activation of plasma cascades and endothelial cells over time was similar in both groups. The incidence of adverse events (AEs) was higher in the intervention arm (any AE, 30% with ConA vs. 19% with SOC alone; serious AE, 27% vs. 15%; death, 11% vs. 0%). None of these were judged as being related to the study drug.
Conclusion: The study results do not support the use of ConA to prevent COVID-19 progression.
Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT04414631.
Competing Interests: MT reports receiving grants from the Swiss National Science Foundation, and having research collaborations with Roche, Novartis, and Idorsia outside the submitted work. WA reports receiving fees and research grants from A. Vogel AG, Gilead, and OM Pharma and fees for attendance of advisory boards to Pfizer, MSD Vifor Pharma, GSK, Sanofi, OM Pharma, and Janssen that were paid to his institution outside the submitted work. MO reports receiving grants from the Swiss National Science Foundation, consulting fees from Pharming Biotechnologies B.V. during the conduct of the study and grants from Pharming Biotechnologies B.V. outside the submitted work. LH reports receiving consulting fees from GlaxoSmithKline and Novartis during the conduct of the study but unrelated to this trial. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Pharming Biotechnologies B.V. The funder was involved in the design of the study at an initial stage and in the trial organization of the study in Brazil and Mexico (e.g., shipment of study drug).
(Copyright © 2023 Urwyler, Leimbacher, Charitos, Moser, Heijnen, Trendelenburg, Thoma, Sumer, Camacho-Ortiz, Bacci, Huber, Stüssi-Helbling, Albrich, Sendi and Osthoff.)