A Phase I Safety and Feasibility Design Thesis: Intravenous DNase I for the Treatment of Sepsis in ICU Patients (IDEAL-SepsisI)

Abstract

Background: Sepsis is a critical health condition characterized by a dysregulated systemic inflammatory response against an infection that can be associated with subsequent organ dysfunction and death. It poses a significant challenge in intensive care units (ICUs) worldwide. The release of neutrophil extracellular traps (NETs) contributes to the complexity of sepsis by promoting thrombosis and tissue hypoperfusion. Intravenous DNase I, an enzyme that degrades extracellular DNA, offers a potential therapeutic strategy by dismantling NETs, thus potentially mitigating some underlying pathogenic mechanisms of sepsis.

Objective: This Phase I study will take a novel approach by assessing the safety, maximum feasible tolerated dose (MFTD), and feasibility of intravenous DNase I administration for critically ill patients with sepsis. The secondary objectives include evaluating the effects of DNase I on clinical outcomes such as organ dysfunction, intensive care unit (ICU) length of stay, and mortality, alongside its impact on blood coagulation and NET dynamics.

Methods: This is an open-label, dose-escalating design enrolling up to 36 patients with sepsis across two sites. Participants will receive DNase I intravenously over 3 or 7 days in increasing dosages across four panels alongside a comparator group of patients with sepsis who do not receive the treatment. The study’s primary measures include safety profiles, adverse events, and dose tolerance, while secondary measures focus on clinical improvements and biological markers indicative of NET breakdown.

Results: This study’s expected results include determining the DNase I dosage that balances efficacy with minimal adverse effects and elucidating the potential benefits of DNase I in reducing the severity of sepsis. Initial safety profiles are expected to show a tolerable range of side effects, providing foundational data for subsequent trials and potentially opening a new avenue of sepsis treatment.

Conclusion: This Phase I trial is designed to explore the feasibility and safety of DNase I in a critical care setting, providing valuable insights into its role in modulating the harmful effects of NETs in sepsis. Data from this study may inform the design of future pilot trials that may have significant implications for patients with sepsis and lay the foundation for a larger Phase II trial. In turn, these trials could integrate DNase I into the therapeutic armamentarium for sepsis, advance the care of critically ill patients with sepsis, and ultimately impact important outcomes.