Intravenous DNase I for the Treatment of Sepsis (IDEALSepsisI)

McMaster University

Status and phase: Enrolling; Phase 1

Conditions: Critical Illness; Sepsis

Treatments: Drug: Intravenous DNase I

Study type: Interventional

Funder types: Other

Identifiers

NCT05453695

IDEALSepsisI

Details and patient eligibility

About

Phase I dose-escalation safety and feasibility of IV DNase I in ICU septic patients.

Full description

In sepsis, the release of 'neutrophil extracellular traps' (NETs) by activated neutrophils may contribute to organ damage by acting as scaffolds that trap blood cells and fibrin clots. Excessive NET formation can occlude the vasculature, promoting thrombosis and tissue hypoperfusion. This is a trial on a novel IV therapy for septic patients that shows promise in multiple animal models of sepsis. The therapy, DNase I, is an enzyme that helps to dismantle NETs by digesting cell-free DNA (cfDNA), the major structural component of NETs. The objective of this study is to conduct a Phase I dose-escalation safety and feasibility of IV DNase I in ICU septic patients. The results of this study may justify a future Phase II trial of the efficacy and safety of DNase I for critically ill patients with sepsis.

This trial proposes

1. • To determine the safety, feasibility and maximum tolerated dose (MTD) of using DNase I in septic patients
2. • To evaluate clinical endpoints common in the critically ill such as organ dysfunction severity and trajectory, ICU length of stay, and mortality.
3. • To describe the effects of DNase I on blood coagulation and NETs release
4. • To collect samples for future studies on coagulation and immune function in sepsis.

Enrollment: 36 estimated patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age of ≥18 years
2. Admitted to the ICU in the last 48 hours
3. Suspected or proven infection as the admitting diagnosis
4. A sequential (sepsis) organ function assessment (SOFA) score of ≥2 above baseline
5. Expected to remain in the ICU for ≥ 72 hours

Exclusion criteria

1. No consent/inability to obtain consent from a substitute decision-maker

2. Have other forms of clinically apparent shock, including cardiogenic, obstructive (massive pulmonary embolism, cardiac tamponade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic shock

3. Have a significant risk of bleeding as evidenced by one of the following:

   • Surgery requiring general or spinal anesthesia within 24 hours before enrolment
   • The potential need for surgery in the next 24 hours
   • Evidence of active bleeding
   • A history of severe head trauma requiring hospitalization
   • Intracranial surgery, or stroke within three months before the study
   • Any history of intracerebral arteriovenous malformation, cerebral aneurysm, or mass lesions of the central nervous system
   • A history of congenital bleeding diatheses
   • Gastrointestinal bleeding within five weeks before the study unless corrective surgery had been performed
   • Trauma is considered to increase the risk of bleeding
   • Presence of an epidural catheter
   • Need for therapeutic anticoagulation

4. Receiving DNase I by inhalation

5. Terminal illness with a life expectancy of fewer than three months

6. Pregnant and/or breastfeeding

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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36 participants in 2 patient groups

Intravenous DNase I

Experimental group

Description:

We will enroll up to 36 Participants; each is receiving repeated unit doses of DNase I, BID, delivered by IV infusion over 3 or 7 consecutive days (12 +/- 1 hour apart) according to the following dose-escalation schedule with up to 6 Participants per dose panel. * Panel 1: 25 µg/kg, BID for 3 days (cumulative dose: 150 µg/kg) * Panel 2: 25 µg/kg, BID for 7 days (cumulative dose: 350 µg/kg) * Panel 3: 125 µg/kg, BID for 3 days (cumulative dose: 750 µg/kg) * Panel 4: 125 µg/kg, BID for 7 days (cumulative dose: 1750 µg/kg)

Treatment:

Drug: Intravenous DNase I

Control

No Intervention group

Description:

We will also enroll 12 septic Participants who do not receive intravenous DNase I (as Comparator Group). These patients will be recruited contemporaneously based on the same inclusion and exclusion criteria.