Intravenous DNase I for the Treatment of Sepsis (IDEALSepsisI) (IDEALSepsisI)

Intravenous DNase I for the Treatment of Sepsis: A Phase I Safety and Feasibility Study in ICU Patients

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

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Critical Illness
• Intervention / Treatment: Drug: Intravenous DNase I

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Alison Fox-Robichaud, MD; Phone Number: 4074 905 521 2100; Email: afoxrob@mcmaster.ca
• Study Contact Backup: Name: Patricia Liaw, PhD; Phone Number: 40788 (905) 521-2100; Email: Patricia.Liaw@taari.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 0A4
      • Recruiting
      • Hamilton Health Sciences
      • Contact: Alison E Fox-Robichaud, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intravenous DNase I; 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)	Drug: Intravenous DNase I; Dose-escalating intravenous infusion of DNase I
No Intervention: Control; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients recruited per month from the start of the study	Number of patients recruited per month	up to 24 months
Number of patients who completed the protocol	The ability to complete study infusion and blood collection as prescribed	up to 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sequential Organ Failure Assessment (SOFA) score	Quantitative variable: Maximal score of SOFA (Sequential Organ Failure Assessment) will be recorded; Value range 0-24 points; Delta SOFA score, defined as maximum versus minimum SOFA during ICU stay; Change in SOFA score within 48 hours	Baseline to Day 10
Organ support free days	Increase of three or more days free from vasopressor therapy, invasive mechanical ventilation or renal replacement therapy.	at Day 28
Duration of ICU admission	Number of days since admission to discharge from the ICU	up to 9 months
Time to Hospital discharge	Time elapsed between enrolment into the study (at admission), and discharge	up to 90 days
Mortality at Day 90	Number of patients alive at day 90	up to day 90
European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score	Average or median EQ-5D-5L score	At day 90
Collection of Research Biomarkers related to inflammation and coagulation	Number of patients with all sets of biomarkers	up to day 14

Collaborators and Investigators

• Sponsor: McMaster University
• Collaborators: Canadian Institutes of Health Research (CIHR)

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2023
• Primary Completion (Estimated): April 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: June 24, 2022
• First Submitted That Met QC Criteria: July 11, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Sepsis; Toxemia; Critical Illness
• Other Study ID Numbers: IDEALSepsisI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No