Intravenous DNase I for the Treatment of Sepsis (IDEALSepsisI)

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

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

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

Conditions
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Sepsis, Critical Illness

Intervention / Treatment
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* Drug: Intravenous DNase I


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of ≥18 years Admitted to the ICU in the last 48 hours Suspected or proven infection as the admitting diagnosis A sequential (sepsis) organ function assessment (SOFA) score of ≥2 above baseline Expected to remain in the ICU for ≥ 72 hours Exclusion Criteria: No consent/inability to obtain consent from a substitute decision-maker Have other forms of clinically apparent shock, including cardiogenic, obstructive (massive pulmonary embolism, cardiac tamponade, tension pneumothorax), hemorrhagic, neurogenic, or anaphylactic shock 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 Receiving DNase I by inhalation Terminal illness with a life expectancy of fewer than three months Pregnant and/or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous DNase I<br>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<br>* Dose-escalating intravenous infusion of DNase I<br>|
| No Intervention: Control<br>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?
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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 |