Critical Illness, Sepsis
Conditions
Brief summary
Phase I dose-escalation safety and feasibility of IV DNase I in ICU septic patients.
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.
Interventions
DRUGIntravenous DNase I
Dose-escalating intravenous infusion of DNase I
Sponsors
McMaster University
Canadian Institutes of Health Research (CIHR)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients recruited per month from the start of the study | up to 24 months | Number of patients recruited per month |
| Number of patients who completed the protocol | up to 7 days | The ability to complete study infusion and blood collection as prescribed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Organ support free days | at Day 28 | Increase of three or more days free from vasopressor therapy, invasive mechanical ventilation or renal replacement therapy. |
| Duration of ICU admission | up to 9 months | Number of days since admission to discharge from the ICU |
| Time to Hospital discharge | up to 90 days | Time elapsed between enrolment into the study (at admission), and discharge |
| Mortality at Day 90 | up to day 90 | Number of patients alive at day 90 |
| Collection of Research Biomarkers related to inflammation and coagulation | up to day 14 | Number of patients with all sets of biomarkers |
| European Quality of Life (EuroQol) - 5 Domain 5 Level Scale (EQ-5D-5L) Utility Score | At day 90 | Average or median EQ-5D-5L score |
| Sequential Organ Failure Assessment (SOFA) score | Baseline to Day 10 | 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 |
Countries
Canada
Contacts
CONTACTAlison Fox-Robichaud, MD
CONTACTPatricia Liaw, PhD
Outcome results
None listed