Intravenous DNase I for Sepsis
(IDEALSepsisI Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: McMaster University
No Placebo Group
Trial Summary
What is the purpose of this trial?Phase I dose-escalation safety and feasibility of IV DNase I in ICU septic patients.
Do I have to stop taking my current medications for this trial?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are receiving DNase I by inhalation, you cannot participate.
What data supports the idea that Intravenous DNase I for Sepsis is an effective treatment?
The available research shows that Intravenous DNase I can be effective in treating sepsis. In a study with mice, DNase I improved survival rates by 60% and reduced inflammation. Another study found that DNase I reduced organ damage and improved outcomes when given later in the treatment process. These studies suggest that DNase I can help reduce harmful effects in sepsis by breaking down extracellular DNA, which is linked to inflammation and organ damage.
12345What safety data exists for Intravenous DNase I treatment?
The provided research does not contain specific safety data for Intravenous DNase I, Deoxyribonuclease I, or DNase I treatment for sepsis. The studies focus on adverse events related to other medical procedures and treatments, such as hematopoietic cell infusion, procedural sedation in pediatric patients, and drug-drug interactions in intensive care units. Therefore, no relevant safety data for Intravenous DNase I is available in the given research.
678910Eligibility Criteria
Adults over 18, recently admitted to the ICU with suspected or confirmed infection leading to sepsis and a SOFA score ≥2 above baseline. They should expect to stay in the ICU for at least 72 hours. Specific details on who can't join are not provided.Inclusion Criteria
I am 18 years old or older.
I was admitted to the hospital because of a suspected or confirmed infection.
You were in the intensive care unit (ICU) in the last 2 days.
+2 more
Participant Groups
The trial is testing the safety and how feasible it is to use Intravenous DNase I in patients with sepsis in intensive care. It's an early-stage study that gradually increases doses to find out what's safe.
2Treatment groups
Experimental Treatment
Active Control
Group I: Intravenous DNase IExperimental Treatment1 Intervention
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)
Group II: ControlActive Control1 Intervention
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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hamilton Health SciencesHamilton, Canada
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Who Is Running the Clinical Trial?
McMaster UniversityLead Sponsor
Canadian Institutes of Health Research (CIHR)Collaborator
References
Deoxyribonuclease I Alleviates Septic Liver Injury in a Rat Model Supported by Venoarterial Extracorporeal Membrane Oxygenation. [2023]Sepsis is an unusual systemic reaction with high mortality and secondary septic liver injury is proposed to be the major cause of mortality. Extracorporeal membrane oxygenation (ECMO) can enhance terminal organ perfusion by elevating circulatory support which is used in severe sepsis patients. However, the interaction of blood components with the biomaterials of the extracorporeal membrane elicits a systemic inflammatory response. Besides, inflammation and apoptosis are the main mediators in the pathophysiology of septic liver injury. Therefore, we investigated the protective effect of Deoxyribonuclease I (DNase I) against septic liver injury supported by ECMO in rats. Sepsis was induced by lipopolysaccharide (LPS) and 24 hours after the administration, the rats were treated with ECMO. Then blood samples and liver tissues were collected. DNase I significantly attenuated the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and significantly decreased hepatic levels of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, myeloperoxidase (MPO), downstream inflammatory factor interleukin-1 β (IL-1 β ) and interleukin-18 (IL-18), and improved neutrophil infiltration. Additionally, DNase I significantly reduced the expression of apoptosis key protein and terminal-deoxynucleotidyl transferase-mediated nick end labeling (TUNEL)-labeled apoptotic hepatocytes. In summary, our findings demonstrated that DNase I alleviates liver injury in ECMO-supported septic rats by reducing the inflammatory and apoptotic responses.
Delayed but not Early Treatment with DNase Reduces Organ Damage and Improves Outcome in a Murine Model of Sepsis. [2015]Sepsis is characterized by systemic activation of coagulation and inflammation in response to microbial infection. Although cell-free DNA (cfDNA) released from activated neutrophils has antimicrobial properties, it may also exert harmful effects by activating coagulation and inflammation. The authors aimed to determine whether deoxyribonuclease (DNase) administration reduces cfDNA levels, attenuates coagulation and inflammation, suppresses organ damage, and improves outcome in a cecal ligation and puncture (CLP) model of polymicrobial sepsis. Healthy C57Bl/6 mice were subjected to CLP, a surgical procedure involving two punctures of the ligated cecum, or sham surgery (no ligation/puncture). Mice were given DNase or saline by intraperitoneal injection 2, 4, or 6 h after surgery. Two hours after treatment, organs were harvested and plasma levels of cfDNA, interleukin-6 (IL-6), IL-10, thrombin-antithrombin complexes, lung myeloperoxidase, creatinine, alanine transaminase, and bacterial load were quantified. Survival studies were also performed. The CLP-operated mice had rapid time-dependent elevations in cfDNA that correlated with elevations in IL-6, IL-10, and thrombin-antithrombin complexes and had organ damage in the lungs and kidneys. Administration of DNase at 2 h after CLP resulted in increased IL-6 and IL-10 levels and organ damage in the lungs and kidneys. In contrast, DNase administration at 4 or 6 h after CLP resulted in reduced cfDNA and IL-6 levels, increased IL-10, and suppressed organ damage and bacterial dissemination. Deoxyribonuclease administration every 6 h after CLP also rescued mice from death. Our studies are the first to demonstrate that delayed but not early administration of DNase may be protective in experimental sepsis.
THE EFFECTS OF DNASE I AND LOW-MOLECULAR-WEIGHT HEPARIN IN A MURINE MODEL OF POLYMICROBIAL ABDOMINAL SEPSIS. [2023]Introduction: Cell-free DNA (CFDNA) has emerged as a prognostic biomarker in patients with sepsis. Circulating CFDNA is hypothesized to be associated with histones in the form of nucleosomes. In vitro, DNA activates coagulation and inhibits fibrinolysis, whereas histones activate platelets and are cytotoxic to endothelial cells. Previous studies have targeted CFDNA or histones in animal models of sepsis using DNase I or heparins, respectively, which has reduced inflammatory and thrombosis markers, thereby improving survival. In this study, we explored the possibility that the combination of DNase I and a low-molecular weight heparin (LMWH) may be a better therapeutic approach than monotherapy in a murine model of abdominal sepsis. Methods: C57Bl/6 mice (8-12 weeks old, both sexes) were subjected to either cecal ligation and puncture or sham surgery. Mice were given antibiotics, fluids, and either saline, DNase I (intraperitoneally, 20 mg/kg/8 h), LMWH (dalteparin, subcutaneously 500 IU/kg/12 h), or a combination of both (n = 12-31). Mice were monitored over 72 h for survival. Organs and blood were harvested for analysis. Levels of LMWH, CFDNA, IL-6, citrullinated histone-H3, thrombin-antithrombin complexes, and protein C were measured in plasma. Results: Administration of either DNase I (81.8%) or LMWH (83.3%, prophylactic range of 0.12 ± 0.07 IU/mL achieved) improved the survival of septic mice compared with saline- (38.7%) and combination-treated mice (48.8%, P
Exogenous deoxyribonuclease has a protective effect in a mouse model of sepsis. [2018]Sepsis is associated with the activation of white blood cells (WBCs) that leads to the production of extracellular traps. This process increases extracellular DNA (ecDNA) that can be recognized by the innate immune system and leads to inflammation. Previous studies have shown that by cleaving ecDNA deoxyribonuclease (DNase) prevents the antibacterial effects of extracellular traps, but also has beneficial effects in sepsis. The aim of our study was to analyze the effects of DNase on WBCs in vitro and on ecDNA in a mouse model of sepsis. Our results confirmed that DNase decreases ecDNA by 70% and prevents the antibacterial effects of WBCs in vitro. Sepsis was induced in mice by intraperitoneal injection of E. coli. DNase was subsequently administered intravenously. In comparison to untreated septic mice DNase treatment improved the survival of septic mice by 60%, reduced their weight loss as well as inflammatory markers. Increased plasma DNase activity led to ecDNA concentrations in plasma comparable with the control group. In conclusion, the study showed that intravenous DNase improves survival of septic mice by cleavage of ecDNA, especially of nuclear origin. Further mechanistic studies are needed to prove the potential of DNase in the treatment or prevention of septic complications.
Early Dynamics of Plasma Dna in a Mouse Model of Sepsis. [2020]Concentration of extracellular DNA (ecDNA) in plasma of septic patients is higher in comparison to healthy controls and is associated with worse prognosis in intensive care patients. Decrease of ecDNA in plasma by treatment with deoxyribonuclease (DNase) showed to have beneficial effects in animal models of sepsis. A previously published study showed that timing of DNase application is crucial for the effect of DNase. No published study monitored plasma ecDNA dynamics during sepsis in detail yet. The aim of our study was to describe the early dynamics of plasma ecDNA but also plasma DNase activity in a mouse model of sepsis. Sepsis was induced using intraperitoneal injection of E. coli and mice were euthanized every hour to obtain sufficient volume of plasma. Our results show that the concentration of plasma ecDNA is rising continuously during the first 5 h after infection and is 20-fold higher 5 h after induction of sepsis in comparison to control mice. Subcellular origin of plasma ecDNA was analyzed but fundamental differences in dynamics between nuclear and mitochondrial ecDNA were not found. DNase activity in plasma seems to rise slowly until the fourth hour, but the interindividual variability is high. In conclusion, this is the first study that describes the dynamics of plasma ecDNA and DNase activity in early sepsis in detail. Our study is the basis for further studies focused on the timing of exogenous DNase treatment in sepsis. Additional studies will be needed to monitor plasma ecDNA in later time points that are more clinically relevant.
Safety of hematopoietic cell infusion in children with malignant and non-malignant diseases. [2018]HPC infusions have been associated with a variety of adverse events related to either patient or HPC product-related factors. Studies documenting infusion-related AEs in children are limited. We reviewed HPC infusion records in 354 children. Infusion-related adverse events were classified as follows: grade 0-absent, grade I-mild, grade II-moderate, grade III-severe, grade IV-life-threatening, and grade V-death. The percentage of patients with grade 0, I, and II-IV AEs was as follows: 0 = 67%, I = 23.4%, and II-V = 9.6% (one patient had fatal anaphylactic reaction to dimethyl sulfoxide). The incidence of grade II-IV hypertension was 7.1%. There was a higher incidence of AEs with infusion of allogeneic bone marrow versus allogeneic PBSCs (47.4% vs 25.3%, P = .001). Cryopreserved products had a lower incidence of infusion-associated AEs compared with fresh HPC products (24% vs 39.4%, P = .003). Allogeneic HPC infusion volume (>100 mL) was a significant risk factor for infusion-associated AEs (P 10 years who received autologous HPC infusions had higher risk of AEs when compared to patients
Adverse events in the neonatal intensive care unit: development, testing, and findings of an NICU-focused trigger tool to identify harm in North American NICUs. [2021]Currently there are few practical methods to identify and measure harm to hospitalized children. Patients in NICUs are at high risk and warrant a detailed assessment of harm to guide patient safety efforts. The purpose of this work was to develop a NICU-focused tool for adverse event detection and to describe the incidence of adverse events in NICUs identified by this tool.
Delayed Adverse Events after Procedural Sedation in Pediatric Patients with Hematologic Malignancies. [2023]Background and objectives: Procedural sedation for bone marrow examination (BME) and intrathecal chemotherapy (ITC) is necessary for pediatric patients with hematological malignancies. There has been no report on adverse events after discharge from the recovery room. This retrospective study evaluated the types and incidences of delayed adverse events among pediatric patients scheduled for BME or ITC under deep sedation in a single center for 3 years. Materials and Methods: The patients were divided into two groups: inpatients (group I) and outpatients (group O). All patients were managed during the procedures and the recovery period. In total, 10 adverse events were assessed; these occurred 2 h (T1, acute), 12 h (T2, early), and 24 h (T3, delayed) after the procedure. The duration of each adverse event was also recorded and was classified as 2 h (D1), 12 h (D2), or 24 h (D3). The data of 263 patients (147 inpatients and 116 outpatients) who met the inclusion criteria were analyzed. Results: The overall incidence of adverse events was statistically significant difference: 48.3% in group I and 33.6% in group O (p = 0.011). The rates of adverse events at T1 and T2 were significantly different between groups I and O (42.8% vs. 11.2% and 7.5% vs. 20.7%, respectively) (p
Adverse drug events caused by three high-risk drug-drug interactions in patients admitted to intensive care units: A multicentre retrospective observational study. [2023]Label="AIMS" NlmCategory="OBJECTIVE">Knowledge about adverse drug events caused by drug-drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR+ ) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential.
The incidence of adverse events and medical error in pediatrics. [2022]In its 2000 report, To Err is Human, the Institute of Medicine concluded that between 44,000 and 98,000 deaths per year occur in United States hospitals as a result of error. These data have resulted in calls for further research, regulatory interventions, third-party payer involvement, and health care organization initiatives to improve this situation. Studies of pediatric inpatients suggest that medication-related harm occurs at a rate as high as 11.1 per 100 admissions, and hospital-related harm occurs in high risk neonatal ICUs at a rate of 74 per 100 admissions. This article discusses differences between error and harm, methods used to measure harm, and available evidence that identifies the incidence of adverse events in pediatric inpatients and outpatients.
Simple purification and properties of bovine pancreatic deoxyribonuclease I. [2019]A simple purification method for pancreatic deoxyribonuclease I (DNase I) [EC 3.1.4.3] was developed by utilizing the technique of isoelectric focusing. The active protein was resolved in to at least four forms with different isoelectric points; the major components a, b, and c had isoelectric points at pH 5.2, 4.9, and 4.8, respectively, and that of the minor component d was at 4.7. The four components (a, b, c, and d) exhibited peaks similar to those observed by Salnikow et al. after phosphocellulose chromatography (A, B, C, and D). The four components were all free from RNase and protease activities and were very stable at 0-2 degrees C for at least four weeks. Further, each of the four peaks exhibited a single protein band after polyacrylamide electrophoresis. DNase I-a antibody was prepared; it was very specific for DNase I and precipitated with the other components (b, c, and d). The mode of endonucleolytic action of pancreatic DNase I-a purified from Worthington DP grade DNase I was investigated. The sedimentation patterns in neutral sucrose gradients of digest of circular duplex DNA in an early stage of hydrolysis suggested that DNase I produces single strand scissions in the initial attack in the presence of divalent metal ions.