Intravenous DNase I for Sepsis

(IDEALSepsisI Trial)

Overseen By Patricia Liaw, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: McMaster University

Must not be taking: Therapeutic anticoagulants

Disqualifiers: Shock, Bleeding risk, Terminal illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 3-7 days

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called intravenous DNase I, an enzyme therapy, to determine its safety and effectiveness for people with sepsis in the ICU. Sepsis is a serious infection that can cause organs to malfunction. The trial includes different groups to evaluate various doses of the treatment. Candidates may include those who have been in the ICU for less than 48 hours and are expected to remain for at least three more days. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this novel therapy.

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.

Do I need to stop my current medications for the 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 in the trial.

Is there any evidence suggesting that intravenous DNase I is likely to be safe for humans?

Research has shown that intravenous DNase I has potential in treating sepsis, based on animal studies. Some studies suggest it can lower harmful inflammation and improve survival in these models. However, caution is needed. Administering DNase too early in sepsis has been linked to increased inflammation and organ damage in experiments.

This trial is in its early stages, focusing mainly on assessing the treatment's safety for people. Currently, little information exists on how humans respond to DNase I for sepsis. This trial aims to gather that important data. DNase has been used safely in other situations, but this trial will determine if it's safe for sepsis patients as well. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sepsis?

Unlike the standard sepsis treatments, which often involve antibiotics and supportive care to manage symptoms, intravenous DNase I targets the condition by breaking down extracellular DNA that contributes to inflammation and blood clots. This unique mechanism could potentially reduce the severity of sepsis by directly addressing one of the underlying causes of inflammation. Researchers are excited about DNase I because it offers a novel approach that might improve outcomes for patients who don't respond well to conventional therapies. Additionally, its delivery via IV infusion ensures that the drug acts quickly, which is crucial in the rapid progression of sepsis.

What evidence suggests that intravenous DNase I might be an effective treatment for sepsis?

Research shows that intravenous DNase I could help treat sepsis. In this trial, some participants will receive intravenous DNase I. Studies in mice found that it can improve survival rates by reducing harmful DNA in the blood. This enzyme breaks down the DNA, which may lower inflammation and prevent blood clots. These effects are crucial as they might reduce sepsis severity. While research in humans continues, these early findings provide a strong basis for further study. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

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 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.

My illness has worsened by at least 2 points on the SOFA scale.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive repeated unit doses of DNase I, BID, delivered by IV infusion over 3 or 7 consecutive days according to the dose-escalation schedule

3-7 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of organ dysfunction, ICU length of stay, and mortality

90 days

Long-term follow-up

Participants are monitored for long-term outcomes such as mortality and quality of life

up to 90 days

What Are the Treatments Tested in This Trial?

Interventions

• Intravenous DNase I

Trial Overview 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.

How Is the Trial Designed?

Group I: Intravenous DNase I Experimental Treatment 1 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: Control Active Control 1 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.

Who Is Running the Clinical Trial?

McMaster University

Lead Sponsor

Trials

936

Recruited

2,630,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

In a review of HPC infusion records from 354 children, 67% experienced no adverse events, indicating that HPC infusion is relatively safe, although 9.6% had moderate to life-threatening reactions, including one fatal case of anaphylaxis.

The study found that allogeneic bone marrow infusions had a higher incidence of adverse events compared to allogeneic peripheral blood stem cells, and that larger infusion volumes (>100 mL) significantly increased the risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of hematopoietic cell infusion in children with malignant and non-malignant diseases. Heneghan, C., Smilow, E., Tanhehco, Y., et al.[2018]

In a mouse model of sepsis, plasma levels of extracellular DNA (ecDNA) increased significantly, reaching 20 times higher than control levels within the first 5 hours after infection, indicating a potential biomarker for sepsis severity.

The study also found that plasma DNase activity gradually increased over time, but with high variability among individuals, suggesting that understanding the timing of DNase treatment could be crucial for therapeutic strategies in sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early Dynamics of Plasma Dna in a Mouse Model of Sepsis. Lauková, L., Bertolo, EMJ., Zelinková, M., et al.[2020]

A new purification method for pancreatic DNase I was developed, resulting in four distinct forms of the enzyme, all of which were stable and free from unwanted RNase and protease activities.

The study revealed that DNase I-a acts by producing single strand scissions in DNA during its initial hydrolysis phase, particularly in the presence of divalent metal ions, which is important for understanding its mechanism of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simple purification and properties of bovine pancreatic deoxyribonuclease I. Funakoshi, A., Tsubota, Y., Fujii, K., et al.[2019]

In a study of 263 pediatric patients undergoing bone marrow examination or intrathecal chemotherapy, the overall incidence of adverse events was higher in inpatients (48.3%) compared to outpatients (33.6%), particularly within the first 12 hours after sedation.

Adverse events, mainly dizziness and headache, were more frequent with higher proportions of ketamine in a propofol-ketamine mixture, but all sedation methods were deemed safe without the need for additional management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed Adverse Events after Procedural Sedation in Pediatric Patients with Hematologic Malignancies. Joo, J., Yu, S., Koh, HJ.[2023]

The Institute of Medicine reported that between 44,000 and 98,000 deaths annually in U.S. hospitals are due to medical errors, highlighting a critical need for improved safety measures in healthcare.

In pediatric patients, medication-related harm occurs at a concerning rate of 11.1 per 100 admissions, and in high-risk neonatal ICUs, hospital-related harm is even higher at 74 per 100 admissions, indicating a significant risk of adverse events in these vulnerable populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The incidence of adverse events and medical error in pediatrics. Sharek, PJ., Classen, D.[2022]

In a study using a mouse model of polymicrobial sepsis, delayed administration of deoxyribonuclease (DNase) significantly reduced harmful cell-free DNA (cfDNA) levels and improved outcomes, including reduced organ damage and increased survival rates.

Administering DNase 4 to 6 hours after the onset of sepsis was beneficial, while early administration (2 hours) led to increased inflammation and organ damage, highlighting the importance of timing in treatment for sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Delayed but not Early Treatment with DNase Reduces Organ Damage and Improves Outcome in a Murine Model of Sepsis. Mai, SH., Khan, M., Dwivedi, DJ., et al.[2015]

In a mouse model of sepsis, intravenous administration of DNase reduced extracellular DNA (ecDNA) levels by 70% and improved survival rates by 60%, indicating its potential as a therapeutic intervention.

DNase treatment also decreased weight loss and inflammatory markers in septic mice, suggesting that it not only helps in reducing ecDNA but also mitigates the inflammatory response associated with sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exogenous deoxyribonuclease has a protective effect in a mouse model of sepsis. Lauková, L., Konečná, B., Bábíčková, J., et al.[2018]

In a murine model of abdominal sepsis, both DNase I and low-molecular weight heparin (LMWH) significantly improved survival rates (81.8% and 83.3%, respectively) compared to saline treatment (38.7%).

The combination of DNase I and LMWH did not enhance survival and may indicate a negative interaction between the two treatments, suggesting that monotherapy could be more effective in reducing inflammation and improving outcomes in sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

THE EFFECTS OF DNASE I AND LOW-MOLECULAR-WEIGHT HEPARIN IN A MURINE MODEL OF POLYMICROBIAL ABDOMINAL SEPSIS. Medeiros, SK., Sharma, N., Dwivedi, D., et al.[2023]

A new NICU-focused trigger tool was developed and tested, revealing a high incidence of adverse events in hospitalized children, with 554 unique adverse events identified across 749 charts, averaging 0.74 events per patient.

The study found that 56% of these adverse events were preventable, highlighting the need for improved safety measures, as only 8% were reported through traditional hospital reporting systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Sharek, PJ., Horbar, JD., Mason, W., et al.[2021]

In a study of 85,422 ICU patients, 38.4% were exposed to high-risk drug-drug interactions (DDIs), with 65.4% of those assessed experiencing actual adverse drug events (DDI-ADEs), highlighting a significant safety concern in critical care.

Most DDI-ADEs were found to be serious (52.9%) and preventable (75.5%), indicating a need for improved monitoring and intervention strategies to enhance patient safety in ICUs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug events caused by three high-risk drug-drug interactions in patients admitted to intensive care units: A multicentre retrospective observational study. Klopotowska, JE., Leopold, JH., Bakker, T., et al.[2023]

In a rat model of sepsis supported by ECMO, treatment with Deoxyribonuclease I (DNase I) significantly reduced liver injury markers, indicating its protective effect against septic liver damage.

DNase I treatment decreased inflammation and apoptosis in the liver by lowering levels of key inflammatory proteins and reducing the number of apoptotic liver cells, suggesting it may be a beneficial intervention in severe sepsis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Deoxyribonuclease I Alleviates Septic Liver Injury in a Rat Model Supported by Venoarterial Extracorporeal Membrane Oxygenation. Zhang, M., Yan, W., Wang, T., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05453695

Study Details | NCT05453695 | Intravenous DNase I for the ... 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 ...

2. withpower.com withpower.com/trial/phase-1-sepsis-6-2022-02f6f

Intravenous DNase I for Sepsis (IDEALSepsisI Trial) Yes, Intravenous DNase I is a promising treatment for sepsis. Studies show that it can improve survival rates in mice with sepsis by reducing harmful DNA in the ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7407206/

Deoxyribonucleases and Their Applications in Biomedicine This review summarizes the currently available published data about DNases, their activity as a potential biomarker and methods used for their assessment.

4. sciencedirect.com sciencedirect.com/science/article/pii/S0024320524001152

Development of a rectally administrable Dnase1 to treat ... In this study, we genetically engineered this enzyme to develop a rectal suppository formulation to treat septic shock.

5. sciencedirect.com sciencedirect.com/science/article/pii/S1538783624007189

Therapeutic potential of DNases in immunothrombosis This data suggests that DNase1 can impact thrombus formation not only by degrading NETs but also by inhibiting ATP-mediated platelet and neutrophil activation.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26009820/

Delayed but not Early Treatment with DNase Reduces ... Our studies are the first to demonstrate that delayed but not early administration of DNase may be protective in experimental sepsis.

7. mdpi.com mdpi.com/2227-9059/12/11/2565

Extracellular DNA and Deoxyribonuclease Activity as ... Several experimental studies of murine sepsis have shown the positive effects of DNase treatment on sepsis outcome, even demonstrating decreased mortality in ...