Clinical trial NCT06626984: Investigation of Novel and Established Therapies in a Human Intravenous Lipopolysaccharide Model of Sepsis
Official title: Investigation of Novel and Established Therapies in a Human Intravenous Lipopolysaccharide Model of Sepsis
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Sepsis
Fluid Overload
Endothelial Dysfunction
Microcirculation
Keywords: Intravenous Fluid Therapy
Imatinib
Lead sponsor: Belfast Health and Social Care Trust
Sponsor class: OTHER
Collaborators: name: Medical Research Council
name: The Royal College of Anaesthetists
First posted: 2024-10-04
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: The first 5 participants recruited to this study will receive intravenous fluid therapy only. This will allow us to directly elucidate the effects of intravenous fluid therapy on markers of vascular injury, markers of systemic inflammation, microcirculatory function and venous congestion in healthy volunteers.

After the first 5 participants have completed the interventions, a 2x2 factorial design will be adopted, in which participants are randomised to:

1. Intravenous fluids or no intravenous fluids, AND TO
2. Imatinib or no imatinib
Primary purpose: BASIC_SCIENCE

Brief summary: Sepsis is a common and life-threatening condition caused by a dysregulated host immune response to infection. Given the prominent role of endothelial breakdown and dysfunction in sepsis, therefore, there is an urgent need to establish strategies to protect the endothelium and preserve microcirculatory function.

This study is a randomised clinical study investigating intravenous fluid therapy and oral imatinib therapy in healthy human volunteers exposed to intravenous lipopolysaccharide (LPS).

The objective of the study is to investigate the biological effects of fluid and imatinib therapy on LPS-induced microcirculatory dysfunction.

Detailed description: The benefits of intravenous fluid administration in sepsis remain uncertain. A growing body of evidence suggests that excessive fluid administration is harmful. An association between a more positive fluid balance and mortality in critically ill patients has been repeatedly demonstrated. Moreover, emerging evidence suggests that intravenous fluid administration induces glycocalyx injury, thought to be mediated by shear stress. In sepsis the rapid administration of intravenous fluids is hypothesised to exacerbate glycocalyx injury, capillary leak and tissue oedema formation.

Recent work has highlighted the protective effects of Imatinib, a tyrosine kinase inhibitor, on endothelial barrier function in animal models of microcirculatory dysfunction as well as in patients with endothelial barrier dysfunction. Moreover, Imatinib has also been demonstrated to attenuate markers of systemic inflammation in animals with a LPS-induced lung injury model of acute respiratory distress syndrome. There is, therefore, a growing body of evidence to support a potential therapeutic role for Imatinib in disease states involving inflammatory vascular leak.

The hypothesis being tested is that:

1. Intravenous fluid therapy will exacerbate the degree of vascular dysfunction and systemic inflammation observed in this model.
2. Imatinib pre-treatment will attenuate the degree of vascular dysfunction and systemic inflammation observed in this model.

Eligibility criteria: Inclusion Criteria:

1. Healthy adult volunteers aged between 18 and 40 years of age
2. Informed consent to participate

Exclusion Criteria:

1. Current participation in a clinical trial
2. Pregnant or breastfeeding
3. Current history of smoking
4. Alcohol intake \> 21 units per week
5. Regular intake of any relevant prescription or over-the-counter medication. Any regular medication use will be reviewed on a case-by-case basis as to (a) risk and (b) potential confounding effect.
6. Oxygen saturation \<95% breathing room air
7. Abnormal findings on history, examination or laboratory tests suggestive of underlying illness (in the opinion of the clinician undertaking screening)
8. History of recurrent vaso-vagal episodes
9. Allergy to Imatinib
10. Positive or equivocal hepatitis B or C serology result

Primary outcomes:
measure: Biomarkers of vascular and glycocalyx injury
timeFrame: Up to 8 hours following LPS administration
Secondary outcomes:
measure: Biomarkers of inflammation
timeFrame: Up to 8 hours following LPS administration
measure: Venous Excess Ultrasound Score
timeFrame: Up to 8 hours following LPS administration
measure: B-lines
timeFrame: Up to 8 hours following LPS administration
Other outcomes:
Locations:
Study officials:
References: