NCT06626984

Investigation of Novel and Established Therapies in a Human Intravenous Lipopolysaccharide Model of Sepsis

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 65 (estimated)
• Sponsor: Belfast Health and Social Care Trust · Academic / Other
• Sex: All
• Age: 18 Years – 40 Years
• Healthy volunteers: Accepted

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.

Conditions

• Sepsis
• Fluid Overload
• Endothelial Dysfunction
• Microcirculation

Interventions

Type	Name	Description
DRUG	Imatinib	Pre-treatment with 600mg Imatinib administered 1 hour prior to intravenous LPS.
DRUG	Compound sodium lactate solution	Total of 30 ml/kg administered 90 minutes following intravenous LPS. 30mls/kg (maximum volume of 2500mls) administered in two divided doses (15mls/kg) intravenously. Each bolus will be administered at a fixed rate of 999mls/hr.

Timeline

• Start date: 2024-12-01
• Primary completion: 2026-02-01
• Completion: 2026-07-01
• First posted: 2024-10-04
• Last updated: 2024-10-04