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

Phase 1

Not yet recruiting

• Conditions: Sepsis; Fluid Overload; Endothelial Dysfunction; Microcirculation
• Interventions: Drug: Imatinib; Drug: Compound sodium lactate solution

• Registration Number: NCT06626984
• Lead Sponsor: Belfast Health and Social Care Trust

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.

Study Timeline

• Study First Submitted: 2023-05-03
• Status Verified: 2024-08
• Study First Submitted QC: 2024-10-02
• Last Update Submitted: 2024-10-02
• Study First Posted: 2024-10-04
• Last Update Posted: 2024-10-04
• Study Start: 2024-12-01
• Primary Completion: 2026-02-01
• Study Completion: 2026-07-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 65

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Intravenous LPS AND Imatinib Therapy	Imatinib	LPS dose 2ng/kg. Imatinib 600mg 1 hour prior to LPS administration.
Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy	Compound sodium lactate solution	LPS dose 2ng/kg. Intravenous fluid 30ml/kg in total (maximum volume of 2500mls). Administered in two divided doses (15mls/kg) intravenously. Each bolus will be administered at a fixed rate of 999mls/hr. The administration is to commence 90 minutes following intravenous LPS. Imatinib 600mg 1 hour prior to LPS administration.
Intravenous LPS AND Intravenous Fluid Therapy*	Compound sodium lactate solution	\*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. LPS dose 2ng/kg. Intravenous fluid 30ml/kg in total (maximum volume of 2500mls). Administered in two divided doses (15mls/kg) intravenously. Each bolus will be administered at a fixed rate of 999mls/hr. The administration is to commence 90 minutes following intravenous LPS.
Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy	Imatinib	LPS dose 2ng/kg. Intravenous fluid 30ml/kg in total (maximum volume of 2500mls). Administered in two divided doses (15mls/kg) intravenously. Each bolus will be administered at a fixed rate of 999mls/hr. The administration is to commence 90 minutes following intravenous LPS. Imatinib 600mg 1 hour prior to LPS administration.

Primary Outcome Measures

Name	Time	Method
Biomarkers of vascular and glycocalyx injury	Up to 8 hours following LPS administration	Change in plasma biomarkers of vascular and glycocalyx injury including but not limited to - Hyaluronan

Secondary Outcome Measures

Name	Time	Method
Biomarkers of inflammation	Up to 8 hours following LPS administration	Change in plasma biomarkers of inflammation including but not limited to - Interleukin-6
Venous Excess Ultrasound Score	Up to 8 hours following LPS administration	Ultrasound measure of venous congestion
B-lines	Up to 8 hours following LPS administration	Ultrasound measure of pulmonary oedema