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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Sepsis; Endothelial Dysfunction; Fluid Overload; Microcirculation
• Intervention / Treatment: Drug: Compound sodium lactate solution; Drug: Imatinib

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 Type: Interventional
• Enrollment (Estimated): 65
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jon Silversides; Phone Number: +44 (0) 28 9097 6378; Email: j.silversides@qub.ac.uk
• Study Contact Backup: Name: Ross McMullan; Phone Number: +44 (0) 28 9097 6378; Email: rmcmullan07@qub.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Intravenous LPS only; LPS dose 2ng/kg.
Experimental: Intravenous LPS AND Intravenous Fluid Therapy*; *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.	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.
Experimental: Intravenous LPS AND Imatinib Therapy; LPS dose 2ng/kg. Imatinib 600mg 1 hour prior to LPS administration.	Drug: Imatinib; Pre-treatment with 600mg Imatinib administered 1 hour prior to intravenous LPS.
Experimental: Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy; 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.	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.; Drug: Imatinib; Pre-treatment with 600mg Imatinib administered 1 hour prior to intravenous LPS.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Belfast Health and Social Care Trust
• Collaborators: Medical Research Council; Royal College of Anaesthetists

Study record dates

Study Major Dates

• Study Start (Estimated): December 1, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: May 3, 2023
• First Submitted That Met QC Criteria: October 2, 2024
• First Posted (Actual): October 4, 2024

Study Record Updates

• Last Update Posted (Actual): October 4, 2024
• Last Update Submitted That Met QC Criteria: October 2, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Intravenous Fluid Therapy; Imatinib
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: 22064JS-AS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No individual participant data will be available to share with other researchers. Anonymised data will be grouped into a database which may be shared with other researchers.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No