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

NCT06626984 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: 22064JS-AS
• Study Type: interventional
• Target: 65
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Sepsis; Fluid Overload; Endothelial Dysfunction; Microcirculation

Keywords

Intravenous Fluid Therapy; Imatinib

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Biomarkers of inflammation

  Up to 8 hours following LPS administration

• Venous Excess Ultrasound Score

  Up to 8 hours following LPS administration

• B-lines

  Up to 8 hours following LPS administration

Study Arms (4)

Intravenous LPS only

NO INTERVENTION

LPS dose 2ng/kg.

Intravenous LPS AND Intravenous Fluid Therapy*

EXPERIMENTAL

\*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

Intravenous LPS AND Imatinib Therapy

EXPERIMENTAL

LPS dose 2ng/kg. Imatinib 600mg 1 hour prior to LPS administration.

Drug: Imatinib

Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy

EXPERIMENTAL

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: Imatinib; Drug: Compound sodium lactate solution

Interventions

Imatinib DRUG

Pre-treatment with 600mg Imatinib administered 1 hour prior to intravenous LPS.

Intravenous LPS AND Imatinib Therapy; Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy

Compound sodium lactate solution DRUG

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.

Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy; Intravenous LPS AND Intravenous Fluid Therapy*

Eligibility Criteria

• Age: 18 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy adult volunteers aged between 18 and 40 years of age
• Informed consent to participate

You may not qualify if:

• Current participation in a clinical trial
• Pregnant or breastfeeding
• Current history of smoking
• Alcohol intake \> 21 units per week
• 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.
• Oxygen saturation \<95% breathing room air
• Abnormal findings on history, examination or laboratory tests suggestive of underlying illness (in the opinion of the clinician undertaking screening)
• History of recurrent vaso-vagal episodes
• Allergy to Imatinib
• Positive or equivocal hepatitis B or C serology result

Sponsors & Collaborators

• Belfast Health and Social Care Trust: lead
• Medical Research Council: collaborator
• The Royal College of Anaesthetists: collaborator

MeSH Terms

Conditions

Sepsis; Edema

Interventions

Imatinib Mesylate; Ringer's Lactate

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Central Study Contacts

Jon Silversides

CONTACT

+44 (0) 28 9097 6378; j.silversides@qub.ac.uk

Ross McMullan

CONTACT

+44 (0) 28 9097 6378; rmcmullan07@qub.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Investigators taking blood samples and performing ultrasound based imaging techniques will be blinded to the treatment allocation.
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: May 3, 2023
• First Posted: October 4, 2024
• Study Start: December 1, 2024
• Primary Completion: February 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: October 4, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share