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

Belfast Health and Social Care Trust

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Endothelial Dysfunction; Fluid Overload; Microcirculation; Sepsis

Treatments: Drug: Imatinib; Drug: Compound sodium lactate solution

Study type: Interventional

Funder types: Other

Identifiers

NCT06626984

22064JS-AS

Details and patient eligibility

About

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.

Full 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.

Enrollment: 65 estimated patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Double Blind

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65 participants in 4 patient groups

Intravenous LPS only

No Intervention group

Description:

LPS dose 2ng/kg.

Intravenous LPS AND Intravenous Fluid Therapy*

Experimental group

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. 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.

Treatment:

Drug: Compound sodium lactate solution

Intravenous LPS AND Imatinib Therapy

Experimental group

Description:

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

Treatment:

Drug: Imatinib

Intravenous LPS AND Intravenous Fluid Therapy AND Imatinib Therapy

Experimental group

Description:

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.

Treatment:

Drug: Compound sodium lactate solution

Drug: Imatinib