Influence of NEP Inhibition on Vascular Leak and Inflammation (NEPi-INFLAMMATION)

Sponsor

Queen Mary University of London (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05600062

Collaborator

Medical Research Council (Other)

Enrollment

Arms

13.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Acute Respiratory Distress Syndrome (ARDS) is a severe type of lung injury that affects 10% of patients admitted to Intensive Care Units worldwide, with an unacceptably high mortality of up to 48% in those with the most severe form of the condition. It is a complex and poorly understood syndrome that results in progressive failure of the lungs. Crucially, the inflamed lungs allow fluid to leak from the circulation into the airspace, so that patients' lungs fill with fluid - "drowning from the inside". As this condition progresses, the patient typically requires increasing amounts of oxygen and eventually, support from a ventilator. To date, there are no effective treatments for ARDS that can limit, stop or repair this process.

This research study is aiming to look at a naturally occurring substance produced by blood vessels, C-type natriuretic peptide (CNP). The investigators have evidence suggesting that CNP plays a role in maintaining the barrier provided by blood vessels that stops fluid leaking out into tissues. This is based on various studies done on CNP by the investigators research group that have established its widespread role in maintaining cells that line blood vessels and play a vital role in lungs' barrier function: the endothelium.

CNP is broken down in part by an enzyme called Neutral endopeptidase and therefore, drugs that inhibit this enzyme would result in increased CNP concentration and activity. If CNP does in fact strengthen the lungs' endothelial barrier, then this class of drug may benefit patients with ARDS. The aim of this experimental medicine study is to assess the effect of using the licensed NEP inhibitor Racecadotril, in a well-established, safe model of inflammation-induced skin blisters in healthy human volunteers to determine primarily whether the fluid accumulation i.e. leak, in these blisters is reduced by treatment with this drug.

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Distress Syndrome	Drug: Racecadotril 100 milligram (MG) Oral Capsule Drug: Placebo	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

48 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Basic Science

Official Title:

Assessment of the Effect of Neutral Endopeptidase Inhibition on Vascular Leak and Leukocyte Accumulation in a Human Cantharidin Blister Model

Anticipated Study Start Date :

Jan 16, 2023

Anticipated Primary Completion Date :

Jan 17, 2024

Anticipated Study Completion Date :

Mar 15, 2024

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo tablet to be taken three times a day for three days	Drug: Placebo Placebo capsule
Experimental: Racecadotril Racecadotril 100 milligrams (mg) three times a day for three days	Drug: Racecadotril 100 milligram (MG) Oral Capsule Licensed NEP inhibitor Other Names: Tiorfan

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Placebo tablet to be taken three times a day for three days

Drug: Placebo

Placebo capsule

Experimental: Racecadotril

Racecadotril 100 milligrams (mg) three times a day for three days

Drug: Racecadotril 100 milligram (MG) Oral Capsule

Licensed NEP inhibitor

Other Names:

Tiorfan

Outcome Measures

Primary Outcome Measures

Powered unpaired inter-patient comparison of change in blister fluid volume following Racecadotril or placebo administration. [24 hours after application of cantharidin]
Powered paired intra-patient comparison of change in blister fluid volume following Racecadotril or placebo admininstration. [24 hours after application of cantharidin]

Secondary Outcome Measures

Powered comparison of sex differences in change in blister volume following Racecadotril or placebo administration. [End of study]
Difference in concentration of blister fluid cytokines; specifically Interleukin (IL) -1β, IL-6, IL-8, IL-10, CXCL1, CXCL2, CCL5 and CCL2 in volunteers receiving Racecadotril compared to placebo. [24 hours after application of cantharidin]
Comparison of change in blister fluid leukocyte count following Racecadotril or placebo administration [24 hours after application of cantharidin]
Comparison of change in pro and anti-inflammatory mediators from blister fluid following Racecadotril or placebo administration [24 hours after application of cantharidin]
Comparison of change in plasma cGMP following oral Racecadotril or placebo administration [24 hours after application of cantharidin]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Healthy male and female volunteers
BMI of 18-40 kg/m2
Aged 18-45
Volunteers who are willing to sign the consent form

Exclusion Criteria:

Healthy subjects unwilling to consent
Smokers
Known sensitivity to Racecadotril
History of any serious illnesses, including recent infections or trauma
A personal history of keloid scarring, or a family history of keloid scarring in a first degree relative with similar skin pigmentation
Subjects taking systemic medication (other than the oral contraceptive pill)
Subjects who are pregnant or any possibility that a subject may be pregnant, unless in the latter case a pregnancy test is performed with a negative result
Women who are breastfeeding
Subjects with recent or current antibiotic use
Subjects with a history of skins conditions.
Subjects with a history of allergic reaction to any topical application or history of angioedema
Subjects with any history of a blood-borne infectious disease such Hepatitis B or C virus, or HIV.