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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Respiratory Distress Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Racecadotril 100 milligram (MG) Oral Capsule

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • William Harvey Research Institute- Heart Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Healthy subjects unwilling to consent
2. Smokers
3. Known sensitivity to Racecadotril
4. History of any serious illnesses, including recent infections or trauma
5. A personal history of keloid scarring, or a family history of keloid scarring in a first degree relative with similar skin pigmentation
6. Subjects taking systemic medication (other than the oral contraceptive pill)
7. 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
8. Women who are breastfeeding
9. Subjects with recent or current antibiotic use
10. Subjects with a history of skins conditions.
11. Subjects with a history of allergic reaction to any topical application or history of angioedema
12. Subjects with any history of a blood-borne infectious disease such Hepatitis B or C virus, or HIV.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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
Powered comparison of sex differences in change in blister volume following Racecadotril or placebo administration.	End of study
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

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Collaborators: Medical Research Council
• Investigators: Principal Investigator: Adrian Hobbs, Queen Mary University London

Study record dates

Study Major Dates

• Study Start (Actual): March 21, 2023
• Primary Completion (Actual): February 1, 2026
• Study Completion (Estimated): June 15, 2026

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 26, 2022
• First Posted (Actual): October 31, 2022

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ARDS; endothelium; Acute lung injury; CNP
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Lung Injury; Respiratory Distress Syndrome; Acute Lung Injury; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Protease Inhibitors; Enzyme Inhibitors; Antidiarrheals; Racecadotril
• Other Study ID Numbers: 288749

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Fully anonymised data will be shared with fellow researchers via conference presentation and via publication of the results in scientific journals. Data will be shared between the research team directly undertaking the research
• IPD Sharing Time Frame: 6 months after publication
• IPD Sharing Access Criteria: Access requests can be made to the investigators by email
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No