Vascular leak and inflammation: a study to understand underlying mechanisms and identify novel treatment options
| ISRCTN | ISRCTN10222161 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10222161 |
| IRAS number | 288749 |
| ClinicalTrials.gov number | NCT05600062 |
| Secondary identifying numbers | IRAS 288749 |
- Submission date
- 27/06/2023
- Registration date
- 20/07/2023
- Last edited
- 18/06/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Other
Plain English summary of protocol
Background and study aims
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 death rate 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 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 the 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 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.
Who can participate?
Healthy volunteers aged 18-45 years
What does the study involve?
Participants will be screened and recruited (Day 0) and on Day 1 a blister will be created on one arm. After 24 hours the blister volume will be measured and the blister fluid collected for analysis. 7 days later participants will be randomly allocated to either placebo (dummy drug) or racecadotril (100 mg, three times daily; licensed dose) for 3 days then an identical blister will be created on their other arm. 24 hours later the blister volume will be measured and the blister fluid collected for analysis.
What are the possible benefits and risks of participating?
This study will not benefit participants directly. However, in the future, the results from this study may benefit patients with various inflammatory conditions, especially an inflammatory condition affecting the lungs called ARDS.
Cantharidin may cause some mild discomfort whilst the blister is forming. Participants may also have mild discomfort and/or bruising after blood-taking.
Racecadotril is widely available as a generic drug and has an established safety record. When used for its licensed indication the most common adverse effects are headache, nausea or constipation. Participants will be counselled thoroughly on these and provided with advice on how to manage any adverse effects that may occur.
Where is the study run from?
William Harvey Research Institute, Queen Mary University of London (UK)
When is the study starting and how long is it expected to run for?
August 2020 to June 2025
Who is funding the study?
Medical Research Council (MRC) (UK)
Who is the main contact?
Dr Aemun Salam, aemun.salam@qmul.ac.uk
Contact information
Public
Translational Medicine &Therapeutics
William Harvey Research Institute
Barts & The London School of Medicine
Queen Mary, University of London
Charterhouse Square
London
EC1M 6BQ
United Kingdom
| Phone | +44 (0)7492042830 |
|---|---|
| aemun.salam@qmul.ac.uk |
Scientific
Translational Medicine &Therapeutics
William Harvey Research Institute
Barts & The London School of Medicine
Queen Mary, University of London
Charterhouse Square
London
EC1M 6BQ
United Kingdom
| Phone | +44 (0)7492042830 |
|---|---|
| aemun.salam@qmul.ac.uk |
Principal Investigator
William Harvey Research Institute
Heart Centre (1st Floor)
Faculty of Medicine & Dentistry
Barts & The London
Queen Mary University of London
Charterhouse Square
London
EC1M 6BQ
United Kingdom
| Phone | +44 (0)207 882 5778 |
|---|---|
| a.j.hobbs@qmul.ac.uk |
Study information
| Study design | Double-blind randomized placebo-controlled single-centre parallel-study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | University/medical school/dental school |
| Study type | Other |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Assessment of the effect of neutral endopeptidase inhibition on vascular leak and leukocyte accumulation in a human cantharidin blister model |
| Study acronym | NEPi-INFLAMMATION |
| Study objectives | The neutral endopeptidase (NEP) inhibitor racecadotril leads to a reduction in cantharidin-induced blister fluid volume and inflammatory infiltrate compared to placebo. |
| Ethics approval(s) |
Approved 15/08/2022, London - South East Research Ethics Committee (Equinox House, Nottingham, NG2 4LA, United Kingdom; +44 (0)2071048263; londonsoutheast.rec@hra.nhs.uk), ref: 22/LO/0496 |
| Health condition(s) or problem(s) studied | Evaluating the role of CNP in fluid movement and inflammatory cell infiltration, and its relationship to inflammation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) |
| Intervention | Healthy volunteers (equal numbers of males and females, with stratification according to sex) will be screened and recruited (Day 0) and on Day 1 a blister (10µl of 0.1% cantharidin; Dormer Labs) will be created on one arm. After 24 hours the blister volume will be measured and the blister fluid collected for analysis including quantification of leukocyte numbers, cytokine concentrations and profiling of pro-inflammatory and anti-inflammatory/pro-resolving mediators. 7 days later volunteers will be randomised to either placebo or racecadotril (100 mg, tid; licensed dose) for 3 days then an identical blister will be created in the contralateral arm. 24 hours later the blister volume will be measured and the blister fluid collected for analysis as above. Method of randomisation Block randomisation, 1:1 group allocation in blocks of 6, using Random Numbers Calculator on Graphpad (https://www.graphpad.com/quickcalcs/randMenu/). |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Mechanistic |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | Racecadotril |
| Primary outcome measure | Blister fluid volume measured by weight at study visits 3 and 5 |
| Secondary outcome measures | 1. Concentration of blister fluid cytokines, specifically interleukin (IL) -1β, IL-6, IL-8, IL-10, CXCL1, CXCL2, CCL5 and CCL2, measured using enzyme-linked immunosorbent assay/bead array, on study visits 3 and 5 2. Blister fluid leukocyte count measured using microscopy and flow cytometry at study visits 3 and 5 3. Pro and anti-inflammatory mediators from blister fluid, measured using enzyme-linked immunosorbent assay/bead array on study visits 3 and 5 4. Plasma cGMP measured using enzyme immunoassay at study visits 3 and 5 |
| Overall study start date | 01/08/2020 |
| Completion date | 01/06/2026 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 45 Years |
| Sex | Both |
| Target number of participants | 48 |
| Key inclusion criteria | 1. Healthy male and female volunteers 2. BMI 18-40 kg/m² 3. Aged 18-45 years 4. Volunteers who are willing to sign the consent form |
| Key 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 as hepatitis B or C virus, or HIV |
| Date of first enrolment | 01/08/2023 |
| Date of final enrolment | 01/05/2026 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Charterhouse Square
London
EC1M 6BQ
United Kingdom
Sponsor information
University/education
69-89 Mile End Road
London
E1 4UJ
England
United Kingdom
| Phone | +44 (0)20 7882 8967 |
|---|---|
| research.governance@qmul.ac.uk | |
| Website | https://www.qmul.ac.uk/ |
"ROR" |
https://ror.org/026zzn846 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 15/06/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal and presentation at relevant meetings The type of data that will be shared: raw data from CRFs Whether consent from participants was required and obtained: included in the consent form for the study Comments on data anonymization: no personally identifiable information will be shared Any ethical or legal restrictions: data sharing will be in line with GCP and ethics approvals |
| IPD sharing plan | The datasets generated during and/or analysed during the current stud will be available upon request from Dr Aemun Salam (aemun.salam@qmul.ac.uk) |
Editorial Notes
18/06/2025: The following changes were made to the trial record:
1. The recruitment end date was changed from 01/06/2025 to 01/05/2026.
2. The overall end date was changed from 15/06/2025 to 01/06/2026.
3. The plain English summary was updated to reflect these changes.
19/07/2023: Study's existence confirmed by the London - South East Research Ethics Committee.
