Investigation of the Distinct Mechanisms Involved in Inflammatory Resolution Between Healthy Men and Women

Inflammation Clinical Trial

— RESOLVE-SEX  

Official title:

Investigation of the Distinct Mechanisms Involved in Inflammatory Resolution Between Healthy Men and Women: RESOLVE-SEX

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05597098
• Other study ID #: 22/YH/0244
• Status: Active, not recruiting
• Phase: Early Phase 1
• Start date: December 12, 2022
• Est. completion date: October 16, 2025

Study information

• Verified date: November 2023
• Source: Queen Mary University of London
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Important differences exist between sexes in incidence, disease patterns and outcomes in coronary artery disease that is not well understood. It is likely that key differences in the underlying biological mechanism, in particular in inflammatory responses, play a part in underpinning these differences. Previous evidence demonstrates that healthy females appear to be more adept at resolving inflammation compared to healthy males. Since inflammation is thought to be a key initiating phenomenon in coronary artery disease the investigators will examine the differences in inflammatory resolution between the sexes in healthy volunteers.

Description:

Inflammation is a key process in triggering events caused by coronary artery disease. Indeed, large scale trials have tested the efficacy of a range of anti-inflammatory approaches. However, whilst some of these confirmed the utility of such approaches in leading to reductions in coronary artery disease; the benefits came at a cost with an increased risk of infection. In their previous work the investigators discovered that, women demonstrate enhanced resolution of inflammation compared to males. This accelerated resolution coincided with improved blood vessel function and health. It is also now accepted that a failure of resolution plays an important part in the enhanced inflammation seen in coronary artery disease. Whether the differences in the incidence of coronary artery disease between men and women might be related to differences in their capacity to mount a resolution response is unknown.

To determine whether inflammatory resolution differs between sexes the investigators will use the validated cantharidin-induced model of acute inflammation in healthy volunteers. Previous published studies have shown when cantharidin is applied to the skin it causes acantholysis and blister formation. It is a safe, reproducible technique with no permanent scarring or ill-effects. The investigators will study the effects on inflammatory responses by measuring the levels of cells, inflammatory mediators and markers of vascular function in blister fluid, urine, saliva and blood. Cantharidin application will be applied to separate areas of the skin over the course of three days to create three small blisters in order to examine different timepoints of the inflammatory process. The blister fluid will then be collected on the fourth day which will be analysed according to standard laboratory techniques including flow cytometry.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 34
• Est. completion date: October 16, 2025
• Est. primary completion date: October 16, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

Inclusion Criteria:

1. Healthy male and female volunteers

2. Aged 18-45

3. Volunteers who are willing to sign the consent form

Exclusion Criteria:

1. Healthy subjects unwilling to consent

2. Pregnant, or any possibility that a subject may be pregnant unless in the latter case a pregnancy test is performed with a negative result

3. Current breast feeding

4. History of any serious illnesses, including recent infections or trauma

5. Subjects taking systemic medication (other than the oral contraceptive pill)

6. Subjects with recent (2 weeks) or current antibiotic use

7. Subjects with any history of a blood-borne infectious disease such as Hepatitis B or C virus, or HIV

Related Conditions & MeSH terms

• Inflammation

Intervention

Drug:
• Cantharidin
0.1% cantharidin solution in acetone from 0.7% stock solution of cantharone is prepared and applied immediately. 10 µl of cantharidin per disc.

Locations

Country	Name	City	State
United Kingdom	The William Harvey Research Institute	London

Sponsors (1)

Lead Sponsor	Collaborator
Queen Mary University of London

Country where clinical trial is conducted

United Kingdom, 

References & Publications (5)

Docherty JR, Stanford SC, Panattieri RA, Alexander SPH, Cirino G, George CH, Hoyer D, Izzo AA, Ji Y, Lilley E, Sobey CG, Stanley P, Stefanska B, Stephens G, Teixeira M, Ahluwalia A. Sex: A change in our guidelines to authors to ensure that this is no longer an ignored experimental variable. Br J Pharmacol. 2019 Nov;176(21):4081-4086. doi: 10.1111/bph.14761. Epub 2019 Aug 23. No abstract available. Erratum In: Br J Pharmacol. 2021 Apr;178(7):1737. — View Citation

Kapil V, Rathod KS, Khambata RS, Bahra M, Velmurugan S, Purba A, S Watson D, Barnes MR, Wade WG, Ahluwalia A. Sex differences in the nitrate-nitrite-NO* pathway: Role of oral nitrate-reducing bacteria. Free Radic Biol Med. 2018 Oct;126:113-121. doi: 10.10 — View Citation

Rathod KS, Jones DA, Jain AK, Lim P, MacCarthy PA, Rakhit R, Lockie T, Kalra S, Dalby MC, Malik IS, Whitbread M, Firoozi S, Bogle R, Redwood S, Cooper J, Gupta A, Lansky A, Wragg A, Mathur A, Ahluwalia A. The influence of biological age and sex on long-te — View Citation

Rathod KS, Kapil V, Velmurugan S, Khambata RS, Siddique U, Khan S, Van Eijl S, Gee LC, Bansal J, Pitrola K, Shaw C, D'Acquisto F, Colas RA, Marelli-Berg F, Dalli J, Ahluwalia A. Accelerated resolution of inflammation underlies sex differences in inflammat — View Citation

Shabbir A, Rathod KS, Khambata RS, Ahluwalia A. Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease. Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:333-359. doi: 10.1146/annurev-pharmtox-010919-023229. Epub 2020 Oct 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison of the presence or not of blister at each timepoint over 24-72h between the sexes	Visual inspection as to the presence of an intact blister of 24hr, 48 hr and 72 hr cantharidin blisters	24 hours, 48 hours, 72 hours
Primary	Comparison of blister volume at each timepoint over 24-72h between the sexes	Blister fluid sampled and weighed to determine volume	24 hours, 48 hours, 72 hours
Primary	Comparison of blister cell number at each timepoint over 24-72 hours between the sexes	Blister fluid collected from 24 hour, 48 hour and 72 hour cantharidin blisters. Fluid will be analysed using standard laboratory techniques including labelled flow cytometry	24 hours, 48 hours, 72 hours
Secondary	Comparison of blister leukocyte subsets (neutrophil and monocyte) between the sexes at each timepoint	Blister fluid collected from 24 hour, 48 hour and 72 hour cantharidin blisters. Fluid will be analysed using standard laboratory techniques including labelled flow cytometry	24 hours, 48 hours, 72 hours
Secondary	Comparison of blister lactate levels and LDH between the sexes at each timepoint	Blister fluid collected from 24 hour, 48 hour and 72 hour cantharidin blisters. Analysis as per standard laboratory techniques.	24 hours, 48 hours, 72 hours
Secondary	Comparison of cell death, necrotic, and apoptotic cell numbers between the sexes at each timepoint	Blister fluid collected from 24 hour, 48 hour and 72 hour cantharidin blisters. Fluid will be analysed using standard laboratory techniques including labelled flow cytometry	24 hours, 48 hours, 72 hours
Secondary	4. Comparison of markers of blister efferocytosis between the sexes at each timepoint	Blister fluid collected from 24 hour, 48 hour and 72 hour cantharidin blisters. Fluid will be analysed using standard laboratory techniques including labelled flow cytometry	24 hours, 48 hours, 72 hours