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Staphylococcus Aureus in Atopic Dermatitis Immunopathology (STADE)

Primary Purpose

Atopic Dermatitis

Status

Recruiting

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

Blood sample (Day -42 to Day -28, Day 3),Skin swab sampling (Day -42 to Day -28, Day 0, Day 13) , patch test application (Day 0) , skin biopsies (Day 13)

Blood sample (Day 0 ,Day 3),Skin swab sampling (Day 0,Day 13), patch test application (Day 1), skin biopsies (Day 13)

About this trial

This is an interventional basic science trial for Atopic Dermatitis focused on measuring Atopic dermatitis, Staphyloccocus aureus, Immunopathology

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Subject over 18 years of age
Subject able to read, understand and give documented informed consent
Subject who gave written informed consent
Subject willing and able to comply with the protocol requirements for the duration of the study
Subjects with health insurance coverage according to local regulations
For woman with childbearing potential;
- Use of a highly effective method of birth control from at least 1 month prior to study enrollment until the last visit
- Negative urine pregnancy test at inclusion visit
Subject with I, II, III or IV skin phototype (according to Fitzpatrick scale)
Subject accepting patch-tests and skin biopsies Specific criteria for AD patients
Subject diagnosed with moderate-to-severe AD, defined as EASI ≥7 and DLQI ≥ 6
Subject with AD involvement of ≥ 5% of Body Surface Area (BSA)
Subject with at least one AD lesion:
- Located either on upper extremities (except hands) or lower extremities (except feet)
- With a sufficient extent to allow all the investigations
- With a lesional area score ≥ 6

Exclusion Criteria:

Pregnancy or breast-feeding women, or planning to become pregnant or breastfeed during the study
History of allergic reaction to local anesthetic product
History of wound healing disorders (e.g. hypertrophic scars, keloids)
Subject with known active infection to HBV, HCV or HIV
Subject with known blood dyscrasia
Subject having applied topical immunomodulators, non-steroidal anti-inflammatory, corticoids, antihistamines, antibiotics or disinfectants on investigational limbs within 1 week before the inclusion visit
Subject treated with cyclosporine, methotrexate oral corticosteroids, azathioprine, mycophenolate-mofetil, and/or any other systemic immunosuppressor/immunomodulator within 4 weeks before the study
Subject treated by a biologic therapy within 3 months before the study
Subject treated with ultraviolet therapy within 4 weeks before study
Subject presenting clinically significant medical disease that is uncontrolled despite treatment that is likely, in the opinion of the investigator, to impact patient's ability to participate in the study or to impact the study efficacy or safety assessments
Subject treated with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit
Subject with immunocompromised people in its close circle
Subject protect by the law (adult under guardianship, or hospitalized in a public or private institution for a reason other than study, or incarcerated)
Subject in an exclusion period from a previous study or who is participating in another clinical trial
Specific criteria for AD patients :
o Subject currently experiencing or having a history of other concomitant skin conditions that would interfere with evaluation of AD
Specific criteria for healthy control :
- Subject currently experiencing or having an history of AD or other concomitant condition that would interfere with evaluation of skin reaction induced by patch test

Sites / Locations

Centre Hospitalier Lyon SudRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Arm Label

Atopic dermatitis patients

Healthy controls

Arm Description

Bacteriological skin swab samples from AD patients will be performed at screening visit. Each sample will be cultured and isolated to be re-applied (via patchtest) to AD patient. After reading the patch test results, skin biopsies will be performed

Bacteriological skin swab samples from AD patients will be performed at screening visit. Each sample will be cultured and isolated to be applied (via patchtest) to a paired (age/sex) healthy volunteer. After reading the patch test results, skin biopsies will be performed.

Outcomes

Primary Outcome Measures

Occurrence of a clinical inflammatory skin lesion after application of patch test containing a solution of methi-sensible (methi-S) S.aureus, in AD patients or healthy volunteers.

A difference of the local AD severity will be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers) according to the lesional scoring and the patch test scoring. A logistic mixed effects model will be performed to model the occurrence of clinical inflammatory skin lesion. For each sub-population (AD patients or healthy volunteers), a linear mixed effect model will be used to model the lesional scoring.

Secondary Outcome Measures

Molecular analysis of cytokine skin expression induced by S.aureus patch test.

Results will be expressed as fold change compared to control skin from the same individual (qPCR analysis). Type 2 inflammation: interleukins (IL)-4, 5, 13, 31 Type 1 inflammation: TNF, IFNγ Type 17-22 inflammation: IL-12, IL-23, IL-17a, IL-22 Innate inflammation: TSLP, IL-25, IL-33, IL-1b, IL-1a, IL-18 Then, a significant difference of each parameter cited above will also be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers).

Type 2 specific cellular and molecular regulatory and inflammatory response in blood - OPTIONAL (only in case of additional funding/grant)

A significant difference of parameters will be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers)

Presence/identification of S. aureus-specific virulence factors inducing a sensitization (immunoblotting) - OPTIONAL (only in case of additional funding/grant)

A significant difference of parameters will be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers).

Differences in clinical skin response against S. epidermidis and mix S. aureus/S. epidermidis.

Results will be expressed as fold change compared to control skin from the same individual (qPCR analysis). Type 2 inflammation: interleukins (IL)-4, 5, 13, 31) Type 1 inflammation: TNF, IFNγ Type 17-22 inflammation: IL-12, IL-23, IL-17a, IL-22 Innate inflammation: TSLP, IL-25, IL-33, IL-1b, IL-1a, IL-18 Then, a significant difference of each parameter cited above will also be searched between S. epidermidis alone, mix S. epidermidis/S. aureus and S. aureus alone patch tests.

Molecular analysis of cytokine skin expression induced by S. epidermidis and mix S. aureus/S. epidermidis.

Full Information

NCT ID

NCT04715087

First Posted

January 14, 2021

Last Updated

April 20, 2023

Sponsor

Hospices Civils de Lyon

1. Study Identification

Unique Protocol Identification Number

NCT04715087

Brief Title

Staphylococcus Aureus in Atopic Dermatitis Immunopathology

Acronym

STADE

Official Title

Staphylococcus Aureus in Atopic Dermatitis Immunopathology

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

October 26, 2022 (Actual)

Primary Completion Date

April 26, 2024 (Anticipated)

Study Completion Date

June 26, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospices Civils de Lyon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

Atopic Dermatitis (AD) is a frequent inflammatory skin disease characterized by recurrent eczema. It associates genetic/epigenetic-induced alterations of epidermal barrier and type-2 inflammation/hypersensitivity, which may be triggered by different antigens that pass through the altered skin . Some studies have reported that environmental pathogens such as house dust mites are able to induce type-2 inflammation through particular activation of innate immunity . Multiple staphylococcal strains are commonly found on the skin of AD patients. Interestingly, recent findings suggest that S. aureus may be a key factor of AD inflammation: (i) 90% of AD patients have S. aureus skin colonization on lesional skin , (ii) AD patients with S. aureus skin colonization have more increased type-2 inflammatory markers in comparison with AD patients without SA skin colonization , (iii) skin colonization by monoclonal S. aureus strains correlate with severe flares and (iv) S. aureus is detected in both epidermis and dermis during AD flares; In this study, our hypothesis is that S. aureus induces AD flares through a type 2 T cell-mediated hypersensitivity against S. aureus, involving innate and adaptive responses. Conversely, S. epidermidis, a commensal strain, has a protective effect against S. aureus dysbiosis. To this end, we will characterize, in the skin and the blood, the immune response induced by cutaneous application of : i) S. aureus isolated from patients with moderate-to-severe AD which will mimic the cutaneous dysbiosis occurring in the natural course of AD; ii) S. aureus toxins without bacteria to evaluate the skin response against those particular proteins; iii) a laboratory strain of S. epidermidis, a common well-tolerated skin commensal bacteria; iv) a mix of S. aureus and S. epidermidis to evaluate the regulatory effect of S. epidermidis on the S. aureus-induced AD inflammation. Importantly, this characterization will be led in AD patients (with alterations of skin barrier), compared to healthy volunteers (without alterations of skin barrier), as controls.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Atopic Dermatitis

Keywords

Atopic dermatitis, Staphyloccocus aureus, Immunopathology

7. Study Design

Primary Purpose

Basic Science

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Atopic dermatitis patients

Arm Type

Other

Arm Description

Arm Title

Healthy controls

Arm Type

Other

Arm Description

Intervention Type

Other

Intervention Name(s)

Blood sample (Day -42 to Day -28, Day 3),Skin swab sampling (Day -42 to Day -28, Day 0, Day 13) , patch test application (Day 0) , skin biopsies (Day 13)

Intervention Description

A 50 mL blood sample will be collected in Lithium Heparin tubes (45 mL) and dry tube (5 mL), by venipuncture, at screening and Day 3. Bacteriological samples from AD patients will be performed by swabbing the skin at screening visit (Day -42 to Day -28). Each sample will be cultured in a RPMI/human serum AB medium and methi.R (methicillin Resistant) strains will be eliminated. Thus, only S. aureus methi.S (methicillin Sensitive) will be isolated to be re-applied (via patchtest) to AD patient. A well-characterized S. epidermidis lab strain will be also applied to AD patients. Patch tests containing S. aureus, S. epidermidis or a mix S. aureus/S. epidermidis will be applied on healed or improved area as defined by a lesional score ≤ 1 or a 2-point change from the baseline lesional score. Patch tests will be applied 48h and reading of the patch tests results and biopsies will be performed 72h after patch test application.

Intervention Type

Other

Intervention Name(s)

Blood sample (Day 0 ,Day 3),Skin swab sampling (Day 0,Day 13), patch test application (Day 1), skin biopsies (Day 13)

Intervention Description

A 50 mL blood sample will be collected in Lithium Heparin tubes (45 mL) and dry tube (5 mL), by venipuncture, at Day 0 and Day 3. Each bacteriological sample from AD patients performed by swabbing the skin at screening visit will be cultured in a RPMI/human serum AB medium and methi.R (methicillin Resistant) strains will be eliminated. Thus, only S. aureus methi.S (methicillin Sensitive) will be isolated to be applied (via patchtest) to a paired (age/sex) healthy volunteer. A well-characterized S. epidermidis lab strain will be also applied to healthy volunteers. Patch tests containing S. aureus, S. epidermidis or a mix S. aureus/S. epidermidis will be applied on healthy skin. Patch tests will be applied 48h and reading of the patch tests results and biopsies will be performed 72h after patch test application

Primary Outcome Measure Information:

Title

Occurrence of a clinical inflammatory skin lesion after application of patch test containing a solution of methi-sensible (methi-S) S.aureus, in AD patients or healthy volunteers.

Description

Time Frame

Day 3

Secondary Outcome Measure Information:

Title

Molecular analysis of cytokine skin expression induced by S.aureus patch test.

Description

Time Frame

Day 3

Title

Type 2 specific cellular and molecular regulatory and inflammatory response in blood - OPTIONAL (only in case of additional funding/grant)

Description

A significant difference of parameters will be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers)

Time Frame

Day 3

Title

Presence/identification of S. aureus-specific virulence factors inducing a sensitization (immunoblotting) - OPTIONAL (only in case of additional funding/grant)

Description

A significant difference of parameters will be searched between baseline and after S. aureus patch test application (in AD patients and healthy volunteers).

Time Frame

Day 3

Title

Differences in clinical skin response against S. epidermidis and mix S. aureus/S. epidermidis.

Description

Time Frame

Day 3

Title

Molecular analysis of cytokine skin expression induced by S. epidermidis and mix S. aureus/S. epidermidis.

Description

Time Frame

Day 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Subject over 18 years of age Subject able to read, understand and give documented informed consent Subject who gave written informed consent Subject willing and able to comply with the protocol requirements for the duration of the study Subjects with health insurance coverage according to local regulations For woman with childbearing potential; Use of a highly effective method of birth control from at least 1 month prior to study enrollment until the last visit Negative urine pregnancy test at inclusion visit Subject with I, II, III or IV skin phototype (according to Fitzpatrick scale) Subject accepting patch-tests and skin biopsies Specific criteria for AD patients Subject diagnosed with moderate-to-severe AD, defined as EASI ≥7 and DLQI ≥ 6 Subject with AD involvement of ≥ 5% of Body Surface Area (BSA) Subject with at least one AD lesion: Located either on upper extremities (except hands) or lower extremities (except feet) With a sufficient extent to allow all the investigations With a lesional area score ≥ 6 Exclusion Criteria: Pregnancy or breast-feeding women, or planning to become pregnant or breastfeed during the study History of allergic reaction to local anesthetic product History of wound healing disorders (e.g. hypertrophic scars, keloids) Subject with known active infection to HBV, HCV or HIV Subject with known blood dyscrasia Subject having applied topical immunomodulators, non-steroidal anti-inflammatory, corticoids, antihistamines, antibiotics or disinfectants on investigational limbs within 1 week before the inclusion visit Subject treated with cyclosporine, methotrexate oral corticosteroids, azathioprine, mycophenolate-mofetil, and/or any other systemic immunosuppressor/immunomodulator within 4 weeks before the study Subject treated by a biologic therapy within 3 months before the study Subject treated with ultraviolet therapy within 4 weeks before study Subject presenting clinically significant medical disease that is uncontrolled despite treatment that is likely, in the opinion of the investigator, to impact patient's ability to participate in the study or to impact the study efficacy or safety assessments Subject treated with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the baseline visit Subject with immunocompromised people in its close circle Subject protect by the law (adult under guardianship, or hospitalized in a public or private institution for a reason other than study, or incarcerated) Subject in an exclusion period from a previous study or who is participating in another clinical trial Specific criteria for AD patients : o Subject currently experiencing or having a history of other concomitant skin conditions that would interfere with evaluation of AD Specific criteria for healthy control : Subject currently experiencing or having an history of AD or other concomitant condition that would interfere with evaluation of skin reaction induced by patch test

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Audrey NOSBAUM, MD, PhD

Phone

04 78 86 12 85

Ext

+33

audrey.nosbaum@chu-lyon.fr

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Audrey NOSBAUM, MD, PhD

Organizational Affiliation

Allergy and Clinical Immunology Department - Centre Hospitalier Lyon Sud

Official's Role

Principal Investigator

Facility Information:

Facility Name

Centre Hospitalier Lyon Sud

City

Pierre-Bénite

ZIP/Postal Code

69495

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Audrey NOSBAUM, M.D, Ph.D

Phone

04 78 86 12 85

Ext

+33

audrey.nosbaum@chu-lyon.fr

First Name & Middle Initial & Last Name & Degree

Jean-François NICOLAS, M.D, Ph.D

First Name & Middle Initial & Last Name & Degree

Florence HACARD, M.D

First Name & Middle Initial & Last Name & Degree

Coline JAULENT, M.D

First Name & Middle Initial & Last Name & Degree

Emmanuelle BESSON, M.D

12. IPD Sharing Statement

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Staphylococcus Aureus in Atopic Dermatitis Immunopathology

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