Dupilumab Impact on Skin Resident Memory T Cells

NCT03983460 | Unknown

• 1 other identifier: 18082A0002
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The main objective of the study consists in characterizing the immune cells that are present/persist in the skin and the blood of atopic dermatitis (AD) patients treated with Dupilumab, as well as with potent/very potent topical corticosteroids (TCS: betamethasone valerate cream 0.1% or clobetasol propionate cream 0.05%). A specific attention will be paid on the presence/persistence of skin Trm and ILCs. The study population will consist of 20 adult patients suffering from moderate to severe Atopic Dermatitis and eligible for Dupilumab treatment. (Patients should have inadequate response, intolerance or contraindication to systemic anti-inflammatory treatments). This is an exploratory, prospective, single-site, randomized, open labeled study. There is a treatment period of 168 days (24 weeks) and a post-treatment follow-up period of maximum 102 days.

Conditions

Atopic Dermatitis

Outcome Measures

Primary Outcomes (1)

• To assess the change of the number (per biopsy or per mL of blood) and/or frequency (among live hematopoietic cells CD45+) of immune cells that are present in the skin and the blood of AD patients after Dupilumab or TCS treatment.

  In this exploratory study, comprehensive immunophenotyping investigations will be conducted on the immune cells extracted from blood, and from the lesional, healed and non lesional skin biopsies of each patient. Capitalizing on the use of mass cytometry technology, which allows comprehensive analysis of 35-40 different markers on the same cell, we will establish a precise mapping of immune cells that circulate or infiltrate/persist the different lesions. A specific focus will determine the frequency/number of Trms and ILCs inside the skin, notably type-2 Trms (such as IL-4/IL-13 producing TH2) and ILC2.

  At Day 0, Day 28 and Day 168.

Secondary Outcomes (3)

• To investigate correlations between each immunological parameter and each clinical score as a continuous quantitative variable, as well as each immunological parameter and quality of life index as a continuous quantitative variable.

  At Day 0, Day 28 and Day 168

• To investigate correlations between each immunological parameter and change in clinical score as a qualitative variable with 2 modalities as well as each immunological parameter and quality of life index, as a qualitative variable with 2 modalities.

  At Day 28 and Day 168.

• To investigate correlations between each immunological parameter and the development of new AD lesions in the 3 following months, as well as each immunological parameter and the interval of time between the end of treatment and AD relapse.

  At Day 0, Day 28,Day 168 and during the 3 months follow-up period.

Study Arms (2)

Dupimulab arm

EXPERIMENTAL

At Day 0, patients will receive Dupilumab treatment. The recommended dose of Dupilumab for adult patients is an initial dose of 600mg followed by 300mg given every two weeks administered as subcutaneous injection. Dupilumab could be self-administered by subcutaneous injection into thigh or abdomen or injected in the upper arm in case of administration by the patient's caregiver. It is recommended to rotate the injection site with each injection. At the end of treatment period, patient with AD IGA \>1 will stop the study and patient with AD IGA≤1 will enter in a 3 months-follow-up period. During this period, they will stop treatment initiated at Day 0 and apply rescue TCS if appearance of AD lesion within 3 months. Patients will note in their diary the applications of rescue TCS. The relapse is defined as the necessity to apply TCS rescues.

Drug: Dupilumab; Procedure: Biopsies; Procedure: Skin prick-test; Procedure: Blood sample collection

Optimized TCS treatment arm

ACTIVE COMPARATOR

At Day 0, patients will receive topical corticosteroid treatment (TCS) adapted to the AD severity (potent and very potent TCS) with a personal therapeutic education for treatment optimization. It will be asked to perform, every day, an application of topical corticosteroid (TCS) (betamethasone valerate cream 0.1%, and if not active, clobetasol propionate cream 0.05%) on active lesions. Once the AD lesion is cleared, the patients will continue to apply TCS on healed lesions, twice a week until the end of the treatment period to prevent relapse. At the end of treatment period, patient with AD IGA \>1 will stop the study and patient with AD IGA≤1 will enter in a 3 months-follow-up period. During this period, they will stop treatment initiated at Day 0 and apply rescue TCS if appearance of AD lesion within 3 months. Patients will note in their diary the applications of rescue TCS. The relapse is defined as the necessity to apply TCS rescues.

Drug: Optimized TCS treatment; Procedure: Biopsies; Procedure: Skin prick-test; Procedure: Blood sample collection

Interventions

Dupilumab DRUG

Each single used prefilled syringe contains 300 mg of Dupilumab in 2 mL solution (150mg/mL) Dupilumab is a fully human monoclonal antibody against interleukin (IL)-4 receptor alpha that inhibits IL-4/IL-13 signaling, produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

Dupimulab arm

Optimized TCS treatment DRUG

Application of betamethasone valerate 0.1% (Betneval 0.1% cream), a potent topical corticosteroid, and if not active, application of clobetasol propionate 0.05% (Dermoval 0.05% cream), a very potent topical corticosteroid. TCS treatment will be associated with a personal therapeutic education for treatment optimization.

Also known as: Betamethasone valerate 0.1% and Clobetasol propionate 0.05%

Optimized TCS treatment arm

Biopsies PROCEDURE

Four skin biopsies (5 mm diameter) and ten microbiopsies (2 \& 3 mm diameter) will be performed according the following schedule: * Day 0 * a 5 mm section biopsy from a non-lesional skin * a 5 mm section biopsy from an active lesion * a 3 mm section microbiopsies from a non-lesional skin * a 3 mm section microbiopsies from an active lesion * a 2 mm section microbiopsies from a non-lesional skin * a 2 mm section microbiopsies from an active lesion * Day 28 * a 5 mm section biopsy on improved/healed lesion * a 3 mm section microbiopsies on improved/healed lesion * a 2 mm section microbiopsies from non lesional skin identified at V1 * a 2 mm section microbiopsies on improved/healed lesion * Day 168 * a 5 mm section biopsy on improved/healed lesion * a 3 mm section microbiopsies on improved/healed lesion * a 2 mm section microbiopsies from non-lesional skin identified at V1 * a 2 mm section microbiopsies on improved/healed lesion

Dupimulab arm; Optimized TCS treatment arm

Skin prick-test PROCEDURE

Skin prick test is a method for medical diagnosis of allergy consisting in introducing a small amount of an allergen into the patient's skin. The allergen penetrates the epidermis by pricking the skin with a pin. Skin Prick test for Derp and Derf will be performed at Day 0, preferentially on the forearms, avoiding lesional areas. For the results interpretation, the two allergen Derp/Derf will be compared to 2 controls: * Negative control : saline solution * Positive control : histamine solution Positive criteria of prick tests results are: * Positive control's diameter ≥ 3mm * And negative control's diameter \< 3 mm * And tested allergen with wheal ≥ positive control, i.e. 3mm

Dupimulab arm; Optimized TCS treatment arm

Blood sample collection PROCEDURE

A 50ml blood sample will be collected by venipuncture at Day 0, Day 28 and Day 168. More specifically a 40 ml blood sample will be drawn on heparinized tubes for immunophenotyping and a 10 mL on serum blood collection tube for analysis of AD biomarkers by mass cytometry and ELISA.

Dupimulab arm; Optimized TCS treatment arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject over 18 years of age
• Subject able to read, understand and give documented informed consent
• Subject willing and able to comply with the protocol requirements for the duration of the study
• Subject 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
• Subject diagnosed with moderate-to-severe AD, defined as SCORAD≥20 and/or EASI≥7 (Eichenfield et al., 2014)
• Subject with AD involvement of 10% (or more) Body Surface Area (BSA) according to component A of SCORAD
• Subject with I, II, III or IV skin phototype (according to Fitzpatrick scale)
• Subject accepting skin prick-tests and skin biopsies
• Subject having a least one non lesional area on the body (off head and neck, feet and hands)
• Subject eligible for systemic treatment
• Failure, intolerance or contraindication to available systemic treatments (i.e. cyclosporine/methotrexate)

You may not qualify if:

• Pregnancy or breast-feeding women, or planning to become pregnant or breastfeed during the study
• Women unwilling to use adequate birth control, if of reproductive potential and sexually active.
• Subject currently experiencing or having a history of other concomitant skin conditions that would interfere with evaluation of AD
• 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 helminth infection
• Subject with known blood dyscrasia
• Subject having an allergen immunotherapy within 3 months before study
• Subject treated by antihistamine 5 days before study. Please note, antihistamine administered to treat allergic rhino conjunctivitis is allowed after V1.
• Subject treated with an investigational drug within 8 weeks or within 5 half-life (if known), whichever is longer, before the baseline 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 5 half-life before the study
• Subject treated with ultraviolet therapy within 4 weeks before study
• Subject treated with a live (attenuated) vaccine within 12 weeks before baseline visit

Sponsors & Collaborators

• Association pour la Recherche Clinique et Immunologique: lead

Study Sites (1)

Service d'Allergologie et Immunologie Clinique - Hôpital Lyon Sud

Pierre-Bénite, 69495, France

RECRUITING

MeSH Terms

Conditions

Dermatitis, Atopic

Interventions

dupilumab; Betamethasone Valerate; Biopsy; Patch Tests

Condition Hierarchy (Ancestors)

Skin Diseases, Genetic; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Dermatitis; Skin Diseases; Skin and Connective Tissue Diseases; Skin Diseases, Eczematous; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Betamethasone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Skin Tests; Immunologic Tests; Immunologic Techniques

Central Study Contacts

Sophie Gilibert, Ph.D.

CONTACT

+33478861859; sophie.gilibert@lyonrechercheclinique.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2019
• First Posted: June 12, 2019
• Study Start: March 9, 2020
• Primary Completion: June 1, 2021
• Study Completion: September 1, 2021
• Last Updated: March 24, 2020

Record last verified: 2020-03

Locations

FR (1)