Longitudinal Endotyping Of Atopic Dermatitis Through Transcriptomic Skin Analysis

Study Overview
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Brief Summary
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This is a multi-center, longitudinal study which will characterize the gene expression profiles and transcriptomic endotypes that underlie mild and moderate-severe Atopic dermatitis (AD) and will determine changes in these expression patterns and endotypes in response to standard-of-care treatment. Participants will complete up to ten study visits with assessment of topical steroid response and dupilumab response (if uncontrolled with topical steroids). Skin samples will be collected at all study visits to determine the gene expression profiles and transcriptomic endotypes that underlie mild vs. moderate-severe AD disease. The investigators will also evaluate the lipidomic, metabolomic, proteomic, and microbiome profiles of AD skin endotypes associated with mild and moderate-severe AD disease. Non-AD participants will serve as a control population. The primary objective of this study is to determine if the type 2-high non-lesional skin (skin tape) endotype is associated with current mild versus moderate-severe AD disease.

Official Title
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Longitudinal Endotyping Of Atopic Dermatitis Through Transcriptomic Skin Analysis (ADRN-12)

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Biological: Dupilumab
* Drug: Vanicream
* Drug: Triamcinolone Acetonide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All Participants: Participant and/or parent guardian must be able to understand and provide informed consent and assent (if applicable) Participants must agree to apply a stable dose of a study provided topical moisturizer (Vanicream (TM)) at least twice daily between the Baseline Assessment and Day 7 Visits to a specified skin target area Individuals with asthma must adhere to asthma controller medication(s) for the duration of the study Females of child-bearing potential who do not self-report as pregnant must have a negative pregnancy test at the Baseline Assessment and Day 7 Visits. Females of child-bearing and sexually active must agree to use Food and Drug Administration (FDA) approved methods of birth control for the duration of the study. These include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy Participant and/or parent guardian must be able to understand and complete study-related questionnaires Non-Atopic dermatitis (AD) Participants: 1. No history of AD or food allergy as diagnosed by a physician AD Participants: A history of Chronic AD, (according to the Atopic Dermatitis Research Network [ADRN] Standard Diagnostic Criteria), that has been present for at least 1 year before the Screening Visit Must agree to refrain from applying topical steroid to a specified target area between the Baseline Assessment and Day 7 Visit Dupilumab-naïve AD participants must have active lesions on the upper or lower extremities or trunk of sufficient size (36 cm^2 area for participants >= 18 years of age, and 32 cm^ 2 for participants < 18 years of age) for specimen collection at the Baseline Assessment and at the Steroid Initiation (Day 7) Visits. The required area may be one contiguous area or may encompass multiple areas Long-term dupilumab participants must be currently receiving dupilumab and must have started dupilumab treatment >= 4 months prior to the Screening Visit Exclusion Criteria: Inability or unwillingness of a participant or parent guardian to comply with study protocol Weight less than 15 kg Known systemic hypersensitivity to any of the excipients of the study treatments (Vanicream (TM), hydrocortisone, triamcinolone, or dupilumab) Have any skin disease other than Atopic dermatitis (AD) that might compromise the stratum corneum barrier (e.g., bullous diseases, psoriasis, cutaneous T cell lymphoma [also called Mycosis Fungoides or Sezary syndrome], dermatitis herpetiformis, Hailey-Hailey, or Darier's disease) Known or suspected immunosuppression, including history of invasive opportunistic infections (e.g. tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution, or otherwise recurrent immune-compromised status, as judged by investigator Known history of human immunodeficiency virus (HIV) infection Ocular disorder that in the opinion of the investigator could adversely affect the individual's risk for study participation. Examples include, but are not limited to, individuals with a history of or active case of herpes keratitis; Sjogren's Syndrome, Keratoconjunctivitis Sicca, or Dry Eye Syndrome that require daily use of supplemental lubrication; or individuals with ocular conditions that require the regular use of ocular corticosteroids or cyclosporine Parasitic infection, except for vaginal trichomoniasis, within 12 months of the Screening Visit, or high risk for contracting parasitic infections (e.g. living in or traveling to endemic areas) History of malignancy within 5 years before the Screening Visit (completely treated in situ carcinoma of the cervix, and completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin or melanoma in situ are not exclusionary) History of non-malignant lymphoproliferative disorders History of alcohol or drug abuse within 2 years before the Screening Visit History of keloid formation (exclusionary for adult participants only) History of serious life-threatening reaction to tape or adhesives Individuals with asthma who have required use of a systemic corticosteroid within 3 months prior to the Baseline Assessment Visit or who require a dose greater than 880 mcg/day of fluticasone propionate or equivalent inhaled corticosteroid to maintain asthma control Past or current medical problems or findings from physical examination that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. This includes hypersensitivity to local anesthetics (e.g., lidocaine or Novocain), bleeding disorders, treatment with anticoagulants or other conditions in adult participants that would make the biopsy procedure inadvisable Planned major surgical procedure during study participation that could affect study participation or outcome assessment, per PI discretion Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks before the Baseline Assessment Visit, or superficial skin infection within 1 week before the Baseline Assessment Visit Pregnant or breast-feeding women, or women planning to become pregnant or breastfeed during the study Use of any systemic (oral, intravenous (IV), intramuscular (IM)) immunosuppressive/immunomodulating therapies (e.g. steroids, cyclosporine, Janus kinase inhibitors, mycophenolate, azathioprine, or methotrexate) within 4 Weeks of the Baseline Assessment Visit, or any condition that, in the opinion of the investigator, will likely require such treatment(s) during study participation Treatment with biologics (other than dupilumab) as follows: Any cell-depleting agents, including but not limited to rituximab, within 6 months before the Baseline Assessment Visit, or until lymphocyte and CD 19+ lymphocyte count returns to normal, whichever is longer Omalizumab, Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra within 16 weeks before the Baseline Assessment Visit for any indication Other biologics within 5 half-lives (if known) or 16 weeks before the Baseline Assessment Visit, whichever is longer Treatment with a live (attenuated) vaccine within 6 weeks before the Baseline Assessment Visit or planning to receive a live vaccine during the study Ongoing participation in an investigational trial or use of an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the Baseline Assessment Visit Use of phototherapy (such as narrowband ultraviolet B [NBUVB], ultraviolet B [UVB], ultraviolet A1 [UVA1], psoralen + UVA [PUVA]) or a tanning booth/parlor within 4 weeks of the Baseline Assessment Visit. Treatment with bleach bath within 1 week before the Baseline Assessment Visit Use of a chlorinated hot tub within 1 week before the Baseline Assessment Visit Initiation of treatment with prescription moisturizers or moisturizers containing ceramide, hyaluronic acid, urea, or filaggrin (FLG) during the study period (participants may continue using stable doses of such moisturizers on body areas other than the target area if initiated before the Baseline Assessment Visit) Planned or anticipated use of any prohibited medications or procedures during study participation.

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab-naïve atopic dermatitis participants<br>On Day 7, dupilumab-naïve AD participants will begin applying triamcinolone 0.1% ointment (provided by the study) twice daily to the specified target area. Additionally, dupilumab-naïve AD participants will apply triamcinolone 0.1% ointment (non-sensitive regions)/ hydrocortisone 2.5% ointment (sensitive regions) twice daily to active lesions on non-target skin. Dupilumab-naïve AD participants will return for a Steroid Assessment Visit at Day 35, when response to triamcinolone will be evaluated at the target site by TAA and targeted EASI scoring, and overall management of AD body-wide by topical steroid/moisturizer treatment will be evaluated by EASI score. | Biological: Dupilumab<br>* Adult dupilumab-naïve topical steroid non-responder (EASI >7) participants beginning treatment with dupilumab will initially receive a loading dose of two 300 mg subcutaneous injections. The two injections will be administered at different sites in the abdomen, thighs, or upper arms. Pediatric dupilumab-naïve topical steroid non-responder participants beginning treatment with dupilumab will receive a loading dose, according to their weight<br>* Other names: Dupixent;Drug: Triamcinolone Acetonide<br>* On Day 7, dupilumab-naïve AD participants will begin applying triamcinolone 0.1% ointment (provided by the study) twice daily to the specified target area. Additionally, dupilumab-naïve AD participants will apply triamcinolone 0.1% ointment (non-sensitive regions)/ hydrocortisone 2.5% ointment (sensitive regions) twice daily to active lesions on non-target skin<br>|
| Experimental: Experienced Dupilumab atopic dermatitis participants<br>AD participants already on dupilumab (for >= 4 months prior to study entry (20 children, 40 adults)) at the start of the study will continue dupilumab treatment as prescribed by their physician outside of the study. After Day 7, long-term dupilumab participants may continue to apply topical steroids/moisturizer body-wide as needed per their physician's orders and will return for assessments and sampling at Days 63 and 140. At Day 140, participants will discontinue applying topical steroids to the specified target area and begin to apply Vanicream™ at least twice daily on the target skin area until their End of Study Assessment visit (Day 168) | Drug: Vanicream<br>* Participants will apply Vanicream at least twice daily to the specified target skin area starting at Day 140 through the End of Study Assessment Visit<br>|
| Active Comparator: Non-atopic dermatitis participants<br>Approximately 150 will be non-AD controls (including approximately 50 children, 6-17 years of age, and 100 adults, = 18 years of age) Non-AD control participants will return for assessment visits at Days 0, 7, 35, 91, 140, and 168. Non-AD participants will apply Vanicream (TM) at least twice daily to the specified target skin area starting at Day 140 through the End of Study Assessment Visit (Day 168) | Drug: Vanicream<br>* Participants will apply Vanicream at least twice daily to the specified target skin area starting at Day 140 through the End of Study Assessment Visit<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-lesional skin tape transcriptome at Day 7 | Skin biopsies from non-lesional sites will be enzymatically digested using an adaptation of a recently developed cold active protease treatment method. A fraction of cells will be cryopreserved and will be later used for the single cell transcriptome RNAseq | At Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-lesional and lesional skin tape transcriptome at Day 7 and Days 168-224 | Skin biopsies from lesional and non-lesional sites will be enzymatically digested using an adaptation of a recently developed cold active protease treatment method. A fraction of cells will be cryopreserved and will be later used for the single cell transcriptome RNAseq | At Day 7 and Days 168-224 |