Response of Children With Atopic Dermatitis (Eczema) to Eucrisa
Condition: Atopic Dermatitis; Eczema
MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to develop biomarkers to predict what medication is best for
      each child with atopic dermatitis (eczema). Participants will come in to Lurie Children's
      Allergy of Dermatology clinic for a skin examination and complete surveys. They will apply
      Eucrisa medication to their skin for 28 days before returning for a second and final skin
      examination and complete surveys. During these skin exams, tape will be placed on the skin
      and removed to collect skin cell samples. Photos will also be taken of the skin where tape
      was placed. There is an optional blood draw.
    

Detailed description: 
      The overall study design is an intervention open-label non-randomized clinical trial of
      Eucrisa treatment (Eucrisa is an FDA approved drug for this indication and in this age group)
      twice daily for 28 days in 5-17 year old children. This study intends to enroll 30 total
      participants. The main purpose of this study is to develop biomarkers to predict
      responsiveness to Eucrisa. The hypothesis that PDE4A is a strong driver of inflammation in
      atopic dermatitis (AD) patients with high PDE4A skin expression, and that they will be highly
      responsive to Eucrisa.

      Based on a previously published study to use minimally invasive tape strip biomarkers to
      differentiate patient groups, a 30-fold difference was noted when comparing PDE4A expression
      levels between TH2 high and TH2 low patients (total n=30). The investigators anticipate that
      ~50% of patients will be responders per the primary outcome of improvement in clinician
      assessed disease severity (Investigator Global Assessment of Investigator's Static Global
      Assessment (ISGA)) defined as clear (0) or almost clear (1) with a 2-grade or more
      improvement from baseline. With a total sample size of 30, the investigators estimate ~15
      will be responders and ~15 non-responders, with alpha=0.05, power=0.8, assuming standard
      deviation of log(2) to log(5) in mRNA expression difference. This would give power to see a
      difference in fold expression in the range of 1.9-4.1, and adequate power to see expected
      differences in the chosen biomarkers. Assuming 80% power, the investigators are also powered
      for secondary analyses to see correlations with biomarkers and secondary outcomes, with a
      correlation coefficient ≥ 0.5.

      The investigators will recruit directly from the various clinics of Ann & Robert H. Lurie
      Children's Hospital (LC). Patients will be contacted for screening over the phone 2 weeks
      prior to their clinic visit and recruited in clinic for study participation.

      If participants give permission over the phone, study staff will meet them when they come in
      for their Allergy or Dermatology clinic visit. On Days 1 (baseline visit) and 28 (final
      visit), the following procedures will be done. Their skin will be examined by a clinician,
      and transepidermal water loss (TEWL) will be measured using the non-invasive AquaFlux
      instrument. Skin samples will be taken from the participant's antecubital fossa and
      photographs will be taken only of the collection site via the tape stripping protocol. The
      samples will be stored without identifiers, only with the participant's study identification
      (ID) number. Photos will be stored on a password-protected computer, accessible only by study
      staff, without any identifiers and will be coded with study ID. Participants and their
      caregivers will also be asked to fill out questionnaires, including Patient-Reported Outcomes
      Measurement Information System (PROMIS) itch forms, PROMIS sleep items, and PROMIS Profile
      25. The child will additionally complete a Patient-Oriented Eczema Measure (POEM) and a
      Children's Dermatology Life Quality Index (CDLQI). Parent and child will also complete daily
      diary entries regarding the child's Eucrisa application and will include a 10-point pruritus
      scale. All of these forms will be administered electronically, and the collected data will be
      maintained in a secure REDCap database. The electronic forms are set up such that
      participants must answer every item to complete the study. If they do not feel comfortable
      answering certain items, they may choose to discontinue involvement in the study without
      consequence. If, at the baseline visit only, the participant is already having blood drawn
      for another clinical indication, blood will additionally be drawn with their consent for
      study purposes (15 mL) for later RNA sequencing. Plasma and peripheral blood mononuclear
      cells (PBMCs) drawn at the initial visit in this subset of patients, will be frozen and
      stored (de-identified, in a locked freezer) at -80°C for later processing and correlation
      with tape strip biomarkers. The correct method of therapy application will be reviewed with
      the patient and/or caregiver. They will be advised to discontinue Eucrisa and seek medical
      attention immediately if signs or symptoms of hypersensitivity occur and to contact the study
      doctor. The research team will submit incident reports regarding adverse events to the Lurie
      Children's Institutional Review Board (IRB) via their Cayuse system. Subject ID numbers will
      be maintained separately from the data set. Source documents and case report forms are kept
      in a secured area (in a locked cabinet in a locked room) in the Department of Allergy &
      Immunology at Lurie Children's, and all electronic data is password-protected and will not be
      transmitted outside the Lurie server.

      After isolating expression of putative biomarkers, specifically PDE4A. Primary analysis will
      compare baseline mean expression levels of PDE4A in "responder" versus "non-responder"
      groups. This will be defined by the primary clinical outcome of disease severity improvement
      by clinician assessment. The investigators anticipate data with a normal distribution, so a
      t-test will compare significance of average expression levels. If data is not normally
      distributed, comparisons will be made using the Mann-Whitney U test. Secondary analyses will
      look at mean differences between other biomarkers (TH2 (IL13, IL4R, CCL26), TH17/22 (IL36G),
      itch (ENKUR), and epidermal genes (FLG, LOR and S100A9) in the "responder" versus
      "non-responder" groups. In exploratory analyses, the investigators will evaluate whether
      these biomarkers changed while on Eucrisa at the 4 week follow up. Specifically, a paired
      samples t-test will be used (or Wilcoxon signed-rank test if data not normally distributed).
      Magnitude of change in biomarkers will also be descriptively compared to magnitude of
      clinical improvement in disease, similar to previously published methods.

      To correlate quality of life measures at baseline with PDE4A expression levels, initially
      data will be graphed to visually inspect the distribution and association, with PDE4A
      expression on the X-axis and quality of life measures on the Y-axis. Pearson correlation
      coefficient will be used to evaluate the strength of the association, if non-normally
      distributed data, a Spearman correlation coefficient will be used to test associations. In
      exploratory analyses, the investigators will look at the relationship of these genes after
      treatment with PDE4A. Further analyses will be conducted to determine if patients will be
      categorized as responders or non-responders on all measures tested using clinically important
      differences in the tested measures. The investigators will compare responses to quality of
      life measures using descriptive statistics. Additionally, the investigators will also
      consider average PDE4A levels in responders versus non-responders using these assessment
      measures.

      The investigators will also attempt to develop a logistic regression model to predict Eucrisa
      responders. Specifically, the investigators will look at the association between each
      biomarker and the outcome of interest. If significant, the investigators will include in the
      final model to determine the key biomarkers predicting Eucrisa responders.

      The Lurie Children's IRB and will ensure that the research complies with all applicable
      policies and regulations through their Post-Approval Monitoring program. Their staff will
      review study documents, schedule and perform site visits with the investigators, and follow
      up with the research team on any findings to take the appropriate actions, if any.
    

Intervention name(s): Crisaborole
Intervention type(s): Drug
Intervention description(s): Crisaborole 2% topical ointment applied twice daily to affected area(s) for 28 days
Other intervention name(s): Eucrisa
Intervention model: Single Group Assignment
Intervention model description: children diagnosed with AD and aged 4 months-17 years old will receive intervention
Masking: None (Open Label)
Primary purpose: Other
Keywords: dermatologic agents; surveys; questionnaires; topical therapy