Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
Condition: Atopic Dermatitis
MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema
Intervention: Ustekinumab; Placebo
Intervention description: Injection of monoclonal antibody against the p40 subunit of IL-12/23; Injection of placebo
Intervention MeSH terms: Ustekinumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Atopic Dermatitis; Eczema

Summary:

      Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects
      most aspects of everyday life in the majority of patients. Acute inflammation and
      extensor/facial involvement is common in infants, whereas chronic inflammation increases in
      prevalence with age, as do localization to flexures. AD has a complex background
      characterized by immune activation, increased epidermal thickness in chronic diseased skin,
      and defective barrier function. In normal, healthy skin, the outer layer of the epidermis,
      the stratum corneum is made up flattened dead cells called corneocytes held together by a
      mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are
      vital in providing a natural barrier function that locks water inside the skin and keeps
      allergens and irritants out. In people with AD, the barrier function is defective, which
      leads to dry skin. As the skin dries out, it cracks allowing allergens and irritants to
      penetrate.

      Mild AD can be controlled with emollients and topical medications. However, moderate to
      severe AD is extremely difficult to control and requires systemic treatment that is often
      unsatisfactory due to impracticality and lack of effectiveness. Only three therapeutic
      options exist for moderate to severe AD, including: 1) oral steroids 2) cyclosporine A (CsA),
      that is not widely used in the US as it is not FDA approved for AD and 3) ultraviolet
      phototherapy. Oral steroids and CsA treatments have major side effects and UV radiation
      therapy is highly inconvenient for patients. Several biologic medications, such as TNF-alpha
      inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have
      thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may
      specifically target AD.

      The investigators study will determine whether there is a reversal of the skin thickness and
      the immune pathways involved in the disease during treatment with Ustekinumab and what
      specific immune cells are involved. The investigators are also interested to understand how
      the clinical reversal of the disease will correlate with tissue reversal of the disease.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Are male or female and ages 18-75.

          -  Have moderate to severe AD (as determined using the Objective SCORAD scale ≥15) and a
             history of therapeutic failure with at least two of the three different treatment
             categories as listed within the inclusion criteria.

          -  Patients must have tried and failed at least two of the three treatment categories of
             the following treatment modalities:

        Category 1 : Hydration plus topical steroids and/or antibiotics Category 2: Systemic
        Steroids and/or Phototherapy Category 3: Cyclosporine and/or Other Immunomodulators
        (Methotrexate, CellCept, Immuran, topical Calcineurin inhibitors)

          -  Patients who initially respond to cyclosporine but cannot sustain a response after the
             drug is discontinued will also be eligible.

          -  Patients that have contraindications to category 3 drugs will also be allowed to
             participate in the study.

          -  A washout period prior to screening will be required for the following medications:

          -  Cyclosporine/Oral Steroids/Imuran/Mycophenolate Mofetil/Other systemic
             immunosuppressants: 4 weeks

          -  Phototherapy/Moderate to High Potency Topical Corticosteroids: 2 weeks

          -  Women of childbearing potential must test negative for pregnancy and be using adequate
             birth control measures (e.g., Abstinence, oral contraceptives, intrauterine device,
             barrier method with spermicide, or have had a tubal ligation or a hysterectomy) during
             the study and for 6 months after receiving the last treatment. Likewise, men capable
             of fathering children must also use appropriate methods of birth control (e.g.,
             abstinence, barrier methods with spermicide, or have had surgical sterilization such
             as vasectomy).

          -  Patients must be in general good health in the opinion of the investigator.

          -  Patients with stable chronic asthma, treated with inhaled corticosteroids, will be
             eligible.

          -  The screening laboratory tests must meet the following criteria:

        Hemoglobin >9 g/dl WBC count >3.5 x 109 cells/L Neutrophils >1.5 x 109 cells/L Platelets
        >100 x 109 cells/L AST/SGOT and ALT/SGPT levels must be within 2 times the upper limit of
        normal for the laboratory conducting the test. Alkaline phosphatase levels must be within 2
        times the upper limit of normal for the laboratory conducting the test.

          -  Are PPD negative at the time of screening.

          -  The patients will be allowed to use topical therapy during the washout period. These
             will include emollients, and mild steroids (class 6 or 7), except on one target area
             that will be the site for the skin biopsies.

        Exclusion Criteria:

          -  Previous treatment with ustekinumab or other agent that specifically targets IL-12 or
             23

          -  Have a history of latent or active granulomatous infection, including TB,
             histoplasmosis, or coccidioidomycosis, prior to screening, or are frequently in
             contact with individuals who carry active TB infection or a non-tubercular
             mycobacterial infection or an opportunistic infection

          -  Are HIV positive by history or POCT on the screening visit

          -  Have documented current active hepatitis B (surface antigen positive or asymptomatic
             chronic carriers) or hepatitis C infection (anti-HCV positive), by history and/or
             screening test

          -  Have a history of substance abuse (drug or alcohol) within the past year before
             screening

          -  Have any serious concomitant illness that could require the use of systemic
             corticosteroids or otherwise interfere with the patient's participation in the trial

          -  Pregnant women or women that are breast-feeding or plan to breast feed. Women of
             childbearing age who plan to get pregnant within 15 weeks of stopping study agent