Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
|ClinicalTrials.gov Identifier: NCT01806662|
Recruitment Status : Completed
First Posted : March 7, 2013
Results First Posted : December 19, 2017
Last Update Posted : December 19, 2017
|First Submitted Date ICMJE||February 28, 2013|
|First Posted Date ICMJE||March 7, 2013|
|Results First Submitted Date||August 17, 2017|
|Results First Posted Date||December 19, 2017|
|Last Update Posted Date||December 19, 2017|
|Start Date ICMJE||March 2013|
|Primary Completion Date||March 2015 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Proportion of SCORAD-50 Response at Week 16. [ Time Frame: Week 16 ]
Greater improvement from their baseline objective SCORAD (SCORing Atopic Dermatitis) at Week 16. The efficacy variable for each randomized group is the proportion of subjects who achieve an improvement of 50% or greater from their baseline objective SCORAD at Week 16 (at crossover). SCORAD-50 is the percentage of decrease in baseline SCOARD at Week 16.
SCORAD is a clinical tool used to assess the extent and severity of eczema. Calculation is based on extent of involvement (skin involvement) and subjective symptoms of itching and loss of sleep. The SCORAD scale ranges from 0 (minimum, lowest possible score, Mild severity) to 103 (maximum, highest possible score, Severe severity) [last observation carry forward].
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01806662 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis|
|Official Title ICMJE||Randomized Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis Who Have Sub-optimal Response to Prior Therapy|
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.
In psoriasis, epidermal hyperplasia is driven by underlying immune activation, whether as a direct response to IL-20 family cytokines that induces hyperplasia and inhibits keratinocyte terminal differentiation or as an indirect response to immune-mediated injury to keratinocytes. The epidermal reaction in psoriasis is largely restored to normal with selective immune suppression. Hence, one might hypothesize that similar epidermal responses should occur in the presence of "generalized" cellular immune activation, in diseases with similar inflammatory infiltrate and epidermal hyperplasia, such as AD. In fact, psoriasis and AD share features of dense T-cells and dendritic cell infiltrates, as well as over-expression of IL-22 in skin lesions. These diseases also share similar epidermal hyperplasia in their chronic phases.
Work from the investigators group showed that IL-22 is a key cytokine in the pathogenesis of both AD and psoriasis. The investigators have demonstrated that in psoriasis, ustekinumab suppresses the production of IL-12, IL-23, and IL-22. Additionally, by RT-PCR the investigators demonstrated that the mRNA expression of p40 cytokine and the IL23R is up-regulated in AD as compared to both normal skin and psoriasis. The investigators therefore hypothesize that ustekinumab will suppress IL-22 and possibly also p40 production in AD lesions and reverse both the epidermal growth/differentiation defects and the underlying immune activation, and hence will suppress disease activity. Interestingly, p40 was also found to be significantly up-regulated in non-lesional AD skin as compared with normal skin.
Although AD is thought to be predominately a disease of Th2-type cells, in the chronic stage, there is large Th1 component. To date, the precise mechanism by which sequential activation of Th2 and Th1 cells in AD is achieved remains unknown. IL-12 induces the differentiation and maturation of human Th cells into Th1-type cells. Recent circumstantial evidence suggests that in AD patients IL-12 may facilitate a change from the Th2-type to a Th1 cytokine profile. IL-12 was recently shown to be highly elevated in pediatric AD and its levels were strongly associated with disease severity.
Expression of IL-12 p40 mRNA is significantly enhanced in lesional skin from AD, suggesting that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for the increased production of IFN-γ in chronic lesions potentially suggesting that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis. Topical steroids which constitute a mainstay of therapy in AD are known to strongly down-regulate IL-12 expression, possibly also indicating that targeted anti IL-12 therapy might important role in treating AD.
Recently, the Th1/Th2 paradigm in autoimmunity and allergy has been revisited to include a role for a new population of IL-17-producing Th cells known as Th17. Th17 cells are characterized by the production of inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-26. One of the key factors involved in naive Th-cell commitment to a Th17 phenotype is IL-23.
Patients with acute AD were found to have increased Th17 T-cells in peripheral blood by flow cytometry and intracellular cytokine staining 26 as well as by immunohistochemistry (IHC) in lesions. Since IL-23 is the major inducer of Th17 T-cells, as well as "T22" T-cells, neutralization of IL-23 could potentially result in both decreased Th17 signal in acute AD as well as decreased "T22/IL22" signal. Therefore the investigators postulate that ustekinumab in AD will act both inhibiting the IL-12-dependent Th1 shift in chronic AD stage as well as the pathogenic IL-22/"T22" axis in this disease.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
|Condition ICMJE||Atopic Dermatitis|
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||March 2015|
|Primary Completion Date||March 2015 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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)
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.
|Ages||18 Years to 75 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01806662|
|Other Study ID Numbers ICMJE||JKR-0737|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Rockefeller University|
|Study Sponsor ICMJE||Rockefeller University|
|Collaborators ICMJE||Not Provided|
|PRS Account||Rockefeller University|
|Verification Date||November 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP