Ignite Creation Date:
2024-05-06 @ 1:25 AM
Last Modification Date:
2024-10-26 @ 11:04 AM
Study NCT ID:
NCT01806662
Status:
COMPLETED
Last Update Posted:
2018-03-14
First Post:
2013-02-28
Brief Title:
Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
Sponsor:
Rockefeller University
Organization:
Rockefeller University
Study Overview
Official Title:
Randomized Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis Who Have Sub-optimal Response to Prior Therapy
Status:
COMPLETED
Status Verified Date:
2018-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 extensorfacial 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
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
Detailed Description:
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 growthdifferentiation 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 Th1Th2 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 T22IL22 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-22T22 axis in this disease
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 growthdifferentiation 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 Th1Th2 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 T22IL22 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-22T22 axis in this disease
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None