Evaluate Reversal of Pathological Epidermal Phenotype in Severe Atopic Dermatitis (AD) With Suppression of Immune Activation During Cyclosporine A Therapy

Atopic Dermatitis Clinical Trial

Official title:

A Study to Evaluate Reversal of the Pathological Epidermal Phenotype in Severe AD With Suppression of Immune Activation During Cyclosporine A Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01149759
• Other study ID #: JKR-0663
• Status: Completed
• Phase: N/A
• First received: June 22, 2010
• Last updated: June 29, 2015
• Start date: June 2010
• Est. completion date: December 2014

Study information

• Verified date: June 2015
• Source: Rockefeller University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Atopic Dermatitis (AD) or eczema is a chronic relapsing inflammatory disease that affects 1-3% of the adults and up to 25% of the children in the United States. Patients with severe AD will be studied during a 24-week study with systemic cyclosporine (Neoral, capsule form) to evaluate the immune suppression and pathological correlation of cyclosporine A in these patients in order to determine the extent to which immune activation drives the pathological epidermal phenotype.

Description:

Patients will be first screened to be sure they are healthy (aside from atopic dermatitis) with a physical exam, and lab tests. These lab tests consist of CBC, biochemical profile, hepatitis B and C profile, urine analysis, HIV, PPD, and urine pregnancy test (if applicable). Patients will return in 2 to 3 days for PPD reading. A repeat serum creatinine will be drawn at this time so as to have 2 baseline values. Patient will begin taking cyclosporine at 5 mg/kg of body weight in 2 divided daily doses for 12 weeks, and after this period the dose will be reduced by 1mg/kg per week (the tapering down will start at 12 weeks of treatment), so that cessation of treatment will occur after 16 weeks from the start of treatment. Patients will then be followed in clinic for an additional 8 weeks for a potential relapse, and if a relapse will occur topical treatment with corticosteroids, immune-modulators or phototherapy may be instituted. Patients will be seen in the outpatient clinic at baseline, wks 1,2, 4, 6, 8, 10, and 12 and every 2weeks until completion of a 24-week study. Biopsies (of lesional and non-lesional skin) will be done to assess histological response at baseline, week 2, week 6 (optional), week 12 and at relapse (optional). Bloods for safety analysis and pregnancy test (if applicable) will be done at each visit, and vital signs will be measured at that time. Serum IgE, eosinophils, and serum cytokines will be done at baseline, and every 2 weeks until week 16, and at week 24. At each visit patients will be assessed for adverse events. Clinical assessment, and ultrasound, will be done at each visit. The most widely accepted clinical assessment tool is known as SCORAD (SCORing for Atopic Dermatitis). This tool combines clinical features of AD such as erythema, dryness, lichenification, percent body surface area, as well as quality of life issues such as pruritus and loss of sleep due to disease. Another assessment tool we will be using is the static IGA (investigator global assessment). The IGA represents an overall evaluation of dermatitis performed by the investigator at every visit. IGA scores utilize a 6-point scale, ranging from 0 (clear) to 5 (very severe disease). IGA scores measure disease severity based on morphology, without referring back to the baseline state. Ultrasound study provides an alternate, non-invasive method of assessing disease activity in the skin. Clinical photos will be done at weeks 0, 6, 12, 16, and 24.In this study, we would like to determine whether AD, like psoriasis, is an immune-driven disease of epidermal hyperplasia and differentiation. To establish the immune contribution to AD, we will treat patients with standard doses of CsA and measure the extent of immune suppression in skin lesions by quantitative measures of pathological leukocytes and expression of inflammatory gene products. At the end of 12 weeks of treatment we will determine whether pathological epidermal hyperplasia is reversed by quantitative and qualitative measures of epidermal hyperplasia and aberrant epidermal differentiation. In addition, we will correlate the extent to which the epidermal phenotype is modulated with the extent to which skin inflammation is suppressed, as the effect of suppression of specific inflammatory molecules on resulting keratinocyte responses is not known. The alternative hypothesis in AD is that it is not an immune-mediated disease, but instead a disease of primary epidermal differentiation due to germline alterations (gene deletions) in filaggrin and other genes that cooperate to differentiate a normal epidermal barrier at the level of stratum corneum. The alternative hypothesis is considered to be the most likely patho-mechanism in AD by a number of current researchers. The alternative hypothesis would be supported by this study if pathologic epidermal hyperplasia persists in the skin regions with significant suppression of the immune/inflammatory pathways induced by CsA treatment.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 9
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Severe AD (defined as having a mean SCORAD score> 40,, with significant disease activity, pruritus, and sleep disturbances (13), suitable for treatment with Cyclosporine, and have failed or unsuitable for other treatment modalities, including topical and or systemic steroids or phototherapy. Patients must also have an IGA score of 3 or greater,

• Males and females age 18 and above (if females are of child-bearing potential they must agree to use acceptable contraception during the study).

• No systemic treatment contraception must commence 2 weeks prior to initiating the drug.

• No systemic treatment for 4 weeks, no topical treatment or phototherapy for 2 weeks

Exclusion Criteria:

• Previously treated with cyclosporine and had unacceptable toxicity

• Past or current history of malignancy (except for treated isolated skin cancers)

• Renal, hepatic, and hematologic laboratory values greater than CTC grade 1 toxicity, such as but not limited to creatinine >1.5 ULN, SGOT>2.5 ULN. Values greater then grade 1 would most likely represent clinically significant renal, hepatic or hematologic disease

• Stage I hypertension is defined as >140/90. Patients with this blood pressure or higher on two separate occasions, whether on medications or not, will be excluded (JNC guidelines www.nhlbi.nih.gov/guidelines/hypertension )

• Significant lipid panel abnormality (any grade 1 toxicity on CTC scale)

• Lactating females

• Other medical condition that would increase the risk of cyclosporine toxicity

• Positive PPD

• Primary or secondary immune deficiency (including known HIV status)

• Possible or known pregnancy

• Serious infection (such as active hepatitis)

• Drug or alcohol abuse

• Inability or lack of willingness to co-operate with regular monitoring

• Severe photodamage/precancerous skin lesions due to previous sunlight exposure, or photo/photochemotherapy

• Concurrent use of PUVA or UVB, other radiation therapy,

• Concurrent use of other immunosuppressive agents such as MTX, Immuran, Cyclophosphamide, Cellcept, etc.(because of the possibility of excessive immunosuppression and the subsequent risk of malignancies)

• Active infections, infections or history of serious infection requiring hospitalization, antibiotics, antivirals,or antifungals within 30 days of baseline

• History of other inflammatory skin conditions (such as psoriasis, pemphigus, etc.

• Patients with background skin conditions that might be directly related to atopic dermatitis (such as post inflammatory hyperpigmentation) will not be excluded as well as common background non-inflammatory skin conditions such as seborrheic keratosis, benign pigmented lesions, acne, etc

Study Design

Endpoint Classification: Bio-equivalence Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atopic Dermatitis
• Dermatitis
• Dermatitis, Atopic
• Eczema

Intervention

Drug:
• Cyclosporine A
5 mg/kg for first 4 weeks, followed by tapering to 1 mg/kg for 12 weeks until discontinuation at 16 weeks

Locations

Country	Name	City	State
United States	The Rockefeller University	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Rockefeller University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of epidermal hyperplasia	Measurement of epidermal hyperplasia, including epidermal thickness and K16 expression of lesional AD skin at week 12 (IHC, and RT-PCR will be used to determine these determinants).	12 weeks	No
Secondary	Inhibition of Th1, Th2, Th17, and regulatory T-cell pathways	Inhibition of Th1, Th2, Th17, and regulatory T-cell pathways and different DC; populations and cytokines	12 weeks	No
Secondary	mRNA expression	mRNA expression of genes related to the various T-cell pathways modulated; during CsA therapy	12 weeks	No