Study to Evaluate the Safety and Efficacy of Alefacept (Amevive) in Subjects With Moderate to Severe Atopic Dermatitis
This study will assess the safety, tolerability, and efficacy of Alefacept in patient with moderate to severe atopic dermatitis who could not be adequately controlled with topical therapies.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase IV, Open Label Study to Evaluate the Safety and Efficacy of Intramuscular (IM) Alefacept (Amevive) 15mg/wk in Subjects 18 Years and Older With Moderate to Severe Atopic Dermatitis|
- Change in Eczema Area Severity Index (EASI) Score From Baseline (Week 1) to Week 16. [ Time Frame: Week 1 to week 16 ] [ Designated as safety issue: No ]The Eczema Area Severity Index (EASI) measures erythema (E), infiltration (I), excoriation (Ex) and lichenification (L) using 0=none, 1=mild, 2=moderate, 3=severe. Head/neck, upper limbs, trunk, lower limbs are rated from 1 to 6 (0=no eruption, 1=1-9%, 2=10-29%, 3=30-49%, 4=50-69%, 5=70-89%, 6=90-100%). The proportional factor for the head/neck =.01, upper limbs=.02, trunk=.03 and lower limbs=.04. The algorithm for calculating the EASI is the sum of E+I+Ex+L multiplied by the area, multiplied by the proportional factor. The total score is the sum of the four body-region scores, max=72, min=0.
- Change in Physician Global Assessment (PGA) Score From Baseline (Week 1) to Week 16. [ Time Frame: Week 1 to week 16 ] [ Designated as safety issue: No ]The Physician Global Assessment (PGA) evaluates the overall severity of Atopic Dermatitis (AD) at a given time using a four point scale (0=clear, 0.5=clear to mild, 1=mild, 1.5=mild to moderate, 2=moderate, 2.5=moderate to severe, and 3=severe).
|Study Start Date:||January 2008|
|Study Completion Date:||October 2009|
|Primary Completion Date:||September 2009 (Final data collection date for primary outcome measure)|
Amevive® has been shown to be a safe and effective agent in the treatment of psoriasis but may prove useful in treating atopic dermatitis at a dose of 15mg IM every week for 12 weeks. Unlike other "biologics" for the treatment of skin diseases, the use of alefacept is not associated with increased infection, congestive heart failure, demyelinating disorders or lupus- like syndromes.
Alefacept 15mg IM every week for 12 weeks
Other Name: Amevive
Atopic dermatitis is a chronic inflammatory skin disease associated with cutaneous hyper-reactivity to environmental triggers that are generally innocuous to healthy, nonatopic individuals (Leung et al. 2004). Acute eczematous skin lesions in atopic dermatitis are characterized by marked epidermal intercellular edema (spongiosis). Chronic lesions are characterized by an acanthotic epidermis with elongation of the rete ridges, parakeratosis, and minimal spongiosis (Leung and Bieber 2003).
A significant mixed inflammatory cell infiltrate is present in both acute and chronic skin lesions, consisting of lymphocytes, immunoglobulin E (IgE)-bearing Langerhans cells, inflammatory dendritic epidermal cells, and macrophages. Eosinophils are also present in varying levels (Leung and Bieber 2003).
Activation and skin-selective homing of peripheral blood T lymphocytes and their subsequent effector functions in the skin represent sequential immunologic events in the pathogenesis of atopic dermatitis (Akdis et al. 2000). More than 90% of skin-infiltrating T lymphocytes in inflammatory skin diseases such as atopic dermatitis express CD44- and the oligosaccharide determinant cutaneous lymphocyte-associated antigen (CLA) (Berg et al. 1991). The migration of CD4+, CLA-positive T lymphocytes across cytokine-activated endothelial cell layers has 2 been shown to be dependent on the interaction of lymphocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1 (Santamaria Babi et al. 1995).
The activation of T lymphocytes plays an important role in atopic dermatitis pathogenesis. In acute atopic dermatitis, a T-helper (TH)2 cytokine profile is predominantly seen, with increased expression of interleukin (IL)-4, lL-5, and IL-13 (Stone 2003). In chronic atopic dermatitis, the cytokine profile changes to a TH1 predominant profile, with increased expression of interferon y (IFN-y) (Leung et al. 2004). Activated T lymphocytes also are responsible for direct cell-mediated keratinocyte apoptosis, which contributes to the spongiosis pattern of epidermal injury characteristic of acute atopic dermatitis (Trautmann et al. 2001),
The interaction of T lymphocytes with antigen-presenting cells (APCs) is one of the initial steps in T lymphocyte activation of an immunologic response to what is perceived by the immune system to be a foreign antigen. Although much attention has been focused on the primary interaction of the T lymphocyte receptor with the major histocompatability complex (MHC)-antigen complex on the APC, several other cell surface components are also involved in, and necessary for, T lymphocyte activation. Ligand pairs necessary for T lymphocyte activation, located on the cell surface of the T lymphocytes and the APC, respectively, include CD2/LFA-3, LFA-1/ICAM-1 (also ICAM-2 and ICAM-3), CD281B7, CD4/MHC Class II, and CD8/MHC Class I. CD2 interaction with LFA.-3 is necessary for T lymphocyte activation, binding, and T-helper cell responses. (Fischer et al. 1986; Springer et al. 1987)
Anievive® (Alefacept) is a dimeric fusion protein that consists of the extracellular CD2 binding portion of the human leukocyte function antigen -3 (LFA-3) linked to the Fc portion of IgG1. Amevive® interferes with lymphocyte activation by specifically binding to CD2 on lymphocytes thereby inhibiting LFA-3/CD2 interaction. Amevive® causes a reduction in CD4+ lymphocytes which play a role in atopic dermatitis. Currently, Amevive® has been shown to be a safe and effective agent in the treatment of psoriasis but may prove useful in treating atopic dermatitis. Unlike other "biologics" for the treatment of skin diseases, the use of alefacept is not associated with increased infection, congestive heart failure, demyelinating disorders or lupus- like syndromes. (1-Lodak and David, 2004)
Ten atopic patients who meet the inclusion/exclusion criteria will be enrolled in the study.
|United States, Illinois|
|Rush University Medical Center - Department of Dermatology|
|Chicago, Illinois, United States, 60612|
|Principal Investigator:||Michael D. Tharp, MD||Rush University Medical Center|