A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Alitretinoin (BAL4079) in the Treatment of Severe Chronic Hand Eczema Refractory to Potent Topical Corticosteroid Therapy
October 2014 | Volume 13 | Issue 10 | Original Article | 1198 | Copyright © October 2014
Joseph F. Fowler MD,a Ole Graff MD,b Abbas G. Hamedanib
aDivision of Dermatology, University of Louisville, Louisville, KY
bStiefel, a GSK Company, Research Triangle Park, NC
Abstract
Severe chronic hand eczema (sCHE) is a persistent, disfiguring disease that responds poorly to conventional treatment and causes substantial physical and psychological disability. The objective of this study was to evaluate efficacy and safety of oral alitretinoin in sCHE in a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study comparing alitretinoin with placebo. Efficacy was assessed every 4 weeks during treatment and 4 weeks after end of treatment (EOT, 24 weeks); responders were assessed every 4 weeks for a further 48 weeks after EOT. The study was conducted at academic and private dermatology centers. The participants were 596 patients with sCHE refractory to potent topical corticosteroids. Patients were treated with daily oral alitretinoin 30 mg or placebo for up to 24 weeks. Primary endpoint was proportion of responding patients based on Physician Global Assessment (PGA) of “clear†or “almost clear†at EOT. Key secondary endpoints: Patient Global Assessment (PaGA), change in modified Total Lesion Symptom Score (mTLSS), time to response (TTR), extent of disease at EOT, and duration of response (DOR). At EOT, 40% of alitretinoin-treated patients were responders vs 15% placebo-treated patients (odds ratio [OR] = 3.78;
P < .001); a greater proportion of alitretinoin-treated patients achieved a PaGA of “cleared†or “almost cleared†(OR = 4.05;
P < .001). A greater decrease in mTLSS occurred from baseline to EOT in alitretinoin- vs placebo-treated patients (treatment difference −24%
P < .001). Median TTR for responders at EOT was shorter with alitretinoin vs placebo (65 vs 117 days;
P < .001). Greater decreases in extent of disease at EOT were observed with alitretinoin vs placebo (treatment difference −22%;
P < .001). The most common treatment-emergent adverse event was headache. Alitretinoin significantly improved signs/symptoms of sCHE, was well tolerated in patients refractory to potent topical corticosteroids, and may provide benefit to this population.
J Drugs Dermatol. 2014;13(10):1198-1204.
INTRODUCTION
Severe chronic hand eczema (sCHE) is associated with persistent and disfiguring changes in hand appearance and causes substantial physical, social, and psychological disability.1-5 Pain, itching, and bleeding from fissures can make manual tasks difficult to perform, and embarrassment caused by skin appearance may prevent participation in social or employment situations.6,7 sCHE can be so severe that the impact on the health-related quality of life (QoL) of patients was rated similar to experiences of patients with asthma or psoriasis,6,8 and conventional CHE treatment yields mostly unsatisfactory results.9 The long-term prognosis is poor, and although the true epidemiology has not yet been characterized, 5% to 7% of patients with CHE are reported to experience sCHE, which interferes with daily activities; those who are refractory to topical treatment are estimated to represent 2% to 4%.10
Alitretinoin (9-cis isomer of retinoic acid [RA]), is a vitamin A (retinol) metabolite with effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion, and immunomodulation mediated by nuclear RA receptors and retinoid X receptors.11-13 Alitretinoin suppresses chemokines involved in recruitment of leukocytes to sites of skin inflammation, reduces expansion of T lymphocytes and antigen-presenting cells mediating inflammatory responses, and suppresses allogeneic leukocyte activation.11,12 This placebo-controlled study investigated once-daily alitretinoin 30 mg for up to 24 weeks for treatment of sCHE refractory to very potent topical corticosteroid (TCS) therapy.
METHODS
Patients
Patients (aged 18 to 75 years) had sCHE lasting ≥ 6 months since initial diagnosis with a Physician Global Assessment (PGA) rating of severe disease refractory to previous topical steroid therapy, and a history of unsatisfactory outcomes. Women of childbearing potential must have agreed to use 2 contraceptive methods unless strictly abstinent from sex. During a 16-week run-in period, patients must have been rated severe (according to PGA) after ≥ 2 weeks treatment with very potent TCS or any
