STUDY Alefacept for Severe Alopecia Areata A Randomized, Double-blind, Placebo-Controlled Study Bruce E. Strober, MD, PhD; Kavita Menon, MD; Amy McMichael, MD; Maria Hordinsky, MD; Gerald Krueger, MD; Jackie Panko, MD; Kimberly Siu, MD; Jonathan L. Lustgarten, PhD; Elizabeth K. Ross, MD; Jerry Shapiro, MD Objective: To assess the efficacy of alefacept for the treat- istration–approved T-cell biologic inhibitor for the treat- ment of severe alopecia areata (AA). ment of moderate to severe plaque psoriasis. Design: Multicenter, double-blind, randomized, placebo- Main Outcome Measure: Improved Severity of Alo- controlled clinical trial. pecia Tool (SALT) score over 24 weeks. Results: Participants receiving alefacept for 12 consecu- Setting: Academic departments of dermatology in the tive weeks demonstrated no statistically significant im- United States. provement in AA when compared with a well-matched placebo-receiving group (P =.70). Participants: Forty-five individuals with chronic and severe AA affecting 50% to 95% of the scalp hair and re- Conclusion: Alefacept is ineffective for the treatment of sistant to previous therapies. severe AA. Intervention: Alefacept, a US Food and Drug Admin- Arch Dermatol. 2009;145(11):1262-1266 LOPECIA AREATA (AA) IS A lesions of AA are transplanted into mice chronic, potentially revers- with severe combined immunodefi- ible autoimmune skin dis- ciency that lack T lymphocytes, hair ease characterized by non- growth may resume, further confirming scarring patchy hair loss the potential pathogenic role of T lym- Ainvolving any hair-bearing surface.1 Alo- phocytes.8 pecia areata often causes considerable emo- Treatment options for more severe pre- tional distress and has limited treatment sentations of AA are limited, and neither Author Affiliations: options. The presentation and course of a cure nor preventive treatment is avail- Departments of Dermatology, AA differ from patient to patient and are able. Most of the effective therapies for AA New York University School of unpredictable.2 Most often involving the are either immunosuppressive or immuno- Medicine, New York scalp, AA typically presents as well- modulatory. Of the therapeutic options, (Drs Strober, Menon, Siu, and demarcated patches of hair loss that may corticosteroids (topical and intrale- Shapiro), Wake Forest be either isolated or numerous.1 Patients sional) remain the most popular, al- University, Winston-Salem, North Carolina may develop total loss of scalp hair (alo- though other therapies, including anthra- (Dr McMichael), University of pecia totalis) or loss of all body hair (alo- lin, minoxidil, systemic corticosteroids, 1,3 Minnesota, Minneapolis pecia universalis). Alopecia areata has an topical immunotherapy, psoralen–UV-A (Dr Hordinsky), University of incidence rate of 0.1% to 0.2%, with a life- (PUVA), and cyclosporine are also com- Utah, Salt Lake City time risk of roughly 1.7%.1,4 Most often it monly used with varying success.1 Inter- (Drs Krueger and Panko), is those with AA of the scalp who present estingly, the biologic agents etanercept Biomedical Informatics, for evaluation. and efalizumab—both effective in treat- University of Pittsburgh, T lymphocytes seem to play a central ing psoriasis, a T-cell–mediated disease— Pittsburgh, Pennsylvania role in AA through a targeted immuno- demonstrate no efficacy in treating AA.3,9 (Dr Lustgarten), Dermatology logic attack on the hair follicle leading to Despite these failures, other biologic and Laser Center NW, 3,5-7 Bellingham, Washington anagen arrest. Histologically, lesions of agents with different mechanisms of ac- (Dr Ross), and Dermatology active AA reveal dense peribulbar lym- tion may be effective. Alefacept (Ame- and Skin Science, University of phocytic infiltration, consisting of acti- vive; Astellas Pharma US Inc, Deerfield, Il- British Columbia, Vancouver, vated T lymphocytes and antigen- linois) is a bioengineered lymphocyte Canada (Dr Shapiro). presenting Langerhans cells.5-7 When function–associated antigen-3/immuno- (REPRINTED) ARCH DERMATOL/ VOL 145 (NO. 11), NOV 2009 WWW.ARCHDERMATOL.COM 1262 ©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 globulin fusion protein that interrupts T-lymphocyte ac- or Յ3 squamous cell carcinomas); a history of active tubercu- tivation by binding to CD2 on T lymphocytes and con- losis (TB) or were currently undergoing treatment for active sequently interrupting the costimulation between antigen- TB; or were pregnant or breastfeeding. Individuals with a his- presenting cells and T lymphocytes.10,11 Perhaps more tory of treatment with alefacept or treatment with another in- important, alefacept specifically induces the apoptosis of vestigational medication also were not allowed to participate ϩ ϩ in the study. Systemic therapies (eg, corticosteroids, fumaric both CD4 and CD8 memory effector T lymphocytes, acid derivatives, cyclosporine A, methotrexate, biologic medi- cells that comprise the peribulbar lymphocytic infiltrate cations, retinoids, azathioprine) and phototherapy (UV-B, 10-14 and have been implicated in the pathogenesis of AA. PUVA) were discontinued for 1 month prior and during the Case reports15,16 have shown that alefacept may be effec- entire study treatment period. Topical therapies (corticoste- tive in the treatment of AA. Herein, we report the re- roids, contact sensitizing agents, tacrolimus, or pimecroli- sults of a double-blind, randomized, placebo-controlled mus) were discontinued for 2 weeks prior to and during the study of alefacept in patients with severe AA. entire study treatment period. The use of prescription medi- cations for conditions unrelated to AA was permitted. Serum samples, measuring hepatic, renal and hematologic METHODS function, and CD4ϩ T-lymphocyte count, were drawn through- out the study, and participants were assessed for signs and symp- The primary objective of this study was to assess the safety and toms of infection. Study medication was withheld if the CD4ϩ therapeutic efficacy of a weekly regimen of intramuscular (IM) T-lymphocyte count fell below 250 cells/mm3. alefacept compared with placebo over a course of 12 weeks in pa- The severity of AA and clinical response were measured with tients with chronic, severe scalp AA. This was a double-blind, ran- the Severity of Alopecia Tool (SALT) as detailed in the Alope- domized, placebo-controlled, multicenter, investigator-initiated cia Areata Investigational Guidelines.17 The SALT score is com- study in a voluntary population of patients with chronic, severe puted by measuring the percentage of hair loss in each of 4 areas scalp AA. There were 5 participating study sites. The study was of the scalp—vertex (40%), right profile (18%), left profile (18%), approved by the institutional review boards at each of the study and posterior (24%)—and adding the total to achieve a com- sites and was conducted in accordance with Good Clinical Prac- posite score. Hair regrowth is reflected by a decrease in the SALT tice guidelines, the US Food and Drug Administration (FDA) score (eg, complete hair regrowth would confer a SALT score guidelines for clinical trials, and the principles set forth by the of 0). The primary efficacy end point was the percentage of par- Declaration of Helsinki. All participants provided written in- ticipants with at least a 50% improvement from the baseline in formed consent prior to the initiation of any study procedures. their SALT score at week 24. Treatment response was also mea- Eligible individuals were randomized to receive either weekly sured at week 12. The SALT score was measured visually by IM administration of placebo or alefacept,15 mg, for 12 weeks, the study physician and corroborated by photographic analy- followed by a 12-week, posttreatment observation period. Safety sis. The participant’s perception of the extent of scalp disease and efficacy were assessed throughout the 24-week study pe- on completion of the treatment phase and at the end of the post- riod. Randomization lists detailing the person’s identification treatment, observational phase was also assessed. (ID) number and medication allocation were provided by a co- ordinating monitor. An unblinded study coordinator or phar- macist maintained the randomization lists responsible for par- STATISTICAL ANALYSIS ticipant ID number assignment and drug shipment and management. Once an individual was deemed eligible for study Efficacy and safety analyses were based on the modified intent- entry, the unblinded study coordinator or pharmacist as- to-treat population, which included all randomized patients who signed the participant an ID number and dispensed study medi- received at least 1 dose of the study medication. For the popu- cation as listed in the randomization list. Participants were moni- lation and safety analyses, patients were separated based on the tored for safety and efficacy throughout the entire study by a treatment groups to which they were randomized. The pro- blinded investigator. Efforts were made to ensure that the same portion of patients who achieved a 50% or greater reduction investigator monitored any specific participant for the entire in their SALT scores in the alefacept and placebo groups was ␹2 study period. analyzed using the test. Participants’ assessment of disease was analyzed by the Wilcoxon rank-sum test. All statistical tests were 2-sided, and all tests for efficacy were performed at the ␣ PATIENT ELIGIBILITY =.05 level. The planned sample