Development of Uniform Protocol for Alopecia Areata Clinical Trials Development of Uniform Protocol for Alopecia Areata Clinical Trials James A. Solomon1,2,3 Developing a successful treatment for alopecia areata (AA), clearly has not been at the forefront of the agenda for new drug/device development among the pharmaceutical and medical device industry. The National Alopecia Areata Foundation (NAAF), a patient advocacy group, initiated a plan to facilitate and drive clinical research toward finding safe and efficacious treatments for AA. As such, Alopecia Areata Uniform Protocols for clinical trials to test new treatments for AA were developed. The design of the uniform proto- col is to accomplish the development of a plug-and- play template as well as to provide a framework wherein data from studies utilizing the uniform proto- col can be compared through consistency of inclu- sions/exclusions, safety, and outcome assessment measures. A core uniform protocol for use by pharma- ceutical companies in testing proof of concept for investigational products to treat AA. The core protocol includes standardized title, informed consent, inclu- sion/exclusion criteria, disease outcome assessments, and safety assessments. The statistical methodology to assess successful outcomes will also be standardized. The protocol as well as the informed consent form has been approved in concept by Liberty IRB and is ready to present to pharmaceutical companies. The Journal of Investigative Dermatology Symposium (2015) 17, 63–66; doi:10.1038/jidsymp.2015.45 INTRODUCTION Developing a successful treatment for alopecia areata (AA) clearly has not been at the forefront of the agenda for new drug/device development among the pharmaceutical and medical device industry. Currently, no Federal Food and Drug Administration (FDA) approved therapy exists (Shapiro et al., 1997; Lachgar et al., 1998; Wiseman et al., 2001; Olsen et al., 2004; Blume-Peytavi et al., 2011; Gilhar et al., 2012). The National Alopecia Areata Foundation (NAAF), a patient advocacy group, initiated a plan to facilitate and drive clinical research toward finding safe and efficacious treatments for AA. NAAF, following FDA Guidelines (FDA, 2010), obtained support in principle from the FDA, to develop Alopecia Areata Uniform Protocols for clinical trials to test new treat- ments for AA. The design of the uniform protocol is meant to accomplish two overall goals: firstly, the uniform protocol is to be a plug-and-play template to entice biopharmaceutical and medical device companies to test medications and devices on AA. Secondly, the AAUP is to be a framework wherein data from clinical trials for the treatment of AA can be easily compared through consistency of inclusions/exclusions, safety, and outcome assessment measures. RESULTS A core protocol for a pharmaceutical investigative product proof of concept was developed and approved by the SAC. The title accepted is ‘‘Uniform Core Protocol for Phase (II /III) of A Double-Blind, Vehicle Controlled, Randomized, Multi-Center Study to Evaluate the Safety and Therapeutic Efficacy of oENTER IP4 Treatment of Adult Patients with Moderate to Severe Scalp Alopecia Areata.’’ The calculation of power follows d1:d2: v (Treatment Dose 1: Treatment Dose 2: Vehicle) For a P-value percentage difference between treatment Dose 1 (d1), Dose 2 (d2), and vehicle (veh)-treated subjects on the primary efficacy end point, treatment d1, d2, and veh-treated subjects will be required to provide p% power with a two-sided test at a significance level of 0.05. Screened: d1 þd2 þvþs Enrolled (Randomized): (d1 þd2 þvþs) * % Planned Complete: d1 þd2 þv. (Dell et al., 2002). Primary objective is The primary objective is to assess the safety and therapeutic efficacy of a 24-week regimen of administration of investiga- tional products (IP) with x treatment frequency, in adult subjects with chronic moderate-to-severe scalp AA. Secondary objectives include Assessment of the durability of the response over a 12-week post-treatment period of observation; the subjects’ perceptions of their scalp disease with treatment, and upon withdrawal of treatment, in relationship to baseline; the change from REVIEW 1Ameriderm Research, Ormond Beach, Florida, USA; 2Department of Dermatology, University of Central Florida College of Medicine, Orlando, Florida, USA and 3Department of Medicine, University of Illinois College of Medicine, Urbana, Illinois, USA Correspondence: James A. Solomon, Ameriderm Research, 725 West Granada Boulevard, Suite 44, Ormond Beach, Florida 32174, USA. E-mail: drjsolomon@ameridermresearch.com Abbreviations: AA, Alopecia areata; AT, Alopecia totalis; AU, Alopecia universalis; FDA, Federal Food and Drug Administration (USA); ICF, Informed Consent Form; IP, Investigative Product; NAAF, National Alopecia Areata Foundation; SAC, Scientific Advisory Committee; SALT, Severity of Alopecia Tool & 2015 The Society for Investigative Dermatology www.jidonline.org 63 http://dx.doi.org/10.1038/jidsymp.2015.45 mailto:drjsolomon@ameridermresearch.com http://www.jidonline.org baseline of the number and width of terminal hairs in the target site using digital photography; and IP-specific changes in the biomarker associated with IP. Inclusion criteria include Subjects 418 years of age with a diagnosis of scalp AA and at least 25% scalp hair loss due to AA, for at least 6 months up to 2 years duration. All subjects taking thyroid medication or hormonal therapy must be on a stable dose for 6 months and maintain such throughout the study. Female subjects who are pregnant or who are nursing or plan pregnancy during the study period are restricted from participation. Exclusion criteria include Less than 25% scalp AA involvement; any co-existent andro- genetic alopecia; prior treatment with IP; active scalp inflam- mation; history of systemic or cutaneous medical, or psychiatric disease which will put patient at risk or interfere with assessments. Disease outcome assessments include Severity of Alopecia Tool (SALT) score (Figure 1); digital photography; IP-related biomarkers, subject oriented AA assessments (Figure 2) Skindex, and Mendoza AA Qol Burden of Disease Questionnaire. Safety assessments include Adverse event history, changes in concomitant medications and/or diseases, physical exam, vital signs, electrocardiogram, chest X-ray, safety blood and urine labs, and IP-specific safety labs. Analysis The methods of analysis will be calculated according to standard statistical methods to maintain significance based on knowledge of the investigative product or device being tested. A minimal significance of Po0.05 two-tailed will be maintained. Wherein possible, one should justify the number of subjects with a preliminary power calculation, as published by Dell et al. (2002) for calculating sample size, using the formula n¼1þ2C(s/d)2, where n¼number to enroll, C is Biological Topical Topical TopicalSystemic Systemic Systemic AA AA AA Immunological AU/AT AU/AT Other AU/AT Core pharmaceutical Figure 1. Map of core protocol for pharmaceutical investigative drug. The pharmaceutical company would edit this protocol with input specific to the investigative drug. Left side: 18% Top: 40% Back: 24% Olsen/Canfield Salt score Site: Subject: Visit: Percentage involvedQuadrant Total Back Top 0.18 0.18 0.40 0.24 Right side Left side ScoreMultiplier Date: Right side: 18% 10 10 10 6 5 4 5 5 4 4 54 6 6 610 Figure 2. Severity of Alopecia Tool (SALT) score methodology (Reprinted from Olsen et al., 2004 with permission from the Journal of the American Academy of Dermatology). JA Solomon Alopecia Areata Uniform Protocol 64 The Journal of Investigative Dermatology Symposium (2015), Volume 17 constant dependent on desired power and significance, s is SD, and d is difference to detect. In summary, the development of the AA core uniform protocols and their modules hopefully will encourage and facilitate the testing of new drugs and devices in patients with AA. Moreover, the uniformity of the process will allow for comparisons between and among treatments studied. Thus, by having uniform protocols available for industry, more treat- ments can be developed and tested with an improved ability to compare the efficacy of one treatment or another for each and all of the AA variants. MATERIALS AND METHODS Members of the NAAF Scientific Advisory Committee (SAC) provided historical protocols for a variety of previous AA investigations. The SAC concurred with an overall plan to develop a uniform protocol made up of two core uniform protocols for all forms of A one for pharmaceutical agents, and another for medical devices. Since there are no currently FDA approved treatments for AA, the initial core protocols are developed for proof of concept investigations. The core has a standardized title, power of study, informed consent form (ICF), inclusion/exclusion criteria set, outcome assessments, and safety assessments.(Olsen et al., 2004; Blume-Peytavi et al., 2011; Olsen, 2011; Gilhar et al., 2012) In light of variable responses that may occur between those patients with patchy AA from those with alopecia totalis (AT) and/or alopecia universalis (AU), subjects with AT (495% scalp) or AU (495% scalp as well as diffuse non-scalp involvement) are included, but are evaluated as separate groups from those with patchy (25–95%) alopecia. From these core protocols, modules can be developed for specific variants in mode of application (topical, oral, injected) frequency of application (twice daily, monthly), pharmacological /immunological concepts; device modus of administration (laser, non-laser). A pharmaceutical or device company may then modify these modules with factors specific to the investigative product or device (Figure 3). Corresponding to this core protocol also developed were an ICF, and source documents. The protocol and ICF were presented to Liberty IRB, Deland FL and approved in concept. CONFLICT OF INTEREST Grant from NAAF (patient advocacy group) went to the author’s employer to develop Uniform Protocol. The authors declare no conflict of interest. ACKNOWLEDGMENTS This work was funded by a grant from NAAF to the author’s institution. Funding for the Summit and the publication of this supplement was provided by the National Alopecia Areata Foundation and was made possible (in part) by a grant (R13AR067088-01) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases and all co-funding support was provided by the National Center for Advancing Translational Sciences. DISCLAIMER The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government. REFERENCES Blume-Peytavi U, Hillmann K, Dietz E et al. (2011) A randomized, single-blind trial of 5% minoxidil foam once daily versus 2% minoxidil solution twice daily in the treatment of androgenetic alopecia in women. J Am Acad Dermatol 65:1126–36 Dell RB, Holleran S, Ramakrishnan R (2002) Sample size determination. ILAR J 43:207–13 FDA (2010) Draft Guidance/Guidance for Industry. Adaptive Design Clinical Trials for Drugs and Biologics. Center for Biologics Evaluation and Research CBER (eds) US Department of Health and Human Services, Alopecia areata is a condition that may affect you. Please rate how severe the following symptoms of your alopecia areata have been in the past week. Please select one response from 0 (symptom has not been present) to 10 (the symptom was as bad as you can imagine it could be) for each item. Not present Did not interfere Interfered completely 0 0 0 0 0 0 0 1 1 1 1 1 1 1 2 2 2 2 2 2 2 3 3 3 3 3 3 3 4 4 4 4 4 4 4 5 5 5 5 5 5 5 6 6 6 6 6 6 6 7 7 7 7 7 7 7 8 8 8 8 8 8 8 9 9 9 9 9 9 9 10 10 10 10 10 10 10 0Work Scalp hair loss Body or eye lashes hair loss Tingling/numbness of the scalp Itchy or painful skin Irritated skin Feeling anxious or worry Feeling sad Your alopecia areata may interfere with your daily functioning. Please rate how the following items were interfered with by alopecia areata in the past week. Please select one response from 0 (did not interfere) to 10 (interfered completely) for each item. Enjoyment of life Interaction with others Daily activities Sexual relationships Quality of life 0 0 0 0 0 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 6 6 6 6 6 6 7 7 7 7 7 7 8 8 8 8 8 8 9 9 9 9 9 9 10 10 10 10 10 10 As bad as you can imagine Figure 3. Alopecia Areata Symptom Impact Scale (AASIS). JA Solomon Alopecia Areata Uniform Protocol www.jidonline.org 65 http://www.jidonline.org Center for Drug Evaluation and Research (CDER) http://www.fda.gov/ downloads/Drugs/Guidances/ucm201790.pdf Gilhar A, Etzioni A, Paus R (2012) Alopecia areata. N Engl J Med 366:1515–1525 Lachgar S, Charveron M, Gall Y et al. (1998) Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol 138:407–11 Olsen EA (2011) Investigative guidelines for alopecia areata. Dermatol Ther 24:311–9 Olsen EA, Hordinsky MK, Price VH et al. (2004) Alopecia areata investiga- tional assessment guidelines Part II. J Am Acad Dermatol 51:440–7 Shapiro J, Lui H, Tron V et al. (1997) Systemic cyclosporine and low-dose prednisone in the treatment of chronic severe alopecia areata: a clinical and immunopathologic evaluation. J Am Acad Dermatol 36:114–7 Wiseman MC, Shapiro J, MacDonald N et al. (2001) Predictive module for immunotherapy of alopecia areata with diphencyprone. Arch Dermatol 137:1063–8 JA Solomon Alopecia Areata Uniform Protocol 66 The Journal of Investigative Dermatology Symposium (2015), Volume 17 http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf http://www.fda.gov/downloads/Drugs/Guidances/ucm201790.pdf Development of Uniform Protocol for Alopecia Areata Clinical Trials Introduction Results Primary objective is Secondary objectives include Inclusion criteria include Exclusion criteria include Disease outcome assessments include Safety assessments include Analysis Figure™1Map of core protocol for pharmaceutical investigative drug.The pharmaceutical company would edit this protocol with input specific to the investigative drug Figure™2Severity of Alopecia Tool (SALT) score methodology (Reprinted from Olsen et™al., 2004 with permission from the Journal of the American Academy of Dermatology) Materials and Methods This work was funded by a grant from NAAF to the authorCloseCurlyQuotes institution. Funding for the Summit and the publication of this supplement was provided by the National Alopecia Areata Foundation and was made possible (in part) by a grant (R13AR067 This work was funded by a grant from NAAF to the authorCloseCurlyQuotes institution. Funding for the Summit and the publication of this supplement was provided by the National Alopecia Areata Foundation and was made possible (in part) by a grant (R13AR067 This work was funded by a grant from NAAF to the authorCloseCurlyQuotes institution. Funding for the Summit and the publication of this supplement was provided by the National Alopecia Areata Foundation and was made possible (in part) by a grant (R13AR067 Disclaimer Figure™3Alopecia Areata Symptom Impact Scale (AASIS)