Effectiveness and Safety of Tofacitinib in Patients With Extensive and Recalcitrant Alopecia Areata
Phase: PHASE4
Conditions: Alopecia Areata
Sponsor: Institute of Dermatology, Thailand

 
 
EFFECTIVENESS AND SAFETY OF TOFACITINIB IN 
PATIENTS WITH EXTENSIVE AND RECALCITRANT ALOPECIA AREATA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator: 
Chinmanat Lekhavat (Tangjaturonrusamee), MD 
Assistant Director of the Institute of Dermatology 
Chief of Hair and Nail Clinic 
Institute of Dermatology, Thailand 
420/7 Rajvithi Road, Rajthevee 
Bangkok 10400, Thailand 
Tel. +66-95-207-2868, +66-95-207-2870 
Email. chinmanat@hotmail.com 
 
 
 
Protocol version  
August 2018 
 
 

Part I:  Type of research study 
 
          New research study 
                      Ongoing research project 
 
Part II:  Components in the preparation of the study 
1. Investigators 
 
1)  Chinmanat Lekhavat (Tangjaturonrusamee), MD  
Principal investigator 
 
2)  Pantip Yimwadsana, RN  
 
 
 
Research assistant 
 
3)  Suntree teepaiboon, RN 
 
 
 
 
Research assistant 
 
4)  Penny Pimonrat 
 
 
 
 
 
Research assistant 
 
5)  Panamat Kamfeung 
 
 
 
 
Research assistant 
 
6)  Ittiwat Kaewbanjak 
 
 
 
 
Research assistant 
2. Main agency and supporting unit 
 
Hair and Nail Clinic, Institute of Dermatology, Department of Medical Services, Ministry 
of Public Health, Thailand; 420/7 Rajvithi Road, Rajthevee, Bangkok 10400, Thailand 
3. Type of research  
 
Clinical trial 
4. Academic disciplines and research subjects  
Medical Sciences (Dermatology) 
5. Keywords 
 
Alopecia areata, Alopecia totalis, Alopecia universalis, Tofacitinib, JAK inhibitor 
6. The importance of the research problem and its origin 
 
Alopecia areata (AA) is a condition that causes sudden hair loss, primarily affecting the 
scalp and beard but can be on any part of the body. This condition affects 0.2% of the population 
and can occur in all age groups and both genders. From outpatient statistical data at the Institute 
of Dermatology, a total of 2,406 patients with patchy AA were treated in 2012, 3,079 patients in 
2013, 2,814 patients in 2014, and 1,887 patients in 2015. Three hundred forty-nine extensive AA 
cases were treated in 2012, 654 in 2013, 691 in 2014, and 455 in 2015. The cause of the disease 
remains unknown. It is believed to be an autoimmune disorder caused by an abnormal immune 
response to hair follicle correlated antigens. Interferon‐gamma (IFN‐γ) is an important cytokine 
inducing and tampering normal immune privilege of the anagen hair bulb to collapse, therefore 
triggering the hair follicle destruction.  
 
AA presents in the shape of oval or round, well-circumscribed, bald patches anywhere all 
over the scalp. Hair loss can extend to the entire scalp, called alopecia totalis, and alopecia 
universalis is the loss of all scalp hair and body hair. It can cause embarrassment and affects the 
quality of life. 

 
There are a few efficacy data for robust treatment of AA. An expert consensus seems to 
treat localized AA with intralesional and topical corticosteroids. In extensive AA, alopecia totalis, 
and alopecia universalis, diphenycyclopropenone or Janus kinase (JAK) inhibitors are good 
treatment options. Other options include the combination of short contact anthralin and topical 
minoxidil or high potency topical corticosteroids with topical minoxidil. Clinical improvement 
after applying short contact anthralin and topical minoxidil is approximately 75% in the case of 
patchy AA and 25% in the case of extensive AA, similar to that of topical corticosteroids with 
minoxidil. There is a 25% chance of hair growth. Systemic corticosteroids may be used to treat 
severe AA with methotrexate, cyclosporine, or azathioprine but should not be used as a routine 
long-term treatment because of the risk of side effects. However, those treatments may not be 
effective for recalcitrant cases. Recently, Janus kinase (JAK) inhibitors such as tofacitinib and 
ruxolitinib have been used to treat patients with extensive AA. Many studies found that patients 
with AA had more significant hair growth (>50%) by 54-81.9% after taking tofacitinib. JAK 
inhibitors are expected to reduce interferon-ɣ and interleukin-15, causing fewer white blood cells 
to destroy hair follicles. 
 
The effectiveness of tofacitinib for AA treatment has not been studied in Thailand, and 
only a few studies reported it in Asians. Although tofacitinib may be a choice in AA standard 
guidelines, the price of this medication may not be affordable. It is essential to prove the 
effectiveness to generate concrete evidence for the debates and stakeholders’ consideration in the 
cost-effectiveness of tofacitinib for extensive AA. 
7. The objective of this study 
 
7.1  Primary objective 
 
To study the effectiveness and safety of tofacitinib in Thai patients with recalcitrant and 
extensive AA at 24 weeks 
 
7.2  Secondary objectives 
 
To measure the quality of life in economic evaluation in Thai patients with recalcitrant and 
extensive AA treated with tofacitinib 
8. The scope of this study 
 
8.1  Study population 
 
 
8.1.1  Specific disease or condition(s): Subjects with extensive and recalcitrant AA 
coming to the hair and nail clinic and outpatient department at the Institute of Dermatology 
 
 
8.1.2   Gender: Male and Female 
8.1.3   Age: Subjects aged 18 years or older 
8.1.4   Number of subjects: calculated from the formula 
 
 
 
 

 
 
 
Zα/2   =  1.96 
   
 
 
P      =  Proportion of the population who had improvement  =  0.87 
 
 
 
d      =  A maximum tolerated error determined by an investigator  =  0.2 
 
 
 
n      =     (1.96)2(0.8) (1-0.8)   =   16 
                                                              (0.2)2      
                       
Therefore, the number of subjects should be approximately 16. Given 
approximately 20% of the number of patients who may have missed follow-up treatments, a total 
of 19 subjects are planned to be collected. 
 
8.2  Selection criteria 
 
 
8.2.1  Inclusion criteria 
 
 
 
8.2.1.1  Thai subjects aged 18 years or over 
8.2.1.2  Subjects with extensive AA greater than 50% of the scalp 
8.2.1.3  Subjects who can come for follow-ups during the first 6 months of  
treatment 
8.2.1.4 Subjects who are unresponsive to diphenylcyclopropenone,  
anthralin, clobetasol cream, and topical minoxidil for at least 6  
months. 
 
 
8.2.2  Exclusion criteria 
 
 
 
8.2.2.1 Subjects with hair loss from other causes, e.g., Telogen effluvium,  
Trichotillomania, onychomycosis (Tinea capitis) 
 8.2.2.2 Subjects with chronic or severe disease with unstable symptoms that 
may affect hair condition during the 6 months prior to screening, 
such as thyroid diseases, iron deficiency anemia, liver diseases 
(subjects with chronic hepatitis but with stable symptoms can 
participate in the study), heart diseases, neurological diseases, 
digestive disorders, reproductive diseases, cancer, and psychiatric 
diseases 
8.2.2.3 Subjects who had been treated for AA with topical corticosteroids or 
topical anthralin or diphenylcyclopropenone within 1 month prior to 
screening, or subjects who had been treated for AA with systemic 
corticosteroids or any other oral medication during 3 months before 
screening 
8.2.2.4 Subjects who are pregnant 
 
8.3 Research site and study period 
8.3.1  Study site: Hair and Nail Clinic, Institute of Dermatology Department of  
          Medicine Ministry of Public Health, Bangkok 
8.3.2  Research period: January 2019 - January 2021 
9.  Theories, hypotheses and conceptual frameworks of this study 

 
Alopecia areata (AA) is a condition in which the body's immune system is sensitive to 
itself. The in vitro studies showed this natural killer gene 2D-expression CD8+ T cell is the leading 
cause of an increase in interleukin-15 in the hair follicle, increasing interferon-ɣ and leading to 
hair follicle destruction. 
 
The standard guideline for extensive AA includes diphenylcyclopropenone, short contact 
anthralin, high potency topical corticosteroids. A recent study found that the combination therapy 
between diphenylcyclopropenone and anthralin was more effective than diphenylcyclopropenone 
monotherapy (55% vs. 88). However, the chance of treatment response is approximately 25-50%, 
upon the severity and duration of the disease. The diphenylcyclopropenone powder is expensive 
and must be mixed with acetone or alcohol solution before use in different concentrations. The 
high cost of diphenylcyclopropenone and the difficulty of mixing in different concentrations are 
why diphenylcyclopropenone solutions are unavailable in most hospitals. Most of the patients, 
especially those in the provincial areas, could not access such services. Inaccessible 
diphenylcyclopropenone treatment leads to inappropriate use of systemic corticosteroids. The 
successful rate of using systemic corticosteroids is only 43%, with a 17% chance of relapse. 
Nevertheless, many patients have poor clinical improvement after receiving various therapies. 
Those patients have reduced their quality of life, lost their self-confidence, and could develop 
stress, anxiety, and depression. 
 
Tofacitinib is a potent, selective inhibitor of the Janus Kinase (JAK) family of kinases and 
was approved by US Food and Drug Administration to treat adults with moderate to severe 
rheumatoid arthritis. This medication can inhibit signaling by receptors associated with JAK3 
and/or JAK1. The inhibition of JAK3 and/or JAK1 disrupts the signals of interferon-ɣ and 
interleukin-15 between white blood cells (WBC) and the nucleus of hair follicle cells, slowing 
down the production of WBC type CD8+NKG2D+ T cell, one of the causes of hair loss. 
 
The safety and effectiveness of tofacitinib for AA treatment have been demonstrated in 
adults. In the three studies, subjects with extensive AA had clinical improvement of about 54-
81.9% during the six months, and the Severity of Alopecia Tool (SALT) score was improved by 
50-90% approximately. 
 
The side effects of the treatment were mild. Subjects may develop headaches, 
hyperlipidemia, upper respiratory tract infection, and a slight increase in hepatic enzyme activity. 
Those side effects usually return to normal even after the patient did not stop taking the drug, and 
in very few cases, erythema, leg swelling, paleness, bone ischemia have been reported. However, 
no cancer was found in patients taking the drug yet, though, the company has a warning about this 
in the drug leaflet. 
10.  Reference  
1. 
Sperling LC, Sinclair, R., Shabrawi-Caelen, L.E. In: Callen JP, Cerroni, L., 
Heymann, W.R., Hruza, G.J., Mancini, A.J., Patternson, J.W., Rocken, M., Schwarz, T., editor. 
Dermatology. 1. 3rd ed. China: Elsevier Limited; 2008. p. 1093-114. 

 
2. 
Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata 
update: part I. Clinical picture, histopathology, and pathogenesis. J Am Acad Dermatol. 
2010;62(2):177-88, quiz 89-90. 
 
3. 
Alkhalifah A, Alsantali A, Wang E, McElwee KJ, Shapiro J. Alopecia areata 
update: part II. Treatment. J Am Acad Dermatol. 2010;62(2):191-202, quiz 3-4. 
 
4. 
Schmoeckel C, Weissmann I, Plewig G, Braun-Falco O. Treatment of alopecia 
areata by anthralin-induced dermatitis. Arch Dermatol. 1979;115(10):1254-5. 
 
5. 
Tosti A, Iorizzo M, Botta GL, Milani M. Efficacy and safety of a new clobetasol 
propionate 0.05% foam in alopecia areata: a randomized, double-blind placebo-controlled trial. J 
Eur Acad Dermatol Venereol. 2006;20(10):1243-7. 
 
6. 
Taylor CR, Hawk JL. PUVA treatment of alopecia areata partialis, totalis and 
universalis: audit of 10 years' experience at St John's Institute of Dermatology. Br J Dermatol. 
1995;133(6):914-8. 
 
7. 
Liu LY, Craiglow BG, Dai F, King BA. Tofacitinib for the treatment of severe 
alopecia areata and variants: A study of 90 patients. J Am Acad Dermatol. 2017;76(1):22-8. 
 
8. 
Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of alopecia areata 
and variants in adolescents. J Am Acad Dermatol. 2017;76(1):29-32. 
 
9. 
Ibrahim O, Bayart CB, Hogan S, Piliang M, Bergfeld WF. Treatment of Alopecia 
Areata with Tofacitinib. JAMA Dermatol. 2017;153(6):600-2. 
 
10. 
Islam N, Leung PS, Huntley AC, Gershwin ME. The autoimmune basis of alopecia 
areata: a comprehensive review. Autoimmun Rev. 2015;14(2):81-9. 
 
11. 
Durdu M, Ozcan D, Baba M, Seckin D. Efficacy and safety of 
diphenylcyclopropenone alone or in combination with anthralin in the treatment of chronic 
extensive alopecia areata: a retrospective case series. J Am Acad Dermatol. 2015;72(4):640-50. 
 
12. 
Shreberk-Hassidim R, Ramot Y, Gilula Z, Zlotogorski A. A systematic review of 
pulse steroid therapy for alopecia areata. J Am Acad Dermatol. 2016;74(2):372-4 e1-5. 
 
13. 
Rencz F, Gulacsi L, Pentek M, Wikonkal N, Baji P, Brodszky V. Alopecia areata 
and health-related quality of life: a systematic review and meta-analysis. Br J Dermatol. 
2016;175(3):561-71. 
 
14. 
Divito SJ, Kupper TS. Inhibiting Janus kinases to treat alopecia areata. Nat Med. 
2014;20(9):989-90. 
 
15. 
Craiglow BG, King BA. Killing two birds with one stone: oral tofacitinib reverses 
alopecia universalis in a patient with plaque psoriasis. J Invest Dermatol. 2014;134(12):2988-90. 
 
16. 
In: Pfizer, editor. Xeljanz. package insert: New York; 2016. 
 
 

11.  Beneficial impact  
The researchers anticipate that the research project results will bring new knowledge as a 
basis for better treatment of hair and scalp conditions and diseases. Clinical outcome data can be 
used as information for patients to make informed decisions about AA treatments. It is also used 
in healthcare policy to make decisions and find the most suitable service for patients with 
recalcitrant AA. 
12.  Plans for transferring technology or results to target groups 
 
12.1. To be published in international medical journals to provide information to the public 
12.2. To be presented at academic conferences both in Thailand and abroad 
13.  Methods of conducting research and place for conducting study/data storage 
 
13.1 Study design 
This is a prospective cohort study conducted at the Institute of Dermatology. Nineteen male 
and female Thai volunteers with extensive hair loss of more than 50% of the head area were 
recruited. 
13.2 Conducting research procedures 
13.2.1 The principal investigator selects the volunteers according to the inclusion 
and exclusion criteria. 
13.2.2 The principal investigator takes a personal history of the volunteers, such as 
date of birth, age, ethnicity, age of onset, stage of disease progression, past medical history, 
weight, and height. 
13.2.3 The principal investigator will ask the volunteers about their health, pre-
existing disease conditions such as allergies, asthma, thyroid disease, psoriasis, vitiligo, 
autoimmune diseases, rheumatoid arthritis, diabetes, irritable bowel syndrome,  
immunodeficiency states, current medications, or medications taken or treated prior to the 
administration for 1month, severe illness and severe stress. 
13.2.4 The principal investigator examines the condition of the scalp, hair, and body 
by measuring the area of hair loss on the scalp, including the body hair by recording the 
SALT score, hair loss on the body, and examining the nail characteristics. 
 
 
 
13.2.5 All subjects will have photos taken from the side, back, and top of their scalp 
with a stereotactic device. 
13.2.6 All subjects will undergo tests prior to treatment, including complete blood 
count, lipid profiles, anti-HIV, HBs Ag, Anti HCV, renal function test (BUN, Cr), liver 
function test (LFT), urine pregnancy test (UPT; female), chest x-ray, stool exam. 
13.2.7 All subjects will be asked to take Tofacitinib 5 mg twice a day. 

13.2.8 All subjects will be evaluated after the treatment every four weeks during 
the 24-week duration of the treatments. The SALT score is assessed each time, including 
the potential side effects. Also, they will have photos taken from the side, back, and top of 
their scalp with a stereotactic device every visit. The treatment with tofacitinib is successful 
should subjects have hair regrowth more than 50% compared to the baseline photo. 
13.2.9 All subjects are required to have blood tests later for CBC, cholesterol, 
triglyceride, low-density lipoprotein (LDL), LFT, BUN, and Cr after weeks 4, 12, 24 of 
treatments. 
13.2.10 All female subjects are required to have UPT every four weeks during the 
24-week duration of the treatments. 
13.2.11 When AA subjects finish treatments either at week 24, or resolved before, 
or discontinue tofacitinib due to the side effects before the end of the treatments, they are 
required to have a follow-up after four weeks of discontinuation. 
 
13.3 Consent Process 
 
Before volunteering to participate in this study, subjects are explained by an investigator 
about the study objective, method, advantages, and disadvantages, including side effects that may 
be caused by tofacitinib. Subjects have the right to choose to participate or not participate in a 
voluntary research study without coercion or persuasion and have the right to terminate their 
participation in the study at any time. The termination will not affect the current and future medical 
care that the subjects will receive. When subjects decide to participate in the study, they will be 
asked to sign their first and last name in the informed consent before enrolling. 
 
13.4 Data Collection 
In this study, subjects' personal records were separated into a specific form with limited 
access to the data. The data was recorded using a programmed computer, and the confidentiality 
of the data was protected. A password is required to access the data of the subjects. Persons who 
can access the subjects' data are the research physician, research team, research sponsor, and the 
Institutional Review Board Committee. 
13.5 Data Analysis 
The research data was then comparatively assessed using the SPSS program. 
13.6 Statistics used in data analysis 
13.6.1 General data will be calculated by using Univariate analysis as a percentage, 
standard deviation, range, mean 
13.6.2 Treatment efficacy will be evaluated by bivariate analysis calculated for a 
percentage of hair loss area at 12 and 24 weeks, compared with pre-treatment data using 
One-way ANOVA. 
13.6.3 Side effects from treatment will be presented with event frequency, the 
number and the percentage of subjects in each event will be compared using Friedman 
Two-way Analysis. 

 
13.7 The place of conducting study and data collection 
 
Hair and nail clinic, Institute of Dermatology, Department of Medical Services, Ministry 
of Public Health, Thailand 
 
Address: 420/7 Rajvithi Road, Rajthevee, Bangkok 10400, Thailand 
Tel: +66-95-207-2868, +66-95-207-2870 
14. Research period and operational plans throughout the study 
The period will be from January 2019 to January 2021. 
15. Factors contributing to research 
The budget was granted by the Institute of Dermatology, Department of Medical Services, 
Thailand. 
16. Research study budget 
 The budget source of money is from National Annual budget of Thailand. 
17. Expected results and value of research 
The researchers anticipate that the results of this study will bring new knowledge as a basis 
for better treatment of hair and scalp conditions and diseases. Clinical outcome data can be used 
as information for patients to make decisions about AA treatment. It is also used as information 
for doctors and policymakers to make policy decisions and find the most suitable service and 
treatment for AA patients.