Clinical trial NCT02299297
Conditions: Alopecia Areata
Keywords: Alopecia Areata
Sponsor: Columbia University
Start date: 2015-01-01; Completion date: 2017-12-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label pilot study of tofacitinib taken daily for 6 months in the treatment of moderate to severe AA, and alopecia totalis or universalis, followed by 6 months follow-up off drug to assess the incidence and timing of recurrence of disease or documentation of delayed response to treatment. There will be the option of increasing the treatment duration up to an additional 6 months beyond the initially scheduled 6 months of treatment, if clinically indicated, and at the discretion of the investigator.

Detailed description:
Alopecia areata (AA) is a common disease of the immune system, known as an "autoimmune" disease. In the disease, the immune system mistakenly destroys the hair follicle, causing hair to fall out. Despite many people having this disease, research into its cause and new, better ways to treat AA has lagged far behind other similar diseases of the immune system. Currently, there are no Federal Drug Administration approved drugs for AA.

Tofacitinib (made by Pfizer) is an intervention known to effectively treat a disease of the joints, known as rheumatoid arthritis. It is also being studied in the treatment of psoriasis, another "autoimmune" disease, by fighting inflammation. There are some genetic and chemical similarities between those with active rheumatoid arthritis, psoriasis, and AA,suggesting that treatment with the same drug is likely to be effective. In mice specially designed for testing drugs for the treatment of human alopecia, this medication worked to prevent the disease AA from starting in mice that would have otherwise developed the disease. To test Tofacitinib, we are going to treat 15 patients with moderate to severe AA for up to 6 months. This is an "open label" study, meaning that there will not be a placebo group; all patients enrolled in the study will receive the active medication. The effectiveness of the medication will be measured by changes in hair re-growth as determined by physical exam and photography, as well as by patient and physician scoring. After the treatment period of up to 6 months is completed, There will be the option of increasing the treatment duration up to an additional 6 months beyond the initially scheduled 6 months of treatment, if clinically indicated, and at the discretion of the investigator. Patients will be followed for another 6 months off of the drug to see if the effects of treatment last and if there is delayed response. The safety of the medication, Tofacitinib, in patients with AA will also be evaluated. Blood work will be collected before medication is started, during the treatment period and after Tofacitinib is stopped in order to monitor for adverse effects of the medication. Small scalp biopsies and peripheral blood will be taken at the beginning of the study before treatment and at weeks 4 and 24. Additional, optional scalp biopsies and blood draws may be suggested at other important time points. The chemical analysis of these skin samples and blood will help us to understand how the disease happens, how the treatment works, and even guide us to better treatments in the future.

Arms: arm 1: Tofacitinib will be self-administered for 6 months, with the option to extend treatment up to an additional 6 months at the discretion of the principal investigator. Patients will then be followed for 6 months off the drug to assess the incidence and timing of recurrence of disease or documentation of delayed response to treatment.
Interventions: intervention 1: Tofacitinib
Intervention descriptions: intervention 1: Dosage/Frequency: 5mg - 10mg, oral, twice daily

Protocol documents:
Prot_SAP_000.pdf: 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
 
AN OPEN-LABEL PILOT STUDY TO EVALUATE THE EFFICACY 
OF TOFACITINIB IN MODERATE TO SEVERE ALOPECIA 
AREATA, TOTALIS AND UNIVERSALIS 
 
 
 
Investigators: 
Julian Mackay-Wiggan, M.D., M.S. 
Assistant Professor and Director, Clinical Trials Unit 
Department of Dermatology 
Columbia University   
jc299@columbia.edu 
 
Angela Christiano, Ph.D. 
Professor in Dermatology and Genetics 
Vice-Chair for Research in Dermatology 
Columbia University 
amc65@columbia.edu 
 
 
Columbia University  
Department of Dermatology - Clinical Research Unit 
161 Fort Washington Avenue, 12th Fl, Rm 1264 
NY, NY 10032 
Tel #: 212-305-6953 
Fax #: 212-305-0286 
 
 
 
 
 
 
[Protocol Version/Date: December 18, 2015] 
 
 


 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
2
Table of Contents 
1 Introduction ...................................................................................................................... 12 
1.1 
Research Hypothesis ........................................................................................................... 12 
1.1.1 
Overview of Alopecia Areata ................................................................................................... 12 
1.1.2 
Pathology and role of T cells in human Alopecia Areata ............................................. 14 
2 Rationale for use of Tofacitinib in AA ......................................................................... 15 
2.1 ..... Preclinical Studies:  JAK1/JAK2 inhibitors effectively treat Alopecia Areata in 
the C3H-HeJ mouse model. ........................................................................................................... 17 
2.1.1 
Genetics of Alopecia Areata ..................................................................................................... 17 
2.2 ............. Efficacy of JAK1/JAK3 inhibitor (tofacitinib) in mouse models of Alopecia 
Areata .............................................................................................................................................. 18 
2.3 
Summary of Results of Investigational Program ...................................................... 22 
2.3.1 
Pharmacokinetics of Oral Formulation ............................................................................... 23 
2.3.2 
Drug Interactions ......................................................................................................................... 25 
2.3.3 
Potential for Other Drugs to Influence the PK of Tofacitinib ..................................... 26 
2.3.4 
Overall safety of Tofacitinib ..................................................................................................... 26 
3 Overall Risk/Benefit Assessment .............................................................................. 27 
3.1 
Current therapeutic options for Alopecia Areata ..................................................... 28 
4 Study Rationale ................................................................................................................ 28 
5 STUDY OBJECTIVES ......................................................................................................... 30 
5.1 
Primary Objective ................................................................................................................ 30 
5.2 
Secondary Objectives .......................................................................................................... 30 
6 Ethical considerations ................................................................................................... 31 
6.1 
Good Clinical Practice ......................................................................................................... 31 
6.2 
Institutional Review Board/Independent Ethics Committee ............................... 32 
6.3 
Informed Consent ................................................................................................................. 32 
7 INVESTIGATIONAL PLAN .............................................................................................. 32 
7.1 
Study Design and Duration ............................................................................................... 32 
7.2 
Inclusion Criteria .................................................................................................................. 35 
7.3 
Exclusion Criteria ................................................................................................................. 36 
7.4 
Prohibited Treatments and/or Therapies .................................................................. 38 
7.5 
Women of Childbearing Potential .................................................................................. 40 
7.6 
Concomitant Treatments ................................................................................................... 40 
7.6.1 
Prohibited and/or Restricted Treatments ........................................................................ 40 
7.6.2 
Other Restrictions and Precautions ..................................................................................... 40 
7.7 
Discontinuation of Subjects from Treatment ............................................................. 41 
8 Treatments ........................................................................................................................ 41 
8.1 
Study Treatment: Tofacitinib ........................................................................................... 41 
8.1.1 
Identification .................................................................................................................................. 41 
8.1.2 
Storage, Handling, and Dispensing ....................................................................................... 42 
8.1.3 
Additional Information for the Handling, Dispensing, and Storage of Tofacitinib  
 
 ............................................................................................................................................................. 42 


 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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8.2 
Selection and Timing of Dose for Each Subject .......................................................... 42 
8.2.1 
Dose Modifications for Adverse Events .............................................................................. 43 
8.3 
Concomitant Treatments ................................................................................................... 43 
8.3.1 
Prohibited and/or Restricted Treatments ........................................................................ 43 
8.3.2 
Other Restrictions and Precautions ..................................................................................... 43 
8.4 
Immunizations....................................................................................................................... 43 
8.5 
Treatment Compliance ....................................................................................................... 44 
9 Study Assessments and Procedures ......................................................................... 44 
9.1 
Time and Events Schedule ................................................................................................. 44 
9.2 
Study Completion or Early Discontinuation Visit ..................................................... 48 
9.2.1 
Study Drug Discontinuation .................................................................................................... 48 
9.3 
Study Materials ...................................................................................................................... 50 
10 Safety Assessments ...................................................................................................... 50 
10.1 
Physical Examinations ..................................................................................................... 50 
10.2 
Tuberculin Skin Testing .................................................................................................. 50 
11 Efficacy Assessment ..................................................................................................... 51 
11.1 
Primary Efficacy Assessment ......................................................................................... 51 
11.1.1 
Secondary Efficacy Assessments ........................................................................................ 52 
11.2 
Other Assessments ............................................................................................................ 53 
12 Adverse Events .............................................................................................................. 56 
12.1 
Serious Adverse Events .................................................................................................... 56 
12.2 
Nonserious Adverse Events ............................................................................................ 57 
12.3 
Assignment of Adverse Event Intensity and Relationship to Tofacitinib ...... 57 
12.4 
Collection and Reporting ................................................................................................. 57 
12.5 
Serious Adverse Events .................................................................................................... 58 
12.6 
Nonserious Adverse Events ............................................................................................ 58 
12.7 
Laboratory Test Abnormalities .................................................................................... 59 
12.8 
Overdose ............................................................................................................................... 59 
12.9 
Pregnancy ............................................................................................................................. 59 
12.9.1 
Requirements for Pregnancy Testing ............................................................................... 59 
12.9.2 
Reporting of Pregnancy .......................................................................................................... 59 
12.10 
Other Safety Considerations ........................................................................................ 60 
13 Statistical considerations .......................................................................................... 60 
13.1 
Sample Size Determination ............................................................................................ 60 
13.2 
Populations for Analyses ................................................................................................. 60 
13.3 
Endpoint Definitions ......................................................................................................... 61 
13.4 
Analyses ................................................................................................................................. 62 
13.4.1 
Demographics and Baseline Characteristics .................................................................. 62 
13.4.2 
Safety Analyses ........................................................................................................................... 62 
13.4.3 
Efficacy Analyses ....................................................................................................................... 62 
14 ADMINISTRATIVE SECTION ....................................................................................... 62 
14.1 
Compliance with the Protocol ....................................................................................... 62 
14.2 
Records Retention ............................................................................................................. 63 
14.3 
Destruction of Investigational Product ...................................................................... 63 


 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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15 Glossary of terms .......................................................................................................... 64 
16 List of Abbreviations ................................................................................................... 65 
17 References ....................................................................................................................... 67 
 
 
 
 
 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
An Open-Label Clinical Trial to Evaluate the Efficacy of 
Tofacitinib in Moderate to Severe Alopecia Areata, 
Totalis and Universalis  
Site Numbers & 
Names: 
Clinical Research Unit 
Department of Dermatology 
Columbia University Medical Center 
Research Hypothesis: 
Among patients with alopecia areata, patients with 
higher disease burdens are unlikely to have satisfactory 
outcomes with current therapies. Our hypothesis is that 
a Janus-Associated Kinase (JAK) inhibitor will be 
effective therapy in moderate to severe alopecia 
areata, totalis and universalis by blocking the IFN-Υ 
pathway. This pathway is prominent in human alopecia 
areata lesional tissue, and is associated with IFN-Υ 
infiltrate that produces the cytotoxic T cell inflammatory 
response underlying alopecia areata.   


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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Study Rationale 
Alopecia areata (AA) is a common autoimmune disease 
resulting from autoimmune attack on the hair follicles. The 
histopathology clearly identifies the “swarm of bees”, 
comprised of T cells encircling the human hair follicle. 
Blockade of the IFN-gamma signaling pathway with 
tofacitinib (inhibits Janus-Associated Kinases (JAK) 1,3, 
leading to disruption of cytokines and growth factor 
signaling pathways) has recently emerged as an effective 
therapy in human T cell mediated diseases. Tofacitinib is 
FDA-approved for the treatment of moderate to severe 
rheumatoid arthritis and is under study for many other 
autoimmune conditions. 
     There is genetic evidence for the importance of the 
interferon response pathway activating a cytotoxic T-cell 
response in human AA. Recent GWAS identified 26 
genetic susceptibility alleles in the interferon response 
pathway that included IFN-gamma itself as well as its 
negative regulator SOCS1 and NKG2D ligands and 
CD8a.ˡ Many of these AA susceptibility alleles are shared 
by other common autoimmune diseases including Celiac 
Disease, Type I Diabetes, and Rheumatoid Arthritis. 
These autoimmune states may share common pathogenic 
mechanisms and may respond to common treatments.  
      These studies also point to a dominant role for 
activated NKG2D-bearing CD8 T cells as the likely culprit.  
Autoaggressive cellular effector CD8+NKG2D+ effector T 
cells dominate the peribulbar infiltrate in human AA and 
are intimately associated with dermal sheath cells 
aberrantly expressing NKG2D ligands.  Unpublished data 
in the mouse has confirmed the human pathological 
findingsˡ identifying activated NKG2D bearing CD8 T cells 
both adjacent to the hair follicle and in the draining lymph 
nodes.  Thus, the immunopathogenesis of the C3H 
mouse model faithfully recapitulates human alopecia. 
Consistent with a primary role for autoimmune T cells in 
the C3H mouse model of alopecia areata, disease can be 
induced in normal unaffected mice by transfer of T cells 
from affected mice or humans.²ˉ⁴  
      Based on these pre-clinical proof-of-concept studies in 
the relevant animal model, the genetic evidence for the 
relevance of the interferon-γ pathway in human alopecia 
areata, and the lack of existing evidence-based data for 
any treatment in alopecia areata, there is a strong 
rationale for testing Jak1,2, & 3 inhibitor treatment in this 
disease.   


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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Study Objectives: 
Primary: 
Secondary: 
The study’s primary efficacy endpoint will be the 
proportion of responders at the end of treatment, which 
may be up to between 24 weeks/6 months to 72 
weeks/18 months of treatment, with response defined 
as 50% or greater hair re-growth from baseline as 
assessed by SALT score at the end of treatment - week 
24 to 72. This is a relatively strict definition for defining 
responders and non-responders and was chosen to 
minimize the potential for spontaneous remission, in 
which fewer than 10% are expected to achieve this 
magnitude of hair regrowth spontaneously. 
 
As additional secondary endpoints, efficacy will be 
measured by changes in hair re-growth as a continuous 
variable as determined by physical exam and Canfield 
photography, as well as patient and physician global 
evaluation scores. To assess the durability of 
responses, patients will continue to be followed for an 
additional 6 months after treatment is completed. 
Response at the end of study, week 72-96, will be 
examined as a secondary outcome. We will compare 
the efficacy of tofacitinib in promoting hair regrowth in 
patients with moderate to severe patch type alopecia 
areata to the efficacy in treating patients with current 
alopecia totalis (AT) or universalis (AU). 
Study Design: 
Open-label pilot study of tofacitinib 5mg to 10mg PO 
BID, for 6 to 18 months in the treatment of moderate to 
severe AA, and alopecia totalis or universalis, followed 
by 6 months follow-up off drug to assess for delayed 
response to treatment and/or the incidence and timing 
of recurrence of disease.  
The initial treatment dose will be tofacitinib 5mg PO 
BID, and may be increased up to 10mg PO BID, if 
clinically indicated at the discretion of the investigator.  
The initial treatment duration will be 6 months, and may 
be extended by up to 12 additional months if clinically 
indicated with an acceptable lab safety profile, at the 
discretion of the investigator. 
Study Schema 
Drugs / Doses /  
Length of Treatment) 
Tofacitinib (5 mg to 10 mg) will be taken orally twice a 
day for up to 24 to 72 weeks. 
Study drug dose may be reduced and/or temporarily 
discontinued if indicated based upon laboratory values. 
Accrual Goal: 
(Total number of subjects) 
15 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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Accrual Rate: 
(Number of subjects 
expected per month) 
1-3 
FPFV: 
LPFV:                              
Follow Up: 
 
October, 1, 2014 
December, 31, 2015   
12 months 
Correlative Studies: 
(PK/PD, etc.) 
Our published work and previous studies in human AA 
have reported increased NKG2DL expression and 
augmented expression of IFN response genes in the 
target hair follicle end organ, and elevated NKG2D 
expression in circulating CD8 T cells and NK cells (Ito 
et al, 2008; Petukhova et al, 2010). 
Clinical Correlative Studies 
Our study will include longitudinal assessment of AA 
biomarkers at baseline and during treatment to 
correlate treatment and disease status with;  
1) Histological improvement with reduced T cell 
peribulbar infiltrates. 
2) Declines in circulating and peribulbar CD8+NKG2D+ 
infiltration and in follicular hair follicle NKG2DL 
expression.  
3) Reduced IFN inflammatory biomarkers in the skin 
and blood. 
Inclusion Criteria: 
Patients between 18 to 65 years of age. 
Patients with a diagnosis of patch type alopecia areata. 
Patients will have >30% and <95% total scalp hair 
loss at baseline as measured using the SALT score 
or patients with 100% scalp hair loss. 
Duration of hair loss greater than 3 months without 
an upper limit of duration as long as there is reason 
to believe that regrowth is possible in the opinion 
of the investigator. 
No evidence of significant active/ongoing regrowth in 
the areas to be assessed present at baseline. 
Patients may be naïve to treatment or unresponsive to 
intralesional (IL) steroids or other treatments for 
alopecia areata. 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
9
Exclusion Criteria: 
 
Patients with a history of or active skin disease on the 
scalp such as psoriasis or seborrheic dermatitis. 
Patients in whom the diagnosis of alopecia areata is in 
question. 
Patients with active medical conditions or malignancies 
(except adequately treated basal or squamous cell 
carcinoma) that in the opinion of the investigator would 
increase the risks associated with study participation, 
including patients with a history of recurrent infections. 
Patients with active infection at baseline. 
Patients undergoing concurrent live vaccination. 
Women of childbearing potential who are unable or 
unwilling to use two forms of birth control for the study 
duration. 
Women who are pregnant or nursing. 
Patients known to be HIV or hepatitis B or C positive. 
Patients with history or evidence of hematopoietic 
abnormality. 
Patients with Hgb <9.0 at baseline.  
Patients with lymphocytes < 500 at baseline. 
Patients with ANC < 1000 at baseline. 
Patients with history or evidence of renal or hepatic 
impairment.  
Patients with history of immunosuppression or history 
of recurrent serious infections. 
Patients with prior history or at risk for GI perforation 
(i.e. active diverticulitis, inflammatory bowel disease 
and other risk factors). 
Patients over the age of 65, as the risk of serious 
infections is reportedly higher in this population 
Patients unwilling or unable to discontinue treatments 
known to affect hair regrowth in AA. 
Patients taking any medication considered a strong 
CYP3A4 inhibitor who is unable or unwilling to stop this 
medication for the duration of the study.  
Patients receiving treatment deemed to affect alopecia 
areata within 2 weeks to one month of baseline visit 
depending on the specific treatment. 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
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Criteria for 
Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
EFFICACY 
Primary endpoint: SALT (Severity of Alopecia Tool) 
Scores: The proportion of scalp involvement is 
determined by dividing the scalp into 4 quadrants and 
estimating the percentage of the scalp surface that all 
the alopecic areas would occupy if placed together. 
 
Secondary endpoint:  Changes in hair re-growth as a 
continuous variable will be determined using physical 
exams and Canfield photography, as well as patient 
and physician global evaluation scores. Additionally, 
patient reported outcomes, safety measures, incidence 
and timing of relapse will be important secondary 
outcomes. 
 
To assess safety, frequent and close monitoring of 
clinical and laboratory findings have been implemented. 
Adverse events will be captured and analyzed as a 
secondary endpoint. 
 
All 
physical 
examination 
findings, 
vital 
sign 
abnormalities, and clinical laboratory abnormalities, will 
be captured as AEs when deemed medically significant 
by the investigator. A qualified physician associated 
with the study will be available to assess clinical signs 
and symptoms that may be indicative of an adverse 
event. Safety will be assessed by summarizing the 
incidence and type of AEs. The proportion of patients 
who discontinued treatment will be summarized. 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
11 
Statistics: 
This is an open-label study to examine the efficacy of 6 to 18 
months of tofacitinib in the treatment of moderate to severe AA, 
and AT/AU. 
 
We have chosen our primary endpoint conservatively (the 
proportion of patients with >50% improvement in SALT index) as 
a relatively strict criteria that should minimize placebo response 
rates to 10% or less (0-1 of 10 subjects). This allows a higher 
degree of confidence that appreciable response rates are 
attributable 
to 
drug 
rather 
than 
spontaneous 
remission.  
Historically, patients with AT or AU are even less likely to 
experience spontaneous remission 
  
Power analysis. Based on two recently completed randomized 
trials (Strober et al, 2008; Price et al, 2009) in similar patient 
populations (moderate to severe AA) we expect placebo response 
rates to be between 6% (>50% improvement in SALT score³ 
(Olsen et al, 1999)) and 12% (>25% improvement). We estimate 
the likelihood of spontaneous regrowth of ≥50% baseline hair loss 
to be approximately 8% and aim to detect a 40% response rate 
with tofacitinib treatment.  
With our sample of n=15, we will have greater than 80% power to 
reject the null hypothesis that the response rate to treatment with 
tofacitinib is the same as the underlying remission rate of 10%, if 
we observe a response rate in our sample of 48% (a 38% effect 
size), holding type I error to 5%. If we assume that the underlying 
remission rate is 30% (the historical response rate in less severely 
affected patch type AA patients), then we have greater than 80% 
power to reject that null hypothesis if the observed rate is 73% or 
above (an effect size of 43%), again holding type I error to 5%. 
 
Since this is a small open-label proof of concept study, we 
recognize that it will likely lack adequate power to conclusively 
demonstrate small efficacy signals. Yet, descriptive summaries of 
all primary and secondary efficacy outcomes (proportions for 
binary outcomes, means for continuous outcomes) will provide a 
preliminary indication of the effect size that will aid in the design of 
subsequent efficacy trials. To assess safety as a secondary 
endpoint, we will summarize, via descriptive statistics, the 
occurrence of adverse events for the study group.  
Accrual projections. The Dermatology clinic and private practice at 
CUMC currently sees 600 AA patients yearly, of which we 
anticipate 20-30% would be eligible (>30% hair loss). Accrual will 
be greatly facilitated by targeted recruitment through our existing 
NAAF registry which includes 500 AA patients in the New York 
area, the majority of which have patchy type disease. Thus, 
complete accrual of 15 subjects should be feasible within 1 year 
from a pool of >100 eligible new subjects yearly. 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
12 
Figure 2. Clinical manifestations of AA.  Patchy 
disease (a and b), In b, the patient is in a 
spontaneous regrowth phase.  For patients with 
alopecia universalis, there is a complete lack of 
body hair and scalp hair (c), while patients with 
alopecia totalis lack scalp hair but not body hair.  
In d, the randomness of hair regrowth is 
observed, with regrowth in the parietal region but 
not either the occipital or temporal regions. 
1 
INTRODUCTION 
1.1 
Research Hypothesis 
Among patients with alopecia areata, patients with higher disease burdens are unlikely to have 
satisfactory outcomes with current therapies. Our hypothesis is that the JAK1/JAK3 inhibitor 
tofacitinib will be effective therapy in moderate to severe alopecia areata by attenuating both 
IL-15 and IFN-gamma signaling, thereby blocking re-activation of CD8+NKG2D+ memory T 
cells, and aborting the cytotoxic T cell inflammatory response underlying alopecia areata.   
1.1.1 
Overview of Alopecia Areata 
Alopecia areata (AA) is a major medical problem and is the most prevalent autoimmune 
disease in the US, with a lifetime risk of 1.7%, affecting both males and females across all 
ethnic groups.⁸ Additionally, AA represents the second most common form of human hair loss, 
second only to androgenetic alopecia, and causes significant disfigurement and psychological 
distress to affected individuals (Figure 2).  
   
Alopecia areata usually presents with patchy  
hair loss. Approximately one-third of these  
patients 
will 
experience 
spontaneous 
remissions within the first year.  However,  
many patients will develop waxing and waning  
disease with some progressing to alopecia  
totalis (total scalp hair loss) or alopecia 
universalis (loss of all body hair). This 
population that suffers from a disfiguring  
disease represents a significant unmet  
medical need.⁹ Alopecia totalis/universalis  
seldom, if ever, remits spontaneously or with  
current treatment. In our targeted population of 
moderate-severe patch-type alopecia, placebo 
response rates in other clinical studies have  
been in the 6-12% range. ⁶̓ ⁷ 
 
Clinical development of innovative therapies in  
AA has lagged far behind other autoimmune conditions. This may be due in part to the 
perception that AA is merely a cosmetic disorder. In reality, AA carries one of the highest 
burdens amongst all skin diseases, particularly among children and adolescents whose self-
image is so closely linked to their appearance. ˡ⁰      


 
 
Tofacitinib in AA, AT, AU 
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There are no evidence-based treatments for AA. A comprehensive Cochrane analysis 
assessment of seventeen randomized clinical trials (RCTs) involving a total of 540 participants 
found no proven treatment of AA.⁵⁴ Each trial included from 6 to 85 participants and assessed 
a range of interventions that included topical and oral corticosteroids, topical cyclosporine, 
photodynamic therapy and topical minoxidil. Overall, none of the interventions showed 
significant treatment benefit in terms of hair growth when compared with placebo. It was 
concluded that the effectiveness of few (if any) treatments for AA are proven. No RCTs on the 
use of diphenlycycloprophenone, dinitrochlorobenzene, intralesional corticosteroids or 
dithranol were found, although these drugs are commonly used for the treatment of AA. 
Similarly, although topical corticosteroids and minoxidil are widely prescribed and appear to be 
safe, there is no convincing evidence that they are beneficial in the long-term. Most trials have 
been poorly reported and/or are so small that any important clinical benefits are inconclusive.    
 
This study will provide data on the efficacy of tofacitinib in alopecia areata. One clear 
advantage of immunotherapeutic studies in the skin is the relative ease of access of the 
target organ. Shared genetic and common pathological pathways provide strong 
rationale for increasing the scope of approved pharmaceuticals (such as tofacitinib) for 
novel indications (such as AA).  Studies of tofacitinib in plaque psoriasis and psoriatic 
arthritis, ankylosing spondylitis, atopic dermatitis (topical), ulcerative colitis, juvenile 
idiopathic arthritis, and Crohn’s disease are underway (Clinical Trials Identifier 
NCT01710046 and NCT01877668, Clinicaltrials.gov).  Indeed, positive studies in any one of 
these autoimmune diseases that share a common cause could serve as the basis for 
advancing common treatments.  
 
Currently, tofacitinib is FDA-approved for the treatment of adult patients with moderate-to-
severe rheumatoid arthritis (RA) who have had an inadequate response or intolerance to 
methotrexate. For the treatment of RA, tofacitinib is approved as monotherapy or for 
combination therapy with methotrexate or other nonbiologic disease-modifying antirheumatic 
drugs (DMARDs). 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
14 
Fi
gure 3. NKG2D axis in human AA:  
Top panels: The NKG2DL ULBP3 is 
upregulated in human AA hair follicles but not in 
control subjects. Bottom panels: 
Immunostaining of a HF bulb shows dense 
infiltration with NKG2D staining CD8 T cells. 
IFN-gamma
control
AAP
AU
0
20
40
60
80
pg/ml
IP-10
control
AAP
AU
0
200
400
600
800
1000
pg/ml
*
IL-8
control
AAP
AU
0
5000
10000
15000
pg/ml
IL-8
*
*
*
Figure 4. Elevated Serum 
Chemokines and Cytokines 
in Human AA. Interferon- 
and IFN-induced chemokines 
(IP-10/CXCL10) are elevated 
in the serum of human AA, in 
some cases correlating with 
disease severity, i.e. patchy 
disease (AAP) vs. universalis 
(AU). 
1.1.2 
Pathology and role of T cells in human Alopecia Areata 
CD8+ Killer T cells in Human AA  
 
Alopecia areata results from autoimmune  
attack on the hair follicles. The relevant  
autoantigens are unknown, but the  
histopathology clearly identifies the  
“swarm of bees” encircling the human hair 
follicle. Infiltrates containing both CD4 and 
CD8 T cells have been described, but our 
recent studies pointed to a dominant role 
for activated NKG2D-bearing CD8 T cells 
that are the likely culprit autoaggressive  
cellular effectors1. Our collaborators  
recently demonstrated that CD8+NKG2D+ 
effector T cells dominate the peribulbar  
infiltrate in human AA that are intimately  
associated with dermal sheath cells  
aberrantly expressing NKG2D ligands 
(Figure 3). 
 
 
 
 
Interferon driven Th1-response in human AA 
Consistent with a pathogenic cellular immune response, AA has been viewed as a Th1-driven 
diseaseˡˡˉˡ³. For instance, elevated Th1 cytokines/chemokines (Figure 4) are seen in the 
peripheral blood of AA patients and IFN-inducible gene signatures have been described in the 
skin of AA patients.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
15 
 
2 
RATIONALE FOR USE OF TOFACITINIB IN AA 
 
Interferon gamma and AA  
 
The hair follicle has been considered a relative immunological sanctuary, expressing little or no 
MHC molecules, and instead expressing 
inhibitory Class I-like molecules such as 
HLA-E. In AA, lesional hair follicles 
express high levels of MHC molecules 
and 
NKG2D 
ligands, 
permitting 
recognition by NKG2D-bearing CD8 
killer cells found intimately associated 
with the hair follicle in the human and in 
mice1. Interferons, as key activators of 
the MHC locus and of the cellular 
immune response, could play a key role 
in eliminating immunologic privilege and 
orchestrating the induction and 
persistence 
of 
the 
inflammatory 
response in mouse and human AA. 
 
In the C3H-HeJ mouse model of 
AA, IFN-γ is required for pathogenesis, 
and administration of IFN-γ accelerates 
disease3,14. 
 
 
 
 
 
Likewise, occurrence of human AA has been noted in several series as a side-effect of Type I 
interferon therapy15-25. Importantly, administration of IFN-γ neutralizing antibodies reverses AA 
pathogenesis in the C3H-HeJ mouse26,2. In our collaborators’ transcriptional profiling studies of 
lesional vs. non-lesional C3H skin, the interferon response was overwhelmingly the dominant 
signature with 17 of the top 20 upregulated genes being interferon response genes. Interferon 
gamma itself was upregulated, but not Type I interferons (data not shown). To confirm this 
finding, our collaborators performed quantitative real-time PCR on cDNA generated from 
affected and non-affected C3H/HeJ mice, utilizing an interferon signaling and response qPCR 
array (Stellarray, Lonza Cat #00189608). This array contains primers that measure the 
expression of genes encoding interferons and their receptors, components of the JAK-STAT 
signaling pathway, interferon-inducing cytokines and response genes, as well as several 
housekeeping genes. The results validate the involvement of the IFN-γ pathway; the IFN-γ 
receptor 1 and the IFN-γ inducible chemokines CXCL9/10/11 (left most red bars up-regulated 
by <10-fold in Fig. 3), are highly overexpressed in affected mice. In contrast, the IFN Type I 
response appears to be markedly repressed in affected mice, as evident by the sharp down 
regulation of Type I interferons (alphaB, alpha 4) and their receptor IFNAR1 (bright blue bars). 
IFN-gamma
control
AA
0.00
0.05
0.10
0.15
IFN-gamma/beta-actin
TNF-alpha
control
AA
0.00
0.05
0.10
0.15
0.20
0.25
TNF-alpha/beta-actin
IL-4
control
AA
0.000
0.002
0.004
0.006
IL-4 / beta-actin
IL-5
control
AA
0.000
0.002
0.004
0.006
0.008
0.010
IL-5 / beta-actin
IL-13
control
AA
0.000
0.005
0.010
0.015
0.020
IL-13 / beta-actin
IL-10
control
AA
0.000
0.005
0.010
0.015
0.020
IL-10 / beta-actin
IL-17A
control
AA
0.00
0.01
0.02
0.03
0.04
0.05
0.06
IL-17A / beta-actin
TH1
TH2
TH17
Figure 1. T cells from human skin biopsies. T cells isolated from 
scalp biopsies from AA patients or healthy controls were 
analyzed for cytokine mRNA after stimulation for 6 hours with 
anti-CD3. Th1 associated cytokines appear higher in T cells 
from AA patients, but it is interesting to note that one AA patient 
(in gray) with the lowest IFN-γ production shows a strong 
upregulation of Th2 associated cytokines, suggesting that in 
terms of cytokine profiles, AA is not a homogeneous disease. 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
16 
Figure 2 
In addition to our data on C3H-HeJ mouse skin, in human AA, transcriptional profiles have 
noted a Type I IFN response in lesional biopsies45 and Th1 skewing and elevated IFN-
response cytokines/chemokines in the peripheral blood2ˉ31 and reviewed in scalp biopsies32. 
The cellular source of IFN-γ are likely T cells; in the C3H/HeJ mice our collaborators 
have shown that IFN-gamma producing CD8+NKG2D+ cells dominate the dermal HF infiltrate 
(unpublished). In human AA, they have shown in Figure 1 that IFN-γ producing cells were 
identified in 4 of 5 dermal crawl-out assays37. Our collaborators’ unpublished data implicate IL-
15 in driving activation of IFN-producing CD8 T cells. Tofacitinib would be predicted to also 
inhibit the IL-15 receptor which signals through JAK1 and JAK3. They have several lines 
of evidence from our translational research program implicating IFN-γ in AA. 
 
GWAS in AA Identifies IFN-γ Pathway Genes 
Since our collaborators initial GWAS publication1, we have identified twenty-six putative 
susceptibility genes (9 with p-values <10-4 and additional 17 with p-values =10-3) in the 
IFN/IFN-response pathway, including IFN-γ itself as well as its negative regulator SOCS1. 
 
T cells from human skin biopsies  
T cells isolated from scalp biopsies from AA patients or health 
controls were analyzed for cytokine mRNA after stimulation for 6 
hours with anti-CD3. Th1 associated cytokines appear higher in T 
cells from AA patients, but it is interesting to note that one AA 
patient (in gray) with the lowest IFN-γ production shows a strong 
up-regulation of Th2 associated cytokines, suggesting that in 
terms of cytokine profiles AA is not a homogeneous disease. 
 
Transcriptional profiling of AA scalp.  
The GWAS identified a set of genes associated with an 
increased risk for AA. In a similar global and unbiased 
manner, our collaborators are investigating whether there are detectable 
differences of gene expression detected in tissue samples of AA patients 
compared to healthy controls. Our collaborators have conducted preliminary 
profiling of the transcriptome comparing mRNA microarray profiles of affected 
scalp samples from 12 AA patients and normal scalp samples from 6 healthy 
controls, and we identified approximately 148 differentially expressed, 
upregulated genes and 120 downregulated genes (Figure 2). This analysis 
revealed a striking interferon gamma signature, as well as genes 
characteristic of cytotoxic CD8 T cells (CD8a, granzyme), which is conserved 
between human AA biopsies and the C3H-HeJ mouse model (Figure 2).  


 
 
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17 
 
2.1 
Preclinical Studies:  JAK1/JAK2 inhibitors effectively treat 
Alopecia Areata in the C3H-HeJ mouse model.  
 
C3H/HeJ mice develop spontaneous alopecia areata and the histopathological changes are 
identical to human alopecia including the importance of IFN-γ producing CD8+ NKG2D bearing 
T cells which are present in alopecic skin, and are massively expanded and activated in AA 
cutaneous lymph nodes (data not shown). As with human alopecia, we have demonstrated 
that IFN-response genes are highly upregulated in C3H/HeJ alopecic skin but not in non-
lesional skin, and is normalized in mice treated with effective therapy (data not shown). 
 
Consistent with a primary role for autoimmune T cells, in C3H mice disease can be induced in 
normal unaffected mice by transfer of T cells (either or both CD4 and CD8 T cells) from 
affected mice or humans²ˉ⁴. Thus the immunopathogenesis of the C3H mouse model faithfully 
recapitulates human alopecia and provides the rationale for preclinical studies in the C3H/HeJ 
mouse.  
 
Proof-of-concept has been provided for the JAK1/JAK3 inhibitor tofacitinib as a 
treatment in the C3H alopecic mouse model.  
 
2.1.1 
Genetics of Alopecia Areata   
Common Cause Hypothesis in Autoimmune Diseases 
The ‘Common Cause’ theory of autoimmunity is well-supported by decades of research 
using various methodologies and provides strong support for the existence of shared disease 
mechanisms. Epidemiological studies first demonstrated that some autoimmune diseases 
cluster within families, suggesting shared pathogenesis. More recently, hypothesis-free 
research strategies in genetics have shifted away from linkage studies in families, to genome-
wide association studies (GWAS) in population-based cohorts. The results of these studies 
have provided tremendous support to the "common cause hypothesis"³³ and have importantly 
identified susceptibility alleles in specific genes that underlie grouped sets of 
autoimmune diseases, arguing for unifying/general mechanisms that dysregulate 
tolerance at one of several multiple end organ sites, with autoimmune destruction in the 
pancreas, joint, or skin, etc., the potential final disease outcome. In fact, outside of the 
HLA, at least 23 such genes have been associated with two or more autoimmune diseases in 
a GWAS³⁴ˉ³⁵. The majority of these shared genes can be mapped onto a discrete set of 
immunological molecular pathways.  
 


 
 
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18 
2.2 
Efficacy of JAK3 inhibitor (tofacitinib) in mouse models of 
Alopecia Areata 
Here, we demonstrated that systemic administration of ruxolitinib (JAK1/2i, Figure 3f-h) and 
tofacitinib (JAK3i, Figure 3k-m) treatment prevented the development of AA and the expansion 
of CD8+NKG2D+ T cells in all grafted recipients. Skin of mice treated with either protein 
tyrosine kinase inhibitor (PTKi) showed no histological signs of inflammation (Figure 3 i,n). 
Global transcriptional analysis of whole skin biopsies showed that both drugs also blocked the 
dermal inflammatory signature, as measured by ALADIN (Alopecia Areata Disease Activity 
Index, Figure 3j,o), a transcriptional biomarker instrument that combines the CTL and IFN 
inflammatory scores, as well as by Gene Expression Dynamic Index (GEDI) analysis.  
 
To evaluate the efficacy of JAK3i in the context of active AA, we next asked whether systemic 
JAK3i treatment could reverse established disease by initiating therapy 7 weeks after grafting, 
a time point at which all mice had developed extensive AA.  Importantly, systemic therapy 
induced hair regrowth all over the body, and likewise eliminated the expansion of 
CD8+NKG2D+ T cells and reversed histological markers of disease (Figure in the middle 
below, a-c), an effect that persisted 2-3 months after the cessation of treatment. 
 
Finally, to test a more clinically relevant route of delivery, we asked if topical administration of 
PTKis could reverse long-standing alopecia areata with similar kinetics as systemic delivery.  
In established disease, we found that topical ruxolitinib, as well as topical tofacitinib, were both 
highly effective in reversing disease in treated lesions (applied to back skin), and complete hair 
regrowth was observed within 12 weeks following topical therapy (Figure 4a,b). Topical 
therapy was associated with the disappearance of CD8+NKG2D+ T cells in the treated skin and 
lymph node (Figure 4c), and the normalization of the ALADIN transcriptional signature (Figure 
4d), as well as the reversal of histological markers of disease (Figure 4e) and correction of the 
GEDI in all treated mice. Notably, untreated areas on the abdomen remained alopecic (Figure 
4a, outlined areas) demonstrating that topical therapy was locally effective and that the 
observed therapeutic effects were not the result of systemic absorption.  
 
Further, these effects were visible as early as 2-4 weeks after onset of treatment 
(Supplementary Figure 14) and were durable 2-3 months after the cessation of treatment 
(Figure 4a, 8 week post treatment, right panels). 
 
Taken together, our data identify CD8+NKG2D+ T cells as the immune cellular effectors 
responsible for autoimmune attack of the hair follicle and provide support for a model of AA 
pathogenesis. We have identified hair follicle expression of NKG2DL/IL-15 as potential 
proximal triggers that activate and sustain IFN-γ-producing CD8+NKG2D+ CTLs.  Conversely, 
we postulate that IFN-γ produced by CD8 T cells leads to the collapse of immune privilege in 
the hair follicle, inducing further production of IL-15 thus completing a feed-forward 
inflammatory loop that conspires to promote Type I cellular autoimmunity.  


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure.  Systemic treatment of AA mice with JAK3 inhibitor.  C3H/HeJ mice with long-standing alopecia areata were 
treated with tofacitinib with Alzet osmotic mini-pumps (pumps, model 2004, Durect Corporation) implanted subcutaneously on the back of each 
mouse to deliver vehicle (poly(ethylene glycol) (PEG)300) or vehicle containing JAK3i tofacitinib (Abmole) at 15 mg/kg/day for 12 wks. a, 
Alopecia areata reversal was complete on both the back and belly. b, Flow cytometric analysis of skin and cutaneous lymph node populations 
shows elimination of the CD8+NKG2D+ T cell population in treated mice (n=3 per group).  c, Immunostaining of skin from mice treated with 
tofacitinib or placebo demonstrates elimination of CD8 infiltration and MHC I and II upregulation in tofacitinib treated mice. 
3
0.38
18
0.29
CD8
NKG2D
Control
JAK3i
PBS 
JAK3i
0
10
20
30
***
CD8NKG2D cells (%)
Skin
PBS 
JAK3i
0
1
2
3
4
***
CD8NKG2D cells (%)
Lymph node
b
 Control
JAK3i
CD4
CD8
MHC- Class I
MHC-Class II
c
Pretreatment 
Treated (10 wks)
Obsevation (12wks)
 Control
JAK3i
a
    Skin        lymph node
CD8 
MHC-class I 
MHC-class II 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
20 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
21 
 
Figure 4 
 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
22 
Tofacitinib in humans with AA 
A recent publication documents complete regrowth of scalp and body hair in a patient with 
alopecia universalis treated with tofacitinib for severe psoriasis. JID June 2014 (Killing Two 
Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in a Patient with Plaque 
Psoriasis.  Brittany G. Craiglow, MD and Brett A. King, MD, PhD. Department of Dermatology, 
Yale University School of Medicine, New Haven, CT.) 
 
In addition, our preliminary data to date, from our ongoing trial of ruxolitinib (previously referred 
to as INCB 18424 - a JAK1/2 inhibitor) CU IRB AAAL7102, suggests a preliminary response 
rate of 66% at 3 months in patients with moderate to severe AA.  The response measure is 
defined as a ≥ 50% change in SALT score, the same primary outcome used in the currently 
proposed study (data unpublished). 
 
2.3 
Summary of Results of Investigational Program 
In November 2012, the U.S. Food and Drug Administration (FDA) approved the first-in-class 
Janus Kinase (JAK) inhibitor, tofacitinib, for treatment of rheumatoid arthritis (RA), 
spearheading the initiation of kinase inhibitors for treatment of rheumatic diseases. Despite 
advances in RA management over the last twenty years with use of cytokine and target cell 
inhibitors, a significant proportion of RA patients do not respond or maintain response efficacy 
to therapy. Rheumatoid arthritis results with the activation of both innate and adaptive immune 
pathways. Cells implicated in the immune system dysregulation use kinases as gatekeepers to 
determine their responsiveness to external stimuli such as antigens, cytokines, and immune 
complexes. New molecule inhibitors targeting cytoplasmic kinases such as the JAK family, 
splenic tyrosine kinase (SYK), or mitogen-activated phosphokinase p38 (p38MAPK), will 
amend the resulting dysregulated immune system through distinct paths and further aid our 
understanding of its complexities. 
In addition to tofacitinib, at least three other JAK inhibitors are currently in phase II studies for 
treatment of RA, psoriasis, and inflammatory bowel disease (see Table 1).  
Table 1 (adapted from The Rheumatologist, June 2013) 
Clinical Trials of current Kinases 
Agent 
Target 
Indication 
Developmental Stage 
Tofacitinib 
Jak3, Jak1 
RA 
FDA approved 
PsO, IBD 
Phase II trial 
Baricitnib 
Jak1, Jak2 
RA, PsO 
Phase II trial 
GLPG-0634 
Jak1 
RA 
Phase II trial 
INCB18424 
Jak1, Jak2 
PsO 
Phase II trial 
VX-509 
Jak3 
RA 
Phase II trial 
R348 
Jak3 + SYK 
RA, PsO 
Phase I trial 
Fostamatinib 
SYK 
RA 
Phase III trial 
Pamapimod 
p38 MAPK 
RA 
Phase II trial 
VX-702 
P38 MAPK 
RA 
Phase II trial 
SCIO-469 
P38 MAPK 
RA 
Phase II trial 
Topicals 
R333 
Jak/SYK Inhibitor 
Discoid Skin Lesions 
Phase II trial 
R348 
Jak3 + SYK Inhibitor 
Keratoconjunctivitis sicca 
Phase I trial 


 
 
Tofacitinib in AA, AT, AU 
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23 
These drugs are unique from the currently available therapies, due to their effects on the 
intracellular signaling apparatus including the JAK pathway utilized by inflammatory cytokines 
and growth factors. JAK kinases are activated after cytokine binding to one or more cytokine 
receptors, leading to JAK phosphorylated-activation and resulting in activation of signal 
transducer and activator of gene transcription (STAT) proteins. Certain cytokines, such as 
interleukin (IL) 6, IL-2, and IL-12/IL-23, are JAK kinase dependent. The JAK family consists of 
four tyrosine kinases. JAK-1, JAK-2, and TYK2 are expressed ubiquitously, whereas JAK 3 is 
limited to lymphoid tissues.1 All JAKs possess two similar phosphate-transferring domains, one 
with actual kinase activity and a pseudokinase domain, which in turn downregulates the 
activating kinase domain.2 Thus JAKs maintain dual regulatory functions. The JAK-STAT 
interaction is responsible for the signal transduction of over 50 members of the 4-helix bundle 
cytokine family, including interferons and growth factors such as leptin, prolactin, GM-CSF, 
and erythropoietin (EPO). 
 
2.3.1 
Pharmacokinetics of Oral Formulation 
Following oral administration of tofacitinib (XELJANZ), peak plasma concentrations are 
reached within 0.5-1 hour, elimination half-life is ~3 hours and a dose-proportional increase in 
systemic exposure was observed in the therapeutic dose range. Steady state concentrations 
are achieved in 24-48 hours with negligible accumulation after twice daily administration. 
 
Absorption 
The absolute oral bioavailability of tofacitinib is 74%. Coadministration of XELJANZ with a 
high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, 
XELJANZ was administered without regard to meals. 
 
Distribution 
After intravenous administration, the volume of distribution is 87 L. The protein binding of 
tofacitinib is ~40%. Tofacitinib binds predominantly to albumin and does not appear to bind to 
α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. 
 
Metabolism and Elimination 
Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% 
renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by 
CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 
65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the 
remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total 
radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule. 
 
Pharmacokinetics in Rheumatoid Arthritis Patients 
Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change 
in tofacitinib exposure, after accounting for differences in renal function (i.e. creatinine 
clearance) between patients, based on age, weight, gender and race (Figure 1). An 
approximately linear relationship between body weight and volume of distribution was 


 
 
Tofacitinib in AA, AT, AU 
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24 
observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter 
patients. However, this difference is not considered to be clinically relevant. The between-
subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be 
approximately 27%. 
 
 
Specific Populations 
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics 
of tofacitinib is shown in Figure 1. 
 
 
 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
25 
2.3.2 
Drug Interactions  
 
Potential for XELJANZ to Influence the PK of Other Drugs 
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the 
major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 
mg twice daily dose. These in vitro results were confirmed by a human drug interaction study 
showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when 
coadministered with XELJANZ. 
 
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, 
indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis 
patients. Therefore, coadministration with XELJANZ is not expected to result in clinically 
relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients. 
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P- 
glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low. 
Dosing recommendations for coadministered drugs following administration with XELJANZ are 
shown in Figure 2. 
 
 


 
 
Tofacitinib in AA, AT, AU 
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26 
2.3.3 
Potential for Other Drugs to Influence the PK of Tofacitinib 
 
Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce 
CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially 
alter the PK of tofacitinib. Dosing recommendations for XELJANZ for administration with CYP 
inhibitors or inducers are shown in Figure 3. 
 
 
 
2.3.4 
Overall safety of Tofacitinib 
 
Safety analyses of pooled data of tofacitinib-treated patients show a similar serious infection 
rate to biologics of 2.7/100 patient-years with opportunistic infections including tuberculosis, 
fungal infections, and pneumocystis reported. Screening for latent tuberculosis is 
recommended. The frequency of serious infections was increased in patients over the age of 
65. In long-term extensions, a slightly higher rate of infections and nonmelanoma skin cancers 
was seen in the 10-mg p.o. b.i.d. studies, and this dose was therefore not approved by the 
FDA. However, a higher incidence ratio (4.5) of herpes zoster was seen compared to other 
biologics (1.32).7 There was no association with neutropenia, lymphopenia, or concomitant 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
27 
nonbiologic DMARDs. No safety data are available on impact of tofacitinib on patients with 
chronic viral hepatitis reactivation, as these patients were excluded from the trials. Prophylactic 
vaccination for herpes zoster and hepatitis B should be updated prior to treatment whenever 
possible, and live virus vaccination during treatment should be avoided. 
 
Malignancies including lymphoma have been reported in conjunction with treatment with 
tofacitinib, and Epstein-Barr virus lymphoproliferative disorders were seen in renal transplant 
studies. 
 
GI perforations occurred in 10 of 5,043 tofacitinib-treated patients in analysis of pooled study 
data from ORAL trials with long-term extensions resulting in 0.144 events per 100 patient-
years. Six of these cases were diverticular in nature, three were appendiceal perforations, and 
one an isolated gastric ulcer. 
 
Laboratory-test monitoring should include initially a complete blood count (CBC), 
comprehensive metabolic panel (CMP), and fasting lipid panel. Minor decreases in absolute 
lymphocyte, neutrophil, and red blood cell counts were seen in less than 1% of patients. 
Transaminitis was also reported, which usually responded to a reduction in dose or 
discontinuation of therapy with only 0.5% reaching three times the upper limit of normal on the 
5-mg p.o. b.i.d. A dose-response change in creatinine (mean <0.1 mg/dl) was seen, which 
generally peaked at six weeks and then plateaued with a return to baseline four to six weeks 
after discontinuation. However, in long-term extensions, discontinuation of therapy only 
occurred due to renal insufficiency in 0.4% of patients in the 5-mg b.i.d. studies. The cause of 
this change is not understood. Mean LDL cholesterol increased by 15% and mean HDL 
increase by 10% with no change in LDL/HDL ratio. This effect was generally present within six 
weeks. A repeat fasting lipid panel is recommended at two to three months of therapy. Initial 
monitoring of CBC and CMP monthly for the first three months and then every two to three 
months thereafter would be prudent as this agent is used in larger, more heterogeneous 
patient populations. 
3 
OVERALL RISK/BENEFIT ASSESSMENT 
The efficacy of tofacitinib in alopecia areata is uncertain and determination of any activity in 
this disease is the objective of this study. The long term safety profile of tofacitinib is 
reassuring and confirms the potential for a favorable positive benefit/risk of tofacitinib in the 
treatment of alopecia areata.  
   
There were no adverse effects reported in the one publication to date regarding tofacitinib in 
the treatment of alopecia universalis. 1 healthy patient with psoriasis and alopecia universalis 
was treated with tofacitinib for 8 months.  
 
 
 
 


 
 
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28 
3.1 
Current therapeutic options for Alopecia Areata 
 
There is no FDA approved drug for alopecia areata.  A recent Cochrane report (Delamere 
et al, 2008) concluded that there was no evidenced based support for any intervention in this 
disease.  Standard of care remains observation for mild disease, and lesional/oral steroids for 
more advanced cases (Alkhalifah et al, 2010a,b). In moderate-severe patch-type alopecia 
placebo response rates have been in the 6-12% range (Price et al, 2008; Strober et al, 
2009). Limited data is available for the response rate in AT/AU. Intralesional steroid responses 
are unpredictable and occur less frequently in subjects with higher disease burdens. This 
population that suffers from a disfiguring disease represents a significant unmet medical need 
(Alkhalifah et al, 2010a,b).  Evidence-based and steroid-sparing interventions are needed.  
 
Use of tofacitinib carries potential risks, including treatment-associated infection. Alopecia 
areata patients as a whole are young (median age 23-30) and otherwise healthy, which 
should mitigate risk of adverse effects.  The target population in this proposed study is 
subjects with greater than 30% hair loss which represents unusually extensive disease, 
affecting fewer than 30% of all alopecia subjects, with disfiguring consequences and severe 
psychosocial morbidity. Although AA does not cause physical pain, several studies have noted 
that AA seriously impairs quality of life (QoL), mainly by altering self-perception and self-
esteem, both of which interfere with social life.  Because AA is chronic, visible to others, 
and often difficult to treat, its impact on quality of life is underappreciated (Bickers et al, 
2006; Hanan et al, 2008; Dubois et al, 2010) and comparable to psoriasis (Bickers et al, 
2006). Patient advocacy groups, including National Alopecia Areata Foundation have 
developed an active disease registry of over 10,000 subjects to document the impact on 
quality of life and encourage clinical investigation in this disease.  
 
4 
STUDY RATIONALE 
Alopecia areata is a prevalent disease with high unmet need with significant psychosocial 
morbidity and no current evidence-based treatments.  Preclinical studies have set the stage for 
evaluation of tofacitinib in alopecia areata. Tofacitinib is a Janus Kinase inhibitor that 
specifically targets JAK1/JAK3. JAKs are intracellular enzymes that conduct signals from 
inflammatory cytokines or growth factor interactions on cell membranes that influence 
hematopoiesis and immune cell function. After cytokines or growth factors bind their respective 
receptors, JAKs phosphorylate and activate Signal Tranducers and Activators of Transcription 
(STATs), which modulate intracellular activity such as gene expression. Tofacitinib interferes 
the signaling pathway via JAK inhibition, preventing phosphorylation and activation of STATs. 
Inflammatory cytokines such as Interleukin (IL) 6, IL-2, and IL-12/IL-23 are dependent on 
Janus Kinases.  
 
Treatment results with tofacitinib has shown dose-dependent reduction of circulating 
CD16/CD56 + natural killer cells (NKCs), with a maximal reduction 8-10 weeks after treatment 


 
 
Tofacitinib in AA, AT, AU 
April 23, 2015 
 
29 
initiation. These changes generally usually resolved within 2-6 weeks after discontinuation. 
Tofacitinib was also associated with dose-dependent increases in B cell counts. 
Preclinical studies have set the stage for evaluation of targeted inhibition of the IFN-γ pathway 
with Janus Kinase (JAK) inhibitors in alopecia areata. Importantly, ruxolitinib, a JAK1/2 
inhibitor, reverses AA pathogenesis in the C3H-HeJ mouse model, preventing development of 
disease. Furthermore based on GWAS studies conducted by our collaboratorsˡ and an 
independent replication study we know that the IFN-γ pathway is relevant in human AA. Based 
on this clear rationale and the relative safety of tofacitinib in this young, otherwise-healthy, 
motivated population, we propose the following RCT pilot study to evaluate tofacitinib as a 
therapeutic modality in AA. 
 
To our knowledge, tofacitinib has never been examined in human AA except for a single case 
report of the treatment of a patient with alopecia universalis and psoriasis with tofacitinib.  That 
patient reportedly regrew all scalp and body hair. We propose an open-label clinical trial to test 
the safety and efficacy of tofacitinib 5mg to 10mg orally, twice-daily dosing for up to 6 to 12 
months, in the treatment of 15 subjects diagnosed with moderate to severe patch-type AA 
and/or AT/AU. This initial clinical experience with tofacitinib, if positive, would provide the basis 
for considering and designing subsequent larger and appropriately powered RCTs.  
 
The study proposed here targets the identical moderate-severe AA patient population as two 
other preceding RCT studies that also evaluated therapeutic effects of immune biologics 
(alefacept and efalizumab) (Price et al, 2008; Strober et al, 2009). In addition, we propose an 
exploratory substudy in a small group of patients with AT/AU. 
 
Since the initial writing of this protocol new preliminary findings have noted significant hair 
regrowth in patients who are treated with tofacitinib at a dose of 10mg PO BID. Based on 
previously a published report of successful treatment of alopecia areata with tofacitinib (JID 
June 2014. Killing Two Birds with One Stone: Oral Tofacitinib Reverses Alopecia Universalis in 
a Patient with Plaque Psoriasis. Brittany G. Craiglow, MD and Brett A. King, MD, PhD. 
Department of Dermatology, Yale University School of Medicine, New Haven, CT.) and 
subsequent unpublished information from Dr. King and other investigators using tofacitinib in 
the treatment of alopecia areata, it is evident that a longer course of treatment may be needed, 
for some patients to achieve full response.  In addition, there have not been serious adverse 
effects noted in this study, or per the unpublished reports of other investigators who have used 
tofacitinib for extended periods in patients with alopecia areata.  Therefore it appears that 
increasing the duration of treatment may be beneficial in some patients and is well tolerated. 
 
 
2. Patients with mild disease are excluded since natural remission is considerably more 
likely in the early stages of disease or in mild disease (involving less than 25% hair loss) where 
spontaneous successful regrowth has been reported in up to 50% of individuals34. In more 
extensive disease, spontaneous remissions are less likely and are usually restricted to 
incomplete hair regrowth involving a minority of scalp areas. Thus to minimize placebo 
response rates this study is specifically focused on subjects with moderate to severe 


 
 
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30 
patch type alopecia areata with greater than 30% hair loss or alopecia totalis or 
universalis and disease duration greater than 3 months.  
 
We have adopted the following study plan to identify a treatment “signal” in alopecia areata:  
 
The standard dosing schedule of tofacitinib 5mg orally twice daily, currently used in rheumatoid 
arthritis treatment, will also be used here to begin treatment of moderate to severe alopecia 
areata or AT/AU. This dose may be increased up to 10mg orally twice daily, if clinically 
indicated and at the investigator’s discretion, for a total treatment duration of up to 6 to 18 
months. 
 
5 
STUDY OBJECTIVES 
5.1 
Primary Objective 
 
The study’s primary efficacy endpoint will be the proportion of responders at the end of 
treatment, after up to 24 weeks/6 months to 72 weeks/18 months of treatment, defined as 50% 
or greater hair re-growth from baseline as assessed by SALT at week 24 to 72. This is a 
relatively strict definition for defining responders and non-responders and was chosen to 
minimize the potential for spontaneous remission, in which fewer than 10% are expected to 
achieve this magnitude of hair regrowth spontaneously. 
The duration of treatment will be up to 6 to 18 months, at the discretion of the investigator, 
dependent on individual subject response as well as safety considerations. 
 
To assess the durability of responses, patients who achieve 50% regrowth from baseline 
during the first 6 to 18 months, will continue to be followed for an additional 6 months off 
treatment or until it is determined that relapse has occurred. 
 
5.2 
Secondary Objectives 
As secondary endpoints, safety and additional efficacy outcomes will be assessed. Additional 
efficacy outcomes will be measured by changes in hair re-growth as a continuous variable as 
determined by physical exam and Canfield photography, as well as patient and physician 
global evaluation scores. To assess the durability of responses, patients who achieve 50% 
reduction in baseline SALT score will continue to be followed for an additional 6 months off 
treatment or until it is determined that relapse has occurred. 
 
Secondary efficacy outcomes in detail 
1. Percent hair regrowth from baseline determined by SALT measurements following end 
of treatment (at 24 to 72 weeks) and during the observational phase at 8, 16, and 24 
weeks after end of treatment. 


 
 
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2. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate (<10%), with response defined as 50% change 
in SALT score (50% regrowth) from baseline, at end of treatment (week 24 to 72), and 
at the end of study (8, 16, and 24 weeks after end of treatment). 
3. Comparison of the proportion of subjects in each group attaining global overall 
improvement SALT score of A5 (100% coverage) supported by ≤ SALT 25 at the end of 
treatment (week 24 to 72), and at the end of study (8, 16, and 24 weeks after end of 
treatment). 
4. Change in PGA (Physician Global Assessment) based on live evaluations and 
evaluation of standardized photographs between baseline, and each subsequent visit 
during the treatment period and the follow up period. 
5. Change in patient global assessment between baseline, and each subsequent visit 
during the treatment period and the follow up period. 
6. Change in patient quality of life assessment from baseline compared to subsequent 
visits during the treatment period and the follow up period. 
7. Frequency of occurrence and timing of relapse (as defined above) in responders 
followed for 6 months off therapy. 
8. Safety will be evaluated as a secondary endpoint using descriptive statistics to 
summarize the cumulative incidence and types of AEs.  
9. The proportion of patients who discontinued treatment will be summarized. 
 
6 
ETHICAL CONSIDERATIONS 
6.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonization (ICH) and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB) approval/favorable opinion before initiation of the study. 
All potential serious breaches must be reported immediately. A serious breach is a breach of 
the conditions and principles of GCP in connection with the study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects 
of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct 
or fraud (e.g., loss of medical licensure; debarment). Systems with procedures that ensure the 
quality of every aspect of the study will be implemented. 


 
 
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32 
6.2 
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator 
should also provide the IRB with a copy of the Investigator Brochure or product labeling, 
information to be provided to subjects, and any updates. The investigator should provide the 
IRB with reports, updates, and other information (e.g., expedited safety reports, amendments, 
and administrative letters) according to regulatory requirements or institution procedures. 
 
6.3 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. Freely given written informed consent must be obtained from every subject before 
clinical study participation, including informed consent for any screening procedures conducted 
to establish subject eligibility for the study. 
The rights, safety, and well-being of the study subjects are the most important considerations 
and should prevail over interests of science and society. 
 
7 
INVESTIGATIONAL PLAN 
7.1 
Study Design and Duration 
Screening: A complete medical history will be taken. Patients will be screened for pre-existing 
renal (basic metabolic and urine analysis), hematologic (CBC with differential and 
reticulocytes) or hepatic dysfunction; lipid panel; prior exposure to tuberculosis (PPD and or 
quantiferon test) or hepatitis; pregnancy tests will be done in women of childbearing potential. 
Assessments: Baseline assessments of disease severity will be done. This will include SALT 
score (Severity of Alopecia Tool, Addendum 1), Physician global assessment (PGA), patient 
global assessment and patient quality of life assessment. In order to minimize or eliminate 
inter-rater variability, every effort will be made to have the same investigator evaluate an 
individual subject at each visit. Whenever possible the same investigator (the PI or her 
designee) will examine the patient’s scalp, determine the SALT score, and grade the 
photographic images. 
Visit Schedule and Assessments 
Screening assessments and all scheduled study visits are outlined in the Table of Study 
Assessments, Addendum 2. 
Baseline to Week 24 (period on study medication) 


 
 
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Patients will be seen at baseline, and at weeks 4, 8, 12, 16, 20 and 24 weeks. Assessments of 
disease severity will be performed via physical exam and photography and will be objectively 
quantified using the SALT, Physician global assessment (PGA) at baseline, and weeks 4, 8, 
12, 16, 20, and 24, and patient global assessment and patient quality of life assessment at 
baseline and weeks 12 and 24. 
PGA and patient evaluations will be based on similar 100mm visual analog scales with 0 
labeled as no scalp hair loss and 100 labeled as complete scalp hair loss. Patients and 
physicians will place a vertical mark along the horizontal line depending on their assessment of 
the degree of hair loss present at the time of assessment. 
Patient quality of life assessments will be based on changes in the Dermatology Life Quality 
Index DLQI, which we have previously used for patient evaluation in the AA registry, and the 
Skindex-29 Questionnaire. 
Photography will be performed at baseline and weeks 4, 8, 12, 16, 20, and 24; skin biopsies 
will be performed at baseline and weeks 4 and 24; blood draws for safety parameters and 
immune studies will be done based on the attached table of study procedures.  
Optional additional biopsies and blood draws may be obtained at the investigator’s discretion 
and with the subject’s permission as indicated by clinical considerations such as variation in 
the timeline to regrowth from one subject to another, focal apparent resistance to treatment, as 
well as other potential unpredictable clinical occurrences. Unscheduled biopsies and blood 
draws will ensure that tissue and blood samples can be obtained at optimal time points to 
evaluate the changes occurring in response (or lack of response) to treatment. The patient will 
be given the option to agree to, or decline, the additional biopsies and blood draws.  
Adverse events will be assessed at every visit. 
 
Week 28 to 72 (Optional treatment extension) 
The treatment duration may be extended by up to 12 additional months beyond the initially 
scheduled 6 months of treatment, if clinically indicated and at the discretion of the investigator. 
Patients will continue to be seen monthly while on extended tofacitinib treatment. Assessments 
of disease severity will continue to be performed via physical exam and photography, and will 
be objectively quantified using the SALT and Physician global assessment (PGA). Patient 
global assessment and patient quality of life assessment will also be completed. 
PGA and patient evaluations will be based on similar 100mm visual analog scales with 0 
labeled as no scalp hair loss and 100 labeled as complete scalp hair loss. Patients and 
physicians will place a vertical mark along the horizontal line depending on their assessment of 
the degree of hair loss present at the time of assessment. 
Patient quality of life assessments will be based on changes in the Dermatology Life Quality 
Index DLQI, which we have previously used for patient evaluation in the AA registry, and the 
Skindex-29 Questionnaire. 
Photography will be performed at all visits. 


 
 
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34 
Optional additional biopsies and blood draws may be obtained at the investigator’s discretion 
and with the subject’s permission as indicated by clinical considerations such as variation in 
the timeline to regrowth from one subject to another, focal apparent resistance to treatment, as 
well as other potential unpredictable clinical occurrences. Unscheduled biopsies and blood 
draws will ensure that tissue and blood samples can be obtained at optimal time points to 
evaluate the changes occurring in response (or lack of response) to treatment. The patient will 
be given the option to agree to, or decline, the additional biopsies and blood draws.  
Adverse events will be assessed at every visit. 
 
8, 16, and 24 weeks after end of treatment (follow-up period off study medication) 
All patients will be seen at 8, 16, and 24 weeks after completion of study drug, to determine 
durability of response or evidence for a delayed effect. Importantly patients who achieved 
≥50% regrowth as measured by SALT score (responders) will be seen at 8, 16, and 24 weeks 
after end of study treatment in order to assess the frequency and timing of relapse or to 
capture the occurrence of further regrowth.  
Relapse will be defined as any recurrence of hair loss in responders (subjects achieving 
greater than 50% decrease in SALT score from baseline during the first 6 to 18 months of the 
study) who had achieved stable regrowth without continued loss for at least 2 months; and loss 
of ≥25% of regrowth in patients who had achieved 50% regrowth during treatment but still had 
chronic low grade hair loss.  
Nonresponders will also be offered the option to continue follow-up in order to assess for 
delayed response. Efficacy evaluations: SALT, PGA, Patient global assessment and patient 
quality of life assessment will be performed. 
Blood draws for safety parameters will be conducted at 8 weeks after end of treatment if 
deemed necessary to assess normalization of any previously abnormal values.  
Adverse events will be assessed at every visit. 
Standardized photographs of the subject’s scalp will be taken at every visit; blood draws for 
safety parameters and immune studies will be done based on the attached table of study 
procedures. Photographs will be used to support determination of percent hair regrowth. 
Photography will be performed using a high resolution digital camera with Intellistudio system 
from Canfield Scientific, Inc., Patients will be positioned using a laser guide, after which 
photographs of the entire scalp will be taken at standardized locations and at a fixed distance. 
Close-up photographs may also be taken using an epiluminescent attachment in order to 
assess for the presence of early regrowth. 
 
Unscheduled Visits 
An unscheduled visit can occur at any time during the study for instance as prompted by signs 
of infection or local injection site reactions. A source document must be maintained for these 
unscheduled visits. The date for the visit and any data generated must be recorded on the 


 
 
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35 
appropriate CRF. At treatment discontinuation/early termination subjects will undergo end off 
study evaluations per the Schedule of Assessments. 
Telephone contact/retention 
Patients will be contacted on a monthly basis, between the planned study visits at 8, 16, and 
24 weeks, in the observational phase of the study to ascertain the occurrence of adverse 
events as well as to assess the status of hair growth or loss.  
Any concerns or questions the patient may have will also be addressed. If deemed necessary, 
the subject may be asked to come in for an unscheduled visit. 
 
Duration of Treatment 
After the screening period, subjects will begin tofacitinib 5mg twice-daily and will continue 
treatment for 6 months. The treatment may be extended by up to 12 additional months if 
clinically indicated at the discretion of the investigator. 
The 18-month treatment period is expected to provide adequate time to assess the short-term 
efficacy and safety of tofacitinib in patients with moderate to severe AA, AT or AU. Responders 
will then be followed for 6 months off drug.  
Study Population                                                                                                                                
For entry into the study, the following criteria MUST be met. Any exceptions must be approved 
by the Principal Investigator and/or IRB before enrollment.  
 
7.2 
Inclusion Criteria 
1) Signed Written Informed Consent 
Before any study procedures are performed, subjects will have the details of the study 
described to them, and they will be given a written informed consent document to read. 
Subjects will have the opportunity to ask questions.  They may also take the Informed 
Consent document home for discussion with family or friends. If subjects consent to 
participate in the study, they will indicate that consent by signing and dating the informed 
consent document in the presence of study personnel. A copy of the signed informed 
consent will be given to the subject. 
2) Men and women between the ages of 18 and 65 years of age. 
3) Patients with a diagnosis of moderate to severe patch type alopecia areata  
4) Patients with alopecia totalis or universalis may be enrolled 
5) Patients will have >30% and <95% total scalp hair loss at baseline as measured using the 
SALT score to qualify as moderate to severe patch type AA; and 95-100% scalp hair loss to 
qualify as alopecia totalis or universalis 
6) Duration of hair loss greater than 3 months without an upper limit of duration as long as 
there is reason to believe that regrowth is possible in the opinion of the investigator. 
7) No evidence of significant active ongoing regrowth present at baseline. 


 
 
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8) Patients with a history of alopecia totalis/universalis can be included as long as the current 
episode of hair loss meets the criteria of 30 to 95% hair loss (i.e. they are not currently AT 
or AU), and as long as in the opinion of the investigator there does appear to be potential 
for regrowth. Patients with current episodes of alopecia totalis/universalis may be included 
in this study. 
9) Vaccinations should be up to date in agreement with current immunization guidelines prior 
to start of tofacitinib. The patient will be asked to obtain verbal verification from their 
primary care provider that this is the case. 
10) Patients may be naïve to treatment or unresponsive to intralesional (IL) steroids or other 
treatments for alopecia areata. 
11) Women of childbearing potential (WOCBP) must use highly effective methods of birth 
control [for at least 12 weeks after the last dose of investigational product] to minimize the 
risk of pregnancy. WOCBP must follow instructions for birth control for the entire duration of 
the study including a minimum of 90 days after dosing has been completed. 
Acceptable methods of highly effective birth control include: 
• Condom with spermicide 
• Diaphragm and spermicide 
• Cervical cap and spermicide 
The use of intrauterine devices, (IUDs) shall be at the discretion of the  investigator.  
a) Women must have a negative serum or urine pregnancy test (minimum sensitivity 
25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational 
product.  
b) Women must not be breastfeeding 
 
7.3 
Exclusion Criteria 
1) Sex and Reproductive Status 
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy 
for the entire study period and for up to 12 weeks after the last dose of study drug.  
b) WOCBP using a prohibited contraceptive method.  
c) Women who are pregnant or breastfeeding. 
d) Women with a positive pregnancy test on enrollment or before administration of 
tofacitinib. 
e) Sexually active fertile men not using effective birth control if their partners are WOCBP. 
 
2) Target Disease Exceptions 
a) Patients with a history of or active skin disease on the scalp such as psoriasis or 
seborrheic dermatitis. 
b) Patients in whom the diagnosis of alopecia areata is in question or in whom the pattern 
of hair loss is such that quantification of hair loss and assessment of regrowth is difficult. 


 
 
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37 
E.g. patients with diffuse alopecia areata. This assessment is at the investigator’s 
discretion. 
c) Patients with active medical conditions or malignancies (except adequately treated 
basal or squamous cell carcinoma) that in the opinion of the investigator would increase 
the risks associated with study participation, including patients with a history of recurrent 
infections. 
d) Patients with hemoglobin levels <9 g/dL, lymphocyte count <500 cells/mm3, absolute 
neutrophil count (ANC) < 1000 cells/mm3,  at baseline. 
e) Patients known to be HIV or hepatitis B or C positive. 
f) Patients with history or evidence of moderate or severe hepatic and/or renal 
impairment. 
g) Patients with history of immunosuppression or history of recurrent serious infections. 
 
3) Coexisting disease or concurrent medications 
a) Patients taking potent inhibitors of Cytochrome P450 3A4 (e.g. ketoconazole) 
b) Patients receiving one or more concomitant medications that result in both moderate 
inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). 
c) Patients known to be HIV or hepatitis B or C positive. 
d) Patients with evidence of infection or active/untreated skin cancer. 
e) Patients who have been treated with intralesional steroids, systemic steroids, anthralin, 
squaric acid, DPCP (diphenylcycloprophenone), protopic, minoxidil or other medication 
which in the opinion of the investigator may affect hair regrowth within one month of the 
baseline visit. 
f) Patients who are impaired, incapacitated, or incapable of completing study-related 
assessments. 
g) Patients with current symptoms of severe, progressive, or uncontrolled renal, hepatic, 
hematologic, gastrointestinal, pulmonary, cardiac, neurologic, or cerebral disease, 
which, in the opinion of the investigator, might place a subject at unacceptable risk for 
participation in the study. 
h) Female patients who have had a breast cancer screening that is suspicious for 
malignancy and in whom the possibility of malignancy cannot be reasonably excluded 
by additional clinical, laboratory, or other diagnostic evaluations. 
i) Patients with a history of cancer in the last 5 years, other than non-melanoma skin cell 
cancers cured by local resection or carcinoma in situ. Existing non-melanoma skin cell 
cancers should be removed, the lesion site healed, and residual cancer ruled out before 
administration of the study drug. 
j) Patients who currently abuse drugs or alcohol. 
k) Patients with evidence (as assessed by the investigator) of active or latent bacterial or 
viral infections at the time of potential enrollment, including subjects with evidence of 
human immunodeficiency virus (HIV) detected during screening. 
l) Patients with herpes zoster or cytomegalovirus (CMV) that resolved less than 2 months 
before the informed consent document was signed. 


 
 
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m) Patients who have received any live vaccines within 3 months of the anticipated first 
dose of study medication. Subjects may not receive live vaccine concurrently with 
tofacitinib. 
n) Patients with a history or symptoms suggestive of gastrointestinal perforation or 
disorders that might increase the risk of GI perforation such as gastric ulcers or 
diverticulitis 
o) Patients who take NSAIDs at high dose or on a frequent basis, which in the 
investigator’s opinion might increase the risks of gastrointestinal perforation 
p) Patients with any serious bacterial infection within the last 3 months, unless treated and 
resolved with antibiotics, or any chronic bacterial infection (e.g., chronic pyelonephritis, 
osteomyelitis, or bronchiectasis). 
q) Patients at risk for tuberculosis (TB). Specifically excluded from this study will be 
subjects with a history of active TB within the last 3 years, even if it was treated; a 
history of active TB greater than 3 years ago, unless there is documentation that the 
prior anti-TB treatment was appropriate in duration and type; current clinical, 
radiographic, or laboratory evidence of active TB; and latent TB that was not 
successfully treated (≥ 4 weeks). 
 
4) Physical and Laboratory Test Findings 
a) Patients must not be positive for HIV, Hepatitis B or C. 
b) Patients who are positive for hepatitis C antibody if the presence of hepatitis C virus 
was also shown with polymerase chain reaction or recombinant immunoblot assay. 
c) Patients with any of the following laboratory values 
i) Hemoglobin <9.0 g/dL 
ii) Lymphocytes <500/mm3  
iii) ANC <1000 cells/mm3  
iv) Serum creatinine >2 times the ULN 
v) Serum ALT or AST >2 times the ULN 
Any other laboratory test results that, in the opinion of the investigator, might place a 
subject at unacceptable risk for participation in the study. 
 
7.4 
Prohibited Treatments and/or Therapies 
a) Patients who have at any time received treatment with any investigational drug within 
28 days (or less than 5 terminal half-lives of elimination) of the Day 1 dose. 
b) Any 
concomitant 
Disease 
Modifying 
Anti-Rheumatic 
Drugs 
(DMARDS) 
or 
immunosuppressants, such as anakinra, methotrexate, adalimumab, etanercept, 
azathioprine, cyclosporine, corticosteroids, etc. 
c) Patients who have been treated with intralesional steroids, systemic steroids, anthralin, 
squaric acid, DPCP (diphenylcycloprophenone), protopic, minoxidil or other medication 
which in the opinion of the investigator may affect hair regrowth within one month of the 
baseline visit. 


 
 
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d) Patients receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., 
ketoconazole) 
e) Patients receiving one or more concomitant medications that result in both moderate 
inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole). 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
patients and to ensure that the results of the study can be used. It is imperative that patients 
fully meet all eligibility criteria.  


 
 
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7.5 
Women of Childbearing Potential 
Women of childbearing potential (WOCBP) include any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy), and who is not postmenopausal. Post menopause is 
defined as:  
 Amenorrhea ≥ 12 consecutive months without another cause, and a documented 
serum follicle stimulating hormone (FSH) level > 35 mIU/mL or  
 Women with irregular menstrual periods and a documented serum follicle stimulating 
hormone (FSH) level > 35 mIU/mL or 
NOTE: FSH level testing is not required for women  62 years old with amenorrhea of  1 year 
 Women on hormone replacement therapy (HRT) 
Women who are using oral or other hormonal contraceptives, such as vaginal products, skin 
patches, or implanted or injectable products, or mechanical products, such as an intrauterine 
device or barrier methods (diaphragm, condoms, spermicides), to prevent pregnancy or who 
are practicing abstinence or who have a sterile (e.g., vasectomy) partner should be considered 
to be of childbearing potential. 
 
7.6 
Concomitant Treatments 
7.6.1 
Prohibited and/or Restricted Treatments 
Any medication known to affect hair growth in alopecia areata including but not limited to 
topical, intralesional or systemic steroids, squaric acid, anthralin, protopic, minoxidil, 
diphenylcyclopropenone, cyclosporine and any other medications, which in the judgment of the 
investigator, may affect hair growth in patients with alopecia areata. 
 
Any medications known to be potent inhibitors of cytochrome P450 3A4 (CYP3A4) (e.g., 
ketoconazole), or one or more concomitant medications that result in both moderate inhibition 
of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole), due to loss or reduced clinical 
response to tofacitinib. 
 
Any immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine), that can 
potentiate risk for immunosuppression. 
 
7.6.2 
Other Restrictions and Precautions 
Not applicable. 


 
 
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7.7 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue study treatment and withdraw from the study for any of the 
following reasons: 
 Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
 Any clinical adverse event (AE), laboratory abnormality, or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the 
best interest of the subject 
 Pregnancy 
 Instruct WOCBP to contact the investigator or study staff immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation. Institutional policy and local regulations should determine the 
frequency of on-study pregnancy tests for WOCBP enrolled in the study. 
 Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (e.g., infectious disease) illness. 
 
8 
TREATMENTS 
8.1 
Study Treatment: Tofacitinib 
An investigational product, also known as investigational medicinal product in some regions, is 
defined as follows: A pharmaceutical form of an active substance or placebo being tested or 
used as a reference in a clinical study, including products already with a marketing 
authorization but used or assembled (formulated or packaged) in a way different from the 
authorized form, or used for an unauthorized indication, or when used to gain further 
information about the authorized form. In this protocol, the investigational product is tofacitinib. 
Other medications used in the study as support or escape medication for preventative, 
diagnostic, or therapeutic reasons as components of a given standard of care are considered 
non-investigational products.  
8.1.1 
Identification 
Tofacitinib is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, 
round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and “JKI 5” 
on the other side. 
 


 
 
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42 
8.1.2 
Storage, Handling, and Dispensing 
The investigational product should be stored in a secure area according to local regulations. 
The investigator is responsible for ensuring that it is dispensed only to study subjects and only 
from official study sites by authorized personnel, as dictated by local regulations. 
All investigational product supplies that will be used in the study must be maintained securely 
under the direct responsibility of the investigator or delegated by the investigator to the hospital 
pharmacist, or other personnel licensed to store and dispense drugs. All drugs shall be 
dispensed in accordance with the investigator’s responsibility to ensure that an accurate record 
of drugs issued and returned is maintained. 
The investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity), as determined by the 
sponsor and defined by the Investigator Brochure or SmPC/ reference label. If concerns 
regarding the quality or appearance of the investigational product arise, do not dispense the 
investigational product and contact the sponsor immediately. Refer to the Investigator 
Brochure for additional information regarding handling, preparation, and storage of tofacitinib.  
 
8.1.3 
Additional Information for the Handling, Dispensing, and Storage of 
Tofacitinib 
 
White, round, immediate-release film-coated tablets, debossed with “Pfizer” on one side, and 
“JKI 5” on the other side, and available in: 
Bottles of 28:   
 
 
 
 
 
NDC 0069-1001-03 
Bottles of 60:   
 
 
 
 
 
NDC 0069-1001-01 
Bottles of 180:   
 
 
 
 
 
NDC 0069-1001-02 
 
Storage and Handling 
Store at 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature]. 
Do not repackage. 
 
8.2 
Selection and Timing of Dose for Each Subject 
Patients will be treated with tofacitinib 5 mg to 10mg twice-daily. Treatment will be continued 
for up to 6 to 18 months to provide adequate time to assess the short-term efficacy and safety 
of tofacitinib in patients with alopecia areata. Study drug dose may be modified or held at the 
discretion of the investigator. Patients will then be followed for an additional 6 months after 
completion of treatment to assess the timing and incidence of relapse or to monitor for delayed 
or continued response after end of treatment. 
 


 
 
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43 
8.2.1 
Dose Modifications for Adverse Events 
If there is evidence of toxicity, as determined by laboratory tests or by clinical assessment that 
could place the subject at increased risk in the judgment of the investigator, administration of 
tofacitinib will be decreased or interrupted. Subjects may be considered eligible to continue 
with tofacitinib treatment only if full resolution of the adverse event is documented. 
 
8.3 
Concomitant Treatments 
8.3.1 
Prohibited and/or Restricted Treatments 
The following medications are prohibited throughout the complete study period: 
 Any medications known to affect hair growth in alopecia areata including but not limited to 
topical, intralesional or systemic steroids, anthralin, squaric acid, diphenylcyclopropenone, 
protopic, cyclosporine or any other medications which in the opinion of the investigator may 
affect hair growth in AA. 
 Live vaccines. 
 Use of any investigational drug other than study medication. 
 Corticosteroid use at unstable dose and/or superior to the equivalent of prednisone 
10 mg/day is not permitted. 
8.3.2 
Other Restrictions and Precautions 
8.4 
Immunizations 
There is limited information available regarding the effectiveness of immunizations in non-
human primates and humans that have been treated with tofacitinib. Limited data are available 
on the effect of therapeutic vaccinations in subjects receiving tofacitinib. 
Due to the risk of infection, vaccination of subjects with any live vaccine is absolutely 
contraindicated during the treatment phase of the study (that is, at any time after entry into the 
induction period), as is the administration of LIVE oral polio vaccine to household contacts. 
The Centers for Disease Control and Prevention Advisory Committee on Immunization 
Practices (CDC-ACIP) recommends that subjects should not be administered a live virus 
vaccination for at least 3 months after discontinuing high-dose corticosteroid therapy (defined 
as more than 20 mg of prednisone per day for more than 2 weeks). In view of the long half-life 
of tofacitinib, study subjects should not be administered a live virus vaccine for a minimum of 
3 months following the last dose of tofacitinib. 
 


 
 
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8.5 
Treatment Compliance 
Compliance will be documented via the use of patient diaries to record the date and time of 
self-administration of medication at home. Study drug reconciliation will be performed at each 
visit during the treatment period. 
 
9 
STUDY ASSESSMENTS AND PROCEDURES 
9.1 
Time and Events Schedule 
The Time and Events Schedule (Section 6, Table 3) summarizes the frequency and timing of 
various measurements. 
 
Pre-screening procedures 
Written informed consent will be obtained for this study by the principal investigator or his/her 
designee from all patients prior to any protocol-specific procedures. The study will be 
conducted in accordance with the Food and Drug Administration (FDA) approved revision of 
the Declaration of Helsinki, current FDA regulations, and International Conference on 
Harmonization (ICH) guidelines.  
 


 
 
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Procedures Performed Prior to Treatment  
Screening (Day -28 to -1):  
The following screening evaluations will be performed within 4 weeks prior to enrollment: 
 Informed consent, inclusion/exclusion criteria, prior concomitant medications 
 Medical history, physical examination, including a dermatological exam 
 Vital signs, body weight 
 Assessments of disease severity (amount of hair loss present) will be conducted 
including SALT (Severity of Alopecia Tool) and Physician's global assessment (PGA) 
 Clinical laboratory evaluation (complete blood count, basic metabolic profile, hepatic 
panel and urinalysis), hepatitis B and C screening panel, HIV test, fasting lipid profile, 
serum pregnancy test for women of child bearing potential. 
 Tuberculosis testing (PPD skin test or quantiferon test) 
 
A visit will be scheduled 48-72 hours after placement of the PPD for reading of the test results. 
If the subject is unable to return for PPD, the results may be interpreted and documented by a 
qualified medical professional. If possible, the PPD reading visit may be combined with the 
baseline visit. The results of all assessments/tests listed above must be reviewed prior to 
enrollment to ensure that the patient meets entry criteria and that no exclusion criteria are 
present. 
 
 Baseline (Day 0) Procedures Performed Prior to treatment 
 Review of inclusion/exclusion criteria 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP 
 Blood collection for immunological studies 
 Scalp biopsy (4mm punch biopsy) 
 
Weeks 4, 8, 12, 16, and 20 (Days 28, 56, 84, 112, and 140)  
Visit days will have an acceptable window of ±3 days. 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment (week 12) 
 Urine pregnancy testing for WOCBP 
 Clinical laboratory evaluation (weeks 4, 8, 12, 16, and 20 weeks and as otherwise 
deemed necessary at the discretion of the investigator to monitor for abnormal values 
and for normalization of those values). In general, labs will be drawn ranging from 
weekly to every 4 weeks, depending on whether they are in or out of range, and to 


 
 
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46 
monitor for resolution of abnormalities. Fasting lipid profiles will be repeated at months 1 
and 2, end of treatment and as needed. Scalp biopsy (4mm punch biopsy) (week 4) 
 Blood collection for immunological studies (week 4) 
 Optional Scalp biopsy (4mm punch biopsy) in addition to weeks 4 and 24. Optional 
additional biopsies and blood draws may be obtained at the investigator’s discretion and 
with the subject’s permission as indicated by clinical considerations such as variation in 
the timeline to regrowth from one subject to another, focal apparent resistance to 
treatment, as well as other potential unpredictable clinical occurrences.  Unscheduled 
biopsies and blood draws will ensure that tissue and blood samples can be obtained at 
optimal time-points to evaluate the changes occurring in response (or lack of response) 
to treatment. The patient will be given the option to agree to, or decline, the additional 
biopsies and blood draws.  
- 
Optional Blood collection for immunological studies, at the discretion of the investigator 
as outlined above.  
 
Week 24 (day 168±7) – End of Treatment  
 Vital signs, body weight 
 Physical and dermatological examination 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP  
 Clinical laboratory evaluation 
 Scalp biopsy (4mm punch biopsy) 
 Blood collection for immunological studies  
 
Weeks 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, and 72 (Optional Treatment Extension)  
The treatment duration may be extended up to 12 additional months if clinically indicated at the 
discretion of the investigator. Visit days will have an acceptable window of ±7 days. 
 Vital signs, body weight 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Urine pregnancy testing for WOCBP 
 Clinical laboratory evaluation (as scheduled and as otherwise deemed necessary at the 
discretion of the investigator to monitor for abnormal values and for normalization of 
those values). 
 Optional Scalp biopsy (4mm punch biopsy). Optional additional biopsies and blood 
draws may be obtained at the investigator’s discretion and with the subject’s permission 
as indicated by clinical considerations such as variation in the timeline to regrowth from 
one subject to another, focal apparent resistance to treatment, as well as other potential 


 
 
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unpredictable clinical occurrences.  Unscheduled biopsies and blood draws will ensure 
that tissue and blood samples can be obtained at optimal time-points to evaluate the 
changes occurring in response (or lack of response) to treatment. The patient will be 
given the option to agree to, or decline, the additional biopsies and blood draws.  
- 
Optional Blood collection for immunological studies, at the discretion of the investigator 
as outlined above.  
 
 8, 16, and 24 Weeks after End of Treatment – Observational Period  
 Vital signs, body weight 
 Physical and dermatological examination (only at End of Study) 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment (weeks 32 and 48) 
 Clinical laboratory evaluation at 8 weeks after End of Treatment for safety parameters 
will be conducted if deemed necessary to assess for normalization of any previously 
abnormal values 
 Optional Scalp biopsy as indicated 
 Optional Blood collection as indicated 
 
Early Termination 
 Vital signs, body weight 
 Physical and dermatological examination 
 Adverse events reporting, concomitant medication review 
 Photography 
 Physician evaluation utilizing the PGA and SALT scale 
 Patient global assessment and quality of life assessment 
 Clinical laboratory evaluation if indicated 
 Optional scalp biopsy and blood collection for immunological studies 
 The reason for early withdrawal/study drug discontinuation must be documented 
 
Unscheduled Visits 
An unscheduled visit can occur at any time during the study. A source document must be 
maintained for these unscheduled visits. The date for the visit and any data generated must be 
recorded on the appropriate CRF. At treatment discontinuation/early termination subjects will 
undergo study evaluations per the Schedule of Assessments.  
 
Duration of Treatment 
Treatment will be continued for up to 6 to 18 months to provide adequate time to assess the 
short-term efficacy and safety of tofacitinib in patients with alopecia areata. Patients will then 
be followed for an additional 6 months to assess the timing and incidence of relapse of AA.   
 


 
 
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9.2 
Study Completion or Early Discontinuation Visit 
At the time of study early withdrawal, the reason for early withdrawal and any new or 
continuing adverse events should be documented. 
 
9.2.1 
Study Drug Discontinuation 
If study drug administration is discontinued, the reason for discontinuation will be recorded. 
 


 
 
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Table 3: Schedule of Assessments 
Visit 
1 
Screening 
2 
Base-
line 
 
3 
Week 
4 
4 
Week 
8 
5 
Week 
12 
6 
Week 
16 
7 
Week 
20 
8 
Week 
24 
± Weeks 
28, 32, 36, 
42, 44, 48, 
52, 56, 60, 
64, 68, 72 
 
8W ṗ 
End of 
Tx 
 
16W ṗ  
End of 
Tx 
 
24W ṗ  
End of 
Tx 
Day 
-28 to -1 
0 
28±3 
56±3 
84±3 
112 
±3 
140 
±3 
168 
±7 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
X 
 
 
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photography 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SALT evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician global 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient quality of life 
assessment, –  
DLQI & Skindex-29 
 
X 
 
 
X 
 
 
X 
Xc 
X 
 
X 
Patient global 
assessment 
 
X 
 
 
X 
 
 
X 
Xc 
X 
 
X 
Clinical laboratory 
evaluation* 
X 
 
X 
X 
X 
X 
X 
X 
X 
Xa 
 
 
Hepatitis & HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Fasting Lipid Profile 
X 
 
X 
X 
 
 
 
X 
Xc 
 
 
 
PPD test and reading 
or quantiferon testing 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Scalp Biopsy 
 
X 
X 
Xb 
Xb  
Xb  
Xb 
X 
Xb 
Xb 
Xb 
Xb 
Phlebotomy for 
immunological studies 
 
X 
X 
Xb  
Xb  
Xb  
Xb 
X 
Xb 
Xb 
Xb 
Xb 
a Clinical laboratory evaluation consists of CBC w/diff, BMP, hepatic panel, fasting lipid panel and urinalysis.  Additional evaluations may be performed (including after the end of 
treatment visit) if needed to monitor or to verify normalization of previously abnormal lab values. 
b Optional additional biopsies and blood draws may be obtained at the investigator’s discretion and with the subject’s permission as indicated by clinical considerations such as 
variation in the timeline to regrowth from one subject to another,  focal apparent resistance to treatment, as well as other potential unpredictable clinical occurrences.  
Unscheduled biopsies and blood draws will insure that tissue and blood samples can be obtained at optimal time points to evaluate the changes occurring in response (or lack of 
response) to treatment. The patient will be given the option to agree to, or decline, the additional biopsies and blood draws.  
C at end of treatment  


 
 
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50 
 
9.3 
Study Materials 
Tofacitinib will be purchased at an approved commercial pharmacy and will be managed and 
dispensed by the Columbia University Research Pharmacy.   
 
10 
SAFETY ASSESSMENTS 
Analysis of safety is included as a secondary endpoint.  All subjects who receive a dose of 
tofacitinib will be evaluated for safety. Safety outcomes include adverse events, clinically 
significant changes in vital signs, laboratory test abnormalities, and clinical tolerability of the 
drug. The investigator will determine the severity of each adverse event as mild, moderate, 
severe, or very severe. Laboratory findings that the investigator feels are clinically relevant 
should be recorded as adverse events. In addition, the investigator will determine the 
relationship of the adverse event to the administration of the study drug. Any occurrence of a 
SAE from time of consent forward, up to and including follow-up visits will be reported. See 
Section 6.5 for the SAE reporting procedures. 
10.1 
Physical Examinations 
During the treatment period, the physical examination is to be performed before administration 
of tofacitinib. While the interim physical examination may not be as comprehensive as the 
complete physical examination, important body systems should be included as deemed 
clinically indicated by the investigator. These body systems may include lymph nodes, liver, 
spleen, and breast. An interim physical examination may note any changes in the subject’s 
condition since the last assessment and does not preclude examination of any of the body 
systems as clinically indicated. 
 
10.2 
Tuberculin Skin Testing 
A tuberculin skin test (PPD test: purified protein derivative tuberculosis skin test) should be 
performed and interpreted according to the applicable local Health Authority and/or Medical 
Society guidelines (those that provide recommendations for tuberculin skin testing for subjects 
who are to receive biologics, who are immunosuppressed, who have a prior history of BCG 
vaccinations(viii,ix),or who have a prior positive test). Tuberculin skin testing is not 
contraindicated for persons who have been vaccinated with BCG. 
QuantiFERON® testing is an acceptable alternative when tuberculin skin testing is not 
appropriate. A tuberculin skin test is not required if one was performed within 1 month of 
screening and documentation of testing is on file. If tuberculin skin testing is performed at 
screening, then the 48-72-hour reading must be completed before administration of tofacitinib. 


 
 
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If the results of Tuberculin skin testing are equivocal or positive, quantiferon testing may be 
done to provide additional clinical information. 
11 
EFFICACY ASSESSMENT 
11.1 
Primary Efficacy Assessment 
The study’s primary efficacy endpoint will be the proportion of 
responders after 6 months of treatment, with response defined as 
50% or greater hair re-growth from baseline as assessed by 
SALT score (Figure 6) at week 24. This is a relatively strict 
definition for defining responders and non-responders and was 
chosen to minimize the potential for spontaneous remission, in 
which approximately 8% or less are expected to achieve this 
magnitude of hair regrowth spontaneously. 
 
SALT – Severity of Alopecia Tool 
A. The proportion of scalp involvement is determined by dividing 
the scalp into 4 quadrants and estimating the percentage of the 
scalp surface that all the alopecic areas would occupy if placed 
together. The following groups will be used: 
 
S: Scalp hair loss 
_____S0 = No hair loss  
 
____S4 = 76%-99% hair loss 
_____S1 = <25% hair loss 
        
_____a = 76%-95% hair loss 
_____S2 = 26%-50% hair loss 
 _____b = 96%-99% hair loss 
_____S3 = 51%-75% hair loss  
____S5 = 100% hair loss 
 
Percentage change from baseline (% regrowth) =  
[(SALT BL – SALT F/U)/ SALT BL]  x 100% = % change from baseline 
 
Absolute regrowth = SALT BL – SALT F/U = absolute change from BL 
Body hair loss 
B0 = No body hair loss 
B1 = some body hair loss 
B2 = total (100%) body hair loss 
 
Nail involvement 
N0 = No nail involvement 
N1 = some nail dystrophy 
N1a = 20 nail dystrophy 
 
 
 
 
 
 
Figure 6. SALT score. The 
percentage of hair loss in any 
one of the four views (areas) of 
the scalp = the percentage hair 
loss x percent surface area of 
the scalp in that area. The 
SALT score then equals the 
sum of the scalp hair loss in 
each area. 


 
 
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52 
11.1.1 
Secondary Efficacy Assessments 
As secondary endpoints, efficacy will be measured by changes in hair re-growth as a 
continuous variable as determined by physical exam and Canfield photography, as well as 
patient and physician global evaluation scores. To assess the durability of responses, patients 
will continue to be followed for an additional 6 months off treatment.  To assess the durability 
of response and the incidence of relapse, patients who achieve 50% regrowth from baseline 
(50% reduction in baseline SALT score) will continue to be followed for an additional 6 months 
off treatment or until it is determined that relapse has occurred.  Relapse will be defined as any 
recurrence of hair loss in responders (subjects achieving greater than 50% decrease in SALT 
score from baseline during the first 6 to 18 months of the study) who had achieved stable 
regrowth without continued loss for at least 2 months; and loss of ≥ 25% of regrowth in patients 
who had achieved 50% regrowth during treatment but still had chronic low grade hair loss.  
Nonresponders to 6 months study treatment (defined as failure to achieve 50% improvement in 
SALT score compared to baseline) will not be required to participate in the 6 month follow-up 
period but may be offered open-label tofacitinib if deemed appropriate by the investigator.  
Partial responders will continue to be followed to assess for delayed achievement of complete 
response. Analysis of safety is included as a secondary endpoint.  All subjects who receive a 
dose of tofacitinib will be evaluated for safety. 
 
Secondary efficacy outcomes in detail 
1. Percent hair regrowth from baseline determined by SALT measurements following end 
of treatment (at 24 to 72 weeks) and during the observational phase at 8, 16, and 24 
weeks after end of treatment. 
2. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate (<10%), with response defined as 50% change 
in SALT score (50% regrowth) from baseline, at end of treatment (week 24 to 72), and 
during the observational phase at 8, 16, and 24 weeks after end of treatment. 
3. Comparison of the proportion of subjects in each group attaining global overall 
improvement SALT score of A5 (100% coverage) supported by ≤ SALT 25 at the end of 
treatment (week 24 to 72), and during the observational phase at 8, 16, and 24 weeks 
after end of treatment. 
4. Change in PGA (Physician Global Assessment) based on live evaluations and 
evaluation of standardized photographs between baseline, and each subsequent visit 
during the treatment period and the follow up period. 
5. Change in patient global assessment between baseline, and selected subsequent visits 
during the treatment period and the follow up period. 
6. Change in patient quality of life assessment from baseline compared to selected 
subsequent visits during the treatment period and the follow up period. 
7. Frequency of occurrence and timing of relapse (as defined above) in responders 
followed for 6 months off therapy. 
8. Safety will be evaluated as a secondary endpoint using descriptive statistics to 
summarize the cumulative incidence and types of AEs.  
9. The proportion of patients who discontinued treatment will be summarized. 
 


 
 
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11.2 
Other Assessments 
Photography  
Photography will be performed using a high-resolution digital camera with Intellistudio system 
from Canfield Scientific, Inc. Patients will be positioned using a laser guide, after which 
photographs of the entire scalp will be taken at standardized locations and at a fixed distance.  
Close-up photographs may also be taken using an epiluminescent attachment in order to 
assess for the presence of early regrowth.  
 
Biopsy 
All punch biopsies will be performed by the study 
doctor at a specific location and time point according 
to the schedule of study assessments or at 
unscheduled time points based on clinical indications. 
The biopsy site will be anesthetized with an injection of 
1% lidocaine with epinephrine. After approximately 1 
minute, the physician applies pressure to the biopsy 
site using a 4mm diameter skin punch (a sterile 
cylindrical tube with a sharp edge).  The punch is 
twisted until the blade of the skin punch has pierced 
the epidermis and dermis of the skin and enters the 
subcutaneous fat. Depending on the thickness of the 
skin in the area being biopsied, the cylindrical blade may be buried to the hub (approximately 
6mm in depth).  After the blade has sufficiently cored or carved out a cylinder of skin, the skin 
punch is removed.  Nontraumatic forceps are used to gently grasp the cored skin, pulling 
upward to remove the core and reveal the subcutaneous fat. Scissors are used to cut the 
cored tissue free from the underlying subcutaneous fat.  The specimen is placed immediately 
into the appropriate media. Once the specimen has been removed, pressure is applied to the 
biopsy site with a sterile 2 x 2 gauze. The biopsy site is then closed with several simple 
interrupted sutures. Either an absorbable or nonabsorbable suture may be used at the 
investigator’s discretion.  Antibiotic ointment is applied and the area is covered with a standard 
BandAid or sterile gauze and paper tape. If the presence of adjacent hair makes adhesion os a 
bandage difficult, antibiotic ointment will be used without a covering.  When necessary, a small 
pressure dressing may be applied.  Subjects will be instructed in wound care and will be 
advised to call the research unit if they have any concerning signs or symptoms during healing. 
 
Biosamples 
 
A recent histological/gene expression study of synovial biopsies from RA patients treated with 
tofacitinib noted only mild changes in cellular synovial infiltrates during treatment.  However, 
marked changes in IFN-γ expression was identified, with significant reductions only seen in the 
clinically responding patients (Buch et al. 2009).  The decrease in IFN-γ production in the 
responders implies that functional inhibition of T cell activity is important for therapeutic 
outcome. Our proposed studies will include longitudinal biopsies that could provide additional 
support for interferonγ modulation and tofacitinib treatment outcome.   


 
 
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54 
 
Our procurement of serial biopsies, sera and PBMCs obtained at baseline and during 
treatment will provide the opportunity to correlate resolution of inflammatory biomarkers with 
treatment response in AA.  
  
Biosamples will be obtained upon entry and again after 4 weeks, and 24 weeks of treatment. 
Biospecimens at each time point will include: 1) a 4 mm skin biopsy; 2) 5 ml of blood for 
serum; 3) 60 ml of blood for PBMCs. 
 
Blood volumes for research: 60 ml of blood is required to insure that sufficient viable cells are 
available after thawing of cryopreserved PBMC aliquots to enable functional T cell studies in 
triplicate. Our experience is that viable recovery of PBMC in freeze-thawed specimens is highly 
variable and range from 0.1-1.0 x 106 per ml of blood. Our blood volume obtained for research 
is 65 ml at one time, a maximum of 130 ml in a 4 week period and 260 ml in total over 6 
months. 
 
Biomarker Assessment and Clinical Correlative Studies 
 
Our mechanistic studies are focused on correlating treatment and disease status with;  
1) histological improvement of T cell infiltrates;  
2) reduced IFN responses in the skin and blood;  
3) reduced HF NKG2DL expression; and  
4) declines in circulating and peribulbar CD4+ and CD8+NKG2D+ infiltration.  
 
Previous studies in AA have reported elevated NKG2D expression in circulating CD8 T cells 
and NK cells (Ito et al. 2008), supporting the feasibility of our approach. Here we will be able to 
correlate the numbers of CD8+NKG2D+ cells in the blood with those infiltrating the target organ 
of patients with each other and as a function of disease status. The limited studies proposed 
here seeking an association of IFN-γ and CD8+NKG2D+ cells and clinical outcome will not, 
however, exhaust the “biobank” and all human materials [frozen biopsy tissue & RNA, serum 
and the remaining (90%) of PBMCs] will remain banked and available for future hypothesis 
driven questions. Subjects consent for retention and future use of blood and tissue will be 
requested in the informed consent. 
 
Flow Cytometry Studies.  
The presence of CD8+NKG2D+ cells will be tracked in the blood and in the skin during 
treatment with Tofacitinib. By assessing CD8+NKG2D+ involvement in longitudinally obtained 
skin biopsies at baseline and during treatment we can correlate disease severity and clinical 
response (progression or regression) with immunopathological evidence of resolution of total 
cellular infiltration (by H&E) or loss of specific CD8+NKG2D+ cells in the skin (by IF) or in the 
blood (flow studies).  CD8+NKG2D+ frequency in the peripheral circulation will be quantified 
using freshly isolated PBMCs obtained from 60 mls of blood obtained upon entry into the trial 
and at 4 wks, and 24 wks during treatment. A portion of the PBMCs 5x106 cells will be stained 
with anti-CD4, anti-CD8, anti-CD25, anti-CD28 and anti-NKG2D antibodies, stimulated with 
PMA/ionomycin in the presence of brefeldin and stained with anti-FOXP3 and anti-IFN-γ Abs. 


 
 
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The remaining PBMCs will be used for RNA analysis (see below) and viably frozen for future 
ancillary studies.  We will seek evidence of a comparable pathogenic T cell subset in the 
human that we observed in C3H mice, namely an activated CD25+ IFN-γ-producing 
CD8+NKG2D+ T cell. 
 
Histology and Immunofluorescence Analysis.  
As shown in previous studies (Ito et al. 2008; Petukhova et al. 2010) in active AA NKG2D 
ligands are upregulated on hair follicles in association with peribulbar NKG2D-bearing CD8+ T-
cells and natural killer cells. We will seek evidence of resolution of total cellular infiltration (by H 
& E) and loss of specific CD8+NKG2D+ cells (by IF) and NKG2D ligands by comparing 
baseline biopsies with biopsies obtained on treatment after 4 and 24 weeks.  Frozen sections 
will be stained with and anti-CD4, anti-CD8, anti-CD56, anti-NKG2D and anti-IFN-γ antibodies 
to visualize the total number of leukocytes, cytotoxic T-cells and NK cells present in the 
baseline and drug treated skin, respectively.  Immunostaining with anti-ULBP3, anti-MICA 
antibodies and recombinant NKG2D soluble receptor (NKG2D-Ig, detects all NKG2D ligands, 
R & D systems) will determine whether NKG2DL “danger/stress” signals are down modulated. 
Punch biopsies from patient skin before and after treatment will be embedded in OCT and 7-8 
micron frozen sections will be cut. The sections will be fixed in 4% paraformaldehyde and 
stained overnight with primary antibodies for NKG2D ligands, receptor and immune markers. 
The following day, sections will be treated for 1 hr with fluorescence labeled antibody, counter-
stained and mounted with DAPI containing media. Frozen sections will also be used to for H&E 
staining. The total number of immune cells, as well as NKG2D bearing cells, will be quantified 
by counting stained cells per magnification field using the NIH imaging software ImageJ and a 
student T-test will be carried out to determine significant changes in the number of infiltrating, 
NKG2D bearing immune cells to quantitatively correlate the simultaneous presence or 
absence of these cells in lesional skin and in circulation (by flow) during active disease or in 
remission.   
 
Analysis of Gene Expression by Quantitative RT-PCR  
We will analyze the transcriptional expression signature of costimulatory and IFN-
response genes in the skin and PMBC of drug-treated AA patients using qPCR as an 
indirect measure of the efficacy of tofacitinib. Signature genes were selected based on their 
differential expression in affected vs. unaffected C3H mice (Carroll et al. 2002), and on 
published studies on human AA patients vs. controls (Subramanya et al. 2010) The genes in 
the list represent mediators and effectors of the IFN response, which we found to be 
instrumental in disease pathology. Briefly, biopsies and peripheral blood from baseline and 
tofacitinib treated patients will be collected at 0, 4, and 24 week time points and possibly 
additional timepoints if clinically indicated. RNA will be extracted from the tissues, and Sybr 
green-based qPCR assays will be performed. Differential gene expression resulting from 
inhibitor treatment will be normalized to the expression of a housekeeping gene. We expect 
many of the genes on this list to revert to a basal level of expression, as compared in 
unaffected skin of an AA patient, or skin from a healthy control.  
 
Serum inflammatory biomarkers 


 
 
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Serum (5 ml) will be obtained at baseline and during treatment and assessed for resolution of 
elevated levels of IFN-inducible chemokines.   
12 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
pre-existing medical condition in a patient or clinical investigation subject administered an 
investigational (medicinal) product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of investigational product, whether or not considered related to the investigational product. 
 
12.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
note below for exceptions) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
5) is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention [e.g., 
medical, surgical] to prevent one of the other serious outcomes listed in the definition 
above.) Examples of such events include, but are not limited to, intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization.)  Potential drug induced liver injury (DILI) is also 
considered an important medical event.  (See Section 6.6 for the definition of potential 
DILI.) 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs and should 
also be reported to the IRB and appropriate regulatory bodies in an expedited manner. 
NOTE: The following hospitalizations are not considered SAEs: 
 a visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event) 


 
 
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 elective surgery planned before signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
 medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
 admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative). 
 
12.2 
Nonserious Adverse Events 
Nonserious adverse events are all adverse events that are not classified as SAEs. 
 
12.3 
Assignment of Adverse Event Intensity and Relationship to 
Tofacitinib 
All adverse events, including those that are serious, will be graded by the investigator as 
follows: 
 Mild (Grade 1): awareness of event but easily tolerated 
 Moderate (Grade 2): discomfort enough to cause some interference with usual activity 
 Severe (Grade 3): inability to carry out usual activity 
 Very Severe (Grade 4): debilitating; significantly incapacitates subject despite symptomatic 
therapy. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used: 
 Related: There is a reasonable causal relationship to investigational product administration 
and the adverse event. 
 Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts (e.g., evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
12.4 
Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. To prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more adverse events. 


 
 
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If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, duration, 
intensity, seriousness, relationship to investigational product, action taken, and treatment 
required. If treatment for the event was administered, it should be recorded in the medical 
record. The investigator must supply the IRB and appropriate regulatory bodies with any 
additional information requested, notably for reported deaths of subjects. 
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported/identified during the course of the study. 
 
12.5 
Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all 
SAEs must continue for 30 days after the last administration of the investigational product. If 
applicable, SAEs must be collected that relate to any later protocol-specified procedure. The 
investigator should notify the IRB and FDA as appropriate of any SAE occurring after this time 
period that is believed to be related to the investigational product or protocol-specified 
procedure. 
All SAEs, whether considered related or unrelated to tofacitinib, must be reported to the IRB 
and FDA (by the investigator or designee) within 24 hours of study personnel becoming aware 
of the event. If only limited information is initially available, follow-up reports are required. The 
original SAE form must be kept on file at the study site. 
For studies conducted under an Investigator IND, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. SAEs should be 
reported 
on 
MedWatch Form 3500A, 
which 
can 
be 
accessed 
at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
12.6 
Nonserious Adverse Events 
The investigator will begin collecting nonserious adverse event (NSAE) information once 
administration of the investigational product is initiated.  


 
 
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All identified NSAEs must be recorded and described in the medical record. If an ongoing 
NSAE worsens in its intensity, or if its relationship to the investigational product changes, a 
new NSAE entry for the event should be completed. NSAEs should be followed to resolution or 
stabilization, or reported as SAEs if they become serious. Follow-up is also required for NSAEs 
that cause interruption or discontinuation of investigational product, or those that are present at 
the end of study participation. Subjects with NSAEs at study completion should receive post-
treatment follow-up as appropriate. 
12.7 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. When reporting a test result that constitutes an adverse event, the 
clinical term should be used; for example, the event should be reported as “anemia” not “low 
hemoglobin.” Test results that constitute SAEs should be documented and reported as such. 
12.8 
Overdose 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
12.9 
Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course of the 
study, in such a manner that the risk of failure is minimized. (See Section 7.5 for the definition 
of WOCBP.)  
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy 
during study participation and of the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form documenting this discussion.  
12.9.1 
Requirements for Pregnancy Testing 
All WOCBP MUST have a negative pregnancy test within 72 hours before receiving 
tofacitinib. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units 
of HCG. If the pregnancy test is positive, the subject must not receive Tofacitinib and must not 
continue in the study. 
In addition, all WOCBP must be instructed to contact the investigator and/or other study 
personnel immediately if they suspect they might be pregnant (e.g., missed or late 
menstrual period) at any time during study participation. 
12.9.2 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after administration, the investigational product will be 
permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for 
subject safety).  


 
 
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Protocol-required procedures for study discontinuation and follow-up must be performed for 
the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. Information regarding the 
course of the pregnancy, including perinatal and neonatal outcome, must be reported to the 
IRB and/or FDA as appropriate. Infants should be followed for a minimum of 8 weeks.  
12.10 
Other Safety Considerations 
Any 
significant 
worsening 
noted 
during 
interim 
or 
final 
physical 
examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether or not these 
procedures are required by the protocol, should also be recorded in the medical record. 
 
13 
STATISTICAL CONSIDERATIONS 
13.1 
Sample Size Determination 
Based on two recently completed randomized trials (Price et al, 2008; Strober et al, 2009) in 
similar patient populations (moderate to severe AA) we expect placebo response rates to be 
between 6% (>50% improvement in SALT score) and 12% (>25% improvement). We have 
chosen our primary endpoint conservatively (proportion of patients with >50% improvement in 
SALT index) as a relatively strict criteria that should minimize placebo response rates to 10% 
or less (0-1 of 10 subjects). This allows a higher degree of confidence that appreciable 
response rates are attributable to drug rather than spontaneous remission.  
 
With our sample of n=15, we will have greater than 80% power to reject the null hypothesis 
that the true underlying remission rate is 10% if we observe a rate in our sample of 48%, 
holding type I error to 5%. If we assume that the underlying remission rate is 30%, then we 
have greater than 80% power to reject that null hypothesis if the observed rate is 73% or 
above, again holding type I error to 5%. 
 
 
13.2 
Populations for Analyses 
The Dermatology clinic and private practice at CUMC currently sees 600 AA patients yearly, of 
which we anticipate 20-30% would be eligible (>30% hair loss). Accrual will be greatly 
facilitated by targeted recruitment through our existing NAAF registry, which includes 500 AA 
patients in the New York area, the majority of which have patchy type disease. Thus, complete 
accrual of 60 subjects should be feasible within 1.0 years from a pool of >100 eligible subjects 
each year. 


 
 
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13.3 
Endpoint Definitions 
1. The study’s primary efficacy endpoint will be the proportion of responders after 6 to 18 
months of treatment, with response defined as 50% or greater hair re-growth from 
baseline as assessed by SALT score at week 24 to 72. 
 
Secondary Endpoints 
1. Percent hair regrowth from baseline determined by SALT measurements following end 
of treatment (week 24 to 72) and during the observational phase at 8, 16, and 24 weeks 
after end of treatment. 
2. Comparison of the proportion of responders in the experimental group with the 
historically known placebo response rate (<10%), with response defined as 50% change 
in SALT score (50% regrowth) from baseline, at end of treatment (week 24 to 72), and 
during the observational phase at 8, 16, and 24 weeks after end of treatment. 
3. Comparison of the proportion of subjects in each group attaining global overall 
improvement SALT score of A5 (100% coverage) supported by ≤ SALT 25% at the end 
of treatment (week 24 to 72), and during the observational phase at 8, 16, and 24 
weeks after end of treatment. 
4. Change in PGA (Physician Global Assessment) based on live evaluations and 
evaluation of standardized photographs between baseline, and selected subsequent 
visits during the treatment period and the follow up period. 
5. Change in patient global assessment between baseline, and subsequent selected visits 
during the treatment period and the follow up period. 
6. Change in patient quality of life assessment from baseline to and each subsequent visit 
during the treatment period and the follow up period.  
7. Frequency of occurrence and timing of relapse (as defined above) in responders 
followed for 6 months off therapy. 
8. Safety will be evaluated as a secondary endpoint using descriptive statistics to 
summarize the cumulative incidence and types of AEs.  
9. The proportion of patients who discontinued treatment will be summarized. 


 
 
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10.  
13.4 
Analyses 
13.4.1 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized via descriptive statistics. 
 
13.4.2 
Safety Analyses  
To assess safety, we will summarize the incidence of adverse events for the study group. 
Analysis of safety is included as a secondary endpoint.  All subjects will receive tofacitinib and 
will be evaluated for safety. Safety outcomes include adverse events, clinically significant 
changes in vital signs, laboratory test abnormalities, and clinical tolerability of the drug. The 
investigator will determine the severity of each adverse event as mild, moderate, severe, or 
very severe. Laboratory findings that the investigator feels are clinically relevant should be 
recorded as adverse events. In addition, the investigator will determine the relationship of the 
adverse event to the administration of the study drug. Any occurrence of a SAE from time of 
consent forward, up to and including follow-up visits will be reported. See Section 12 for the 
SAE reporting procedures. 
 
13.4.3 
Efficacy Analyses 
Since this is a small open label proof of concept study, we recognize that it will likely lack 
adequate power to conclusively demonstrate small efficacy signals (particularly if the assumed 
detectable difference of 38% is not met). Yet, descriptive summaries of all the primary and 
secondary efficacy outcomes (proportions for binary outcomes, means for continuous 
outcomes) will provide a preliminary indication of the effect size (even if smaller than 38%) that 
will aid design of subsequent efficacy trials.  
 
14 
ADMINISTRATIVE SECTION 
14.1 
Compliance with the Protocol 
The study must be conducted as described in the final IRB-approved protocol. No protocol 
amendments will be implemented until written approval has been given by the IRB, except 
when necessary to eliminate an immediate hazard to study subjects.  
If a protocol amendment mandates a revision to the informed consent, the revised consent 
must be used to obtain consent from subjects currently enrolled in the study if it affects them 
(e.g., if it contains new information regarding safety), and the revised consent must be used to 
obtain consent from new subjects before enrollment.  
 


 
 
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14.2 
Records Retention 
The investigator will retain, in a confidential manner, all data pertinent to the study for all 
treated subjects as well as those entered as control subjects. The investigator will retain 
source documents and accurate case histories that record all observations and other data 
pertinent to the investigation (e.g., the medical record) for the maximum period required by 
applicable regulations and guidelines or following institutional procedures.  
The Columbia University Research Pharmacy or responsible research pharmacy will ensure 
that a current record of disposition of investigational product is maintained at each study site 
where the investigational product is inventoried and disposed. Records or logs must comply 
with applicable regulations and guidelines and should include: 
 amount received and placed in storage area 
 amount currently in storage area 
 label identification number or batch number and use date or expiry date 
 dates and initials of person responsible for each inventory entry/movement 
 amount dispensed to and returned by each subject, including unique subject identifiers 
 amount transferred to another area/site for dispensing or storage 
 non-study disposition (e.g, lost, wasted, broken), and 
 amount destroyed at study site. 
 
14.3 
Destruction of Investigational Product 
All study drug dispensation, monitoring and disposal will be managed by the Columbia 
University Research Pharmacy or responsible research pharmacy according to applicable 
regulations, guidelines, and institutional procedures. Appropriate records of the disposal will be 
maintained. 


 
 
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15 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that 
are suspected (related to the investigational 
product) and unexpected (i.e., not previously 
described in the Investigator Brochure), or that 
could be associated with the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction 
as termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which 
is not consistent with the applicable product 
information (e.g., Investigator Brochure for an 
unapproved investigational product) 
 


 
 
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16 
LIST OF ABBREVIATIONS 
AA 
Alopecia areata 
AE 
Adverse event 
ALT 
Alanine Transaminase  
AST 
Aspartate Transaminase  
BCG 
Bacillus Calmette-Guérin  
CBC 
Complete Blood Count  
CDC-ACIP  
Centers for Disease Control and Prevention Advisory 
Committee on Immunization Practices  
CFR 
Code of Federal Regulations  
CMV 
Cytomegalovirus  
CRF 
Case Report Forms  
CTLA 
Cytotoxic T-Lymphocyte Associated  
DMARD 
Disease-Modifying Anti-Rheumatic Drug  
DNA 
Deoxyribonucleic Acid  
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone  
GCP 
Good Clinical Practice  
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor  
HCG 
Human Chorionic Gonadotropin  
HIV 
Human Immunodeficiency Virus  
HLA 
Histocompatibility Leukocyte Antigen  
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization  
IEC 
Independent Ethics Committee  
IL 
Interleukin  
IRB 
Independent Review Board  
IU 
International Unit  
IV 
Intravenous  
MHC 
Major Histocompatibility Complex  
NSAE 
Non-Serious Adverse Event 


 
 
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NSAID 
Non-Steroidal Anti-inflammatory Drug  
PCR 
Polymerase Chain Reaction  
PPD 
Purified Protein Derivative  
RA 
Rheumatoid Arthritis  
SAE 
SALT 
Serious Adverse Event  
Severity of alopecia tool 
Se 
Sensitivity  
SmPC 
Summary of Product Characteristics  
Sp 
Specificity  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis  
TNF 
Tumor Necrosis Factor  
ULN 
Upper Level of Normal  
WBC 
White Blood Cell  
WOCBP 
Women of Childbearing Potential  
 


 
 
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17 
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