Conditions: Alopecia Areata
Keywords: alopecia alopecia areata alopecia universalis alopecia totalis dupixent dupilumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 60
Healthy volunteers: no

Brief summary:
Alopecia areata is a medical condition, in which the hair falls out in patches. The hair can fall out on the scalp or elsewhere on the face and body. Alopecia areata is an autoimmune skin disease, which means that the immune system is recognizing the hair follicles as foreign and attacking them, causing round patches of hair loss. It can progress to total scalp hair loss (alopecia totalis) or complete body hair loss (alopecia universalis). The scalp is the most commonly affected area, but the beard or any hair-bearing site can be affected alone or together with the scalp. Alopecia areata occurs in males and females of all ages, and is a highly unpredictable condition that tends to recur. Alopecia areata can cause significant distress to both patients and their families. In this study, the aim is to assess the effects of dupilumab in patients with alopecia areata.

Detailed description:
The purpose of this study is to assess whether dupilumab can be a helpful treatment for alopecia areata.

This is a randomized, double-blind, placebo-controlled pilot study of a total of 54 subjects with moderate to severe alopecia areata involving 30-100% of the scalp. The researchers expect one third of these subjects to have concomitant alopecia areata (AA) and atopic dermatitis (AD).

The researchers' experience in AD, and past experience in psoriasis showed that biomarker studies in skin tissues are critical to the understanding of key pathogenic pathways that are upregulated in each disease and how well they are suppressed with effective treatment. These mechanistic studies coupled with clinical trials are key in the disease to shed light on important disease mechanisms, and to explain which molecules are suppressed by each therapeutic target. Data shows that IL-13 is significantly upregulated in both AD and AA lesions compared to nonlesional skin. It is very important to associate the clinical responses with suppression of this cytokine and related molecules as well as other pathway cytokines in skin tissues. Both the whole genomic profiling and individual molecular and cellular markers are very important in order to understand how well anti-IL-13 will change/suppress AA-associated pathways and compare with those that will be suppressed in AD.

Since this study is designed to gain basic knowledge rather than to yield information directly related to patient care, the results are not entered in the participants' medical records. If, at a later date, correlations of in-vitro tests and the patients' clinical situation suggest that the results do bear on the patients' health, an amended protocol will be submitted to the IRB so that results can be made available to the medical record.

Arms:
arm 1: An initial dupilumab dose of 600 mg (two 300 mg subcutaneous injections), followed by dupilumab 300 mg given every week arm 2: Matching placebo in prefilled syringes identical to the dupilumab syringes

Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: A total of 24 doses intervention 2: A total of 24 doses

Protocol document:
Prot_SAP_000.pdf: 
 
1
Defining reversal of alopecia areata (AA) phenotype with dupilumab in 
patients with and without associated atopic dermatitis (AD) 
 
 
 
Principal Investigator: 
Emma Guttman-Yassky, MD/PhD 
 
 
 
 
 
 
Co-Investigators: 
 
James G. Krueger, MD/PhD 
 
 
 
 
Mark Lebwohl, MD 
 
 
 
 
 
 
 
 
 
 
 
Study Sites:  
 
Icahn School of Medicine at Mount Sinai 
 
 
 
 
Departments of Dermatology and the Immunology Institute 
 
 
 
 
5 East 98 Street, 5th Floor, Box 1048 
New York, NY 10029 
 
The Laboratory for Investigative Dermatology 
The Rockefeller University 
1230 York Avenue, Box 178 
New York, NY 10065 
 
 
Expert Consultant:  
Dr. David Norris, MD 
 
 
 
 
Professor and Chair, Department of Dermatology 
University of Colorado School of Medicine 
1665 Aurora Court 
Anschutz Cancer Pavilion Building, 3rd Floor 
Aurora, CO 80045 
 
 
Protocol Version: 
 
December 7, 2016 
 
 
 
 
January 31, 2018 Amendment # 1 
 
 
 
 
May 15, 2018 Amendment # 2 
 
 
 
 
January 08, 2020 Amendment # 3 
 
 
 
 
 
 
 
 
 
 
 
 


 
2
 
Table of Contents: 
 
Background  ………………………….… 3 
Treatment Rationale……………….….. 
4 
Hypothesis……………………….….…. 
9 
Objectives……………………….….….. 
9 
Endpoints…………………………..…… 9 
Study Design Overview……………….. 10 
Independent Expert Assessment……… 12 
Mechanistic Analyses…………………... 12 
Inclusion Criteria……………………….... 13 
Exclusion Criteria………………………... 14 
Potential Risks of Dupilumab…………… 16 
Prior Treatment………………………..… 16 
Concomitant Treatment…………………. 16 
Prohibited Treatment……………………. 16 
Procedures……………………………….. 17 
Laboratory Testing………………………. 21 
Safety Monitoring……………………..…. 21 
Study Withdrawal……………………..…. 22 
Total Volume of Blood ………………….. 22 
Discontinuation of Treatment  
 
and Withdrawal of Subjects……………. 23 
Measures to Minimize/Avoid Bias……… 25 
Investigational Drug Supply 
And Blinding…………………………….... 25 
Statistical Considerations……………….. 26 
References……………………………….. 29 
Table 1. Schedule of Events………….… 33 
Appendix 1 Clinical Assessments……… 35 
Appendix 2 AASIS and AA-QLI………… 39 
Amendment # 1 ……………………..….. 42 
Amendment # 2 …………………………. 44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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BACKGROUND: 
 
Alopecia areata (AA) is a common, complex immune-mediated disease characterized by 
non-scarring hair loss [1]. The clinical presentation of hair loss is variable. The most 
common presentation is AA with one or more bald circumscribed patches on the scalp. 
Hair loss can sometimes progress to total loss of all scalp hair (alopecia totalis, AT) and 
all scalp and body hair (alopecia universalis, AU). A few patients experience a diffuse 
type of AA or preferential loss of pigmented hair. Nail changes are also seen in 20% of 
AA patients. Typically, the affected skin has no sign of inflammation, although pruritus 
has been occasionally reported in AA patients. Short fragile hairs (so-called exclamation 
point) are often seen in the periphery of lesions [1-3]. The histologic hallmark of AA is 
perifollicular inflammation and a peribulbar infiltrate of predominantly lymphocytes around 
anagen hair follicles, known as a “swarm of bees.” This feature is typically seen in patients 
with active disease, and may not be present in chronic cases [1].  
 
The lifetime risk of AA in the United States has been estimated to be approximately 2%, 
and the severe forms of AA (AT and AU) occur in 14 - 25% of all AA cases [5]. The peak 
incidence occurs in young adults and 66% of patients debut before 30 years of age [1]. 
In general, there is no gender predilection, although a few studies have indicated a slightly 
higher prevalence in young males [4, 6]. Patients with disease onset before age 30 have 
positive family history in 37 % of cases [7], and progeny of AA patients have a 3-fold 
higher lifetime risk of developing AA [8, 9]. In addition, personal or family history of atopy 
predispose to AA [10]. Rapid disease progression and debut at young age are poor 
prognostic factors [1, 11]. Other commonly associated diseases include thyroid disease 
and autoimmune diseases such as thyroiditis and vitiligo [2]. While spontaneous regrowth 
is common in patients with minimal scalp involvement with AA [3], there is a minimal rate 
of spontaneous regrowth in patients with ≥50% hair loss, with only 8% of these patients 
re-growing at least 25% of the hair on placebo treatment. Relapses are common in AA 
patients, and only one-third of all cases achieve long-lasting remission that lasts 10 to 15 
years [13, 14]. These data suggest a high unmet need for effective treatments for patients 
with extensive hair loss [15].  
 
AA can cause tremendous emotional and psychosocial distress in affected patients and 
their families [16]. There is a lack of effective treatments for patients with AA, with no 
universally proven therapy that induces and sustains remission and there is no cure [3]. 
Topical treatments are minimally effective, probably because of limited penetration. Nor 
is there robust evidence for efficacy of topical tacrolimus, cryotherapy or ultraviolet light 
A combined with oral psoralens (PUVA). Intralesional injections of corticosteroids are 
effective but can only be considered for patients with limited involvement. For more 
extensive alopecia forms, including AT or AU, for which spontaneous regrowth is rare, 
systemic immunosuppressants (systemic corticosteroids, cyclosporine A, mycophenolate 
mofetil, azathioprine, and Janus kinase inhibitors) have shown some efficacy but are 
associated with side effects that preclude long-term use [5, 17, 18]. Furthermore, hair loss 
recurs usually after treatment cessation [19]. Despite the multiple side effects associated 
with these treatments, these are still widely used due to the absence of other treatment 
options [3, 6]. 


 
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TREATMENT RATIONALE: 
 
The current systemic treatments for severe AA are broad acting, and therefore bear many 
adverse effects. Moreover, none of these therapies show effective, long lasting results 
[20]. Many patients, especially those with extensive involvement such as AT and AU, are 
willing to risk significant adverse drug effects and attempt off-label use of various 
treatments, including JAK kinase inhibitors which carry a black box warning due to 
potential serious infections and increased malignancies [18, 21]. There is an unmet need 
for targeted therapeutic strategies for patients with severe AA, similarly to the new 
effective treatment approaches that are now used or tested for other immune mediated 
diseases such as psoriasis and atopic dermatitis (AD) [22-25]. New biological treatments 
approved or in development for inflammatory skin conditions, such as AD, rely on 
targeting specific activated cytokine pathways. This revolutionary approach leads to a 
change in treatment paradigms for these diseases, with development of highly efficacious 
and safer therapeutics. 
 
The immunopathogenesis of AA is poorly understood. While previous studies have 
primarily focused on the role of Th1 in AA [26], there is increasing evidence for the role 
of the Th2 axis in this disease. First, AD is the strongest risk factor for AA, and the two 
diseases commonly co-occur in patients [27]. In a study of more than 3500 AA patients, 
atopy (e.g. allergic rhinitis, asthma, and/or eczema) was the most common comorbidity, 
affecting more than 38.2% of AA patients [28]. Second, several studies have reported 
high levels of Th2 cytokines (e.g. IL-4, IL-5, IL-10) in the skin [27] and the serum of AA 
patients [29], as well as eosinophilia and elevated IgE levels in the blood [30-32]. Finally, 
genetic studies in AA have identified polymorphisms in filaggrin, IL-4, and IL-13 [28, 33]. 
Filaggrin mutations are associated with a more severe AA phenotype [33], and IL-13 is a 
known susceptibility locus for other autoimmune conditions, including atopy [34]. These 
findings provide strong biologic and genetic evidence for the observed relationship 
between AA and AD, and the possible pathogenic role of the Th2 axis in AA. 
 
Our recent data from a cohort of 27 AA patients ranging from mild to severe (total body 
hair loss) suggest that similar to psoriasis and AD, AA is a highly inflammatory disease 
with robust activation of Th1, Th2, and IL-23 (both p19 and p40 subunits) cytokine 
pathways (Figure 1) [35]. Using RT-PCR, we showed that the IL-13 cytokine showed the 
highest increases in gene expression in lesional AA scalp compared to non-lesional AA 
scalp.  Significant down-regulation of hair-associated keratins was also observed and is 
a hallmark of AA (Figure 2).  Finally, we found that lesional scalp of patients with 
extensive AA involvement is associated with greater immune and keratin dysregulation 
compared with that of patients with limited disease. Importantly, patients with and without 
concurrent AD were shown to have a similar AA scalp phenotype, and similar activation 
of the Th2 pathway [35]. 
 
 
 
 
 


 
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Figure 1.  Alopecia areata (AA) scalp lesions are characterized by up-regulation of Th1 
(IFN, CXCL9, CXCL10), Th2 (IL-13, CCL5, CCL18), and T cell activation (IL-2, IL-2RA, IL-15) 
related products as well as IL-23 (p19 and p40) cytokine. Real-time (RT)-PCR comparisons of 
inflammatory markers in lesional (LS), non-lesional (NL), and healthy scalp and skin samples from 
patients with alopecia areata (AA), atopic dermatitis (AD), or psoriasis (Pso) and normal skin from 
Th1/IFN 
 T Cell Activation 
IL-23 
Th2 


 
6
healthy subjects. Expressions are normalized to hARP (Human acidic ribosomal protein). Mean 
(log2 expression/hARP) ± SEM. *P < .05, **P < .01, and ***P < .001. 
Early Keratins: 
     
 
 
Middle Keratins: 
 
 
Late Keratins: 
 
 
Figure 2.  Early, mid, and late hair keratins in normal scalp as compared to lesional 
and non-lesional scalp of alopecia areata (AA) patients. The mRNA expressions of 
hair keratins in LS and NL AA scalp were compared to normal scalp by RT-PCR. 
hARP/human acidic ribosomal protein. Mean (log2 expression/hARP)  SEM. *p-value 
<0.05; **p<0.01; ***p<0.001. LS/Lesional, NL/non-lesional. 
 


 
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We also recently treated 3 patients with moderate-to-severe AA with ustekinumab, an 
anti-IL12/IL-23p40 inhibitor, and followed clinical responses with mechanistic studies in 
pre- and post-treatment scalp biopsies after 16 weeks of therapy [36]. Interestingly, 
although ustekinumab blocks the IL-12/IL-23 cytokines, the highest and most significant 
reductions coupled with successful hair regrowth were seen in the Th2 cytokines, 
including CCL13, CCL18, and CCL26, that are also highly up-regulated in AD and go 
down with dupilumab according to prior studies [37]. Interestingly, the suppression of the 
Th2 axis with ustekinumab was more consistent and significant than that of interferon/Th1 
genes. We also observed suppression of T-cell and dendritic cell genes. This series is 
the first report to link targeted immune antagonism to clinical and molecular AA reversal, 
including suppression of immune markers and up-regulation of hair keratin genes.  
 
In another recent report, in which we identified biomarkers of hair regrowth in AA patients 
using intra-lesional steroid injections, we also observed significant modulation of IL-13 
cytokine in post treatment lesions, as well as up-regulation of hair keratins [38]. Further, 
Wang et al. (J Invest Dermatol 2016) isolated PBMCs from AA patients with no prior 
history of atopy and showed increased expression of IL-13 and chemokine ligand 5 (CCL5 
or RANTES) following stimulation with known AA autoantigens, thus providing further 
evidence for the role of Th2 T-cell populations in the pathogenesis of AA. 
 
Taken together, these studies suggest that perhaps AA may provide a similar model to 
AD in which cytokines inhibit hair keratinocytes (instead of inhibiting terminal 
differentiation as in AD), and provide a strong rationale for studying the efficacy of Th2 
targeted therapies such as dupilumab for AA patients. We are aware of 3 patients treated 
with dupilumab for AD who also experienced improvement in their concurrent AA: 2 from 
our AD trial at Mount Sinai who experienced significant improvement in hair regrowth 
during dupilumab treatment—an African American AD patient that also had patchy AA 
(Figure 3A-D), as well as another European American male patient treated at MSSM with 
dupilumab that accompanied Dr Guttman to Sanofi and talked about his AA that resolved 
with dupilumab (he also included it in his PPT, but pre-treatment pictures are unavailable 
to us). The third patient was treated at another site, and shared her experience and 
pictures with Dr Guttman during a Sanofi-organized meeting in France, giving permission 
to share them in this protocol.  
  
Therefore, we hypothesize that dupilumab will be able to clinically and mechanistically 
reverse AA and induce hair regrowth in AA patients, regardless of concurrent AD. 
 
A large trial with dupilumab in AA patients might not only change the treatment paradigm 
for AA patients and provide a safe systemic treatment option, but will also expand the 
mechanistic understanding of the AA phenotype in patients with and without AD, 
ultimately leading to rapid therapeutic developments, similar to those now occurring in 
AD. 
 
 


 
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Figure 3. Two of 3 patients we are aware of, with concomitant AA and AD who 
experienced full hair regrowth of their AA during dupilumab therapy for their 
moderate-to-severe AD.  A) Photo of a patient from the dupilumab study at Mount Sinai 
Hospital prior to dupilumab treatment, showing patchy AA areas and B) after 16 weeks 
of dupilumab therapy (patient is in the long-term extension study). Of note, patient shaved 
her hair due to the AA lesions, and new hair growth clearly shows no AA patches as seen 
in the upper picture. C) Photo of a second patient treated with dupilumab at another site 
who sent us photos of her hair before (showing a large AA patch in frontal scalp) and D) 
after dupilumab therapy with full hair regrowth. The latter patient also shared the story of 
her AD and AA reversal during the Sanofi meeting in France that EG attended. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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HYPOTHESIS: 
 
Primary Hypothesis 
 
 Dupilumab is superior to placebo for induction of hair regrowth in patients with 
moderate to severe alopecia areata. 
 
OBJECTIVES: 
 
Primary Objective 
 
 To study the efficacy of dupilumab for induction of hair regrowth in patients with 
moderate to severe alopecia areata. 
 
Secondary Objectives 
 
 Investigate the mechanism of action for dupilumab in patients with moderate to 
severe alopecia areata. 
 
 To study the safety of dupilumab in patients with moderate to severe alopecia 
areata. 
 
ENDPOINTS: 
 
Primary Endpoint 
 
 Determine change from baseline in the Severity of Alopecia Tool (SALT) score at Week 
24 (baseline minus Week 24 value) The SALT is a validated instrument for measuring the 
amount of scalp hair loss at a single point in time (see details regarding SALT score in 
Appendix 1). 
 
Secondary Endpoints 
 
 Determine the change from week 24 in the SALT score at Week 48 (week 24 minus 
week 48 value). 
 
 Determine the change from baseline in the SALT score at week 48 (baseline minus 
week 48 value). 
 
 The proportion of patients achieving at least 50% improvement in Severity of 
Alopecia Tool (SALT) score (SALT-50) at Weeks 24 and 48 compared to Baseline. 
 
 The proportion of patients achieving at least 50% improvement in Severity of 
Alopecia Tool (SALT) score (SALT-50) at Week 48 compared to week 24. 
 
 The proportion of patients achieving at least 75% improvement in Severity of 
Alopecia Tool (SALT) score (SALT-75) at Weeks 24 and 48 compared to baseline. 
 


 
10 
 The proportion of patients achieving at least 90% improvement in Severity of 
Alopecia Tool (SALT) score (SALT-90) at Weeks 24, 48 compared to Baseline. 
 
 Change in the Alopecia Areata Symptom Impact Scale (AASIS) at Weeks 24 and 
48 compared to baseline. 
 
 Change in the Alopecia Areata Quality of Life questionnaire (AA-QoL) at Weeks 
24 and 48 compared to baseline. 
 
 Proportion of AA patients with Alopecia Areata Physician’s Global Assessment 
(aaPGA) = 0-1 at Weeks 12, 24, 36, and 48 (see details in Appendix 1). 
 
 Change in eyelash and eyebrow scores (see details in Appendix 1) at Weeks 
12, 24, 36, and 48 compared to baseline. 
 
 Change in eyelash and eyebrow scores (see details in Appendix 1) at Week48 
compared to Week24. 
 
 Change from baseline in Eczema Area and Severity Index (EASI) at Weeks 12, 
24, 36, and 48 (see details in Appendix 1). 
 
 Change from week 24 in EASI at weeks 36 and 48 (see details in Appendix 1). 
 
 Proportion of patients with Eczema Area and Severity Index (EASI)-50 (≥50% 
reduction from baseline in EASI scores) at Weeks 12, 24, 36, and 48. 
 
 Proportion of patients with Eczema Area and Severity Index (EASI)-75 (≥75% 
reduction from baseline in EASI scores) at Weeks 12, 24, 36, and 48. 
 
 Proportion of patients with Eczema Area and Severity Index (EASI)-90 (≥90% 
reduction from baseline in EASI scores) at Weeks 12, 24, 36, and 48 (see details 
in Appendix 1). 
 
 Semi-quantitative score using SALT subclasses (0 = no hair loss; 1 = <25% hair 
loss; 2 = 25-49% hair loss; 3 = 50-74% hair loss; 4 = 75-99% hair loss; 5 = 100% 
hair loss). 
 
 Safety profile of dupilumab in subjects with AA by reported adverse effects, 
physical examinations and laboratory parameters.  
 
Mechanistic (Exploratory) Endpoints 
 
 Determine the effect of dupilumab therapy on the immune cell populations (e.g. T 
cells, dendritic cells, eosinophils, and mast cells) and related cytokines, 
chemokines, and inflammatory cells found in the blood and skin of study subjects. 
RT-PCR will be used to determine these effects. 
 
 


 
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STUDY DESIGN OVERVIEW: 
 
This is a prospective, randomized, double blind, placebo-controlled clinical trial. The study 
will take place at two sites: Icahn School of Medicine at Mount Sinai, and Rockefeller 
University. This trial will include a total of 60 patients with moderate to severe AA 
(affecting more than 30% of the scalp) at the time of screening. AA subject must have 
evidence of hair regrowth within 10 years of their last episode of hair loss (see Exclusion 
Criteria below). Approximately one-third of subjects (20 out of 60 subjects) will also have 
concomitant AD (i.e. active AD skin lesions or a history of atopic dermatitis at the 
Screening and Baseline visits). Additionally, subjects with a history of alopecia totalis (AT) 
or alopecia universalis (AU) will be limited to no more than 50% of the total subjects (30 
out of 60 subjects). Once the required number of subjects in each of these sub-categories 
is met, additional subjects in those categories will not be enrolled. Power calculation 
rationale is detailed below under “Statistical Considerations.” 
 
In Phase I, subjects will be randomized (2:1) to either receive dupilumab or placebo for 
24 weeks (Weeks 0 to 24).   
 
At Week 24 (Primary Endpoint), both groups will enter Phase II of the study in which all 
subjects receive active drug (dupilumab) for an additional 24 weeks (Weeks 24 to 48). All 
subjects will return for monthly visits between Weeks 24 and 48. The treatment period will 
conclude at Week 48 (a secondary endpoint), and subjects will be asked to follow up at 
Weeks 60 and 72 (exploratory endpoints) as shown below for continued observation of 
skin and hair changes. 
 
 
 
After providing consent, subjects will be assessed for study eligibility during the screening 
period (within 4 weeks of Baseline), which includes a review of past and current medical 
conditions, detailed review of past and current medications, a physical examination, 
clinical assessments (SALT,  and eyebrow/eyelash assessment score), and additional 
skin assessments if he/she concurrently has atopic dermatitis (EASI, IGA, SCORAD). 
The following laboratory tests will be performed on all patients: complete blood count 
(CBC) with differential, complete metabolic panel (CMP), lactate dehydrogenase (LDH), 


 
12 
C-reactive protein (CRP), Total serum IgE, HIV, hepatitis B surface antigen (HbsAg) and 
hepatitis C virus antibodies, and serum pregnancy (where applicable). 
 
Subjects who meet inclusion and exclusion criteria for eligibility will undergo Baseline 
assessments at Week 0, including hair examination, clinical assessments (SALT and 
eyebrow/eyelash scores), additional skin assessments if he/she concurrently has atopic 
dermatitis (EASI, IGA, SCORAD), review of medications, standardized clinical 
photography (optional), questionnaires (AASIS and AA-QLI), and urine pregnancy testing 
(where applicable). Blood samples and skin biopsies will be collected for mechanistic 
studies (described below), as well as DNA, RNA, and protein analyses. Two 4.5 mm scalp 
biopsies will be performed at Baseline: one from an area with active AA (i.e. the peripheral 
edge of a scalp lesion with active hair loss) and one from an adjacent uninvolved area of 
the scalp. If the subject has 100% hair loss at Baseline exam, a single biopsy of the 
posterior scalp will be collected. For subjects with concomitant AD, an additional lesional 
skin biopsy will be collected from an active AD lesion as outlined in the schedule of events. 
At this Baseline visit, subjects will undergo randomization and be given their first injection 
of the study drug (dupilumab or placebo). 
 
The first dose  will be a loading dose of 600mg (given as two injections of dupilumab or 
placebo), provided in the clinic (including a 30-minute post-injection follow-up), followed 
by the patient’s weekly self-administration of 300 mg (one injection of dupilumab or 
placebo) at home (assuming the patient and the care team feel that the patients is ready 
to self-inject at home). 
 
After sufficient training and when the subject feels comfortable to self-inject, the subject 
will be provided with the study drug (dupilumab or placebo), and will receive weekly 
dosing through Week 24.  
 
During Phase I and II of the study, subjects will return for visits every four weeks for repeat 
clinical assessments, medication reviews, and monitoring for adverse events. Female 
subjects will undergo a urine pregnancy test (where applicable) at each of these visits. 
 
At Week 48, if subjects want to seek other treatment options (including commercially 
available dupilumab) for AA, they may do so through their own dermatologist/physician.  
Any treatments will be documented as concomitant medications.  
 
INDEPENDENT EXPERT ASSESSMENT: 
 
Dr. David Norris, Professor and Chairman of the Department of Dermatology-University 
of Colorado School of Medicine, has agreed to serve as a hair expert and provide full 
support and expertise throughout the entire study period.  Dr. Norris will also review study 
progress for all participants every 3-6 months. We will arrange monthly teleconference 
calls every 3-6 months to discuss progress and biannual visits to New York for both sites 
to jointly look at collected data and analyses.  
 
 
 
 


 
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MECHANISTIC ANALYSES: 
 
In order to identify the molecular and cellular immune profiles of AA at baseline and 
identify treatment response biomarkers with dupilumab (including immune and hair 
keratin biomarkers). 
 
Based on biomarkers recently identified in AA lesions [35-36, 38-39], we plan to perform 
one LS and one NL 4.5 mm punch biopsy at Baseline, and one LS biopsy at Weeks 12 
and 24 (from the same area previously biopsied, but at least 1 cm away from the previous 
scar). If the subject has 100% hair loss at the Baseline exam, a single biopsy of the 
involved posterior scalp will be collected.  An optional scalp biopsy at 48 weeks will also 
be performed. From patients that have both AD and AA, we will also perform a LS skin 
biopsy from a representative lesion at Baseline, and also after 24 weeks of treatment. 
This will serve to characterize similar response biomarkers to AD and AA in the same 
patients. 
 
Gene expression studies (RT-PCR and gene arrays) will also be performed. The 
expression levels of markers of the different immune pathways, including: Th1 (IFN-
gamma, CXCL9, CXCL10, STAT1), Th2 (IL-13, IL-5, IL-10, CCL5, CCL13, CCL17, 
CCL18, CCL26), Th17 (IL-17A, IL23p19, IL23p40, CCL20, CXCL1, elafin/PI3), Th9/IL-9, 
Treg/FOXP3, Th22/IL-22, and the IL-17/IL-22 regulated S100A7 gene will be evaluated. 
We will also assess for modulation of inflammatory markers (MMP12, S100A12) and an 
innate immune genes (IL-1B, IL-8). We will also assess for other AA biomarkers such as 
IL-16, IL-15, IL-2, IL-32, PDE4, JAK-1, JAK-3, STAT-3, that we have recently associated 
with AA activity. IL-4R, IL-12R, IL-23R, IL-15R and IL-2RA will also be evaluated. We will 
also assess for hair keratins (keratin 35, 40, 75, 83, 84, 85, 86) and keratin-associated 
proteins (KRTAP1) that are good biomarkers of AA and serve as good treatment 
response markers of hair regrowth with treatment. Gene arrays (Affymetrix U133A Plus 2 
gene array platform) will also be performed.  
 
Blood Analyses 
OLINK proteomic platform will be used to assess for biomarkers in blood. This platform is 
able to evaluate ~200 analytes, including all the inflammatory markers that are analyzed 
in skin, as well as cardiovascular markers, and neuro-immunological markers, including 
IL-13 and all the above Th2 chemokines, IFN gamma and the Th1 chemokines, as well 
as IL-17A, IL-22, PDE-related markers, and many other markers. Blood assessments will 
be performed on serum obtained at baseline, and Weeks 12, 24, 36, and 48. 
 
A complete list of the biomarkers we will assess via OLINK can be found at: 
http://www.olink.com/proseek-multiplex/complete-biomarker-list/ 
 
INCLUSION CRITERIA: 
 
1) Male of female subjects who are at least 18 years old at the time of informed 
consent. 
 
2) Subject is able to understand and voluntarily sign an informed consent document 
prior to participation in any study assessments or procedures. 


 
14 
 
3) Subject is able to adhere to the study visit schedule and other protocol 
requirements. 
 
4) Females of childbearing potential (FCBP) must have a negative pregnancy test at 
Screening and Baseline. While on investigational product and for at least 28 days 
after taking the last dose of investigational product (IP), FCBP who engage in 
activity in which conception is possible must use one of the approved 
contraceptive options described below:  
 
a. Option 1: Any one of the following highly effective methods: hormonal 
contraception (oral, injection, implant, transdermal patch, vaginal ring); 
intrauterine device (IUD); tubal ligation; or partner’s vasectomy;  
 
OR  
 
b. Option 2: Male or female condom (latex condom or non-latex condom NOT 
made out of natural [animal] membrane [for example, polyurethane]); PLUS 
one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap 
with spermicide; or (c) contraceptive sponge with spermicide.  
 
5) If subject is a female of non-childbearing potential, she must have documented 
history of infertility, be in a menopausal state for one year, or had a hysterectomy, 
bilateral tubal ligation, or bilateral oophorectomy. 
 
6) Subject has a history of at least 6 months of moderate to severe AA (≥ 30% scalp 
involvement) as measured using the SALT score; OR subject has ≥ 95% loss of 
scalp hair for enrollment as AA totalis (AT) or universalis (AU) subtypes.  
a. AT/AU will be limited to no more than 50% of the total subjects enrolled. 
b. Approximately one-third of subjects will have active AD skin or a 
concomitant history of AD at the time of the Screening and Baseline visits. 
 
7) Subject has a negative Tuberculin purified protein derivative (PPD) or 
QuantiFERON TB-Gold test (QFT) prior to baseline. Subjects with a positive or 
indeterminable PPD or QFT result must have a documented negative workup for 
tuberculosis and/or completed standard tuberculosis therapy. 
 
8) Subjects must meet the following laboratory criteria: 
 
a. White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (≤ 14 
x 109/L).  
b. Platelet count ≥ 100,000/μL (≥ 100 x 109/L).  
c. Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L).  
d. AST (SGOT) and ALT (SGPT) ≤ 2 x upper limit of normal (ULN). If the initial 
test shows ALT or AST > 2 times the ULN, one repeat test is allowed during 
the Screening Phase.  
e. Total bilirubin ≤ 2 mg/dL (34 μmol/L). If the initial test shows total bilirubin > 
2 mg/dL (34 μmol/L), one repeat test is allowed during the Screening Phase.  


 
15 
f. Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L). 
 
9) Subject is judged to be in otherwise good overall health following a detailed 
medical and medication history, physical examination, and laboratory testing. 
 
EXCLUSION CRITERIA: 
 
The presence of any of the following will exclude a subject from enrollment: 
 
1) Subject is pregnant or breastfeeding. 
 
2) Subject’s cause of hair loss is indeterminable and/or they have concomitant 
causes of alopecia, such traction, cicatricial, pregnancy-related, drug-induced, 
telogen effluvium, or advanced androgenetic alopecia (i.e. Ludwig Type III or 
Norwood-Hamilton Stage ≥ V). 
 
3) Subject has a history of AA with no evidence of hair regrowth for ≥ 10 years since 
their last episode of hair loss. 
 
4) Subject has an active bacterial, viral, or helminth parasitic infections; OR a history 
of ongoing, recurrent severe infections requiring systemic antibiotics 
 
5) Subject with a known or suspected underlying immunodeficiency or immune-
compromised state as determined by the investigator. 
 
6) Subject has a concurrent or recent history of severe, progressive, or uncontrolled 
renal, hepatic, hematological, intestinal, metabolic, endocrine, pulmonary, 
cardiovascular, or neurological disease. 
 
7) Active hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or positive 
HIV serology at the time of screening for subjects determined by the investigators 
to be at high-risk for this disease. 
 
8) Subject has a suspected or active lymphoproliferative disorder or malignancy; OR 
a history of malignancy within 5 years before the Baseline assessment, except for 
completely treated in situ non-melanoma skin and cervical cancers without 
evidence of metastasis. 
 
9) Subject has received a live attenuated vaccine ≤ 30 days prior to study 
randomization. 
 
10) Subject has any uncertain or clinically significant laboratory abnormalities that 
may affect interpretation of study data or endpoints. 
 
11) Subject has any other medical or psychological condition that, in the opinion of 
the investigator, may present additional unreasonable risks as a result of their 
participation in the study and/or interfere with clinic visits and necessary study 
assessments. 


 
16 
 
12) History of adverse systemic or allergic reactions to any component of the study 
drug. 
 
13) Severe, untreated asthma or a history of life-threatening asthma exacerbations 
while on appropriate anti-asthmatic mediations. 
 
14) Use of systemic immunosuppressive medications, including, but not limited to, 
cyclosporine, systemic or intralesional corticosteroids, mycophenolate mofetil, 
azathioprine, methotrexate, tacrolimus, or ultraviolet (UV) phototherapy 
with/without Psoralen Ultraviolet A (PUVA) therapy within 4 weeks prior to 
randomization. 
 
15) Use of an oral JAK inhibitor (tofacitinib, ruxolitinib) within 12 weeks prior to the 
Baseline visit. 
 
16) Subject has used topical corticosteroids, and/or tacrolimus, and/or pimecrolimus 
within 1 week before the Baseline visit. 
 
17) Subject has been previously treated with dupiliumab. 
 
18) Subject currently uses or plans to use anti-retroviral therapy at any time during 
the study. 
 
POTENTIAL RISKS OF DUPILUMAB: 
 
Dupilumab showed good safety based on early and late phases in AD and asthma [37, 
39-42]. Based on the nature of dupilumab, its mechanism of action, data from human and 
animal studies, and what is known about other similar drugs, possible risks include: 
 
 Infections, including those caused by parasites (e.g. intestinal worms). 
 Injection site reactions: Injection site reactions observed in dupilumab clinical trials 
have been generally mild to moderate and resolved without requiring any 
treatment.  Occasionally, such reaction may be severe and last more than 24 
hours. 
 Hypersensitivity/allergic reactions. 
 Adverse consequences of forming antibodies to dupilumab 
 Cancer: A potential risk for medications interfering with the immune system. 
 Potential for interactions with other medications:  It is not known if dupilumab may 
increase or decrease the effect of other medications. 
 Inflammation of the eye: a potential risk of conjunctivitis has been reported. 
 
PRIOR TREATMENT: 
 
All relevant treatment received by the subject within 30 days before screening will be 
recorded. Over-the-counter drugs (e.g. vitamins, acetaminophen) taken by the subject 
within 14 days before screening will also be recorded. 
 


 
17 
CONCOMITANT TREATMENT: 
 
Concomitant medications are permitted for the treatment of stable, chronic illness.  Use 
of such concomitant medication or other medications that may be required throughout the 
study will be recorded (including the reason for treatment and name, dose, unit, route, 
and the date of treatment as appropriate) until week 72 or Early Termination.  
 
At Week 48, if subjects want to seek other treatment options (including commercially 
available dupilumab) for AA, they may do so through their own dermatologist/physician.  
If a subject initiates a new treatment or obtains commercially available dupilumab at Week 
48, then that treatment must be documented as a concomitant medication.    
 
 
PROHIBITED TREATMENT:  
 
All treatments prohibited during the screening period are also prohibited throughout the 
course of the study. No live attenuated vaccinations are permitted through the study. All 
subjects treated previously with dupilumab will be excluded from the study as above. 
 
PROCEDURES: 
 
Monitoring of AEs will begin at signing of the informed consent form and will be continued 
throughout the study. All study procedures will be completed at designated times during 
the study (see Table 1). 
 
Trained assessors will perform clinical assessments. It is suggested that the same 
assessor/s perform these assessments for a subject. 
 
Visit 1 – Screening (within 4 weeks of Baseline)*  
 
 Sign and date an IRB-approved consent and HIPPA agreement 
 Review Inclusion and Exclusion Criteria 
 Record gender, race, ethnicity, and medical history (including personal and family 
history of AA, atopic dermatitis, asthma, allergies, and autoimmune diseases) 
 Complete physical exam and vitals, including: height (cm), weight (kg), blood 
pressure, and heart rate 
 Record all concomitant medications as well as all those received within the past 
month prior to screening 
 Record all prior systemic and topical therapies/treatments, including phototherapy, 
used for AA 
 PPD placement or Quantiferon blood test as outlined in Inclusion/Exclusion criteria 
 Serum HCG for all female subjects of child-bearing potential to confirm subject is 
not pregnant 
 HIV, HBV, and HCV serology 
 Complete blood count (CBC) and Comprehensive metabolic panel (CMP)  
 Total serum IgE, Lactate dehydrogenase (LDH), and C-reactive protein (CRP)  
 AA Clinical assessment (SALT, , and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 


 
18 
 
*If more than 4 weeks has lapsed between screening and Baseline/Visit 2, then all 
procedures should be repeated except for TB screening and HIV/HBV/HCV 
serologies. 
 
 
Visit 2 – Baseline (Week 0) 
 
 Confirm all inclusion and exclusion criteria have been met 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Randomize subject 
 Obtain vital signs 
 AA Clinical assessments (SALT and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Collect blood sample for mechanistic endpoints 
 Standardized clinical photography  
 Perform biopsies of lesional and non-lesional skin of the scalp, or a single lesional 
biopsy for subjects with AT or AU 
 Perform a biopsy of lesional skin for subjects with a concomitant history of AD and 
active AD lesions 
 Record concomitant medications and adverse events 
 Dispense/administer study drug 
 
 
Visit 3 – Week 4 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 4 – Week 8 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 5 – Week 12 
 


 
19 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT,  aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Standardized photographs 
 Obtain CBC, CMP, LDH, CRP, and Total serum IgE 
 Collect blood sample for mechanistic endpoints  
 Perform biopsy of lesional skin of the scalp 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 6 – Week 16 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Standardized photographs 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 7 – Week 20 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Standardized photographs 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 8 – Study Cross Over (Week 24) 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Standardized photographs 
 Obtain CBC, CMP, LDH, CRP, and Total serum IgE 
 Collect blood sample for mechanistic endpoints 
 Perform biopsy of lesional skin of the scalp 


 
20 
 Perform a biopsy of lesional skin for subjects with a concomitant history of atopic 
dermatitis and active AD lesions if present; if no active AD lesions, biopsy of skin 
will be collected near biopsy performed at Baseline 
 Dispense/administer study drug (subjects previously on dupilumab will receive 1 
injection of 300 mg dupilumab and 1 injection of placebo to maintain the blind of 
the study; subjects previously on placebo will receive 2 injections of 300 mg 
dupilumab). All subjects should be observed for 30 minutes following the injection 
to preserve the blind.  
 Record concomitant medications and adverse events 
 
Visit 9 – Week 28 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
Visit 10 – Week 32 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 11 – Week 36 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Standardized photographs 
 Obtain CBC, CMP, LDH, CRP, and Total serum IgE 
 Collect blood sample for mechanistic endpoints 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 12 – Week 40 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 


 
21 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Standardized photographs 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
Visit 13 – Week 44 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Standardized photographs 
 Dispense/administer study drug 
 Record concomitant medications and adverse events 
 
 
Visit 14 – Week 48 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Standardized photographs 
 Obtain CBC, CMP, LDH, CRP, and Total serum IgE 
 Collect blood sample for mechanistic endpoints 
 Record concomitant medications and adverse events 
 Obtain optional biopsy of lesional scalp 
 Obtain optional biopsy of lesional skin for subjects with a concomitant history of 
atopic dermatitis 
 
Visit 15 – Week 60 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Record concomitant medications and adverse events 
 
Visit 16 – Week 72 
 
 Obtain vital signs 
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 


 
22 
 Questionnaires (AASIS and AA-QLI) 
 Standardized photographs 
 Record concomitant medications and adverse events 
 
 
 
LABORATORY TESTING: 
 
Each site may utilize their own local lab for CBC, CMP, LDH, CRP, IgE, HIV, HBV, HCV, 
Quantiferon Gold, and pregnancy testing. Lab certifications for any lab used should be 
kept in the study binder.  RU will have to transport biopsy samples as well as blood 
samples for mechanistic testing (and potentially IgE testing) to Mount Sinai via proper 
and documented means.  
 
SAFETY MONITORING: 
 
The study will be conducted in accordance with our department’s Standard Operating 
Procedures, which are based on US FDA Title 21 Code of Federal Regulations and ICH 
Good Clinical Practice guidelines.  An investigator will review all laboratory results and 
assess for adverse events.  The principal investigator will be informed of all adverse 
events.  In the event that a subject’s safety is compromised, the investigator will 
discontinue the subject immediately. 
 
STUDY WITHDRAWAL: 
 
In the event a study subject wants to withdraw early from the study or the subject is being 
discontinued from the study for any reason, the following procedures should be followed: 
 
 Urine pregnancy test for all female subjects of child-bearing potential to confirm 
subject is not pregnant  
 Obtain vital signs 
 Obtain CBC, CMP, LDH, CRP, and Total serum IgE 
 Collect blood sample for mechanistic endpoints  
 AA Clinical assessments (SALT, aaPGA, and eyebrow/eyelash) 
 AD Clinical assessments, if applicable (EASI, IGA, SCORAD) 
 Questionnaires (AASIS and AA-QLI) 
 Standardized Photographs 
 Perform biopsy of lesional skin of the scalp 
 Perform a biopsy of lesional skin for subjects with a concomitant history of atopic 
dermatitis and an active AD lesion if present 
 Record all changes in medications and adverse events 
 
Considering there is no current treatment that is very effective in treating alopecia areata, 
these subjects are highly motivated to participate in a study that provides a treatment 
option. 
 
TOTAL VOLUME OF BLOOD COLLECTED DURING THE STUDY: 
 


 
23 
 
Blood volume (mL) 
Visit 
1 
2 
5 
8 
11 
14 
Week 
Screen 
0 
12 
24 
36 
48 
Serum HCG 
(where 
applicable) 
10 
n/a 
n/a 
n/a 
n/a 
n/a 
HIV 
10 
n/a 
n/a 
n/a 
n/a 
n/a 
HBV, HCV 
10 
n/a 
n/a 
n/a 
n/a 
n/a 
CBC with diff 
4 
4 
4 
4 
4 
4 
CMP, CRP, LDH 
10 
10 
10 
10 
10 
10 
Total Serum IgE 
10 
10 
10 
10 
10 
10 
Mechanistic 
studies 
n/a 
10 
10 
10 
10 
10 
Total volume 
54 
34 
34 
34 
34 
34 
 
The total estimated blood volume is 224 mL. Additional volumes may be required for 
repeat testing or as part of unscheduled visits. 
 
 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL OF SUBJECTS: 
 
The reasons why a subject may discontinue or be withdrawn from the study include, but 
are not limited to the following: subject request, protocol violation, loss to follow up, 
subject non-compliance, study termination by investigators, and a confirmed grade 3 or 
higher adverse event, which is suspected to be related to test article administration. 
Subjects that elect to withdraw from the trial due to lack of efficacy and/or exacerbation 
of disease will undergo the following: vitals; urine pregnancy test (if applicable); lesional 
biopsy of the scalp (if withdrawing before the Week 24 visit); lesional biopsy of the AD 
lesion (if applicable, and if withdrawing prior to the Week 24 visit); blood evaluations 
(CBC, CMP, LDH, CRP, Total serum IgE, and blood sample for mechanistic endpoints); 
clinical evaluation (SALT, SCORAD, EASI, aaPGA, and eyebrow/eyelash scores); 
subject evaluations (AASIS and AAQLI); and photographs.  
 
Stopping Rules 
Patients will be permanently discontinued from study treatment in the event of: 
 
 Anaphylactic reaction or other severe systemic reaction to study drug injection 
 Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, 
or squamous or basal cell carcinoma of the skin 
 Evidence of pregnancy 
 Any infection that is opportunistic, such as active TB and other infections whose 
nature or course may suggest an immuno-compromised status 
 Severe laboratory abnormalities: 
o Neutrophil count ≤0.5 x 103/μL 
o Platelet count ≤50 x 103/μL 


 
24 
o Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
values >3x upper limit of normal (ULN) with total bilirubin >2x ULN (unless 
elevated bilirubin is related to confirmed Gilbert’s Syndrome) 
o Confirmed AST and/or ALT >5 x ULN (for more than 2 weeks) 
 Treatment with any prohibited concomitant medication or procedure 
 Other reasons that may lead to the permanent discontinuation of study drug 
include certain AEs deemed related to the study drug. 
 
Study drug dosing may be temporarily suspended in the event of: 
 Clinically important laboratory abnormalities, such as: 
o 
Neutrophil count ≤1.0 x 103/µL but >0.5 x 103/µL 
o 
Platelet count ≤100 x 103/µL but >50 x 103/µL 
o 
Creatine phosphokinase (CPK) >10x ULN 
 Other intercurrent illnesses or major surgery 
 An infection that requires systemic treatment with antibiotic, antifungal, 
antiviral, anti-parasitic, or anti-protozoal agents or requires oral treatment with 
such agents for longer than 2 weeks 
 Treatment with systemic corticosteroids or non-steroidal immunosuppressive/ 
immunomodulating medications (eg, cyclosporine, methotrexate, azathioprine, 
mycophenalate-mofetil, Janus kinase inhibitors, biologic agents, etc). 
 
Duration of study drug suspension should be reviewed on a case by case basis and can 
be discussed among the PIs.  
 
Unblinding 
In case of an emergency, when knowledge of the test article assignment is required for 
the medical management of an individual subject, the subject will be unblinded. The code 
should be broken only in the event of a medical emergency, when knowing the treatment 
assignment is absolutely necessary. The investigators will notify the IRB, FDA and any 
other regulatory group, within 24 hours after determining that it is necessary to unblind 
the treatment assignment. The investigator must also indicate in source documents and 
in the CRF that the blind was broken and provide the date, time, and reason for breaking 
the blind. Any AE or SAE associated with breaking the blind must be recorded and 
reported as specified in this protocol. 
 
A clinical data manager will assemble all the patient data by groups (treatment versus 
placebo) and the biostatistician may request the unblinding of subject treatment 
assignment for analyzing safety data, upon the appearance of unequal adverse events. 
 
Safety Evaluation 
This is a phase II study. Safety and tolerability will be evaluated from the AEs, physical 
examinations, vital sign measurements, and clinical laboratory test results. More frequent 
safety evaluations may be performed if clinically indicated or at the discretion of the 
investigator. 
 
Aggregated AEs will be evaluated monthly by the PI/research teams. 
 


 
25 
Safety data will be reviewed by the investigators, study teams, biostatisticians, who will 
monitor the study on a regular basis and meet regularly (approximately every 3 months, 
depending on the number of subjects enrolled). The local IRBs and FDA will be notified 
of adverse events (as required by each institution). 
 
 
Physical Examination/Vital Signs 
A licensed physician, physician assistant, nurse practitioner, or registered nurse will 
perform physical examinations at the time of screening. Body weight (kg), height (cm), 
blood pressure, and heart rate will be measured at screening. At all other visits, only blood 
pressure and heart rate will be measured.  
 
Physical examination consists of assessments of general appearance; skin; head, eyes, 
ears, nose, and throat (HEENT); heart; lungs; abdomen; extremities; neurological 
function; and lymph nodes. 
 
Safety Laboratory Determinations 
Laboratory evaluations will be performed according to the flowchart on page by a CLIA 
certified laboratory at the study site.  All laboratory tests with clinically important abnormal 
results identified after test article administration will be repeated until the values return to 
normal, baseline or non-clinically significant, as appropriate. Each abnormal lab will be 
indicated as clinically significant or not clinical significant. 
 
Biopsy Site Wound Infections 
If a wound infection occurs at the site of the biopsy, the site will perform a bacterial culture 
as part of standard of care procedures.   
 
MEASURES TO MINIMIZE/AVOID BIAS:  
 
Subject Identification  
Subjects are numbered sequentially. Each subject will be assigned a unique number and 
will keep this number for the duration of the study. Subject numbers will not be reassigned 
or reused for any reason. Subjects who discontinue or withdraw from the study before 
receiving a treatment assignment code, who re-enroll at a later time must be assigned a 
new subject number. Subjects should be identified only by their assigned identified code 
number. The investigator must maintain a subject master log linking the subject number 
to the subject’s name. The investigator must follow all applicable privacy laws in order to 
protect a subject’s privacy and confidentiality.  
 
Randomization and Blinding 
A subject who meets all of the inclusion and exclusion criteria will be assigned a 
randomization number pre-dose on day 0/baseline. The randomization number is distinct 
from the subject number. 
 
After fulfilling the enrollment criteria, the subjects enrolled will be randomized in a 2:1 ratio 
of dupilumab to placebo. 
 


 
26 
The randomization for both sites will be performed by the designated Research 
Pharmacist/personnel at the Icahn School of Medicine utilizing the Web site 
http://www.randomization.com (or similar). The method uses random block sizes and 
randomly permuted blocks.  
 
Approximately 60 subjects will be enrolled in the study in order to have at least 54 subjects 
complete (taking into account a 10% drop out rate). Subjects will be assigned a 
randomization number on day 0/Baseline. The randomization schema will be kept 
confidentially after generation. 
 
INVESTIGATIONAL DRUG SUPPLY AND BLINDING: 
 
Regeneron Pharmaceuticals will provide dupilumab 300 mg for 40 subjects in Phase I 
and for all 60 subjects during Phase II (a total of 25 doses in Phase I to those 40 subjects 
randomized to receive dupilumab, followed by another 24 doses in Phase II; a total of 24 
doses in Phase II to the 20 subjects who received placebo in Phase I).  
 
Eligible patients will receive a 600 mg SC dupilumab loading dose (300 mg initial dose, 
followed by a 300 mg loading dose) on day 0/Baseline, and then continue with 300 mg 
SC dupilumab once weekly starting on day 8. At Week 24, subjects previously on 
dupilumab will receive 1 injection of 300 mg dupilumab and 1 injection of placebo to 
maintain the blind of the study; subjects previously on placebo will receive 2 injections of 
300 mg dupilumab. All subjects should be observed for 30 minutes following the injections 
at Baseline and at Week 24.  
 
Matching placebo prefilled syringes (that will appear identical to the dupilumab syringes) 
will be provided by the company to the study sites. The subjects and the staff will remain 
unaware of the individual treatment assignment during the study. All study medication will 
be stored in a secure cool area between 2-8°C. Study drug will be administered to subjects 
at each study visit, with subsequent weekly injections performed by the patients at home. 
Patients (and/or caregivers) who are willing and able to administer dupilumab outside of 
the clinic will be trained on injecting study drug during the initial clinic visit.  
 
We will query the subjects during each study visit on any missed injections and document 
this information. The investigative sites will account for all study drug dispensed and 
stored during the study. 
 
STATISTICAL CONSIDERATIONS: 
 
Sample Size Calculation 
The primary outcome for this study is the SALT change at week 24. For patients with 
similar disease severity, a change in SALT of less 5 units was observed  (Guttman et al, 
2019). Assuming that dupilumab will induce a change in SALT of at least 25 units with a 
standard deviation of 10 atweek 24, a sample size of 54 completed patients randomized 
2:1 treatment to placebo (i.e. 36 in the treatment arm, 18 in the placebo arm) will provide 
97% power to detect differences with Placebo based on a two-sided Student’s t-test with 
a 0.05 type I error. Assuming that 10% of patients drop out of the study, we plan to enroll 
60 total patients (i.e. 36 in the treatment arm, 18 in the placebo arm).  


 
27 
 
Demographics and Other Baseline Characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented 
for all subjects and tabulated by treatment group. Presentations of age, sex, ethnicity, 
race and baseline will also be given. Other baseline characteristics include height, weight, 
and vital signs, duration of the AA and AD, concurrent diagnoses from medical history 
and indications for concomitant medication, concomitant medication, and previous AA 
and AD treatments. 
 
Analysis of Primary Endpoint 
A Mixed effect Model Repeated Measurement (MMRM) will be used to detect any overall 
differences in the treatment effect at week 24 compared to baseline.  
 
Analysis of Secondary Endpoints 
A Mixed effect Model Repeated Measurement (MMRM) will be used to detect any overall 
differences in the treatment effect at week 48 compared to baseline, as well as at week 
48 compared to week 24. This formulation intrinsically models the within patient 
correlation structure as in the case of a paired t-test. This approach introduces less bias 
than restricting the analysis for those patients who completed the study. A similar model  
will be used to evaluate the change in eyelashes and eyebrows scores, as well as in 
Eczema Area and Severity Index (EASI) at each visit compared to baseline. 
 
A two-sided Fisher exact test will be used to compare the percentage of patients who 
achieve 50% improvement in SALT, eyelashes, eyebrows and EASI scores (calculated 
as 100 x (SCOREbaseline - SCOREW24)/ SCOREbaseline) between drug and placebo groups. 
The same approach will be used for other discrete variables, SALT-75, and SALT-90 at 
each visit compared to baseline. 
 
Analysis of Exploratory Endpoints 
The change from Baseline in molecular markers in skin biopsies after treatment will be 
analyzed using a mixed effect linear model with treatment and time interaction as a fixed 
effect and a random effect for each patient. This formulation intrinsically models the within 
patient correlation structure as in the case of a paired t-test, and introduces less bias than 
restricting the analysis for those patients who completed the study. 
 
Analysis of Mechanistic Endpoints 
For comparison of expression levels of lesional, and non-lesional AA skin, we will use 
RT-PCR by Taqman Low-density arrays and RNA-sequencing. RT-PCR values will be 
normalized to the housekeeping gene RPLP0 (validated in our AD and AA studies) and 
log-2 transformed prior to analysis. RNA-sequening data will be pre-processed using 
standard pipeline (exhaustively used by our group in a large number of studies) and log-
2 voom-transformed expression. Mixed effect modelwill be used and p-values for the 
moderated t-tests and paired-t-test will be adjusted by Benjamini-Hochberg procedure. 
 
Extensive bioinformatics tools will be employed to gain insights into the results and test 
hypotheses that are generated in the “data mining stage”. This will include (but will not be 
limited to) pathway and gene-set enrichment analyses using Ingenuity software, GSEA, 
the R package GSVA (Gene Set Variation Analysis) and other in-house codes produced 


 
28 
by our group. To define cellular and molecular biomarkers of AA in skin biopsies, 
biomarkers will be divided into those that show significant group differences and those 
that do not. Multiple regression models will be used to determine the best set of 
biomarkers that predict disease activity and response. 
 
Gene expression changes in hair keratins and the immune axes (Th1, Th2, Th17, Th22) 
will be jointly correlated with clinical responses by multivariate analysis using multivariate 
u-statistics and R package muStat, as previously reported [43]. 
 
Data Transfer and Management 
Data including the patient info, demographics, clinical scores and treatment allocation 
code will be sent to our Biostatistical Team in password-protected files.  
 
Data from the Guttman Lab (where all mechanistic blood and skin studies will be done), 
including FASTQ  files, real-time PCR (RT-PCR), and serum proteomics will be deposited 
in the Mount Sinai Box and Amazon S3 bucket, having the necessary safeguards for 
protection of human subjects research. Dr. Guttman lab members will not have access to 
the treatment code until all lab work has been completed and the data transferred to our 
Biostatistical Team. 
 
All data management steps taken to reformat and merge the clinical and laboratory data 
will be carried out using R codes, so all the steps of the processes can be reproduced.  
 
Management of the Analysis  
Analysis of RT-PCR and RNA-sequencing will all be conducted using R language and 
bioconductor packages. Codes will be QC-ed by at least one independent member of the 
Biostatistical Team, other than the member who coded the analysis. 
 
Analysis will be run in our desktops, with a backed up copy in the Mount Sinai Box. 
Analysis results will be shared with the study teams of Drs. Guttman, Lebwohl, and 
Krueger, as well as Dr. Jason Hawkes who holds joint appointments at Rockefeller 
University and Mount Sinai, and Dr Norris who is our study consultant, via the Mount Sinai 
Box.  Once the analysis is finalized, all data will be deposited in Dr. Guttman’s and Dr. 
Krueger’s central file storage system (CFS), which is accessible to all research members. 
Both Mount Sinai Box and the CFS have backup capabilities and are encrypted and 
password protected.  Access to the Mount Sinai Box specific for the project will be shared 
with the Rockefeller team and Dr Norris. 
 
Analysis of Safety and Tolerability 
Safety will be evaluated by tabulations of adverse events (AEs) and will be presented with 
descriptive statistics at each visit. AEs will be coded using the CTCAE, Common 
Terminology Criteria for Adverse Events, V 4.0. The number and percentage of 
subjects/lesions experiencing an AE/SAE will be stratified by system organ class, or a 
preferred term, and/or severity of the adverse event, and recorded and tabulated overall 
by each sub-strata. Each subject will be counted only once within a system organ class 
or a preferred term using the adverse events with the highest severity within each 
category. All information pertaining to adverse events noted during the study will be listed 
by subject, detailing verbatim given by the investigator, preferred term, system organ 


 
29 
class, date of onset, date of resolution, severity, and relationship to treatment. A 
tabulation of AEs will be provided by subject. The rates of AEs will be compared between 
treatment groups. If the rate of AE occurs in ~5% in either treatment group will be 
compared using the Fisher’s exact test. 
 
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1) 
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2) 
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3) 
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4) 
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Kyriakis KP, Paltatzidou K, Kosma E, Sofouri E, Tadros A and Rachioti E. Alopecia 
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8) 
Price VH and Colombe BW. Heritable factors distinguish two types of alopecia 
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risk for alopecia areata in first degree relatives of severely affected patients. An 
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11) Goh C, Finkel M, Christos PJ and Sinha AA. Profile of 513 patients with alopecia 
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12) Islam N, Leung PS, Huntley A, Eric Gershwin M. The Autoimmune Basis of Alopecia 
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30 
13) Price VH, Hordinsky MK, Olsen EA, Roberts JL, Siegfried EC, Rafal ES, et al. 
Subcutanous efalizumab is not effective in the treatment of alopecia areata. J Am 
Acad Dermatol 58(3):395-402, 2008. 
 
14) Mitchell AJ and Balle MR. Alopecia areata. Dermatol Clin 5: 553-564, 1987.  
 
15) Hordinsky MK. Overview of alopecia areata. J Investig Dermatol Symp Proc 
16(1):S13-5, 2013. 
 
16) Picardi A, Pasquini P, Cattaruzza MS, Gaetano P, Baliva G, Melchi CF, et al. 
Psychosomatic factors in first-onset alopecia areata. Psychosomatics 44: 374-381, 
2003.  
 
17) Otberg N. Systemic treatment for alopecia areata. Dermatol Ther 24: 320-5, 2011. 
 
18) Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is 
driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med 20: 
1043-9, 2014. 
 
19) Park KY, Jang WS, Son IP, Choi SY, Lee MY, Kim BJ, et al. Combination therapy 
with cyclosporine and psoralen plus ultraviolet a in the patients with severe alopecia 
areata: a retrospective study with a self-controlled design. Ann Dermatol 25: 12-6, 
2013. 
 
20) Delamere FM, Sladden MM, Dobbins HM and Leonardi-Bee J. Interventions for 
alopecia areata. Cochrane Database Syst Rev CD004413, 2008.  
 
21) Jabbari A, Dai Z, Xing L, Cerise JE, Ramot Y, Berkun Y, et al. Reversal of Alopecia 
Areata Following Treatment With the JAK1/2 Inhibitor Baricitinib. EBioMedicine 
26;2:351-5, 2015. 
 
22) Noda S, Krueger JG, Guttman-Yassky E. The translational revolution and use of 
biologics in patients with inflammatory skin diseases. J Allergy Clin Immunol 
135:324-36, 2015. 
 
23) Haider AS, Lowes MA, Suárez-Fariñas M, Zaba LC, Cardinale I, Khatcherian A, et 
al. Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and 
inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation 
through pharmacogenomic study of cyclosporine A in psoriasis. J Immunol 
180:1913-20, 2008. 
 
24) Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab 
treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med 
371:130-9, 2014. 
 
25) Krueger JG, Ferris LK, Menter A, Wagner F, White A, Visvanathan S, et al. Anti-IL-
23A mAb BI 655066 for treatment of moderate-to-severe psoriasis: Safety, efficacy, 


 
31 
pharmacokinetics, and biomarker results of a single-rising-dose, randomized, 
double-blind, placebo-controlled trial. J Allergy Clin Immunol 136(1):116-24, 2015. 
 
26) Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is 
driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 
Sep;20(9):1043-9, 2014. 
 
27) Barahmani N, Schabath MB, Duvic M; National Alopecia Areata Registry. History of 
atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol. 
Oct;61(4):581-91, 2009. 
 
28) Huang KP, Mullangi S, Guo Y, Qureshi AA. Autoimmune, atopic, and mental health 
comorbid conditions associated with alopecia areata in the United States. JAMA 
Dermatol. Jul;149(7):789-94, 2013. 
 
29) Shohat M, Mimouni D, Ben-Amitai D, Sredni B, Sredni D, Shohat B, et al. In vitro 
cytokine profile in childhood alopecia areata and the immunomodulatory effects of 
AS-101. Clin Exp Dermatol. Jul;30(4):432-4, 2005. 
 
30) Zhang X, Zhao Y, Ye Y, Li S, Qi S, Yang Y, et al. Lesional infiltration of mast cells, 
Langerhans cells, T cells and local cytokine profiles in alopecia areata. Arch 
Dermatol Res. May;307(4):319-31, 2015. 
 
31) Attia EA, El Shennawy D, Sefin A. Serum Interleukin-4 and Total Immunoglobulin E 
in Nonatopic Alopecia Areata Patients and HLA-DRB1 Typing. Dermatol Res Pract. 
2010:503587, 2010. 
 
32) Kasumagić-Halilović E, Prohić A. Serum levels of total immunoglobulin e in patients 
with alopecia areata: relationship with clinical type of the disease. Acta 
Dermatovenerol Croat. 14(3):149-52, 2006. 
 
33) Betz RC, Pforr J, Flaquer A, Redler S, Hanneken S, Eigelshoven S, et al. Loss-of-
function mutations in the filaggrin gene and alopecia areata: strong risk factor for a 
severe course of disease in patients comorbid for atopic disease. J Invest Dermatol. 
Nov;127(11):2539-43, 2007. 
 
34) Jagielska D, Redler S, Brockschmidt FF, Herold C, Pasternack SM, Garcia Bartels 
N, et al. Follow-up study of the first genome-wide association scan in alopecia 
areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide 
significance. J Invest Dermatol. Sep;132(9):2192-7, 2012. 
 
35) Suárez-Fariñas M, Ungar B, Noda S, Shroff A, Mansouri Y, Fuentes-Duculan J, et 
al. Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without 
parallel TH17/TH22 skewing. J Allergy Clin Immunol. Nov;136(5):1277-87, 2015. 
 
36) Guttman-Yassky E, Ungar B, Noda S, Suprun M, Shroff A, Dutt R, et al. Extensive 
alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism. J Allergy Clin 
Immunol. Jan;137(1):301-4, 2016. 


 
32 
 
37) Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. 
Dupilumab improves the molecular signature in skin of patients with moderate-to-
severe atopic dermatitis. J Allergy Clin Immunol. Dec;134(6):1293-300, 2014. 
 
38) Fuentes-Duculan J, Gulati N, Bonifacio KM, Kunjravia N, Zheng X, Suárez-Fariñas 
M, et al. Biomarkers of alopecia areata disease activity and response to 
corticosteroid treatment. Exp Dermatol. Apr;25(4):282-6, 2016. 
 
39) Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab 
efficacy and safety in adults with uncontrolled persistent asthma despite use of 
medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a 
randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. 
Lancet. Jul 2;388(10039):31-44, 2016. 
 
40) Thaçi D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and 
safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately 
controlled by topical treatments: a randomised, placebo-controlled, dose-ranging 
phase 2b trial. Lancet. Jan 2;387(10013):40-52, 2016. 
 
41) Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab 
treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. Jul 
10;371(2):130-9, 2014. 
 
42) Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab 
in persistent asthma with elevated eosinophil levels. N Engl J Med. Jun 
27;368(26):2455-66, 2013. 
 
43) Suárez-Fariñas M, Tintle SJ, Shemer A, Chiricozzi A, Nograles K, Cardinale I, et al. 
Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation 
defects and variable immune abnormalities. J Allergy Clin Immunol. Apr;127(4):954-
64.e1-4, 2011. 
 
 
 
 
 
 


 
33
Table 1. Schedule of Events 
 
Visit Week 
(D -31 to -1) 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
60 
72 
 
Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Early 
Termination  
Visit Type 
Screening 
Baseline 
Tx 
Tx 
Tx 
Tx 
Tx 
Cross- 
Over 
Tx 
Tx 
Tx 
Tx 
Tx 
Tx 
F/U F/U 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inc/Exc Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and Medical Hx1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TB Screening3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV, HBV, and 
HCV 4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC, CMP 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
LDH, CRP 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Total Serum IgE 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Blood Sample 
(Mechanistic) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy Test5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
AA Clinical 
Assessments 
(SALT, 
eyelash/eyebrow) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AA Clinical 
Assessment 
(aaPGA) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AD Clinical 
Assessments 
(EASI, IGA, 
SCORAD)13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaires 
(AASIS and AA-QLI)  
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Standardized 
Photographs 
 
X 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
X 
X 
Dispense Drug 
 
X11 
X 
X 
X 
X 
X 
X12 
X 
X 
X 
X 
X 
 
 
 
 
Scalp Biopsy 
 
X6 
 
 
X8 
 
 
X8 
 
 
 
 
 
X10 
 
 
X8* 
Skin Biopsy 
 
X7 
 
 
 
 
 
X9 
 
 
 
 
 
X10 
 
 
X9* 
Concomitant 
Medications 
X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
 


 
34
1Includes personal and family history of alopecia, atopic dermatitis, asthma, allergies, and autoimmune conditions; 
2Includes height and weight (only at screening), blood pressure, and pulse; 
3PPD or QuantiFERON TB-Gold test; 
4HBS-ag and HCV-ab;  
5Where applicable; serum HCG at screening and urine pregnancy tests at all other visits; 
6  One lesional and one non-lesional biopsy; or only one lesional in those with AT or AU;  
7  Where applicable, one biopsy of lesional skin for subjects with concomitant AD and active lesion;   
8  One biopsy of lesional AA skin close to the lesional biopsy performed at baseline;  
9   For AD pts, one biopsy of lesional skin close to the biopsy performed at baseline.  If no biopsy was performed at baseline, then no biopsy 
     required at this visit (regardless of active lesions); 
10 Optional biopsy of lesional scalp and lesional AD skin (if applicable);  
11 Initial dose will be a loading dose of 600mg (two injections of 300 mg dupilumab or placebo), followed by a required 30 minute observation 
     period;  
12 Subjects previously on dupilumab will receive 1 injection of 300 mg dupilumab and 1 injection of placebo to maintain the blind of the study;  
      subjects previously on placebo will receive 2 injections of 300 mg dupilumab. Both groups will be observed for 30 minutes following the  
     injections.  
13  For subjects with active AD lesions at Screening and/or Baseline, these assessments should be done at each visit. 
* Performed only if Early Termination visit occurs prior to Week 24. 


 
35 
Appendix 1. Clinical Assessments/Scoring 
 
Alopecia Areata Assessments: 
 
Severity of Alopecia Tool (SALT) 
Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of 
scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of 
scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface 
area of the scalp in that area. SALT score is the sum of percentage of hair loss in all 
areas. 
 
SALT score:  
 
Left Side 
(18%) 
Right Side 
(18%) 
Top  
(40%) 
Back 
(24%) 
  
Percentage Hair 
Loss 
 
 
 
 
 
Percentage X 
Area 
X 0.18 
X 0.18 
X 0.4 
X 0.24 
 
Total 
+ 
+ 
+ 
= 
 
 
 
Eyelash/Eyebrow Assessment Score 
0= None 
1= Minimal eyelashes/eyebrows 
2= Moderate eyelashes/eyebrows 
3= Prominent eyelashes/eyebrows 
4= Very prominent eyelashes/eyebrows 
 
 
Alopecia Areata Physician’s Global Assessment (aaPGA): 
The aaPGA is used to assess the clinical response to treatment based on a 6-point scale 
ranging from 0 (no regrowth) to 5 (100% regrowth): 
 
No regrowth 
<25% 
regrowth 
25-49% 
regrowth 
50-74% 
regrowth 
75-99% 
regrowth 
100% 
regrowth 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 


 
36 
Atopic Dermatitis Assessments: 
 
Scoring atopic dermatitis (SCORAD) 
3 components: A) % body surface area involvement (the rule of 9); B) Intensity of eczema 
evaluated on representative lesions, rating 5 lesions (scale 0 to 3) for features including 
erythema, thickness, excoriations, wound/scab formation, lichenification, and xerosis; C) 
Functional impact based on pruritus (0 to 10) and sleep disturbance (0 to 10).  Final score 
determined by SCORAD = A/5 + (7 x B/2) + C 
 
 
 
 
 


 
37 
VAS 
 
 
 
 
 
 
 
 
 
 
 
 


 
38 
Eczema Area and Severity Index (EASI) 
The EASI is used to assess the severity and extent of AD. Four AD disease characteristics 
will be assessed (0 = absent to 3 = severe). Area of AD involvement will be assessed as 
a percentage by involved body area of the head, trunk, arms, and legs, and converted to 
a score of 0 to 6. 
 
 
 
 
IGA (Investigator’s Global Assessment) 
IGA Severity  
Features 
4 – Severe Disease 
Severe erythema and severe papulation/infiltration 
3 – Moderate Disease 
Moderate erythema and moderate papulation/infiltration 
2 – Mild Disease 
Mild erythema and mild papulation/infiltration 
1 - Almost Clear 
Just perceptible erythema and just perceptible papulation/infiltration 
0 - Clear 
No inflammatory signs of AD 
EASI 
 
Head & Neck 
Upper 
Extremities 
Trunk, Axillae 
and Genitals 
Lower Extremities & 
Buttocks 
Erythema 
 
 
 
 
Infiltration / 
Papulation 
 
 
 
 
Excoriation 
 
 
 
 
Lichenification 
 
 
 
 
Sum 
 
 
 
 
Area Score 
 
 
 
 
Sum x Area 
Score 
 
 
 
 
x 
X   .1 
X   .2 
X   .3 
X   .4 
Total 
 
 
 
 
Area Score (of the respective body region):   
0=No Eruption    1=< 10%,   2= 10%-29%;   3=30%-49%,   4 = 50% - 69%;   5= 70% - 89%,   6= 90% - 100% 
Erythema 
0 -  None 
1 – Mild               Faintly detectable erythema; very light pink 
2 – Moderate      Dull red, clearly distinguishable 
3 – Severe          Deep / dark red 
Infiltration / 
Papulation 
0 -  None 
1 – Mild               Barely perceptible elevation 
2 – Moderate      Clearly perceptible elevation but not extensive 
3 – Severe          Marked and extensive elevation 
Excoriations 
 
0 -  None 
1 – Mild               Scant evidence of excoriations with no signs of deeper skin damage (erosion,crust) 
2 – Moderate      Several linear marks of skin with some showing evidence of deeper skin injury  
                            (erosion,crust) 
3 – Severe          Many erosive or crusty lesions 
Lichenification 
 
 
0-None 
1 – Mild               Slight thickening of the skin discernible only by touch and with skin markings  
                            minimally exaggerated 
2 – Moderate      Definite thickening of the skin with skin markings exaggerated so that they form a  
                            visible criss-cross pattern 
3 – Severe          Thickened indurated skin with skin markings visibly portraying an exaggerated 
criss- 
                            cross pattern 


 
39 
Appendix 2. Subject Questionnaires (AASIS and AA-QLI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
40 
Alopecia Areata Quality of Life Index (AA-QLI) 
 
Subjective symptoms 
 
 
1. 
I feel uncomfortable using a wig 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
2. 
I tend to hide my scalp with hats or bandages 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
3. 
I am sad about the appearance of my 
hair/eyebrows/eyelashes 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
4. 
I worry about having this hair problem for the 
rest of my life 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
5. 
I cannot forget that I have this hair problem 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
6. 
I worry that it might spread 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
7. 
I do not take my wig/hat/bandana off in front 
of my partner/relatives/ friends 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
8. 
It costs me a lot of money to look after my 
hair 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
9. 
I am afraid my children may have alopecia 
areata 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
 
 
Relationship 
 
 
10. 
I feel that people find it unpleasant to look at 
me 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
11. 
I think that other people notice my 
hair/eyebrows/eyelashes problem 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
 


 
41 
12. 
I am afraid that other people think my hair 
looks badly cared for 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
13. 
I am embarrassed when going out to a party 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
14. 
I have to explain to others what is wrong with 
my hair/eyebrows/eyelashes 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
15. 
I feel that others are afraid of catching 
diseases from me 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
16. 
I feel I have sexual difficulties because of 
alopecia areata 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
17. 
I feel I have difficulties in establishing 
relationships with friends and/or relatives 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
18. 
My work/studying has deteriorated because of 
alopecia areata 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
 
Objective signs 
 
 
19. 
My scalp is visible 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
20. 
I lose tufts of hair when I comb or shampoo 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
21. 
I feel itchy on my scalp 
Very much 
A lot 
A little 
Not at all 
☐ 
☐ 
☐ 
☐ 
 
 
 
 
 
 
 


 
42 
Amendment #1 Description 
 
Page 1 – Amendment # 1 January 31, 2018 added 
 
Page 2 – Table of Contents added 
 
Page 7, 3rd paragraph – EG changed to Dr. Guttman and sentence clarified.  
 
Page 10, last paragraph (Study Design Overview) – Added “The study will take place at  
 
two sites: Icahn School of Medicine at Mount Sinai, and Rockefeller University.” 
Also “(20 out of 60 subjects)” was added for clarification of the number of subjects 
allowed to have AA and AD. 
 
Page 11, 1st paragraph – Added “(30 out of 60 subjects)” to clarify number of subjects 
allowed to have AT or AU.  
Added “Once the required number of subjects in each of these sub-categories is 
met, additional subjects in those categories will not be enrolled” for clarification. 
 
Page 11, 4th and 5th paragraph – Description regarding clinical assessments was 
split into two types to distinguish between those for all subjects (AA) and those for 
the subset of subjects with AA + AD: “clinical assessments (SALT, and 
eyebrow/eyelash assessment score), and additional skin assessments if he/she 
concurrently has atopic dermatitis (EASI, IGA, SCORAD)”. 
 
Page 12, 1st paragraph – Size of biopsy was corrected to 4.5 mm (which matches 
 consent form). 
 
Page 12, 2nd and 3rd paragraph – sections clarified regarding the loading dose and all  
 
other doses. 
 
Page 12, 5th paragraph (Independent Expert Assesment) -  Dr Norris will not approve 
screening photos as both PIs are experts in diagnosing AA, thus that statement  
has been deleted. Dr. Norris will still review photographs of those subjects that  
consent to them, to assess improvement/progress during the study.  
 
Pages 17-21 - Description regarding clinical assessments was split into two types to 
distinguish between those for all subjects (AA) and those for the subset of subjects 
with AA + AD: “clinical assessments (SALT, and eyebrow/eyelash assessment 
score), and additional skin assessments if he/she concurrently has atopic 
dermatitis (EASI, IGA, SCORAD)”. 
 
Page 17 – Standardized Clinical Photography deleted from Screening visit and added to  
Baseline visit. 
 
Page 19 Visit 8 – Added for clarification regarding Week 24 injections “(subjects 


 
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previously on dupilumab will receive 1 injection of 300 mg dupilumab and 1 
injection of placebo to maintain the blind of the study; subjects previously on 
placebo will receive 2 injections of 300 mg dupilumab). All subjects should be 
dupilumab). All subjects should be observed for 30 minutes following the injection 
to preserve the blind.  
 
Page 21 – Added section: 
 
LABORATORY TESTING: 
Each site may utilize their own local lab for CBC, CMP, LDH, CRP, IgE, HIV, HBV, 
HCV, Quantiferon Gold, and pregnancy testing. Lab certifications for any lab used 
should be kept in the study binder.  RU will have to transport biopsy samples as 
well as blood samples for mechanistic testing (and potentially IgE testing) to Mount 
Sinai via proper and documented means.  
 
Page 22 – (Study Withdrawal) - Description regarding clinical assessments was split 
into two types to distinguish between those for all subjects (AA) and those for the 
subset of subjects with AA + AD: “clinical assessments (SALT, and 
eyebrow/eyelash assessment score), and additional skin assessments if he/she 
concurrently has atopic dermatitis (EASI, IGA, SCORAD)”. 
 
Page 24 after first bullet – added “Duration of study drug suspension should be 
reviewed on a case by case basis and can be discussed among the PIs” in cases 
of temporary discontinuation of drug.  
 
Page 25 Added (or similar) in reference to the website used to create the randomization 
code. 
 
Page 26, 1st paragraph – added for clarification: “At Week 24, subjects previously on 
dupilumab will receive 1 injection of 300 mg dupilumab and 1 injection of placebo 
to maintain the blind of the study; subjects previously on placebo will receive 2 
injections of 300 mg dupilumab. All subjects should be observed for 30 minutes 
following the injections at Baseline and at Week 24.” 
 
Page 28, 2nd paragraph – Typo corrected as well as clarifications made, and statement  
 
added regarding the sharing of photos and results with Dr Norris.  
 
Page 33 and 34 (Schedule of Events) – Clinical assessments split into multiple rows for  
clarification; corrections as to when specific procedures are done; and clarifications 
made to the footnotes.  
 
Page 35-38 Additional calculation tables added to descriptive details regarding 
assessments. 
 
Page 39-41 Added “Appendix # 2 Subject Questionnaires (AASIS and AA-QLI)  
 
Page 42 – Added Amendment # 1 Description. 


 
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Amendment #2 Description 
 
Page 24 Unblinding Section Paragraph 2 – “the data safety monitoring board” was deleted 
as there is no DSMB for this study.  It had been originally included in error.  
 
 
Amendment #3 Description 
 
Page 1 – Jason Hawkes was removed as a co-investigator and Protocol Version was 
added: January 08, 2020 Amendment # 3 
 
Pages 9, 10  and 11 Endpoints -  Statistician reviewed protocol and recommended some 
revisions to the endpoints. Primary endpoint was revised to only compare Week 24 to 
Baseline instead of comparing both Week 24 and 48 to Baseline as Week 24 ends the 
blinded placebo controlled phase. Three secondary endpoints evaluating lower 
improvements in SALT scores were deleted. Second mechanistic endpoint analyzing 
relapse was removed. 
 
Page 27 and 28 Statistical Consideratons – The statisitical analyses sections were 
updated to correlate with the updated Primary and Secondary Endpoints. The sections 
defining Analysis of Mechanistic and Exploratory Endpoints have been expanded upon 
and updated with the most recent information available to date.  
 
Page 13 Study Design Overview – The option for subjects to seek other treatments (or 
obtain commercially available dupilumab) at Week 48 was added.   
 
Page 17 – Concomitant Treatment -  If subjects seek other treatments (or obtain 
commercially available dupilumab) at Week 48, then these treatments must be 
documented as concomitant medications.