Conditions: Alopecia Areata
Keywords: Alopecia areata
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
Alopecia areata (AA) 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 to assess the effects of a new treatment called apremilast in patients with alopecia areata. A total of 30 patients will be included in the study, which will run for a total of 52 weeks.

Detailed description:
This is a randomized, double-blind, placebo-controlled pilot study consisting of two phases. A total of 30 subjects with moderate to severe alopecia areata (including universalis and totalis) involving 50-100% of the scalp will be enrolled. A possible maximum of 15 patients (approximately 7 patients each) with current episodes of AA totalis / universalis may be included in this study.

In Phase 1, subjects will be randomized (2:1) to either receive apremilast or placebo for 24 weeks.

In Phase 2, eligible subjects will receive apremilast from Week 24 through Week 48. The following subjects will be eligible to enter into Phase 2:

1. Subjects who received placebo in Phase 1 of the study
2. Subjects who received apremilast in Phase 1 of the study, and who achieved a minimum of 50% regrowth (SALT50) at Week 24, compared to Baseline.

Arms:
arm 1: Apremilast 30mg twice daily arm 2: Placebo pills twice daily

Interventions: intervention 1: Apremilast intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects will get drug or placebo intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
1 
 
A randomized placebo-controlled single center pilot study of the safety and 
efficacy of Apremilast in subjects with moderate to severe alopecia areata 
PI: Emma Guttman, MD, PhD 
NCT02684123 
Document Date: 10-27-2016 
 
 
 
 
 


 
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A randomized placebo-controlled single center pilot study of the 
safety and efficacy of Apremilast in subjects with moderate to severe 
alopecia areata 
 
 
 
Institution: 
 
Icahn School of Medicine at Mount Sinai 
Department of Dermatology  
, Box 1048 
New York, NY 10029 
Tel:  212-241-3288 
Fax: 212-876-8961 
 
Investigators: 
 
Principal Investigator:  
 
Emma Guttman, MD, PhD 
 
Co-investigators: 
 
 
 
Mark Lebwohl, MD 
 
Yasaman Mansouri, MD 
 
 
Protocol Version: August 28, 2015 
Amendment #1: October 27, 2016 
 
 
 


 
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HYPOTHESES: 
 
Primary Hypothesis: 
 
1. It is hypothesized that apremilast is superior to placebo for induction of hair 
regrowth in patients with moderate to severe alopecia areata (AA). 
 
 
 
OBJECTIVES and ENDPOINTS: 
 
Primary objective: 
 
1) To study the efficacy of apremilast for induction of hair regrowth in patients with 
moderate to severe AA. 
  
Secondary objectives: 
 
1) To study the safety of apremilast in patients with moderate to severe alopecia 
areata. 
2) To study the mechanism of action of apremilast in patients with moderate to 
severe alopecia areata. 
 
Primary endpoints: 
 
1) Percentage of patients achieving 50% or greater improvement in their Severity of 
Alopecia Tool (SALT) score (SALT50) at Week 24 compared to Baseline.  
 
Secondary endpoints: 
 
1) Percentage change in SALT score at Week 24, 48. 
2) Proportion of subjects achieving an alopecia areata Physician’s Global 
Assessment (aaPGA) score of 3 or above at Weeks 24 and 48 (0, no regrowth; 
1, <25% of regrowth; 2, 25%-49% of regrowth; 3, 50%-74% of regrowth; 4, 75%-
99% of re- growth; 5, 100% of regrowth). 
3) Percentage change from Baseline in the Alopecia Areata Symptom Impact Scale 
(AASIS) at Weeks 24 and 48.  
4) Percentage change from baseline in the Alopecia Areata Quality of Life 
questionnaire (AA-QoL) at Weeks 24 and 48 
5) Semiquantitative 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) at week 24 and 48. 
 
 
 
Mechanistic (exploratory) endpoint: 
 
1) Change from baseline in cellular, and molecular markers in skin biopsies after 
treatment. 


 
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INTRODUCTION: 
 
Alopecia areata (AA) is an auto-immune disease characterized by non-scarring hair loss 
that can sometimes progress to total loss of all scalp and body hair.1 The life-time risk of 
AA has been reported to be 1.7%.2 AA can cause tremendous emotional and 
psychosocial distress in affected patients and their families. There is a lack of effective 
treatments for patients with alopecia areata. Topical treatments are usually not very 
effective, probably because of limited penetration. Intralesional injections of 
corticosteroids are effective but can only be considered for patients with limited 
involvement. Immunotherapy with diphencyprone or squaric acid dibutyl is effective in 
some patients but is usually limited to treatment of scalp involvement and can cause 
significant pruritus and dermatitis. None of these therapies are targeted to the 
underlying mechanism for disease pathogenesis. There is a need for new treatment 
options for patients with alopecia areata especially based on the recently evolving 
understanding of the disorder.  
 
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. While the etiology of AA remains unknown, studies have suggested 
infiltration of CD4+ and CD8+ T cells and a predominant Th1 cytokine profile in the 
etiology of this disease, leading to destruction of the hair follicle immune privilege site.  
 
During the last decade, interleukin (IL)-23 has been recognized as essential in the 
development of multiple autoimmune diseases, including psoriatic disease, vitiligo, 
inflammatory bowel disease, and autoimmune encephalomyelitis.3, 4 
The pathogenesis of alopecia areata has also been linked to IL-17, which is produced 
by Th17 cells. In particular, studies have shown the IL-17 RA gene polymorphism to be 
associated with increased susceptibility to alopecia areata in the Korean population.5  
Early study findings have demonstrated markedly elevated IL-17 levels in blood from 
patients with alopecia areata (unpublished but presented at the EADV in 2013).  IL-23 is 
known to regulate IL-17 production and to promote the expansion of Th17 cells.6  
Increased levels of the cytokine IL-12 have been sown in both serum and lesional skin 
of AA patients.7 Furthermore, preliminary analyses from our laboratory (Fig. 1) showed 
an elevation of IL-12 mRNA expression by RT PCR. Our analyses have further shown 
that p40, IL-13, IFN-γ, IL-12RB1, IL-22, JAK3 are all significantly induced in AA (p<0.05) 
in a similar fashion as in AD when comparing lesional with nonlesional skin. 
 


 
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Apremilast is an oral small molecule phosphodiesterase-4 (PDE4) inhibitor that has 
been shown to regulate inflammatory mediators.8 Apremilast enters cells by passive 
diffusion and, once intracellular, binds PDE4. PDE-4, the dominant phosphodiesterase 
expressed in immune cells, degrades cyclic AMP (cAMP) into AMP. PDE4 inhibition 
thereby elevates intracellular cAMP, which can down-regulate the inflammatory 
responses such as TNF-α, IFN-γ, interleukins (IL) 2, 12, 17, and 23 through 
mechanisms such as partially inhibiting expression of inflammatory cytokines and 
increasing expression of anti-inflammatory mediators such as IL2 and IL10.8 Apremilast 
further downregulates target organ MHC class II expression.9 A recent pilot study 
demonstrated that apremilast suppresses experimentally induced AA in a humanized 
mouse model.10 We therefore hypothesize that apremilast may have beneficial effects in 
AA. The U.S. Food and Drug Administration (FDA) approved apremilast for the 
treatment of adult patients with active psoriatic arthritis in March 2014, and for patients 
with moderate-to-severe plaque psoriasis in September 2014. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Figure 1 
 
 
Fig 1. Figure 1 shows comparable cytokine expression of the defining Th2 cytokine/IL-
13, the defining Th1 cytokine/IFN gamma, and the Th17/IL-23 cytokines/IL-17A and 
IL12/23p40 in AA and AD.  Lesional psoriasis skin tissues show a significantly higher 
expression of both IL-17A and IFN gamma, with significantly lower expression of IL-13 
as compared with both AA and AD. Significant decreases in mRNA expression of IL-13, 
and IL12/23p40 are seen after treatment with intralesional corticosteroids, without 
significant changes in the other cytokines. P value= 0.0002 for the IL-13, and p=0.1 for 
the IFN gamma lesional vs non-lesional alopecia skin comparisons. JAK3 shows similar 
activation in AA, AD, and Psoriasis. NL- non lesional skin from scalp of AA patients; L- 
lesional skin from scalp of AA patients; PTX- post intralesional steroid treatment skin 
from scalp of AA patients; PS-psoriasis lesional skin; AD- AD lesional skin. N=6 patients 
for both NL and L, and 4 for PTX. 
 
 
 


 
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STUDY DESIGN: 
 
This is a randomized, double-blind, placebo-controlled pilot study consisting of two 
phases. A total of 30 subjects with moderate to severe alopecia areata (including 
universalis and totalis) involving 50-100% of the scalp will be enrolled.  A possible 
maximum of 15 patients (approximately 7 patients each) with current episodes of AA 
totalis / universalis may be included in this study. 
In Phase 1, subjects will be randomized (2:1) to either receive apremilast or placebo for 
24 weeks.  
 
In Phase 2, eligible subjects will receive apremilast from Week 24 through Week 48. 
The following subjects will be eligible to enter into Phase 2: 
1. Subjects who received placebo in Phase 1 of the study 
2. Subjects who received apremilast in Phase 1 of the study, and who achieved 
any minimum of 50% regrowth (SALT50)  at Week 24, compared to Baseline. 
 
After providing informed consent, subjects will be assessed for study eligibility at the 
Screening visit (day -28 to day -1), which includes limited physical examination, 
assessment of regrowth pattern, SALT scoring, review of medical history and 
concomitant as well as prior medications/treatments, and serum pregnancy test (if 
applicable). Laboratory tests will be performed for complete Blood Count (CBC) and 
white blood cell count (WBC) with differentials (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), serum chemistry for albumin, alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), aspartate aminotransferase (AST), creatinine, potassium, 
sodium and total bilirubin, as well as hepatitis B surface antigen (HbsAg) and hepatitis C 
antibody.  
 
Subjects who meet eligibility criteria will undergo Baseline / Day 0 assessments. These 
assessments include hair examination, SALT scoring, aaPGA scoring, review of 
concomitant medications, clinical photography, questionnaires (AASIS and AA-QoL), 
and urine pregnancy test (if applicable). Blood samples will be collected for mechanistic 
studies, DNA analysis and RNA and proteomic analysis. Two biopsies of the scalp will 
be performed: one from an area affected with alopecia areata and one from an area that 
is not affected. If the subject has 100% hair loss, then only one biopsy from an affected 
area will be performed.  At this Baseline visit, subjects will undergo randomization, and 
will receive the first oral dose of study drug (apremilast or placebo). 
 
Subjects will be provided with the study drug, and will receive twice daily (BID) dosing of 
study drug (apremilast or placebo orally) through Week 24.  
 
Subjects will return for visits every four weeks through Week 24 (Weeks 4, 8, 12, 16, 20 
and 24) so that a review of concomitant medications and adverse events can be 
assessed.  Females of childbearing potential will undergo a urine pregnancy test at 
each of these visits. Additional study drug will be dispensed every 4 weeks. In addition, 
the following procedures will be collected at various time points: 
 
 
Week 4: assessment of regrowth pattern, SALT scoring, aaPGA scoring.  
 
 
 


 
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Week 8: assessment of regrowth pattern, SALT scoring, aaPGA scoring, and 
clinical photography. 
 
 
Week 12: assessment of regrowth pattern, SALT scoring, aaPGA scoring, clinical 
photography, blood tests (for mechanistic studies, Pax RNA and proteomic 
analysis), and questionnaires (AASIS and AA-QoL). One optional biopsy of the 
scalp (close to the involved area that was biopsied at Baseline) may be performed. 
 
Weeks 16 and 20: assessment of regrowth pattern, SALT scoring, aaPGA scoring.  
 
Week 24: limited physical examination, assessment of regrowth pattern, SALT 
scoring, aaPGA scoring, clinical photography, questionnaires (AASIS and AA-
QoL), blood tests (for mechanistic studies, RNA and proteomic analysis), and one 
scalp biopsy will be performed (in the vicinity of the involved area biopsied at 
Baseline).  
 
At the Week 24 study visit, eligible subjects will be allowed to enter into Phase 2 of the 
study, in which all eligible subjects will receive apremilast. Subjects who received 
placebo in Phase 1 of the study, will start apremilast as per appropriate titration dose. 
Subjects who received apremilast in Phase 1, and who achieved any  regrowth 
compared to Baseline will enter into Phase 2 and will continue their current dose of 
apremilast (30 mg twice daily). Subjects who received apremilast in Phase 1 and 
showed  no regrowth will be discontinued from the study.  
 
Subjects continuing in Phase 2 will return to the site every 4 weeks through Week 52 
(Weeks 28, 32, 36, 40, 44, 48 and 52) so that a review of concomitant medications and 
adverse events can be assessed.  Females of childbearing potential will undergo a 
urine pregnancy test at each of these visits (except Week 52). In addition, the following 
procedures will be collected at various time points: 
 
Weeks 28 and 32: assessment of regrowth pattern, SALT scoring, aaPGA scoring 
and clinical photography. 
 
Week 36: assessment of regrowth pattern, SALT scoring, aaPGA scoring, clinical 
photography, and questionnaires (AASIS and AA-QoL). 
 
Weeks 40 and 44: assessment of regrowth pattern, SALT scoring, aaPGA scoring 
and clinical photography. 
 
Week 48: limited physical examination, assessment of regrowth pattern, SALT 
scoring, aaPGA scoring, clinical photography, and questionnaires (AASIS and AA-
QoL).  
 
Subjects will end treatment with apremilast at Week 48 and will be asked to return for a 
follow-up visit at Week 52.  At this visit, subjects will undergo assessment of regrowth 
pattern, SALT scoring, aaPGA scoring, and assessment of any adverse events and 
change in concomitant medications. 
 
If a subject terminates early or chooses to discontinue the study, he/she will be asked to 


 
9 
 
return for a final visit, which would include: limited physical examination, examination of 
hair, SALT scoring, aaPGA scoring, clinical photography and questionnaires (AASIS 
and AA-QoL).  If the subject terminates or discontinues prior to Week 24, then the Early 
Termination Visit will also include blood tests (for mechanistic studies, RNA and 
proteomic analysis) and one scalp biopsy (in the vicinity of the involved area biopsied at 
Baseline). 
 
Subjects will not receive any other active treatment for alopecia areata (outside of the 
study drug) while participating in the study.  
 
Apremilast will be provided as 10-, 20-, or 30-mg tablets. Apremilast will be taken orally 
twice daily, approximately 12 hours apart. Apremilast can be administered without 
regard to meals, and tablets should not be  crushed, split, or chewed.  
When subjects first start to take apremilast, the dose will be titrated in 10-mg/day 
increments. Following the 5-day titration, the recommended maintenance dosage is 30 
mg twice daily taken orally starting on Day 6. This titration is intended to reduce the 
gastrointestinal symptoms associated with initial therapy.  
 
Day 1: 10 mg in morning 
Day 2: 10 mg in morning and 10 mg in evening 
Day 3: 10 mg in morning and 20 mg in evening  
Day 4: 20 mg in morning and 20 mg in evening  
Day 5: 20 mg in morning and 30 mg in evening  
Day 6 and thereafter: 30 mg twice daily 
 
 
Safety will be assessed by evaluation of adverse events, physical examinations and 
laboratory parameters. Safety, laboratory, and clinical assessments will be performed at 
specified clinic visits. A serum pregnancy test will be performed at Screening and urine 
pregnancy tests will be performed at Baseline and every 4 weeks thereafter, in females 
of childbearing potential.   
 
Efficacy will be evaluated using the Severity Alopecia Tool (SALT)11 score, and the 
alopecia areata Physician Global Assessment (aaPGA). The SALT score is a 
mathematical approach to the determination of hair loss and hair regrowth.12 The 
percentage of scalp hair loss in each of the sides, back and top of the scalp are 
determined independently, and are multiplied by the percentage scalp covered in that 
area of the scalp and the products of each section summed for a final total percentage 
hair loss, designated as the SALT score. (Appendix 1). 
 
Alopecia areata Physician Global Assessment (aaPGA): a static PGA score is widely 
used as a primary efficacy point of treatment success in many studies of dermatological 
diseases. The static aaPGA score represents an overall static evaluation of the 
alopecia, performed by the investigator at each visit. It utilizes a scale of 6-points, 
ranging from 0 (no regrowth) to 5 (100% regrowth), with 0:no regrowth; 1:<25% of 
regrowth; 2: 25%-49% of regrowth; 3:50%-74% of regrowth; 4:75%-99% of re- growth; 
5:100% of regrowth). (Appendix 2). 
 


 
10 
 
Quality of life will be evaluated using the Alopecia Areata Symptom Impact scale 
(AASIS)13 and the Alopecia Areata Quality of Life Index (AA-QLI).14 (Appendices 3 and 
4). 
 
Skin biopsies from the scalp will be performed on all subjects at Baseline and Week 24 
or Early Termination visit (if prior to Week 24). At Baseline, biopsies will be obtained 
from involved and uninvolved areas of the scalp (except in the case of 100% 
involvement, when only 1 biopsy of involved scalp will be biopsied). At Week 24 or Early 
Termination visit, the biopsy will be performed in the vicinity of the involved area 
biopsied at baseline. An optional biopsy will be performed at Week 12, close to the area 
that was involved at baseline. All skin biopsies will be 4.5 mm in diameter. 
 
At Baseline, serum will be obtained for DNA (1 PaxGene), RNA (2 PaxGene), and 
proteomic analysis (2 tubes serum). Studies of RNA, and proteomic analysis will further 
be performed at Weeks 12 and 24. Serum levels of various biomarkers such as 
interferon gamma, IL-2, IL-12, IL-13, IL-17A, IL-5, IL-10, IL-31 and IL-4 have been 
shown to be elevated in patients with alopecia areata. Thus, for mechanistic research 
purposes, we will assess Th1 (interferon gamma) and Th2 (IL-13) cytokines, as well as 
a panel of ten Th1 and Th2 chemokines (CXCL9, CXCL10, CCL17, CCL18, CCL22, 
CCL26, CCL2, CCL3, CCL4, CCL5) (using MSD) in serum before and after apremilast 
treatment.  
 
 INCLUSION CRITERIA:  
 
Subjects must satisfy the following criteria to be enrolled in the study:  
 
1. Males or females, 18 years or older at the time of signing the informed consent 
document. 
 
2. Understand and voluntarily sign an informed consent document prior to any 
study-related assessments/procedures are conducted. 
 
3. Able to adhere to the study visit schedule and other protocol requirements.  
4. Subject with a diagnosis of patchy scalp alopecia areata present for at least 6 
months, and up to a maximum of 10 years. 
5. Patients with ≥50% and <95% total scalp hair loss at Baseline as measured using 
the SALT score to qualify as moderate to severe AA; and 95%-100% scalp hair 
loss to qualify as AA totalis/universalis.  
6. 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.  


 
11 
 
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.  
f. Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L).  
 
7. 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: 
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  
 
Option 2: Male or female condom (latex condom or nonlatex condom NOT made 
out of natural [animal] membrane [for example, polyurethane]); plus spermicide 
PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical 
cap with spermicide; or (c) contraceptive sponge with spermicide. 
 
 
8. Male subjects (including those who have had a vasectomy) who engage in 
activity in which conception is possible must use barrier contraception (male latex 
condom or nonlatex condom NOT made out of natural [animal] membrane [for 
example, polyurethane]) while on IP and for at least 28 days after the last dose of 
IP.  
 
9. No evidence of hair regrowth present at Baseline. 
 
 
EXCLUSION CRITERIA:  
The presence of any of the following will exclude a subject from enrollment:  
1. Clinically significant (as determined by the investigator) cardiac, endocrine, 
pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, or immunologic 
disease, or other major uncontrolled diseases that will affect the health of the 
subject during the study or interfere with the interpretation of study results.  
2. Hepatitis B surface antigen positive at Screening (Visit 1).  
3. Hepatitis C antibody positive at Screening (Visit 1).  
4. History of positive human immunodeficiency virus (HIV), or congenital or 
acquired immunodeficiency (eg, Common Variable Immunodeficiency [CVID]). 
Subjects deemed at risk by the study investigator, may also undergo testing for 


 
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human immunodeficiency virus (HIV). Subjects deemed at risk include those with 
a history of injection drug use, homosexual subjects, and subjects with known 
sexual contact with an HIV positive partner. 
5. Active TB or a history of inadequately treated TB. 
6. Active substance abuse or a history of substance abuse within six months prior 
to Screening.  
7. Pregnant or breast feeding.  
8. History of allergy to any component of the IP.  
 
9. Major surgery within eight weeks prior to Screening (Visit 1) and/or planned 
surgery during the length of the study.  
10. Malignancy or history of malignancy, except for:  
a. treated (ie, cured) basal cell or squamous cell in situ skin carcinomas;  
b. treated (ie, cured) cervical intraepithelial neoplasia (CIN) or carcinoma in 
situ of the cervix with no evidence of recurrence within 5 years prior to 
Screening (Visit 1). 
11. Unstable asthma (eg, acute episodes of exacerbation [nocturnal episodes, 
sudden episodes triggered by unidentifiable factors] despite a stable regimen of 
anti-asthmatic medications); prior episode(s) of life-threatening asthma; or 
asthma that requires inhaled budesonide or equivalent at >1200 μg/day or 
fluticasone propionate at > 880 μg/day along with another anti-asthmatic drug 
such as a long-acting beta-agonist.  
 
12. A history of and/or concurrent condition of serious hypersensitivity (eg, 
anaphylaxis) to drugs, foods, or other allergens without access to emergency 
rescue medication such as epinephrine.  
13. Persistent or recurring bacterial infection requiring systemic antibiotics, or 
clinically significant viral or fungal infections, within two weeks of Screening (Visit 
1). Any treatment for such infections must have been completed at least two 
weeks prior to the Screening Visit and no new/recurrent infections should have 
occurred prior to the Baseline Visit.  
14. Active skin infection requiring systemic antimicrobials at Baseline/Randomization 
(Visit 2).  
15. Skin lesion(s) due to conditions other than AA that would interfere with the study 
specified assessments.  


 
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16. Prior treatment with apremilast, or participation in a clinical study involving 
apremilast.  
17. Use of phototherapy (ie, UVB, UVA) or systemic immunosuppressive drugs 
(including, but not limited to, cyclosprine, corticosteroids, mycophenolate mofetil, 
azathioprine, Methotrexate, or tacrolimus), or oral preparations of herbal 
immunomodulatory medications within four weeks prior to 
Baseline/Randomization (Visit 2).  
18. Use of interferon-γ within 12 weeks prior to Baseline/Randomization (Visit 2).  
19. Use of abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, 
infliximab, or tocilizumab within 12 weeks prior to Baseline/Randomization (Visit 
2).  
20. Use of oral janus kinase (JAK) inhibitors (e.g. tofacitinib, ruxolitinib) within 12 
weeks prior to Baseline/Randomization (Visit 2). 
21. Use of omalizumab, rituximab, ustekinumab, alefacept, briakinumab, or other 
therapeutic antibody products within 24 weeks prior to Baseline/Randomization 
(Visit 2).  
22. Use of any investigational drug within four weeks or five PK or PD half lives 
(whichever is longer) prior to Baseline/Randomization (Visit 2).  
23. Use of topical corticosteroid preparations, topical calcineurin inhibitors, or other 
topical preparations with immunomodulatory properties within 2 weeks prior to 
Baseline/Randomization (Visit 2).  
24. Prior history of suicide attempt at any time in the subject’s lifetime prior to 
Baseline (Visit 2) or major psychiatric illness requiring hospitalization within 3 
years prior to Baseline (Visit 2).  
25. History of male or female pattern hair loss Ludwig stage III or Hamilton > stage V.  
26. Patients in whom the diagnosis of alopecia areata is in question, or subjects with 
scarring alopecia. 
 
RISKS OF APREMILAST 
As of 10 May 2014, apremilast has been given to about 5200 subjects (people).  The 
following are the most commonly seen risks, discomforts and side effects in subjects 
who have taken apremilast:  headache including tension headache, stuffiness or 
infections of the nose and throat (upper respiratory tract infections including 
nasopharyngitis), stomach upset (nausea), vomiting and diarrhea.  Most of these side 
effects were mild to moderate in intensity and resolved with continued treatment.  


 
14 
 
Similar side effects have been observed in studies that are running now.  About 8 out of 
every 100 subjects treated have discontinued the study drug because of side effects.   
The following side effects are the ones that may be associated with the use of 
apremilast: 
 Very common: diarrhea, nausea (stomach upset), vomiting.  
 Common: Upper abdominal (stomach) pain, indigestion, frequent bowel 
movement, heartburn, fatigue, bronchitis (infection of the tubes to the lungs), 
redness/swelling/pain in the sinuses, inflammation or infections of the nose and 
throat, weight loss, decreased appetite, back pain, headache (including tension 
and migraine), difficulty sleeping, depression, cough, rash, dizziness, weakness, 
flu, muscle pain, numbness, itchiness. 
 Uncommon: allergic reaction. 
Reports of various types of cancers, heart problems, and serious infections have been 
found from apremilast studies. However, these events in patients being treated with 
apremilast happened as often as those being treated with placebo (sugar pill).  
Drugs in the same family as apremilast have been shown to produce inflammation 
around the vessels of the skin (vasculitis) in rats and mice. Skin vasculitis has been 
rarely reported equally in patients taking apremilast or placebo.   
Depression and weight loss have been reported with the use of apremilast, thus, 
subjects will be questioned about any mood changes and weight loss at each visit.  
 
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.   
The Principal Investigator will provide safety data to an independent Data and Safety 
Monitoring Board every 12 months.  This DSMB will be comprised of board certified 
dermatologists who are not directly related to this study. The DSMB will review the data 
and provide a report of their findings to the Principal Investigator.   
 
EARLY TERMINATION 
Any individual whose health or well being may be threatened by continuation in this 
study will be discontinued by the investigator.  


 
15 
 
If a female subject becomes pregnant at anytime during the study, she will be discontinued 
immediately.  She will be asked to provide the investigator with medical updates 
throughout her pregnancy and on the final outcome of the pregnancy.   
Any subject who chooses to discontinue the study, or is discontinued from the study by 
the investigator will be asked to return for a final visit to have some or all of the following 
procedures: limited physical examination; blood test; pregnancy test; clinical 
photography; assessment of regrowth pattern; hair evaluation; SALT assessment; 
aaPGA; questionnaires (AASIS and AA-QoL); assessment of concomitant medication 
and adverse events; biopsy of scalp. 
 
ADVERSE EVENTS 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence 
occurring at any dose that may appear or worsen in a subject during the course of a 
study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or 
any concomitant impairment of the subject’s health, including laboratory test values (as 
specified by the criteria below), regardless of etiology. Any medical condition that was 
present prior to study treatment and that remains unchanged or improved should not be 
recorded as an AE. If there is a worsening of that medical condition this should be 
considered an AE. A diagnosis or syndrome should be recorded on the AE page of the 
Case Report From rather than the individual signs or symptoms of the diagnosis or 
syndrome. 
All AEs will be recorded by the Investigator(s) from the time of signing the informed 
consent through the end of the designated follow-up period. 
Abnormal laboratory values defined as adverse events 
An abnormal laboratory value is considered to be an AE if the laboratory abnormality is 
characterized by any of the following: 
 Results in discontinuation from the study. 
 Requires treatment, modification/interruption of study drug dose, or any other 
therapeutic intervention. 
 Is judged by the Investigator(s) to be of significant clinical importance. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page of the CRF. If the 
abnormality was not a part of a diagnosis or syndrome, then the laboratory abnormality 
should be recorded as the AE. 
Serious adverse event 
A serious adverse event (SAE) is any AE which: 
 Results in death 
 Is life-threatening (i.e., in the opinion of the Investigator(s) the subject is at 
immediate risk of death from the AE) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 


 
16 
 
 Results in persistent or significant disability/incapacity (a substantial 
disruption of the subject’s ability to conduct normal life functions) 
 Is a congenital anomaly/birth defect 
 Constitutes an important medical event 
Important medical events are defined as those occurrences that may not be 
immediately life threatening or result in death, hospitalization, or disability, but may 
jeopardize the subject or require medical or surgical intervention to prevent one of the 
other outcomes listed above.  Medical and scientific judgment should be exercised in 
deciding whether such an AE should be considered serious. 
Events not considered to be SAEs are hospitalizations which: were planned before 
entry into the clinical study; are for elective treatment of a condition unrelated to the 
studied indication or its treatment; occur on an emergency outpatient basis and do not 
result in admission (unless fulfilling other criteria above); are part of the normal 
treatment or monitoring of the studied indication and are not associated with any 
deterioration in condition. 
If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form 
must be completed. 
For each SAE, the Investigator(s) will provide information on severity, start and stop 
dates, relationship to study drug, action taken regarding study drug, and outcome. 
Classification of severity 
For both AEs and SAEs, the investigator(s) must assess the severity of the event. The 
AEs will be evaluated for severity according to the following scale: 
Grade 1 = Mild 
Grade 2 = Moderate 
Grade 3 = Severe 
 
Classification of Relationship/Causality of adverse events (SAE/AE) to study drug 
The Investigator(s) must determine the relationship between the administration of study 
drug and the occurrence of an AE/SAE as Not Suspected or Suspected as defined 
below: 
Not 
suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship 
unlikely or remote, or other medications, therapeutic 
interventions, or underlying conditions provide a sufficient 
explanation for the observed event 
Suspected: 
The temporal relationship of the adverse event to study 
drug administration makes a causal relationship 
possible, and other medications, therapeutic 
interventions, or underlying conditions do not provide a 
sufficient explanation for the observed event. 


 
17 
 
Immediate reporting of serious adverse events 
Any AE that meets the any criterion for a SAE requires the completion of an SAE Report 
Form in addition to being recorded on the AE pages of the CRF.  The Investigator(s) is 
required to ensure that the data on these forms is accurate and consistent.  This applies 
to all SAEs, regardless of relationship to study drug, that occur during the study, those 
made known to the Investigator(s) within 30 days after a subject’s last dose of study 
drug, and those made known to the investigator(s) at anytime that are suspected of 
being related to study drug. 
The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ 
knowledge of the event) to Celgene Safety by facsimile or email.  A written report 
(prepared by the Investigator(s) using an SAE Report Form or a 3500A Medwatch form  
is to be faxed to Safety (see below for contact information). 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:(908) 673-9115 
E-mail: drugsafety@celgene.com 
 
The SAE report should provide a detailed description of the SAE.  If a subject has died 
and an autopsy has been performed, copies of the autopsy report and death certificate 
are to be sent to Celgene as soon as these become available.  Any follow-up data will 
be detailed in a subsequent SAE Report Form or Medwatch form and sent to Celgene. 
The Investigator(s) is responsible for informing the Institutional Review Board/Ethics 
Committee (IRB/IEC) of the SAE and providing them with all relevant initial and follow-
up information about the event. The Investigator(s) must keep copies of all SAE 
information, including correspondence with Celgene and the IRB/IEC, on file.  All SAEs 
that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until either the event resolves completely, stabilizes, resolves with 
sequelae, or returns to baseline (if a baseline value is available). 
 
Contraception Education 
The risks to a fetus or to a nursing child from apremilast are not known at this time.  
Results of the animal and in vitro studies can be found in the IB.    
All females of childbearing potential (FCBP) must use one of the approved 
contraceptive options as described under inclusion criterion # 7 while on investigational 
product and for at least 28 days after administration of the last dose of the 
investigational product.  Male subjects (including those who have had a vasectomy) 
who engage in activity in which conception is possible must adhere to inclusion criterion 
# 8 while on investigational product and for at last 28 days after administration of the 
last dose of investigational product.  


 
18 
 
When a subject’s contraceptive methods or ability to become pregnant changes at any 
time during the study, the Investigator will educate the subject regarding options and 
correct and consistent use of effective contraceptive methods in order to successfully 
prevent pregnancy. 
 
 
Pregnancies 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age or disease state) of a female subject or the female partner of a male subject 
occurring while the subject is on study drug, or within 30 days of the subject’s last dose 
of study drug, are considered immediately reportable events.  Study drug is to be 
discontinued immediately and the subject instructed to return any unused portion of the 
study drug to the investigator(s).  The pregnancy, suspected pregnancy, or positive 
pregnancy test must be reported to Celgene Safety immediately via facsimile or email 
using the Pregnancy Report form provided by Celgene. 
The female should be referred to an obstetrician-gynecologist experienced in 
reproductive toxicity for further evaluation and counseling. 
The Investigator(s) will follow the female subject until completion of the pregnancy, and 
must notify Celgene Safety of the outcome of the pregnancy as a follow-up on the follow 
up Pregnancy Reporting form. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE 
(i.e., spontaneous or therapeutic abortion [any congenital anomaly detected in an 
aborted fetus is to be documented], stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator(s) should follow the procedures for 
reporting SAEs (i.e., report the event to Celgene Safety by facsimile within 24 hours of 
the Investigator’s knowledge of the event). 
In the case of a live “normal” birth, Celgene Safety should be advised by facsimile within 
24 hours of the Investigator’s knowledge of the event. 
All neonatal deaths that occur within 30 days of birth should be reported, without regard 
to causality, as SAEs.  In addition, any infant death after 30 days that the Investigator(s) 
suspects is related to the in utero exposure to the study drug should also be reported to 
Celgene Safety by facsimile within 24 hours of the Investigators’ knowledge of the 
event. 
If the female is found not to be pregnant, any determination regarding the subject’s 
continued participation in the study will be determined by the Investigator(s).  
 
Proposed Mechanistic studies: 
In order to identify the molecular and cellular profiles of alopecia areata at Baseline, and 
identify treatment response biomarkers, we plan to perform lesional (LS) and  
nonlesional (NL) 4.5 mm punch biopsies at Baseline and after 24 weeks of treatment 
(LS only) as above (from the same area previously biopsied, but not from the scar).  
 


 
19 
 
Gene expression studies (RT-PCR and gene arrays), and immunohistochemistry will be 
performed.  
 
The expression levels of markers of the different immune pathways, including: Th1 
(IFN-gamma, CXCL9, CXCL10, MX1, IL-12RB1, IL-12RB2), Th17 (IL-17A, IL23p19, 
IL23p40, CCL20, CXCL1, elafin/PI3), Th2 (IL-13, IL-4, IL-5, IL-10, CCL17, CCL18, 
CCL22, CCL5), T22/IL-22 cytokine and IL-17/IL-22 regulated S100s genes (S100A12), 
Th9/IL-9, and general T-cell activation (IL-2, IL-15, IL-2RA, IL-15RA), JAK3, as well as 
IL-16, and IL-32, and keratin associated genes (Keratins 35, 75, 85, 86), will be 
evaluated using RT-PCR. We will also assess for modulation of inflammatory markers 
(i.e MMP12), and innate immune genes (IL-1b, IL-8) by RT-PCR.  
 
Gene arrays will also be performed. The Affymetrix U133A Plus 2 gene array platform 
will be used.   
 
Skin infiltration by T-cells, DCs, and Langerhans cells will be assessed by 
immunohistochemistry. The following markers will be used: CD3 and CD8 for T cells, 
Langerin for Langherans cells, CD11c for myeloid DCs. A similar score to ALADIN will 
be used, however, taking into account more hair and keratin biomarkers.  
 
STATISTICAL ANALYSES: 
Sample size considerations 
This is an exploratory study therefore the sample size has been kept relatively low. Data 
collected from this study will be used to obtain estimates of differences and variability of 
the study outcomes. Therefore there will be no formal hypothesis testing and power 
calculation in this study.   
Nevertheless, consider the primary outcome is the % of patients who achieve a 50% 
improvement in their SALT score after 24 weeks of treatment, with a sample size of 
20:10 on drug and placebo groups respectively will allow to detect  approximately 40% 
superiority. This calculation is based on the use of a one-tail Fisher’s exact test at 
alpha=0.05 level, 80% power and was obtained with the software Gpower.  
Impact of the sample size on the biomarkers outcomes: Gulati et.al. (2014) )[3]  reported 
a standard deviation equal to 3.45 for IFNg’s log2FCH between baseline and after 
DPCP treatment at Week 14 in a cohort of 11 patients. Assuming this standard 
deviation, the sample size of 20 patients allows us to detect an effect size of 0.87 (which 
corresponds to a log2FCH larger than 3) with power of 95% in a 95% two-side t-Test for 
paired samples. Considering Bonferroni correction for 5 biomarkers, the same effect 
size could be detected with a power of 80%. 
Statistical Analysis 
Primary outcome: A one-tail Fisher exact test will be used to compare the percentage 


 
20 
 
of patients who achieve 50% improvement in the SALT score after 24 weeks of 
treatment between drug and placebo groups.   
Secondary Outcomes: 
A Mixed effect model repeated measures (MMRM) will be used to detect any overall 
differences in the treatment effect as compared to placebo. The differences in SALT 
score between Baseline values and those at Weeks 4, 8, 12, 16, 20, and 24 will be 
estimated considering the missing values for patients who prematurely discontinued the 
study. Changes after 24 weeks of treatment will be estimated using this model and 
presented as percentage. 
The differences in semi-quantitative SALT scores between Baseline and after 24 weeks 
of treatment will be compared using a two-tailed Wilcoxon matched-pairs test. 
The change from Baseline in cellular and molecular markers in skin biopsies after 
treatment will be analyzed using two-tailed t-Student test for paired samples. 
Similar analysis will be carried out for the secondary endpoints at Week 48. 
 
MECHANISTIC STUDIES STATISTICAL ANALYSES: 
For comparison of expression levels of lesional, and non-lesional AA skin, we will use 
RT-PCR, and gene-arrays. RT-PCR values will be normalized to the housekeeping 
gene hARP (validated in all our AD studies) and log2-transformed prior to analysis. 
Microarray data will be preprocessed using standard pipeline (exhaustively used by our 
group in a large number of studies) and log-2 transformed expressions. Adjustments by 
batch effect and clinical variables will be carried out if needed using ComBat.  Mixed 
effect model on R’s limma framework will 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 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. Similar approaches will be 
carried out for blood analyses. 
Gene expression changes in Th2/IL-13, “T22”/IL-22, S100A7 and S100A8, Th1/IFN-
gamma, and Th17/IL-17A will be jointly correlated with clinical responses by multivariate 
analysis using multivariate u-statistics and R package muStat, as we have previously 


 
21 
 
reported.  
The change from Baseline in the Alopecia Areata Symptom Impact Scale (AASIS) at 
Week 24 and the change from Baseline in the Alopecia Areata Quality of Life 
questionnaire (AA-QoL) at Week 24 will be evaluated using a two-sided Wilcoxon 
signed rank test for each item. To analyze the score created by summarizing a group of 
items a two-tailed t-Student test for paired samples will be used. 
Safety and Tolerability Analysis 
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 class, date of onset, date of resolution, severity, and relationship to treatment. A 
tabulation of AEs will be provided by subject. For local subcutaneous adverse events, 
the rate of AEs will be compared between groups. The proportion of lesions in each 
treatment group reporting adverse events that occur in ~ 5% in either treatment group 
will be compared using the Fisher’s exact test. 
 
LABORATORY SPECIMENS 
All blood and urine samples will be processed through the Mount Sinai Center for Clinical 
Laboratories, One Gustave Levy Place, New York, NY 10029. 
INSTITUTIONAL REVIEW BOARD 
Prior to beginning this study, approval for all study related documents (protocol, consent 
form, advertising) would be obtained from the Icahn School of Medicine at Mount Sinai 
Program for the Protection of Human Subjects (Institutional Review Board), One 
Gustave Levy Place, Box 1081, New York, NY 10029. 
 


 
22 
 
Flow Chart 
Procedures 
Screening 
(Day -28 to 
Day -1) 
Baseline 
Day 0 
Week 
4  
Week 
8 
Week 
12 
 
 
Week 
16  
 
 
Week 
20 
 
 
Week 
24 
Week  
28  
Week  
32 
 
 
Week 
36 
 
 
Week 
40 
 
 
Week 
44 
 
 
Week 48 
/ Early 
Term 
 
 
Week 
52 
 F-UP 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past Medical History 
(including previous therapies 
for AA) and Demographic 
Data collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited Physical Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HBsAg and Hepatitis C 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry and hematology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for mechanistic studies 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X3 
 
DNA analysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
RNA and proteomic analysis 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X3 
 
SALT assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
aaPGA 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of regrowth 
pattern  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical photographs 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
AASIS and AA-QoL 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Pregnancy Test1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Product Dispensing 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Scalp Biopsies2 
 
X 
 
 
X4 
 
 
X 
 
 
 
 
 
X3 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events (including 
assessment of mood 
changes and weight loss) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
23 
 
 
1 Serum pregnancy test for females of childbearing potential at screening and urine test at other visits.  
2 Two biopsies will be collected at Baseline (affected and nonaffected areas). In case of 100% hair loss, only one biopsy of the affected area will be biopsied. One biopsy will be collected at Week 24 from 
the vicinity where the affected skin biopsy was taken at Baseline. 
3 To be collected only if early termination visit is being performed prior to Week 24. 
4 Optional: One biopsy will be taken at Week 12 (from the vicinity of the affected area biopsied at baseline) if consented to by subject.     


 
24 
 
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Investig Dermatol Symp Proc 2013;16:S51-2. 
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