Characterizing the Molecular Cutaneous Phenotype of Seborrheic Dermatitis and Treatment Response to Ruxolitinib 1.5% Cream
Phase: PHASE2
Conditions: Seborrheic Dermatitis
Sponsor: Icahn School of Medicine at Mount Sinai

Characterizing the Molecular Cutaneous Phenotype of Seborrheic Dermatitis and Treatment
Response to Ruxolitinib 1.5% Cream
PI: Benjamin Ungar, MD
NCT05787860
Document Date: 12/2/2022

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Characterizing the Molecular Cutaneous Phenotype of Seborrheic Dermatitis and 
Treatment Response to Ruxolitinib 1.5% Cream
Principal Investigator:
Benjamin Ungar, MD
Emma Guttman, MD, PhD
Investigators:
Joel Correa da Rosa, PhD 
Study Site:
Icahn School of Medicine at Mount Sinai
Department of Dermatology and The Immunology Institute
5 East 98 Street, 5th Floor, Box 1048
New York, NY 10029
Protocol Version:
March 15, 2021
Amendment #1:
May 25, 2022
Amendment #2:
October 24, 2022
Effective Date: 12/2/2022
End Date:7/27/2023

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Table of Contents
Background  …………………………………......
3
Treatment Rationale…………………................
3
Hypothesis……………………….…….………....
4
Objectives……………………….….…..………...
4
Endpoints………………………..……………......
4
Study Design Overview………………................
5
Mechanistic Analyses……………….…..............
6
Patient Population 
Inclusion Criteria…………………….…....
6
Exclusion Criteria…………………….…...
7
Potential Risks of Ruxolitinib 1.5% Cream…….
9
Prior Treatment………………………...………...
9
Prohibited Treatment………………………….....
9
Procedures……………………………………......
10
Safety Monitoring……………………..…………..
13
Study Withdrawal……………………..….............
13
Discontinuation of Treatment and 
Withdrawal of Subjects……………..........
13
Subject Identification……………………………..
15
Study Drug Supply……………...........................
15
Statistical Considerations………………………..
16
Table 1. Schedule of Events………….………...
19
References……………………………….............
20
Appendix 1. Clinical Assessments…...………...
22
Appendix 2. Dermatology Life Quality Index…...
23
Appendix 3. CYP3A4 Inhibitors…………………
25
Appendix 4. Study Drug Label…………………..
26
Appendix 5. Amendment Details………….…….
27
Effective Date: 12/2/2022
End Date:7/27/2023

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BACKGROUND:
Seborrheic dermatitis (SD) is a very common skin condition affecting tens of millions of 
Americans, with over $300 million spent annually on over-the-counter treatment 
products (1, 2). Clinically, it is characterized by erythematous, yellowish scaly plaques in 
the scalp, eyebrows, ears, forehead, nasolabial folds, chest, axillae, and inguinal areas 
(3). The pathophysiology of SD is not well understood, with three general factors 
believed to play a role: Malassezia colonization, increased production of lipids by 
sebaceous glands, and immune abnormalities (4). SD is also more common in men, 
implicating androgens as a contributing factor. Current clear treatment guidelines are 
lacking, with some evidence to support topical antifungals (5) and broad-acting topical 
anti-inflammatory treatments such as steroids and calcineurin inhibitors (6), and non-
pharmacological approaches also used (7). That these treatments have been shown to 
be better than placebo support the contributions of both Malassezia and immune 
dysregulation in the pathophysiology of the disease. However, as long-term use of 
steroids is contraindicated, alternative topical approaches are needed and remain under 
investigation (8, 9). The immune dysregulation underlying SD has not been well 
characterized, but upregulation of several cytokines and cytokine pathways have been 
suggested, including Th1, Th2, Th17, (i.e., IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-
12, IL-17, TNF-α, and IFN-γ) (10-12). Furthermore, treatment of SD with anti-
inflammatory agents such as crisaborole has shown some promise in early studies (9).
TREATMENT RATIONALE:
Current treatments for SD center around topical antifungals, based on the role that 
Malassezia is believed to play in disease pathogenesis, and anti-inflammatory agents 
such as topical steroids, which are broad-acting and cannot be applied chronically due to 
the risk of multiple side effects (11). The pathogenesis of SD is poorly understood, but 
dysregulated immune markers from different pathways have been suggested, including 
Th1, Th2, Th17, (i.e., IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, TNF-α, and 
IFN-γ).
Ruxolitinib is an inhibitor JAK1 and JAK2 signaling, which suppresses the majority of the 
proposed SD-related cytokines simultaneously. In experimental models of dermatitis, 
ruxolitinib cream successfully reduced itch and down-regulated multiple inflammatory 
pathways (13). Although modulation of molecular biomarkers with application of ruxolitinib 
cream is lacking in humans, clinical efficacy has been shown in the Th2-driven disease 
atopic dermatitis in phase 2 (14) and phase 3 (15) studies, demonstrating the ability to 
normalize the pathogenic immune dysregulation in atopic dermatitis as well as in a phase 
2 study of vitiligo (16), in which Th1 signaling is believed to play a major role. Furthermore 
topical approaches with immunomodulatory medications in SD [e.g., crisaborole (9)] have 
been used in small studies, supporting this approach.
Therefore, we hypothesize that topical ruxolitinib cream will be able to reverse the 
immune dysregulation seen in SD, leading to clinical improvement.
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HYPOTHESIS:
Primary Hypothesis

Twice daily application of ruxolitinib 1.5% cream for 4 weeks will be clinically 
efficacious in treating moderate-to-severe seborrheic dermatitis.
OBJECTIVES:
Primary Objectives

To characterize the clinical responses to treatment with topical ruxolitinib 1.5% 
cream applied twice daily for 4 weeks in moderate-to-severe SD patients.
Secondary Objectives

To characterize the molecular cutaneous phenotype of SD.

To compare molecular biomarker expression in SD patients with healthy controls.

To characterize the molecular responses to treatment with topical ruxolitinib 1.5% 
cream applied twice daily for 4 weeks in moderate-to-severe SD patients.

To correlate the molecular and clinical responses to treatment with topical 
ruxolitinib 1.5% cream applied twice daily in order to identify biomarkers of 
treatment response in SD patients

To validate a clinical SD disease severity score using assessments by two 
independent investigators

To evaluate the safety and tolerability of topical ruxolitinib 1.5% cream applied 
twice daily for 4 weeks in moderate-to-severe SD patients
ENDPOINTS:
Primary Endpoint

The proportion of patients who achieve an IGA 0/1 at 4 weeks of treatment with 
ruxolitinib 1.5% cream applied twice daily
Secondary Endpoints

Change from baseline in IGA score at 4 weeks of treatment with ruxolitinib 1.5% 
cream applied twice daily

Change from baseline in overall clinical SD score at 4 weeks of treatment with 
ruxolitinib 1.5% cream applied twice daily
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
Change from baseline in each component of the clinical SD score at 4 weeks of 
treatment with ruxolitinib 1.5% cream applied twice daily (scale, erythema, pruritus)

Change in overall clinical SD at 6 weeks (i.e., 2 weeks after treatment cessation) 
from baseline and from 4 weeks

The frequency, duration, and severity of AEs

Changes in vital signs

Changes in laboratory data for hematology, serum chemistry, and urinalysis
Mechanistic (Exploratory) Endpoints

Determine the molecular cutaneous phenotype of SD at baseline compared with 
healthy controls, using transcriptomic and proteomic approaches from skin 
samples acquired by tape-strips

Identify molecular markers that correlate with disease activity in SD at baseline 

Characterize the change in molecular responses with treatment of topical 
ruxolitinib 1.5% cream after 4 weeks of treatment

Identify molecular markers that correlate with treatment response at 4 weeks
STUDY DESIGN OVERVIEW:
This study is an open-label prospective interventional trial. The study will take place at 
Icahn School of Medicine at Mount Sinai.  
The study will include 25 adult patients with moderate-to-severe-SD as well as 20 age- 
and gender-matched healthy control subjects for comparison. The SD patients will have 
baseline clinical score of at least 6 using the SD Severity Score in Appendix 1, or an 
Investigator Global Assessment (IGA) score of at least 3. Enrolled SD subjects will apply 
topical ruxolitinib 1.5% cream twice daily for 4 weeks. They will return for visits at weeks 
2, 4, and 6 following study treatment initiation for repeat clinical assessments, medication 
reviews, tape-strip, blood and urine sample collections, and monitoring for adverse 
events. 
After providing consent, all subjects will be assessed for study eligibility, which includes 
a review of the subjects past and current medical conditions, familial medical history and 
detailed review of past and current medications. SD subjects will also undergo a review 
of past topical treatments/therapies for SD, and clinical assessments (clinical SD score 
and IGA). 
Subjects who meet inclusion criteria for eligibility may continue with the Baseline Visit 
(Week 0) or can be scheduled to return for the Baseline Visit within 28 days of the 
Screening Visit. 
SD Subjects: 
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At Baseline/Week 0, subjects will undergo clinical assessments (clinical SD Severity 
Score and IGA), review of concomitant medications, standardized clinical photography, 
and a Dermatology Life Quality index (DLQI) questionnaire (Appendix 2). Subsequent 
clinical assessments including standardized clinical photography, and questionnaire 
completion will be performed at follow up visits at Week 2, Week 4, and Week 6. Skin 
tape-strip samples will be collected for mechanistic studies (described below) at baseline 
(lesional and non-lesional facial skin), Week 2 (lesional facial skin), Week 4 (lesional facial 
skin), and Week 6 (lesional facial skin). Additional blood samples will be collected and 
stored at baseline and at Week 4 (or early termination, whichever is first) for potential 
future mechanistic analyses.
Control Subjects:
At Baseline/Week 0, subjects will undergo a review of concomitant medications, skin 
tape-strip samples will be collected for mechanistic studies (described below) of non-
lesional facial skin, blood and urine sample collection for standard laboratory testing, and 
a blood sample for possible future mechanistic analyses.
MECHANISTIC ANALYSES:
We will characterize the molecular immune profiles of patients with SD at week 0 and 
week 4, with comparison to baseline profiles in healthy control subjects.
We plan to obtain lesional and non-lesional tape strip samples from facial skin of SD 
patients at week 0 and lesional facial skin samples at Week 4 (Primary Endpoint). 
Additionally, lesional facial skin samples will be collected at Week 2 and Week 6 and 
stored for potential future analysis. Blood samples at baseline and at Week 4 will be 
collected and stored for potential future analysis.
Gene expression studies on tape strip samples will be performed using Illumina NovaSeq 
6000 for RNA-seq, and proteomic studies on tape strip samples will be performed using 
the Olink Explore panel, which includes >1,500 protein analytes.
PATIENT POPULATION:
Prior to enrollment, all subjects must meet the following inclusion and exclusion criteria:
Inclusion Criteria For SD Subjects:
1)
Male or female subjects ≥ 18 years of age at the time of signing the informed 
consent document.
2)
Subject is able to understand and voluntarily sign an informed consent document 
prior to participation in any study assessments or procedures.
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End Date:7/27/2023

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3)
Subject is able to adhere to the study visit schedule and other protocol 
requirements.
4)
Baseline SD score of IGA ≥ 3 with facial involvement
5)
Subject agrees to discontinue all treatments for SD from screening through study 
completion aside from the study drug
6)
Subject has failed an adequate course of treatment with at least one available 
therapy (topical antifungals or low-potency topical corticosteroids)
7)
Subject is judged to be in otherwise good overall health as judged by the 
investigator, based on medical history, physical examination, and laboratory 
testing. (NOTE: The definition of good health means a subject does not have 
uncontrolled significant co-morbid conditions).
8)
Females of childbearing potential (FCBP) must have a negative pregnancy test at 
Screening and Baseline.  While on the study drug and for at least 90 days after 
the last application  of the study drug, male and female participants must be willing 
to take appropriate contraceptive measures to avoid pregnancy or fathering a 
child. 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 contraceptive 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 one 
additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with 
spermicide; or (c) contraceptive sponge with spermicide.
The female subject’s chosen form of contraception must be effective by the time 
the female subject is enrolled into the study.
Exclusion Criteria For SD Subjects:
The presence of any of the following will exclude a subject from enrollment:
1)
SD clinical severity of IGA <3 and SD Severity Score <6.
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2)
Subjects with other skin diseases that would interfere with the study assessment 
in the opinion of the investigator.
3)
Active bacterial, fungal, or viral skin infection within 2 weeks from study initiation.
4)
Subject has clinically significant (as determined by the investigator) renal, hepatic, 
hematologic, intestinal, endocrine, pulmonary, cardiovascular, neurological, 
psychiatric, immunologic, or other major uncontrolled diseases (e.g., malignancy, 
TB, HIV, HBV, HCV, thromboembolic events) that will affect the health of the 
subject during the study, or interfere with the interpretation of study results.
5)
Subject has previously received treatment with oral or topical JAK inhibitors
6)
Current other topical treatments (e.g., topical corticosteroids, topical calcineurin 
inhibitors) within 1 week of baseline
7)
Use of systemic immunosuppressive medications, including, but not limited to, 
cyclosporine, systemic or intralesional corticosteroids, mycophenolate mofetil, 
azathioprine, methotrexate, tacrolimus within 4 weeks of study initiation
8)
Concurrent use of strong CYP3A4 inhibitors within 7 days or 5 half-lives 
(whichever is longer). A list of CYP3A4 inhibiting medications can be found in 
Appendix 3.
9)
History of adverse systemic or allergic reactions to any component of the study 
drug.
10) Current participation in any other study with an investigational medication
11) Subject who is pregnant or breast feeding
 
Inclusion Criteria For Control Subjects:
1)
Male or female subjects ≥ 18 years of age at the time of signing the informed 
consent document.
2)
Subject is able to understand and voluntarily sign an informed consent document 
prior to participation in any study assessments or procedures.
3)
Subject does not currently have and does not have a history of SD. 
4)
Female of childbearing potential (FCBP) must have a negative pregnancy test at 
Screening and Baseline
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Exclusion Criteria For Control Subjects:
1) Active bacterial, fungal, or viral skin infection within 2 weeks from 
Screening/Baseline visit.
2)
Subject has uncontrolled clinically significant (as determined by the investigator) 
renal, hepatic, hematologic, intestinal, endocrine, pulmonary, cardiovascular, 
neurological, psychiatric, immunologic, or other disease. 
3)
Subject has previously received treatment with oral or topical JAK inhibitors
4)
Current other topical treatments (e.g., topical corticosteroids, topical calcineurin 
inhibitors) within 1 week of baseline
5)
Use of systemic immunosuppressive medications, including, but not limited to, 
cyclosporine, systemic or intralesional corticosteroids, mycophenolate mofetil, 
azathioprine, methotrexate, tacrolimus within 4 weeks of study initiation
6)
Current participation in any other study with an investigational medication
7)
Subject who is pregnant or breast feeding
POTENTIAL RISKS OF RUXOLITINIB 1.5% CREAM:
Based on phase 2 and phase 3 studies in atopic dermatitis, as well as phase 2 studies in 
vitiligo, topical application of ruxolitinib 1.5% cream shows a good safety profile. The most 
commonly experienced adverse events in the atopic dermatitis studies were application 
site burning and pruritus, which occurred more commonly in the vehicle control group 
(15). These results were mirrored in the phase 2 vitiligo study, with the additional 
observation of 18% of vitiligo patients experienced development of acne as a treatment-
related adverse event (16). Although oral ruxolitinib has been associated with the risk of 
hematologic abnormalities in patients treated for polycythemia vera or myelofibrosis, 
pharmacokinetic analysis performed in the phase 3 studies in atopic dermatitis patients 
with up to 20% body surface area involvement demonstrated plasma ruxolitinib 
concentrations substantially lower than those required for systemic activity (17). 
PRIOR TREATMENT:
All relevant treatment received by the subject within 30 days before screening will be 
recorded. 
PROHIBITED TREATMENT: 
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All treatments prohibited during the screening period are also prohibited throughout the 
course of the study. All subjects treated previously with a topical or oral JAK inhibitor will 
be excluded from the study as above.
PROCEDURES:
Monitoring of Aes will begin at the time of signing the informed consent form and will be 
continued throughout the course of the study. All study procedures will be completed at 
designated times during the study period (see Table 1).
Trained assessors will perform clinical assessments. It is strongly recommended that the 
same assessor/s perform clinical assessments for a subject at all study visits.
For SD Subjects
Visit 1 – Screening (within 28 days of Baseline)* 

Obtain signed IRB-approved informed consent and HIPPA agreement

Review Inclusion and Exclusion Criteria

Record gender, race, ethnicity, and medical history

Review personal and family history of SD and other inflammatory skin diseases

Record all concomitant medications as well as all those received within 30 days 
prior to screening

Record all prior therapies for SD

Urine pregnancy test for all female subjects of child-bearing potential 

SD Clinical assessments (IGA, SD Severity Score)

Record adverse events
* If subject meets all entry criteria at Screening, he/she can complete Baseline Visit 
on the same day (identical procedures do not need to be repeated). If more than 28 
days has lapsed between screening and Baseline/Visit 2, then all procedures should 
be repeated except for re-obtaining informed consent. If subject has used a topical 
medication, then Baseline/Visit 2 will occur only after a 1 week washout period.
Visit 2 – Baseline (Week 0)

Confirm all inclusion and exclusion criteria have been met

Record concomitant medications and adverse events

DLQI questionnaire

Standardized clinical photography (including photographs of subject’s entire face 
and close up photographs of the following facial regions: 1. Left cheek, 2. Right 
cheek, 3. Forehead and glabella)

SD clinical assessments (IGA, SD Severity Score)

Urine pregnancy test for all female subjects of child-bearing potential 
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
Collect blood samples for CBC with differential, Comprehensive metabolic panel 
(CMP), and C-reactive protein (CRP) 

Collect blood sample for possible future mechanistic analyses

Urinalysis

Perform tape strips of lesional and non-lesional skin. Lesional skin tape strips will 
be taken from area of worst clinical involvement

Dispense/administer study drug
Visit 3 – Week 2

Record concomitant medications and adverse events

DLQI questionnaire

SD clinical assessments (IGA, SD Severity Score)

Urine pregnancy test for all female subjects of child-bearing potential 

Perform tape strips of lesional skin. Lesional skin tape strips will be taken from the 
same location as the lesional tape strips taken at Baseline.

Dispense study drug and assess compliance. Subjects will report each study drug 
application, with 4 missed doses from Baseline considered non-compliance.
Visit 4 – Week 4

Record concomitant medications and adverse events

DLQI questionnaire

Standardized clinical photography (including photographs of subject’s entire face 
and close up photographs of the following facial regions: 1. Left cheek, 2. Right 
cheek, 3. Forehead and glabella)

SD clinical assessments (IGA, SD Severity Score)

Urine pregnancy test for all female subjects of child-bearing potential 

Collect blood samples for CBC with differential, Comprehensive metabolic panel 
(CMP), and C-reactive protein (CRP) 

Collect blood sample for possible future mechanistic analyses

Urinalysis

Perform tape strips of lesional skin. Lesional skin tape strips will be taken from the 
same location as the lesional tape strips taken at Baseline and Week 2.

Assess study drug dosing compliance and retrieve all remaining study drug from 
subject. Subjects will report each study drug application, with 4 missed doses from 
Week 2 considered non-compliance. 
Visit 5 – Week 6

Record concomitant medications and adverse events

DLQI questionnaire
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
Standardized clinical photography including photographs of subject’s entire face 
and close up photographs of the following facial regions: 1. Left cheek, 2. Right 
cheek, 3. Forehead and glabella)

SD clinical assessments (IGA, SD Severity Score)

Urine pregnancy test for all female subjects of child-bearing potential 

Perform tape strips of lesional skin. Lesional skin tape strips will be taken from the 
same location as the lesional tape strips taken at Baseline, Week 2, and Week 4.
Early Termination Visit (if applicable)

Record concomitant medications and adverse events

DLQI questionnaire

Standardized clinical photography (including photographs of subject’s entire face 
and close up photographs of the following facial regions: 1. Left cheek, 2. Right 
cheek, 3. Forehead and glabella)

Urine pregnancy test for all female subjects of child-bearing potential 

Collect blood samples for CBC with differential, Comprehensive metabolic panel 
(CMP), and C-reactive protein (CRP) 

Collect blood sample for possible future mechanistic analyses

Urinalysis

SD clinical assessments (IGA, SD Severity Score)

Perform tape strips of lesional skin. Lesional skin tape strips will be taken from the 
same location as the lesional tape strips taken at Baseline and Week 2 (if 
applicable)

Assess study drug dosing compliance and retrieve all remaining study drug from 
subject 
For Control Subjects
Visit 1 – Screening (within 28 days of Baseline)* 

Obtain signed IRB-approved informed consent and HIPPA agreement

Review Inclusion and Exclusion Criteria

Record gender, race, ethnicity, and medical history

Review personal and family medical conditions/diseases

Record all concomitant medications as well as all those received within 30 days 
prior to screening

Urine pregnancy test for all female subjects of child-bearing potential 

Record adverse events
* If subject meets all entry criteria at Screening, he/she can complete Baseline Visit 
on the same day (identical procedures do not need to be repeated). If more than 28 
days has lapsed between screening and Baseline/Visit 2, then all procedures should 
be repeated except for re-obtaining informed consent.
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Visit 2 – Baseline (Week 0)

Confirm all inclusion and exclusion criteria have been met

Record concomitant medications and adverse events

Urine pregnancy test for all female subjects of child-bearing potential 

Collect blood samples for CBC with differential, Comprehensive metabolic panel 
(CMP), and C-reactive protein (CRP) 

Collect blood sample for possible future mechanistic analyses

Urinalysis

Perform tape strips of non-lesional skin
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 for any reason, the 
subject will be asked to return for a final visit to have some or all of the following 
procedures and assessments as listed for Visit 5/Week 6: vital signs; blood test; 
pregnancy test (if applicable); clinical photography; SD clinical assessments; DLQI 
questionnaire, assessment of concomitant medication and adverse events; blood 
collection for future mechanistic analysis; lesional tape strip collection. 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL OF SUBJECTS:
The reasons why a subject may discontinue or be withdrawn from the study by the 
investigator include, but are not limited to the following: subject request, protocol 
violation, loss to follow up, subject non-compliance,  defined as 4 missed applications 
during the 2 week period between study Visits, study termination by investigators, and a 
confirmed grade 3 or higher adverse event, which is suspected to be related to study 
drug administration. Subjects that elect to withdraw from the trial due to lack of efficacy 
and/or exacerbation of disease will undergo the following: vital signs; blood test; 
pregnancy test (if applicable); clinical photography; SD clinical assessments; DLQI 
questionnaire, assessment of concomitant medication and adverse events; blood 
collection for future mechanistic analysis; lesional tape strip collection. 
Stopping Rules
Patients will be permanently discontinued from study treatment in the event of:
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
Anaphylactic reaction or other severe systemic reaction to study drug application 

Pregnancy at anytime during the study period 

Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix, 
or squamous or basal cell carcinoma of the skin

Any infection that is opportunistic, whose nature or course may suggest an 
immuno-compromised status

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.

If the following lab results are abnormal, participants will be retested in a window 
of 7-10 days and reassessed. If the test results remain abnormal, participants will 
be discontinued from the study:
Hematology
Absolute Neutrophil Count:<1000/mm3; <1.0 x109/L
Hemoglobin:  <8.0 g/dL; <4.96 mmol/L; <80 g/L
Hemoglobin drop ≥2 g/dL from baseline on two consecutive blood draws with 
associated symptoms; or hemoglobin drop ≥3 g/dL from baseline on two 
consecutive blood draws without associated symptoms. 
Platelet count: <75,000/mm3; <75.0x109/L
Lymphocytes: <500/mm3; <0.5x109/L
Chemistry
AST >3.0x ULN
ALT >3.0x ULN
Total bilirubin >1.5x ULN
CPK >10x ULN
Total bilirubin ≥1.5 x ULN; subjects with a history of Gilbert's syndrome may have 
a direct bilirubin measured and would be eligible for this study provided the direct 
bilirubin is  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 (e.g., cyclosporine, methotrexate, azathioprine, 
mycophenalate-mofetil, Janus kinase inhibitors, biologic agents, etc.).
Safety Evaluation
Safety and tolerability will be evaluated from the Aes, physical examinations, and vital 
sign measurements. More frequent safety evaluations may be performed if clinically 
indicated or at the discretion of the investigator.
Aggregated Aes will be evaluated by the PI/research teams. The local IRB, FDA, and 
Incyte will be notified of adverse events.
Effective Date: 12/2/2022
End Date:7/27/2023

Seborrheic Dermatitis Ruxolitinib Cream Protocol
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15
The Principal Investigator (PI) must report all Serious Adverse Events (SAEs) to Incyte 
within 24 hours of learning of an event, regardless of the PI’s causality assessment. 
This notification should be provided on a completed Serious Adverse Event (SAE) form.  
SAE reporting for each subject begins the day the informed consent is signed by the 
patient and within 14 days after subject has completed or discontinued from the study or 
has taken last dose of the study drug, or as described in the protocol.
SAEs, occurring using Incyte study drug, are reported in accordance with the effective 
protocol.  SAEs occurring with any other commercial drug are reported to the 
manufacturer of that drug in accordance with regulations and protocol. 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@Incyte.com  or fax (+) 1-866-981-2057.  SAE reports should be for a 
single subject.  SAE forms should be sent with a cover sheet and any additional 
attachments.
All adverse event information is reported to Incyte on the Principal 
Investigator’s/Institution’s Adverse Event Report Form, or a CIOMS-I or MedWatch 
Form FDA 3500A, or on an Adverse Event Report Form which may be provided by 
Incyte upon request. The Principal Investigator does not provide medical records (e.g., 
discharge summary) to Incyte, unless specifically requested.
 
Reporting of Pregnancy to Incyte
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 24 hours of discovery 
of a pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner 
for a subject who has taken the Incyte product.  The “Follow-up Pregnancy Report Form” 
or equivalent must be completed and emailed to SafetyReporting@Incyte.com or faxed 
to (+) 1-866-981-2057 within 30 days after delivery, so that Incyte is provided with 
information regarding the outcome of the pregnancy.  If the pregnancy results in any 
events which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting 
process needs to be followed and the timelines associated with a SAE should be followed.
SUBJECT IDENTIFICATION
Subjects are numbered sequentially. Each subject will be assigned a unique screening 
number for the duration of the study. Subject screening numbers will not be reassigned 
or reused for any reason. The investigator must maintain a 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. 
STUDY DRUG SUPPLY:
Effective Date: 12/2/2022
End Date:7/27/2023

Seborrheic Dermatitis Ruxolitinib Cream Protocol
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16
Eligible patients will receive a supply of ruxolitinib 1.5% cream which they will apply to 
affected skin on the face only twice daily. Patients will be instructed not to use more than 
60g of cream per week.
All study medication will be stored in a secure cool area between 15-30°C. Study drug will 
be provided to subjects at each study visit, with initial application performed at that time 
and subsequent applications performed by the patients at home. 
Subjects will be queried during each study visit on any missed applications.
STATISTICAL CONSIDERATIONS:
Sample Size Calculation
A sample size of n=20 SD patients guarantees 90% power at 2.1% significance to detect 
a minimum proportion of 75% of patients with IGA 0/1 at week 4. This calculation assumes 
the application of the one-sided binomial test with a null hypothesis proportion of 40%. 
This proportion is based on the vehicle response benchmark reported by Zirwas et 
al.(2021)  when comparing IGA 0/1 at week 8 in 154 patients treated with roflumilast foam 
0.3% vs. 72 patients in the vehicle-controlled group(18). Accounting for a 20% dropout 
rate, we, therefore, propose a sample size of n=25 patients. 
Mechanistic Endpoint
To the best of our knowledge, this is the first study to evaluate differences in the 
transcriptome between SD and healthy subjects. A previous study (19) evaluated a fold-
change (FCH) of 5 in IL-10 cell counts with coefficient of variation of 50% when comparing 
10 SD subjects to 4 healthy volunteers. Assuming similar variability, a sample size of n = 
20 SD subjects and n= 20 controls would provide 90% power at 5% significance to detect 
FCH>2.65 when comparing IL-10 expression between SD and controls, based on a two-
sided unpaired t-test applied to log2-transformed RNA-seq data and fold-changes back 
transformed. 
Demographics and Other Baseline Characteristics
Descriptive statistics of demographics and other baseline characteristics of patients will 
be summarized. Other baseline characteristics include height, weight, vital signs, duration 
of SD disease, concurrent diagnoses from medical history and indications for concomitant 
medication, concomitant medication, and previous SD treatments.
Analysis of Primary Endpoint
The one-sided binomial test will be used to verify the hypothesis that the proportion of 
patients achieving IGA 0/1 at 4 weeks of treatment with ruxolitinib 1.5% cream applied 
twice daily is greater than 0.4.
Analysis of Secondary Endpoints
The two-sided Wilcoxon signed-rank test will assess the significance of changes from 
baseline in:  
Effective Date: 12/2/2022
End Date:7/27/2023

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
IGA score at 4 weeks of treatment

Components of clinical SD scoring (scale, erythema, and pruritus) at 4 
weeks of treatment.
The two-sided paired t-test will assess the significance of changes from baseline in: 

Overall clinical SD scoring at 4 and 6 weeks of treatment.

Vital signs measured in interval or ratio scale 

Analytes measured in interval or ratio scale from laboratory tests 
(hematology, serum, chemistry, and urinalysis) at 4 weeks of treatment
The p-values will be adjusted by the Bonferroni method. The frequency, duration, and 
severity of AEs will be summarized with tables and summary statistics.
Analysis of Mechanistic (Exploratory) Endpoints
The baseline immune and molecular cutaneous profile of SD at baseline compared with 
healthy controls and the change in the immune and molecular cutaneous profile of SD 
with treatment will be assessed by MMRM approach. Gene/Protein expression data will 
be modeled using a mixed effect model with the interaction between tissue type (non-
lesional/ lesional / healthy) and timepoint as fixed effects and a random effect for each 
subject. 
RNA-sequencing data will be profiled by Illumina NovaSeq 6000. RNA-sequencing data 
will be pre-processed using standard quality control metrics, such as FastQC and 
MultiQC, sequence alignment by STAR RNA-sequencing aligner and sequencing reads 
assignment to genomic features by featureCounts, followed by voom-transform. Mixed 
effect models will be used on R’s limma framework 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. This will include (but 
will not be limited to) pathway and gene-set enrichment analyses by R package GSVA 
(Gene Set Variation Analysis) and by eXploring Genomic Relations (XGR) that uses prior 
biological knowledge and relationships from public databases.
We will perform proteomic biomarker studies in serum using the OLINK high-throughput 
proteomic platform, with the Explore panel that evaluates >1,500 protein analytes. Protein 
expression data will be modeled using a MMRM approach, with the interaction of study 
group (treatment /control) and timepoint as fixed effects and a random effect for each 
subject.
We will use the Spearman coefficient to correlate: 1) molecular markers with disease 
activity in SD at baseline; 2) changes from baseline in molecular markers with changes 
from baseline in IGA and overall clinical SD scoring at 4 weeks of treatment.
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. 
Effective Date: 12/2/2022
End Date:7/27/2023

Seborrheic Dermatitis Ruxolitinib Cream Protocol
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Data from the Guttman Lab (where all mechanistic studies will be done), including 
sequencing data and proteomics will be deposited in the Mount Sinai Box, which has the 
necessary safeguards for protection of human subjects research.
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 
Analyses will be run in our desktops, with a backed-up copy in the Mount Sinai Box 
account. Once the analysis is finalized, all data will be deposited into the 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. 
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 5.0. 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. 
DLQI (Dermatology Life Quality Index)
The DLQI is a validated questionnaire consisting of 10 questions that has been used in 
many randomized controlled trials in dermatology (20, 21).
Scoring
The scoring of each question is as follows:
Very much
scored 3
A lot
scored 2
A little
scored 1
Not at all
scored 0
Not relevant
scored 0
Effective Date: 12/2/2022
End Date:7/27/2023

Seborrheic Dermatitis Ruxolitinib Cream Protocol
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The DLQI is calculated by summing the score of each question. The maximum score is 
30 and minimum score is 0. Higher score represents a quality of life that is more 
impaired.
Definition of DLQI Scores
0-1 = no effect at all on patient's life 
2-5 = small effect on patient's life 
6-10 = moderate effect on patient's life 
11-20 = very large effect on patient's life 
21-30 = extremely large effect on patient's life
A change in DLQI score of at least 4 points is considered clinically important (22). Such 
change suggests that there has actually been a meaningful change in that patient's 
quality of life since the previous measurement of his/her DLQI scores.
Question unanswered
scored 0
Effective Date: 12/2/2022
End Date:7/27/2023

Seborrheic Dermatitis Ruxolitinib Cream Protocol
Incyte IIR
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Table 1. Schedule of Events  
Visit Week
(Up to -28 
Days before 
Baseline)
0
2
4
6
X
Control 
Subjects
Visit #
1
2
3
4
5
Early 
Term-
ination 
1
Visit Type
Screening
Baseline
Tx
Tx
F-up
Screening 
/ Baseline
 
Informed Consent
X
X
Inclusion / Exclusion
Criteria
X
X3
X
Demographics and Medical Hx1
X
X
Urine Pregnancy Test
X
X3
X
X
X
X
X
CBC w/differential; CMP;  
Urinalysis
X
X
X
X
Blood Sample Stored for Future 
Analysis
X
X
X
X
CRP
X
X
X
SD Clinical Assessments 
(IGA, SD Severity Score)
X
X3
X
X
X
X
Dermatology Life Quality Index 
(DLQI)
X
X
X
X
X
Standardized Photographs
X
X
X
X
Dispense Drug
X
X
Assess Application Compliance
X
X
X
Lesional Tape Strip
X
X
X
X
X
Non-lesional Tape Strip
X
X
Concomitant Medications
X2
X3
X
X
X
X
X
Adverse Events
X
X3
X
X
X
X
X
1 Includes current and past medical conditions in addition to personal and family history of inflammatory
   skin diseases
2 Includes prior therapies/treatments for SD and any medications received within 30 days of screening. 
3 Does not need to be repeated if Screening and Baseline occur on the same day.
Effective Date: 12/2/2022
End Date:7/27/2023

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REFERENCES:
1.
Borda LJ, Wikramanayake TC. Seborrheic Dermatitis and Dandruff: A 
Comprehensive Review. J Clin Investig Dermatol. 2015;3(2).
2.
Manuel F, Ranganathan S. A new postulate on two stages of dandruff: a clinical 
perspective. International journal of trichology. 2011;3(1):3-6.
3.
Naldi L, Rebora A. Clinical practice. Seborrheic dermatitis. The New England 
journal of medicine. 2009;360(4):387-96.
4.
Adalsteinsson JA, Kaushik S, Muzumdar S, Guttman-Yassky E, Ungar J. An 
update on the microbiology, immunology and genetics of seborrheic dermatitis. 
Experimental dermatology. 2020;29(5):481-9.
5.
Okokon EO, Verbeek JH, Ruotsalainen JH, Ojo OA, Bakhoya VN. Topical 
antifungals for seborrhoeic dermatitis. The Cochrane database of systematic reviews. 
2015(5):CD008138.
6.
Kastarinen H, Okokon EO, Verbeek JH. Topical anti-inflammatory agents for 
seborrheic dermatitis of the face or scalp: summary of a Cochrane Review. JAMA 
dermatology. 2015;151(2):221-2.
7.
Piquero-Casals J, Hexsel D, Mir-Bonafe JF, Rozas-Munoz E. Topical Non-
Pharmacological Treatment for Facial Seborrheic Dermatitis. Dermatol Ther (Heidelb). 
2019;9(3):469-77.
8.
Piquero-Casals J, La Rotta-Higuera E, Francisco Mir-Bonafe J, Rozas-Munoz E, 
Granger C. Non-Steroidal Topical Therapy for Facial Seborrheic Dermatitis. Journal of 
drugs in dermatology : JDD. 2020;19(6):658-60.
9.
Pena SM, Oak ASW, Smith AM, Mayo TT, Elewski BE. Topical crisaborole is an 
efficacious steroid-sparing agent for treating mild-to-moderate seborrhoeic dermatitis. 
Journal of the European Academy of Dermatology and Venereology : JEADV. 
2020;34(12):e809-e12.
10.
Schwartz JR, Messenger AG, Tosti A, Todd G, Hordinsky M, Hay RJ, et al. A 
comprehensive pathophysiology of dandruff and seborrheic dermatitis - towards a more 
precise definition of scalp health. Acta dermato-venereologica. 2013;93(2):131-7.
11.
Wikramanayake TC, Hirt P, Almastadi M, Mitchell H, Tomic-Canic M, Romero L, 
et al. Increased IL-17-expressing gammadelta T cells in seborrhoeic dermatitis-like 
lesions of the Mpzl3 knockout mice. Experimental dermatology. 2018;27(12):1408-11.
12.
Wikramanayake TC, Borda LJ, Miteva M, Paus R. Seborrheic dermatitis-Looking 
beyond Malassezia. Experimental dermatology. 2019;28(9):991-1001.
13.
Scuron MD, Fay BL, Connell AJ, Peel MT, Smith PA. Ruxolitinib Cream Has Dual 
Efficacy on Pruritus and Inflammation in Experimental Dermatitis. Frontiers in 
immunology. 2020;11:620098.
14.
Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME, et al. Treatment of 
atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. The 
Journal of allergy and clinical immunology. 2020;145(2):572-82.
15.
Papp K, Szepietowski JC, Kircik L, Toth D, Eichenfield LF, Leung DYM, et al. 
Efficacy and Safety of Ruxolitinib Cream for the Treatment of Atopic Dermatitis: Results 
From Two Phase 3, Randomized, Double-Blind Studies. Journal of the American 
Academy of Dermatology. 2021.
Effective Date: 12/2/2022
End Date:7/27/2023

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16.
Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, et al. 
Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet. 
2020;396(10244):110-20.
17.
Gong X, Chen X, Kuligowski ME, Liu X, Liu X, Cimino E, et al. Pharmacokinetics 
of Ruxolitinib in Patients with Atopic Dermatitis Treated With Ruxolitinib Cream: Data from 
Phase II and III Studies. American journal of clinical dermatology. 2021;22(4):555-66.
18.
M Z, ZD D, J D, L K, A M, L SG, et al. Efficacy and safety of roflumilast foam 0.3% 
in patients with seborrheic dermatitis in a randomized, double-blind, vehicle-controlled 
phase 2 study. JAAD. 2021;85(3).
19.
Faergemann J, Bergbrant IM, Dohse M, Scott A, Westgate G. Seborrhoeic 
dermatitis and Pityrosporum (Malassezia) folliculitis: characterization of inflammatory 
cells and mediators in the skin by immunohistochemistry. The British journal of 
dermatology. 2001;144(3):549-56.
20.
Le Cleach L, Chassany O, Levy A, Wolkenstein P, Chosidow O. Poor reporting of 
quality of life outcomes in dermatology randomized controlled clinical trials. Dermatology. 
2008;216(1):46-55.
21.
Both H, Essink-Bot ML, Busschbach J, Nijsten T. Critical review of generic and 
dermatology-specific health-related quality of life instruments. J Invest Dermatol. 
2007;127(12):2726-39.
22.
Basra MK, Salek MS, Camilleri L, Sturkey R, Finlay AY. Determining the minimal 
clinically important difference and responsiveness of the Dermatology Life Quality Index 
(DLQI): further data. Dermatology. 2015;230(1):27-33.
Effective Date: 12/2/2022
End Date:7/27/2023

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Appendix 1. Clinical Assessments
SD Severity Score
a0-4 for each clinical feature (0 = absence, 1 = mild, 2 = moderate, 3 = significant, 4 = 
severe)
Investigator Global Assessment
Clinical Feature
Scorea
Scale
0-4
Erythema
0-4
Pruritus
0-4
Total Score
0-12
Clinical severity
Scored
Features
Clear
0
No signs of SD
Almost Clear
1
Just perceptible erythema and just perceptible scaling
Mild
2
Mild erythema and mild scaling
Moderate
3
Moderate erythema and moderate scaling
Severe
4
Severe erythema and severe scaling
Effective Date: 12/2/2022
End Date:7/27/2023

S e b orr h eic D er m atitis R ux oliti ni b Cr e a m Pr ot oc ol
I nc yt e II R
Oct o b er 2 4, 2 0 2 2
2 4
A p p e n di x 2.
D er m at ol o g y Lif e Q u alit y I n d e x
T h e ai m of t hi s q u e sti o n n air e i s t o m e a s ur e h o w m u c h y o ur s ki n pr o bl e m h a s aff e ct e d 
y o ur lif e O V E R T H E L A S T W E E K.  Pl e a s e c h e c k o n e b o x f or e a c h q u e sti o n.
1.
O v er t h e l a st w e e k, h o w it c h y, s or e , p ai nf ul  or 
sti n gi n g  h a s y o ur s ki n b e e n ?
V er y m u c h
A l ot
A littl e
N ot at all




2.
O v er t h e l a st w e e k, h o w e m b arr a s s e d  or s elf 
c o n s ci o u s  h a v e y o u b e e n b e c a u s e of y o ur s ki n ?
V er y m u c h
A l ot
A littl e
N ot at all




3.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n 
i nt erf er e d wit h y o u g oi n g s h o p pi n g  or l o o ki n g 
aft er y o ur h o m e  or y ar d ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
4.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n 
i nfl u e n c e d t h e cl ot h e s  y o u w e ar ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
5.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n 
aff e ct e d a n y s o ci al  or l ei s ur e a cti viti e s ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
6.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n m a d e 
it diffi c ult f or y o u t o d o a n y s p ort ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
O v er t h e l a st w e e k, h a s y o ur s ki n pr e v e nt e d y o u 
fr o m w or ki n g  or st u d yi n g ?
y e s
n o


N ot r el e v a nt 
7.
If " N o", o v er t h e l a st w e e k h o w m u c h h a s y o ur s ki n 
b e e n a pr o bl e m at w or k  or st u d yi n g ?
A l ot
A littl e
N ot at all 



Eff e cti v e D at e: 1 2/ 2/ 2 0 2 2
E n d D at e: 7/ 2 7/ 2 0 2 3

S e b orr h eic D er m atitis R ux oliti ni b Cr e a m Pr ot oc ol
I nc yt e II R
Oct o b er 2 4, 2 0 2 2
2 5
8.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n 
cr e at e d pr o bl e m s wit h y o ur p art n er  or a n y of y o ur 
cl o s e fri e n d s or r el ati v e s? 
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
9.
O v er t h e l a st w e e k, h o w m u c h h a s y o ur s ki n 
c a u s e d a n y s e x u al diffi c ulti e s ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
1 0. O v er t h e l a st w e e k, h o w m u c h of a pr o bl e m h a s t h e 
tr e at m e nt f or y o ur s ki n b e e n, f or e x a m pl e b y 
m a ki n g y o ur h o m e m e s s y, or b y t a ki n g u p ti m e ?
V er y m u c h
A l ot
A littl e
N ot at all




N ot r el e v a nt 
Eff e cti v e D at e: 1 2/ 2/ 2 0 2 2
E n d D at e: 7/ 2 7/ 2 0 2 3

Seborrheic Dermatitis Ruxolitinib Cream Protocol
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October 24, 2022
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Appendix 3 CYP3A4 Inhibitors.
CYP3A4 Inhibitors
Amiodarone
Indinavir
Amprenavir
Isavuconazole
Aprepitant
Itraconazole
Atazanavir
Ketoconazole
Boceprevir
Lopinavir
Casopitant
Mibefradil
Cimetidine
Mifepristone (RU486)
Ciprofloxacin
Nefazodone
Clarithromycin
Nelfinavir
Cobicistat
Netupitant
Conivaptan
Nilotinib
Crizotinib
Norfloxacin
Cyclosporine
Norfluoxetine
Danoprevir
Posaconazole
Darunavir
Ritonavir
Delavirdine
Saquinavir
Diltiazem
Schisandra sphenanthera
Dronedarone
Telaprevir
Elvitegravir
Telithromycin
Erythromycin
Tipranavir
Faldaprevir
Tofisopam
Fluconazole
Troleandomycin
Gestodene
Verapamil
Grapefruit Juice, marmalade
Viekira pak
Idelalisib
Voriconazole
Imatinib
Effective Date: 12/2/2022
End Date:7/27/2023

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Appendix 4 – Study Drug Label
                         
                          Department of Dermatology
                                       212-241-3288
GCO#22-0672 Seborrheic Dermatitis and Treatment Response to 
Ruxolitinib 1.5% Cream
Subject #________  Subject Initials:___________  Date:__________
Ruxolitinib 1.5% Cream - Apply as directed by the study doctor
PI: Dr Benjamin Ungar  (212) 241-3288.
Store at controlled room temperature, away from light and humidity.
Caution: New Drug--Limited by Federal (USA) law to investigational use.
Effective Date: 12/2/2022
End Date:7/27/2023

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Appendix 5. Amendment Details
Amendment #1 May 25, 2022
Page 1 – Title Page – Added Amendment #1: May 25, 2022; Revised Date of protocol in footer.
Page 2 Table of Contents – Revised Page numbers and added Subject Identification and 
Appendices 3, 4 and 5.
Page 7 Inclusion Criteria for SD Subjects – Removed SD Severity Score as a criterion and added 
inclusion criterion: “Subject has failed an adequate course of treatment with at least one available 
therapy (topical antifungals or low-potency topical corticosteroids).”
Page 8 Exclusion Criteria for SD Subjects – Added Exclusion criterion: “Concurrent use of strong 
CYP3A4 inhibitors within 7 days or 5 half-lives (whichever is longer). A list of CYP3A4 inhibiting 
medications can be found in Appendix 3.”
Page 14 Stopping Rules – Added the following stopping rules:

If the following lab results are abnormal, participants will be retested in a window of 7-10 
days and reassessed. If the test results remain abnormal, participants will be 
discontinued from the study:
Hematology
Absolute Neutrophil Count:
<1000/mm3; <1.0 x109/L
Hemoglobin:  <8.0 g/dL; <4.96 mmol/L; <80 g/L
Hemoglobin drop ≥2 g/dL from baseline on two consecutive blood draws with associated 
symptoms; or hemoglobin drop ≥3 g/dL from baseline on two consecutive blood draws 
without associated symptoms. 
Platelet count: <75,000/mm3; <75.0x109/L
Lymphocytes: <500/mm3; <0.5x109/L
Chemistry
AST >3.0x ULN
ALT >3.0x ULN
Total bilirubin >1.5x ULN
CPK >10x ULN
Total bilirubin ≥1.5 x ULN; subjects with a history of Gilbert's syndrome may have a 
direct bilirubin measured and would be eligible for this study provided the direct bilirubin 
is  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 (e.g., cyclosporine, methotrexate, azathioprine, 
mycophenalate-mofetil, Janus kinase inhibitors, biologic agents, etc.).
Effective Date: 12/2/2022
End Date:7/27/2023

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Page 22 Appendix 1. Clinical Assessments – added a description of features associated with 
the individual scores of the Investigator Global Assessment.
Page 25 – Added Appendix 3 CYP3A4 Inhibitors
Page 26 – Added Appendix 4 Study Drug Label
Page 27 – Added Appendix 5 Amendment Details
Amendment #2 - October 24, 2022
Page 1 – Title Page – Added Amendment #2: October 24, 2022; Revised Date of protocol in 
footer.
Page 4 – Primary Endpoint
Revised from: “Percent of patients who achieve an IGA of 0 or 1 at 4 weeks of treatment 
with ruxolitinib 1.5% cream applied twice daily”
To: “The proportion of patients who achieve an IGA 0/1 at 4 weeks of treatment with 
ruxolitinib 1.5% cream applied twice daily”
Page 16 - Sample Size Calculation
Revised from: “30 moderate-to-severe patients treated with crisaborole for four weeks 
showed 67.8% average improvement in IGA with a standard deviation of approximately 
50% (9). Assuming similar biological variation (sd = 50%), a sample size of n=20 SD 
patients provides 95% power at 5% significance to detect a minimum average 
improvement in IGA of 42.5% with the application of a two-sided paired t-test. Accounting 
for a 20% dropout rate, we, therefore, propose a sample size of n=25 patients.”
To: “A sample size of n=20 SD patients guarantees 90% power at 2.1% significance to 
detect a minimum proportion of 75% of patients with IGA 0/1 at week 4. This calculation 
assumes the application of the one-sided binomial test with a null hypothesis proportion 
of 40%. This proportion is based on the vehicle response benchmark reported by Zirwas 
et al.(2021)  when comparing IGA 0/1 at week 8 in 154 patients treated with roflumilast 
foam 0.3% vs. 72 patients in the vehicle-controlled group(18). Accounting for a 20% 
dropout rate, we, therefore, propose a sample size of n=25 patients. “
Page 16 - Analysis of Primary Endpoint
Revised from “A Mixed-effects ordinal logistic regression model will be used to test 
differences in IGA between time points with time (Weeks 0, 2, 4, and 6) as a fixed effect, 
a random intercept for subjects, and inclusion of baseline characteristics as covariates. “
To: “The one-sided binomial test will be used to verify the hypothesis that the proportion 
of patients achieving IGA 0/1 at 4 weeks of treatment with ruxolitinib 1.5% cream applied 
twice daily is greater than 0.4.
Effective Date: 12/2/2022
End Date:7/27/2023

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Page 16 – Analysis of Secondary Endpoints
Revised from: “The mixed-effects model for continuous outcomes will also be used to 
detect any overall changes in clinical SD scoring over time compared with baseline with 
time (Weeks 0, 2, 4, and 6) as a fixed effect, a random intercept for subjects, and potential 
covariates. Changes in each component of the SD Severity Score, will also be evaluated 
using the same approach.” 
To: “The two-sided Wilcoxon signed-rank test will assess the significance of changes from 
baseline in:  

IGA score at 4 weeks of treatment

Components of clinical SD scoring (scale, erythema, and pruritus) at 4 weeks of 
treatment.
The two-sided paired t-test will assess the significance of changes from baseline in: 

Overall clinical SD scoring at 4 and 6 weeks of treatment.

Vital signs measured in interval or ratio scale 

Analytes measured in interval or ratio scale from laboratory tests (hematology, 
serum, chemistry, and urinalysis) at 4 weeks of treatment
The p-values will be adjusted by the Bonferroni method. The frequency, duration, and 
severity of AEs will be summarized with tables and summary statistics.”
 Page 17 - Analysis of Mechanistic (Exploratory) Endpoints
Revised from: “The baseline immune and molecular cutaneous profile of SD at baseline 
compared with healthy controls and the change in the immune and molecular cutaneous 
profile of SD with treatment will be assess by MMRM approach. Gene/Protein expression 
data will be modeled using a mixed effect model with tissue type and time as a fixed effect 
and a random effect for each subject.”
To: “The baseline immune and molecular cutaneous profile of SD at baseline compared 
with healthy controls and the change in the immune and molecular cutaneous profile of 
SD with treatment will be assessed by MMRM approach. Gene/Protein expression data 
will be modeled using a mixed effect model with the interaction between tissue type (non-
lesional/ lesional / healthy) and timepoint as fixed effects and a random effect for each 
subject.”
Revised from: “We will perform proteomic biomarker studies in serum using the OLINK 
high-throughput proteomic platform, with the Explore panel that evaluates >1,500 protein 
analytes. Protein expression data will be modeled using a MMRM approach, with time 
interaction as a fixed effect and a random effect for each subject.”
To: “We will perform proteomic biomarker studies in serum using the OLINK high-
throughput proteomic platform, with the Explore panel that evaluates >1,500 protein 
analytes. Protein expression data will be modeled using a MMRM approach, with the 
interaction of study group (treatment /control) and timepoint as fixed effects and a random 
effect for each subject.
Effective Date: 12/2/2022
End Date:7/27/2023

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We will use the Spearman coefficient to correlate: 1) molecular markers with disease 
activity in SD at baseline; 2) changes from baseline in molecular markers with changes 
from baseline in IGA and overall clinical SD scoring at 4 weeks of treatment.”
Effective Date: 12/2/2022
End Date:7/27/2023