Conditions: Atopic Dermatitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
Open label phase 2 investigational study of efficacy and safety of apremilast 30 mg twice a day (BID) in chronic atopic dermatitis when added to the FDA approved treatment dupilumab for atopic dermatitis that is not providing adequate clinical responses.

Detailed description:
The purpose of this study is to determine if apremilast as a combined treatment for atopic dermatitis will provide increased efficacy outcomes in subjects who are currently using the FDA approved therapy of dupilumab but have responded only partially or inadequately to this therapy. Our hypothesis is that adding apremilast will allow patients to go from an inadequate response to dupilumab to an adequate response defined as an Investigator Global Assessment (IGA) of 0 (clear) or 1 (almost clear).

Arms:
arm 1: Apremilast will be administered to patients as 30 mg oral tablets taken twice daily for 24 weeks. An initial 5-day titration will be implemented to improve tolerability.

Interventions: intervention 1: Apremilast
Intervention descriptions: intervention 1: 30 mg twice daily (BID)

Protocol document:
Prot_002.pdf: 
Page 1 of 23 
 
PROTOCOL 
 
 
Study Title: 
Apremilast 30 mg BID combined with Dupilumab for the 
Treatment of Recalcitrant Moderate-to-Severe Atopic Dermatitis 
 
Study Drug: 
Oral Apremilast 30 mg BID 
 
Sponsor: 
 
 
 
 
David Rosmarin, MD 
Tufts Medical Center 
Department of Dermatology 
800 Washington Street, Box 114 
Boston, MA  02111 
Phone: (617) 636-7462 
 
 
 
 
 
 
Fax: (617) 636-9169 
E-mail: drosmarin@tuftsmedicalcenter.org 
 
 
 
Coordinators:  
 
 
 
Courtney Kachuk RN, Nicole Dumont 
 
 
    
 
 
 
Version and Date: 
 
 
            Version June 2, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 of 23 
 
 
I. 
Aim and Hypotheses: The purpose of this study is to determine if apremilast as a combined treatment 
for atopic dermatitis will provide increased efficacy outcomes in subjects who are currently using the 
FDA approved therapy of dupilumab but have responded only partially or inadequately to this therapy. 
Our hypothesis is that adding apremilast will allow patients to go from an inadequate response to 
dupilumab to an adequate response defined as an Investigator Global Assessment (IGA) of 0 (clear) or 1 
(almost clear). 
 
II. 
Background and rationale:  
 
Background and Rationale:  
 
Dupilumab is FDA approved for atopic dermatitis and has activity against the shared alpha-chain 
subunit of the IL-4 and IL-13 receptor system. While type 2 inflammation is the predominant problem in 
atopic dermatitis, Th1 and TH17 inflammation is also part of the pathogenesis. Apremilast alone is 
unable to sufficiently block the dominant type 2 immune pathway in atopic dermatitis; however, 
apremilast can decrease multiple cytokine pathways through PDE4 inhibition. Apremilast blocks 
inflammatory mediators such as TNF-α, IL-12, IL-2 production in AD patients and may improve 
pruritus by this mechanism.1–3 We believe adding apremilast to patients already treated with dupilumab 
will lead to further improvement in atopic dermatitis and select out the patient population that will most 
benefit from apremilast. One study using apremilast 30 mg BID versus apremilast 20 mg BID as 
monotherapy for atopic dermatitis saw a clinical effect after 3 months in the 30 mg BID group only.4 We 
will be using apremilast in combination with dupilumab, and think the results may be synergistic. 
 
Our hypothesis is that the addition of apremilast to dupilumab will allow patients with an inadequate 
response to dupilumab monotherapy to potentially achieve an Investigators’ Global Assessment (IGA) 
score of 0 (clear) or 1 (almost clear). 
 
 
 
2.2) Apremilast (CC-10004): 
CC-10004, N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-1,3-dioxoisoindolin- 4-
yl}acetamide (S-enantiomer), is a phosphodiesterase type 4 (PDE4) inhibitor. Phosphodiesterase 4 
(PDE4) is a protein involved in the breakdown of cyclic adenosine 3’,5-monophosphate (cAMP). 
[Schafer 2012 and 2014] By preventing the breakdown of cAMP, apremilast is able to enhance cAMP’s 
ability to reduce both the T-helper 1 (Th1) and (Th2) responses that are unregulated in plaque psoriasis, 
resulting in improved psoriasis skin clearance.3  
 
 
2.2.1) Pertinent human studies: 
 
ESTEEM-1 and ESTEEM-2: The efficacy and safety of apremilast in the treatment of moderate-to-
severe plaque psoriasis were evaluated in two multi-center randomized, double blind, placebo-controlled 
phase 3 trials of comparable design. ESTEEM-1 (n=844) and ESTEEM-2 (n=413) patients were 
randomized 2:1 to receive apremilast 30 mg twice daily or placebo for 16 weeks, and from Weeks 16-
32, all patients received apremilast 30 mg BID (maintenance phase). The approval of apremilast was 
based on the data at 16 weeks from these trials. In both studies, the primary endpoint was the proportion 
of patients who achieved PASI-75 at Week 16. The major secondary endpoint was the proportion of 
patients who achieved an sPGA score of clear (0) or almost clear (1) at Week 16. At week 16, the 
proportion of patients achieving a PASI 75 response (a 75% improvement from baseline in Psoriasis 
Area Severity Index) was 33% of patients taking apremilast versus only 5% of placebo patients in 
ESTEEM-1, and 29% of patients taking apremilast versus only 6% of placebo patients in ESTEEM-2 (p 


Page 3 of 23 
 
< 0.0001). Significant results were also noted in favor of apremilast for the percent change from baseline 
in affected Body Surface Area and PASI score, as well as the percentage of patients achieving a PASI 
50. Overall, in both studies apremilast was found to be effective and associated with a favorable safety 
profile. The most frequently reported adverse events were diarrhea, upper respiratory tract infection, 
nausea, nasopharyngitis, and headache. Adverse events were mild to moderate in severity, with 
generally mild gastrointestinal complaints occurring early in the course of treatment and resolving with 
time, and there was no need for laboratory monitoring.5,6  
 
PALACE 1, PALACE 2, and PALACE 3: The efficacy and safety of apremilast for the treatment of 
psoriatic arthritis was evaluated in 3 multi-center, randomized, double blind, placebo controlled studies 
of similar design. A total of 1493 adult patients with active psoriatic arthritis (PsA) (≥ 3 swollen joints 
and ≥ 3 tender joints) despite prior or current treatment with disease-modifying antirheumatic drug 
(DMARD) therapy were randomized to placebo (n=496), apremilast 20 mg (n=500), or apremilast 30 
mg (n-497) given orally twice daily. Patients were allowed to receive concurrent DMARD therapy. The 
primary endpoint, the percentage of patients achieving American College of Rheumatology (ACR) 20 
response at week 16, was achieved by 38%, 32% and 41% of patients taking apremilast 30 mg twice 
daily +/- DMARDs in PsA-1, PsA-2, and PsA-3, respectively, with only 18-19% of patients on placebo 
+/- DMARDs achieving this response. Overall, Apremilast +/- DMARDs compared with placebo +/- 
DMARDs resulted in greater improvement in psoriatic arthritis symptoms and was associated with a 
favorable safety profile. The most common adverse reactions leading to discontinuation for patients 
taking OTEZLA were nausea (1.8%), diarrhea (1.8%), and headache (1.2%).7 
 
A Pilot Study of an Oral Phosphodiesterase Inhibitor (Apremilast) for Atopic Dermatitis in Adults): this 
open-label study tested the effects of apremilast 20 mg BID (APR20) and apremilast 30 mg BID (APR 30) 
in sixteen adults with atopic dermatitis. After three months, the group receiving APR20 had significant 
reductions in pruritus and the Dermatology Life Quality Index (DLQI), but not in the Eczema Area and 
Severity Index (EASI). The APR30 group had significant reductions in the EASI and DLQI.4  
 
A. Objectives: 
 
Efficacy Endpoints: 
a. Primary Endpoint Measures:  
i. Proportion of patients who achieve an Investigator’s Global Assessment (IGA) score of 0 
(clear) or 1 (almost clear) at Week 16. Clinical improvement in a patient’s eczematous 
lesions corresponds with a decrease in IGA, and a score of 0 (clear) or 1 (almost clear) is 
considered a significant clinical response. 
b. Secondary Outcome Measures 
i. Proportion/percentage of subjects achieving BSA < 3%  
ii. Mean and percentage change from baseline in percent of BSA involvement  
iii. Mean and percent change of the Dermatology Life Quality Index (DLQI) from baseline  
iv. Mean and percentage change from baseline in itch on Numerical Rating Scale (NRS) 
pruritus scale 
v. Mean and percentage change from baseline in Eczema Area and Severity Index (EASI) 
score at week 16 
Safety Endpoints: 
Safety and tolerability will be evaluated according to the frequency and severity of adverse events and 
changes in physical examinations or vital signs.  
 
II. 
Research Plan   


Page 4 of 23 
 
 
A. Overall Study Design:  
Open label phase 2 investigational study of efficacy and safety of apremilast 30 mg BID in chronic 
atopic dermatitis when added to the FDA approved treatment dupilumab for atopic dermatitis that is not 
providing adequate clinical responses. The study will have 1 phase: 
 
 Open label treatment period apremilast 30 mg BID 
 
Following informed consent, subjects will be screened on the basis of atopic dermatitis severity and 
inadequate treatment response to current therapies. IGA, BSA, pruritus NRS, EASI, complete physical 
examination, medical history, and concomitant medications will be reviewed. Eligible subjects will be 
administered treatment with apremilast 30 mg BID while continuing their prior inadequate atopic 
dermatitis treatment regimen. During the treatment phase, study drug will be provided in an oral form 
and will be titrated over 5 days and then taken twice daily thereafter. Subjects return to clinic for re-
evaluation. Efficacy endpoints will be assessed at weeks 2, 4, 8, 16, and 24. Week 16 is the last week of 
study drug dispensation. Efficacy and safety indices will be assessed as per the Schedule of 
Assessments.  
 
Treatment Assignment and Randomization 
No randomization will be used, as this is an open label study. There will be no blinding and investigators 
will have knowledge of the treatment each subject is administered.  
 
All patients seen in the Tufts Dermatology Clinic during the enrollment period who are not currently 
responding to existing FDA approved atopic dermatitis therapy and thus have not achieved a IGA of 0 
or 1 at screening, and meet all other inclusion/exclusion criteria, will be offered participation in the 
study.  
 
B. Statistical methods:  
 
Sample size: We will screen up to 20 patients to ensure that 16 patients complete the study. 
 
 
 
General statistical Methods: A clinical response to apremilast for the purposes of this study will be 
defined as an Investigator Global Assessment score of 0 (clear) or 1 (almost clear). The end points of the 
study will be assessed at Week 16. A period of 16 weeks was chosen, as this was the time frame utilized 
for primary endpoint reporting in the ESTEEM clinical program.6,8 An additional 8 weeks of study drug 
will be provided to assess enhanced clinical benefit with continued use at 24 weeks. A rate of 
incompletion and/or drop out of subjects has been factored in to assure great than 16 patients will 
complete the study. 
 
The analysis will be primarily descriptive. Mean, standard deviation, median, minimum, maximum, and 
95% confidence interval for mean will be provided for continuous variables. Changes and percent 
changes from pre-treatment to on-treatment time points will be calculated for continuous efficacy points. 
Graphical displays of changes over time may be presented for key outcomes. Counts, percentages, and 
95% confidence intervals will be provided for categorical variables. Subgroup analyses, such as gender 
stratification and stratification based on baseline treatment regimens, will be performed to identify a 
patient population that achieves the most benefit.  
 
Efficacy analyses will only use data from participants who complete at least 16 weeks of study treatment 
in order to evaluate the primary endpoint. 
 


Page 5 of 23 
 
Efficacy:  
Primary Endpoint 
Patients’ Investigator’s Global Assessment (IGA)9 will be assessed at weeks 2, 4, 8, 16, and 24, with the 
primary endpoint being the proportion of patients with an IGA of 0 (clear) or 1 (almost clear) at Week 
16. 
 
Secondary Endpoints 
Secondary endpoints will be assessed according to the scale of the outcome variable of interest. BSA 
and Eczema Area and Severity Index10 will be assessed along with IGA at all study visits. For quality of 
life outcomes, the Dermatology Life Quality Index (DLQI)11 will be used to assess changes from 
baseline in overall score will be provided. Assessment of outcomes of each protocol-scheduled time 
point (Weeks 2, 4, 8, 16, and 24) will be performed for each endpoint. Various schemes will be assessed 
for missing data imputation if needed. The change in the patient’s Numerical Rating Scale for Pruritus 
(NRS) will be assessed.12 
 
Background and demographic characteristics: 
Subjects’ age, weight, height and other continuous demographic and baseline characteristics will be 
summarized using descriptive statistics (mean, standard deviation, minimum and maximum), while 
gender, race and other categorical variables will be summarized with frequency tabulations. Medical 
history data will be summarized using frequency tabulations. Individual subject listings will be 
provided. A table of baseline demographic information of subjects who received study medication and 
controls will be provided for comparison between the two groups.   
 
Safety: 
Safety Primary Endpoints 
The safety analysis will be descriptive in nature. All subjects who take at least 1 dose of the study 
medication will be included in the safety analyses. Safety and tolerability will be evaluated by 
tabulations of adverse events, which will be recorded from the time the subject signs informed consent. 
Adverse events will be classified on the basis of Common Terminology Criteria for Adverse Events 
(CTACAE) coding and summarized for each treatment. Adverse events will be summarized by system 
organ class, preferred term, relationship to study drug, and severity. Serious AEs and AEs leading to 
death or resulting in premature discontinuation will be tabulated and listed separately. Study medication-
related AEs will be listed separately. Drop-out rate and reasons for early termination will be reviewed 
and tabulated. 
 
Prior and concomitant medications will be reviewed and tabulated by treatment. Physical examination 
changes and vital signs including weight will be assessed for potential clinical significance; changes 
from pre-treatment to on-treatment time points will be tabulated for continuous parameters; as 
warranted.  
 
Assessment of flare of atopic dermatitis will be summarized descriptively.  
 
 
C. Subject Characteristics 
 
Inclusion criteria:  
1. Signed and dated informed consent indicating the subject has been informed of all aspects of the study 
D. Non-English speakers may be enrolled in the study in accordance with the IRB’s short form 
policy.  


Page 6 of 23 
 
2. Subject is willing and able to comply with treatment plan, study drug administration, and study protocol 
requirements 
3. Male or females of any ethnic origin or race at least 18 years of age at time of informed consent 
4. Subject has a documented clinical diagnosis of chronic atopic dermatitis for at least 6 months prior to 
screening visit and is a candidate for systemic therapy 
5. Subjects must fulfill criteria outlined in the following clinical categories: 
 Subjects must be currently using and experiencing an inadequate response to dupilumab 
which is FDA approved for the treatment of moderate to severe atopic dermatitis. An 
inadequate response is defined as an IGA of 2 or more. 
 At the time of screening, subject must have a partial or inadequate response to their 
current treatment regimen. A partial or inadequate response at screening is defined as 
having both of the following: 
 Not having achieved an Investigator’s Global Assessment score of 0 (clear) or 1 
(almost clear). 
 Subjects must be on dupilumab for at least 12 weeks and willing to continue on 
dupilumab on a stable dose (40 mg weekly or every other week) while also receiving the 
study drug  
6. 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, 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 one additional barrier method: (a) diaphragm 
with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide. 
7. 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 non-latex condom NOT made out of 
natural [animal] membrane [for example, polyurethane]) while on study medication and for at least 28 
days after the last dose of study medication 
8. If receiving concomitant medications for any reason, must be on a stable regimen and willing to stay on 
a stable regimen. This includes emollients, which should stay stable throughout the study. 
 
Exclusion criteria:  
1. Prior hypersensitivity reaction or exposure to apremilast  
2. Untreated or unstable depression or suicidality, including prior history of suicide attempt at any time in 
the subject's lifetime prior to Baseline Visit or major psychiatric illness requiring hospitalization within 
3 years prior to Baseline Visit. Depression and suicidality will be assessed through standard-of-care 
questioning. 
3. Other than atopic dermatitis, any clinically significant (as determined by the Investigator) cardiac, 
endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, 
or other major disease that is currently uncontrolled. 
4. Any condition, which places the subject at unacceptable risk if he/she were to participate in the study or 
confounds the ability to interpret data from the study  


Page 7 of 23 
 
5. Subjects with a known history of CrCl<30 mL/min based on outside lab testing. No new lab testing will 
be performed during the study. 
6. Pregnant or lactating females  
7. Concomitant therapy with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, 
phenytoin), which may cause loss of efficacy of apremilast 
8. Prolonged sun exposure or use of tanning booths, which may confound the ability to interpret data from 
the study. 
9. Active substance abuse or a history of substance abuse within 6 months prior to Screening. Subjects will 
be asked about any history of substance use using standard of care questioning. This will be recorded on 
the subject’s inclusion/exclusion worksheet, which will contain the subject’s study number without any 
other personal identifying information. Only the PI will have access to the link between the subject’s ID 
number and identifying information. A record of the reasons for a screen-fail or other exclusion is 
necessary for reporting purposes to Amgen and for explanation in research publication. 
10. Malignancy or history of malignancy, except for: 
 treated [i.e., cured] basal cell or squamous cell in situ skin carcinomas;  
 treated [i.e., cured] cervical intraepithelial neoplasia (CIN) or carcinoma in situ of cervix  
with no evidence of recurrence within the previous 5 years. 
11. Use of dupilimab in combination with any other systemic immunosuppressant medication within 4 
weeks prior to randomization or 5 pharmacokinetic/pharmacodynamic half lives, whichever is longer. 
12. Use of any investigational drug within 4 weeks prior to randomization, or 
5 pharmacokinetic/pharmacodynamic half lives, if known (whichever is longer) 
 
Prior/Concomitant Medications 
Subjects may take any medication that is not restricted by the protocol and would not be expected to 
interfere with the conduct of the study. As the purpose of this study is to evaluate the efficacy of 
apremilast 30 mg BID when combined with dupilumab, subjects must continue on a stable dose of 
dupilumab while also receiving the study drug.  
 
All medications (prescription and non-prescription), treatments and therapies taken from screening 
through the last dose of study medication, including those initiated prior to the start of the study, must be 
recorded on the appropriate page of the subject documents. Record the dose, route of administration, 
indication, and the start and end date (when the medication was taken).  
 
Permitted Concomitant Therapy: 
The subject is required to continue on a concomitant stable dose of dupilumab treatment regimen 
throughout the study, given that they have been using the treatment for the minimum amount of time 
deemed necessary by the investigator to have experienced an inadequate clinical response. Once 
informed consent has been signed, subjects may not have additional atopic dermatitis medications 
prescribed outside of their existing atopic dermatitis treatment regimen listed at screening.  
 
The following commonly used products are acceptable for use throughout the study: acetaminophen, 
loratadine, pseudoephedrine, guaifenesin, and calcium. Subjects must check with study personnel before 
initiating use of prescribed or over-the-counter medications during the study. 
 
A nonmedicated emollient, i.e., Eucerin® cream (supplied by the study doctor), will also be allowed 
during the study; use must be stable throughout the study  
 
Any patient found to have cellulitis on physical exam during the study will be treated with appropriate 
antibiotics. It is at the investigator’s discretion whether the study drug will be continued or held.  
 


Page 8 of 23 
 
 
Prohibited Concomitant Therapy:  
 Use of any investigational medication 
 Concomitant therapy with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, 
carbamazepine, phenytoin), which may cause loss of efficacy of apremilast  
 All atopic dermatitis therapies outside of the subject’s existing treatment regimen at screening 
are prohibited 
 
Treatment Compliance: 
Study personnel will review the instructions printed on the package insert with subjects prior to 
dispensing the study medication. New study medication will be dispensed according to the Schedule of 
Assessments. The subject will be instructed to return the study medication packaging, including any 
unused medication, to the study site at each visit for assessment of compliance. Subjects will be asked 
whether they have taken their medication as instructed at each study visit. Any problems with 
compliance will be reviewed with the subject.  
 
Compliance will be assessed in two ways. Subjects will be responsible for returning unused study drug 
to the site. Pills will be counted to determine compliance. Subjects will also be responsible for recording 
the date and time they take the study drug in a medication diary. Compliance is defined as taking 
between 75%-125% of dispensed study medication.  
 
Dupilumab injections will also be recorded in the medication diary. 
 
Withdrawal/Termination criteria:  
The following are considered sufficient reasons for discontinuing a subject from study drug: 
 
Adverse events that the investigator believes may cause severe or permanent harm or which rule 
out continuation of study drug 
 
Lack of therapeutic effect: 
o Subjects who experience a significant flare of atopic dermatitis, as defined by a sudden 
intensification of eczema, or as a diagnosis of erythrodermic atopic dermatitis may be 
discontinued from treatment and enter the observational follow- up phase of the study. 
o In addition, if the subject, in his or her opinion, feels that their disease is worsening or not 
responding to treatment, they may withdraw consent to participate.  
 
Subject withdraws consent 
 
Subject lost to follow-up 
 
Death 
 
Protocol violation 
 
The reason for discontinuation will be recorded in the subject’s medical records. 
 
D. Risk/benefit assessment:  
 
1. Physical risk: Physical risk includes potential side effects or unknown adverse events related 
to study medication. It is unknown how the combination of apremilast with dupilumab will 
affect subjects. Side effects may be worse or intensified on this combination. Subjects may 
be at a slightly higher risk of infection than those taking the drugs individually, but this is 
unknown. It is unknown if this combination will improve atopic dermatitis. AD could stay 
the same or get worse. 
i. The most common risks of apremilast include diarrhea, nausea, indigestion, and upper 
respiratory infection. Weight loss and depression have also been shown to occur. 
 
2. Psychological risk: Psychological risk includes potential emotional stress related to oral 
administration of study medication or potential lack of improvement of atopic dermatitis 


Page 9 of 23 
 
lesions. 
 
3. Social risk: There are no anticipated social risks. 
 
4. Economic risk: Economic risks include costs related to travel to and from study site, as well 
the potential costs related to obtaining the study medication such as travel to a pharmacy and 
insurance payments.  
 
5. Benefit of participating in the study: It is unknown if the addition of apremilast to a 
subject’s existing treatment regimen will improve the patient’s atopic dermatitis. There is a 
potential for improvement given apremilast’s efficacy in prior clinical trials for atopic 
dermatitis, but there is a potential the patient’s condition could stay the same or worsen. 
Information may be obtained through this study to enable physicians to more appropriately 
prescribe apremilast to maximize its benefits for patients. The patient may also benefit from 
checking vital signs at screening and follow up visits.  
 
Study Drug Materials and Management 
 
Supplier: Amgen will supply all study medication to the principal investigator.  
 
Dosage Regimen: Apremilast will be administered to patients as 30 mg oral tablets taken twice 
daily for 24 weeks. An initial 5-day titration will be implemented to improve tolerability. The 
study drug will be started the morning of Day 1 at 10 mg. On Day 2, the study drug will be taken 
at 10 mg in both the morning and evening. On Day 3, the study drug, will be taken at 10 mg in the 
morning and 20 mg in the evening. On Day 4, the study drug will be taken at 20 mg in both the 
morning in evening. On Day 5, the study drug will be taken at 20 mg in the morning and 30 mg in 
the evening. On Day 6 and thereafter, the study drug will be taken at 30 mg in morning and 
evening. Doses should be 12 hours apart. Subjects will be instructed that apremilast can be taken 
with or without food and that the tablets should not be crushed, split, or chewed. Subjects will also 
be instructed to store tablets below 30°C (86°F). Subjects will simultaneously continue on their 
prior atopic dermatitis treatment regimens in addition to taking apremilast. If a subject misses a 
dose of the study drug, they may take it as soon as they remember, as long as it is more than 6 
hours before the next scheduled dose. In this case, the subject will take the missed pill, and then 
take their next pill at their usual dosing time and resume their normal dosing schedule. If the 
subject forgets to take a dose and it is <6 hours before their next scheduled dose, they should not 
take the forgotten pill and should not double-dose. Subjects should take their next scheduled dose 
at their usual time and resume their normal dosing schedule. Subjects will be responsible for 
recording the dates and times that they dose, and mark any missed dose as “missed” in their dosing 
diary. Treatment compliance will be assessed as described on page 8 of the protocol. 
  
Record of administration: Accurate recording of all study drug administration (including 
dispensing and dosing) will be made in the appropriate section of the subject’s source documents.  
 
Study Medication Accountability: The investigator or designee(s) is responsible for accounting 
for all study medication that is issued to and returned by the subject during the course of the study. 
If any study drug is lost or damaged, its disposition should be documented in the subject’s source 
documents.  
 
 
E. Specific methods and techniques used throughout the study:  
 
1. Study Procedures: At the initial visit, a Investigator’s Global Assessment (IGA) of disease will 
be performed to determine if the patient meets the inclusion criteria. A score on the NRS Pruritus 


Page 10 of 23 
 
scale will be determined. A thorough medical history and a review of prior/concomitant 
medications will be taken at the screening visit. A complete physical examination including 
weight and vital signs (temperature, blood pressure) will also be performed. At the following 
visits according to the Schedule of Assessments, a IGA, BSA, DLQI survey, vital signs, NRS 
pruritus scale, EASI, a complete or targeted physical exam and review of concomitant 
medications and adverse events will be performed. Additionally, drug dispensing and 
accountability will also occur at all visits after the screening visit according to the Schedule of 
Assessments.  
 Lab monitoring is not standard of care for patients using apremilast in clinic 
settings for the treatment of psoriatic disorders. Patients with psoriasis are 
frequently prescribed apremilast in addition to psoriasis biologic injectables, and 
it is not standard of care to perform lab tests for these patients that is outside of 
what is recommended for monitoring the safety of their injectable biologic alone. 
Atopic dermatitis patients taking apremilast are not at any increased risk 
compared to psoriasis patients taking apremilast. Dupilumab is a biologic, but this 
specific biologic does not require lab monitoring. For these reasons, lab 
monitoring will not be performed during this study as it would cause research 
subjects to undergo unnecessary testing.However, for all patients taking 
apremilast, it is standard of care to monitor weight at treatment visits and to ask 
patients about adverse symptoms. Both of these will be performed during the 
study based on the schedule of assessments. 
 
2. Subject Timeline: 24 week duration of study treatment. 
 
F. Assessment of Subject Safety and Development of a Data and Safety Monitoring Plan 
 
 AE data will be collected at each study visit by asking the subject about their symptoms. The  PI 
will review all AE data as they are collected, and the PI will sign off on AEs during the study 
visit. The AEs for the subjects will be stored in the subject’s study documents and updated at 
each study visit. AEs will be collected from the time of ICF signature through the end of the 
study at all study visits. 
 AEs of Special Interest such as infections and malignancies will be reviewed ongoing throughout 
the study as they are reported.  In the instance that there are 3 serious related infections or 2 new 
malignancies (excluding non-melanoma skin cancers) the PI will place a pause on enrollment 
until further evaluation is conducted.   
 At the end of the study, all AE data collected in the subjects’ study documents will be compiled 
into an excel spreadsheet where the data will be analyzed by the PI. There will be no interim 
review of these data (with the exception of AEoSI). 
 The PI may terminate individual subjects from the trial if he determines that the subject’s safety 
is at risk due to their AE. 
 Definition of Serious Adverse Event (SAE) and Adverse Event (AE) for this study: All observed 
or volunteered adverse events regardless of suspected causal relationship to the investigational 
product would be recorded. An adverse event is any untoward medical occurrence in a subject 
administered a clinical investigation medication. Examples include progression/worsening of 
underlying disease, abnormal test findings, changes in vital signs or physical examination 
findings, and clinically significant symptoms and signs. The investigator and/or site staff will 
determine if the adverse event meets criteria for a significant adverse event.  
 


Page 11 of 23 
 
A significant adverse event is any untoward medical occurrence that results in death, is life 
threatening, requires inpatient hospitalization, results in significant disability, or results in 
congenital anomaly or birth defect. 
 It is at the discretion of the PI and sponsor whether an SAE requires the termination of the 
research. 
 
 Reporting timeframe for SAEs and AEs: AE’s will be recorded in the subject’s patient chart as 
they occur. The subject will detail all information pertaining to adverse events noted during the 
study, including date of onset, date of resolution, severity, and relationship to study drug.  
The SAE must be reported immediately (i.e., within 24 hours of the Investigators’ knowledge of the 
event) to Amgen Global Safety by facsimile.  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). 
Amgen Safety Contact Information: 
 
 Amgen Global Drug Safety  
Fax:                 1-888-814-8653 
E-mail:             svc-ags-in-us@amgen.com 
 
Reportable new information will be reported to the IRB per the Tufts Health Sciences IRB’s 
Reportable New Information policy. 
 
 Accountability procedures as they relate to drugs, devices, and data: The investigator or 
designee(s) is responsible for accounting for all study medication that is issued to and returned 
by the subject during the course of the study. If any study drug is lost or damaged, its disposition 
should be documented in the subject’s source documents.  
 The study drug will be stored in the investigational pharmacy. IDS will be responsible for 
dispensing medication. All unused drug will be returned to IDS at the end of the study. The 
research coordinator is responsible for communicating with IDS. The PI is responsible for 
signing all drug order forms. 
 
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 
in section II:C:6 while on investigational product and for at least 28 days after administration of the last dose of 
the investigational product. 
When a female subject of childbearing potential’s contraceptive measures or ability to become pregnant 
changes at the time of study entry or 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 


Page 12 of 23 
 
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 Amgen Safety immediately facsimile using the Pregnancy Report 
form provided by Amgen.  An authorization form to request the collection of this information from the 
pregnant partner of a male subject will be submitted to the IRB for review and approval prior to the 
collection of this information. The study team will request that subject approach their pregnant partner to 
obtain authorization, and the pregnant partner may contact the study team for more information.  
 
G. Subject Participation 
 
1. Recruitment: Recruitment will occur through the outpatient dermatology clinic at Tufts Medical 
Center once IRB approval is obtained. Goals for recruitment in terms of screening treatment 
regimens include: 16 subjects completing the study. Up to 20 may be screened to allow for 
screen fails. 
 Dermatologists in the TMC department of dermatology will be informed about the 
ongoing trial and its key inclusion/exclusion criteria. Dermatologists can inform their 
patients about the study during the patient’s regular scheduled clinic visit. If a patient 
is interested, research staff will come down to the dermatology clinic to inform the 
patient further. If the subject chooses to proceed with a screening visit, this will be 
conducted in a private research room where informed consent will be obtained. 
Alternatively, the screening visit can be scheduled for a future date. Dermatologists 
may also tell their patients about this study and provide research staff contact 
information to the patient 
 The clinical recruitment website will provide online information about the study. 
Additionally, this trial will be listed on clinicaltrials.gov. Study team contact 
information will be provided in both of these websites, and interested subjects may 
call the department for more information. There are no other recruitment materials. 
 These two methods have been effective in the past for our recruitment of other 
investigator-initiated trials of similar sample sizes. 
 
2. Registration: Not applicable. 
 
3. Screening Interview/questionnaire: Screening will occur once subject has had ample time to 
review and sign the informed consent form. The screening visit will be performed by Dr. David 
Rosmarin and other qualified research staff members at the Tufts Medical Center Dermatology 
Research Department.   
 
4. Transportation: Subjects will arrange for their own transportation to and from the Tufts 
Medical Center. 
 
5. Informed consent process and timing of obtaining of consent: Providing detailed and 
comprehensive information about the study and obtaining written informed consent will be done 
by Principal Investigator or other qualified research staff members prior to any study-related 
procedures. Subjects will have adequate time to review informed consent, ask site staff 
questions, discuss study participation with their family or friends, and then sign informed 
consent if they choose to participate in the study. Explaining the study, answering of questions, 
and obtaining written consent will be carried out in a private patient room to ensure patient 


Page 13 of 23 
 
confidentiality. The original consent form signed and dated by the subject must be maintained in 
the investigator’s study files and a copy given to the subject. In addition, if a protocol is amended 
and it impacts on the content of the informed consent, the informed consent must be revised. 
Subjects participating in the study when the amended protocol is implemented must be re-
consented with the revised version of the informed consent. The revised consent form signed and 
dated by the subject and by the person consenting the subject must be maintained in the 
investigator’s study files and a copy given to the subject. 
 
6. .Location where study will be performed: The study will take place at the Dermatology Clinic 
at Tufts Medical Center.  
 
7. Personnel who will conduct the study, including: All personnel with delegated responsibilities 
will have completed appropriate GCP and CITI training for biomedical research. 
 
 The PI is a board-certified dermatologist with over a decade of clinical and research 
experience. He currently serves as the PI for all our active research studies, as well as 
past research studies that are currently closed. 
 Nicole Dumont is a skilled research-coordinator with almost two decades of 
experience in our department as the coordinator. She served as the coordinator for all 
of our active and past studies. 
 Courtney Kachuk is a registered nurse with a decade of experience in our department 
as the study nurse. She has delegated responsibility as the study nurse in all our active 
trials and past trials. 
 There will be no sub-PI for the study; all visits will be scheduled on a day when the 
PI is present at the study site. 
 Research fellows listed on the IRB Form 1 as involved with this study include current 
TUSM students and international MD holders. All research fellows have clinical 
experience. Fellows will not be added to the research team or the delegation log of 
this study until they have been adequately trained. Training will be provided by the 
research coordinator and study nurse, who will delegate responsibilities at their 
discretion. The IRB will be informed of any additions to the research team.   
 The entire research team will be trained in the protocol, their roles and 
responsibilities, before initiation of the trial. If new members are to be added to the 
research team, it is the responsibility of the research coordinator to provide ongoing 
training. 
a. Present during study procedure(s) and their proximity during the study: David 
Rosmarin MD, Nicole Dumont, Courtney Kachuk, RN, Research fellows listed as members 
of the research team on the IRB Form 1. 
 
b. Primary responsibility for the following activities:  
 
i. Obtaining informed consent: David Rosmarin, MD 
ii. Providing on-going information to the IRB: David Rosmarin, MD, Nicole Dumont,  
 
iii. Maintaining participant's research records: David Rosmarin, MD, Nicole Dumont, 
Courtney Kachuk, RN 
 
8. Subject fees: There will be no direct subject fees and no reimbursement fees.  
 


Page 14 of 23 
 
9. Study results: The only results that will be given to the patient are abnormal vital signs, in 
which case the site staff will discuss the abnormal results and schedule appropriate follow up.   
 
10. Procedures to protect subject confidentiality: Subject information will be documented and 
safely protected in Tufts Dermatology medical center in locked cabinets which only the 
investigator and permitted research staff will have access to.  All data collected at study visits 
will be stored on password-protected computers in locked rooms. 
 
 All visits will take place in a private research room in the department of dermatology. Study 
procedures will be explained to subjects in language that is appropriate for their educational 
level and medical understanding. Subjects will interact with a small group of research staff 
for their entire participation in the study, who will introduce themselves to the subjects at the 
beginning of the study and as procedures need to be performed. 
 
11. Confidentiality: 
 
a. Certificate of Confidentiality: This will be obtained if necessary and as per Tufts 
Medical Center IRB regulations. 
 
b. How data will be coded, recorded, and stored to protect confidentiality: The 
Principal Investigator will code all subject samples with a unique code number. Only 
Principal Investigator and site staff will be able to link code number to subject name. 
Data will be recorded through code number and stored in a locked cabinet in locked 
office in research department office. The investigator must ensure that the records and 
documents pertaining to the conduct of the study and distribution of the study drug are 
complete, accurate, and filed and retained. The “Confidentiality and Data Security 
Guidelines for Electronic Research Data” for electronic data will be followed. Data will 
be stored and maintain for 7 years after study closure with the IRB and as described in 
the record retention policy of the “SOP – Records Retention Timeframe – Investigators”. 
 
c. Parties who will have access to the data, including the key to the identity code: 
Principal Investigator and research staff. 
 
d. Parties who will have access to research records: The subject’s right to protection 
against invasion of privacy will be upheld throughout the study. In compliance with 
United States federal regulation, only permitted research staff will have access to 
subject’s medical records, and when necessary, representatives of the FDA or other 
regulatory authorities to review and/or copy and medical records relevant to the study in 
accordance with local laws. 
 
12. Collaboration: Data will be available to principal investigator, site staff, Amgen, Institutional 
Review Board of Tufts Medical Center, and potentially certain government agencies such as the 
U.S. Food and Drug Administration. Otherwise, there is no collaboration with another 
institution.  
 
13. Alternatives: An alternative is not to participate in the study. In the event the subject decides not 
to participate, the principal investigator and/or site staff can discuss other treatment options for 
plaque atopic dermatitis with the patient including the following: 
a. Continuation of existing regimen without participation in this study 


Page 15 of 23 
 
b. Topical medications such as corticosteroids (triamcinolone, clobetasol, etc.), topical 
calcineurin inhibitors (tacrolimus, Protopic, etc), and Eucrisa (crisaborole) 
c. Oral medications for eczema include steroids (Prednisone, etc.), or 
immunosuppressants (CellCept, cyclosporine, etc.).  
d. Participation in a different clinical trial for another investigational product 
e. The study drug, apremilast, is not available at this time for atopic dermatitis. It is 
currently approved for the treatment of psoriasis and psoriatic arthritis. 
Dermatologists may attempt to gain insurance coverage for off-label prescribing of 
this medication for AD at the end of the study. Dupilumab is currently standard of 
care for AD, and can be prescribed at the end of the study by the subject’s regular 
dermatologist 
 
14. How new information will be conveyed to the study subject and how it will be documented: 
New information will be conveyed through IRB approved amendment to the Informed Consent 
form. 
 
15. Payment, including a prorated plan for payment: Subjects will be paid $50.00 per visit for 
this study. Subjects will be paid via clincard. Subjects will be paid after each visit attended. 
Subjects will not be paid for any missed visits. Subjects can make up to $300.00 for completion 
of the entire study. 
 
16. Payment for a research-related injury: Research related injuries at not anticipated in this study 
and if an injury does occur, an appropriate plan of action will be determined by principal 
investigator at that time. 
 
I. Outcome: Study results and outcomes will be prepared in a manuscript for peer-reviewed journal 
publication. Success will be determined as described above in the “objectives” section. 
  
J. Tissue banking considerations: Not applicable.  
 
 
 
 
 
 


Page 16 of 23 
 
Schedule of Assessments  
 
Protocol 
Activity 
Visit 1: 
Screening/
Baseline1  
Visit 2 
Week 2 
± 3 
days 
Visit 3 
Week 4 ± 
3 days 
Visit 4 
Week 8 
± 3 
days 
Visit 5 
Week 
16 ± 3 
days 
Visit 6 
Week 
24 ± 3 
days 
Early 
Termi-
nation 
Informed 
Consent 
X 
 
 
 
 
 
 
Atopic 
Dermatitis 
diagnosis, 
medical history 
X 
 
 
 
 
 
 
Concomitant/prio
r Medications 
X 
X 
X 
X 
X 
X 
X 
Complete 
physical 
examination2 
X 
 
 
 
 
 
X 
Targeted physical 
examination3 
 
X 
X 
X 
X 
X 
 
Vital signs 
(Temperature, 
resting pulse, 
seated blood 
pressure) 
X 
X 
X 
X 
X 
X 
X 
Demographic 
information4 
X 
 
 
 
 
 
 
CLINICAL 
EVALUATION 
 
 
 
 
 
 
 
Assessment of 
atopic dermatitis5 
X 
 
 
 
 
 
 
Investigator’s 
Global 
Assessment of 
disease (IGA) 
X 
X 
X 
X 
X 
X 
X 
Body Surface 
Areas (BSA) 
X 
X 
X 
X 
X 
X 
X 
NRS Pruritus 
scale 
X 
X 
X 
X 
X 
X 
X 
Eczema Area and 
Severity Index 
(EASI) 
X 
X 
X 
X 
X 
X 
X 
Photography 
X 
X 
X 
X 
X 
X 
X 
PATIENT 
REPORTED 
OUTCOMES 
 
 
 
 
 
 
 
Dermatology 
Life Quality 
Index (DLQI) 
X 
X 
X 
X 
X 
X 
X 
OTHER 
ACTIVITIES 
 
 
 
 
 
 
 
Study Drug 
Dispensing 
X 
 
X 
X 
X 
 
 
Drug 
Accountability 
 
X 
X 
X 
X 
X 
X 
Adverse Event 
Reporting 
 
X 
X 
X 
X 
X 
X 
Review 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy 
test6 
X 
X 
X 
X 
X 
 
 
 
1 Baseline visits may occur at the same time as the screening visit, or within 4 weeks of the screening visit. 


Page 17 of 23 
 
2Complete physical examination includes weight, general appearance, skin, HEENT (head, eyes, ears, nose, 
throat), heart, lungs, abdomen, lower extremities, neurologic and lymph nodes. Height will be recorded at 
screening only.  
3 Targeted physical examination consists of weight, examination of heart, lungs, abdomen, lymph nodes, and 
lower extremities, as well as any area of patient-reported AEs. 
4  Demographic information including but not limited to age, race, gender, ethnicity  
5 For study eligibility, subjects must have active atopic dermatitis at Screening, which has been diagnosed or 
confirmed by a dermatologist.   
6 Urine pregnancy test (human chorionic gonadotropin; HCG) is required only for women of child-bearing 
potential  
                                                    
 
 
Assessments of Efficacy: 
 
Investigators Global Assessment (IGA)  
 
Body surface area (BSA) of involved skin will be measured at Screening, Baseline, and at following 
visits according to the Schedule of Assessments until study completion. 
 
Numerical Rating Scale (NRS) Pruritus Scale 
 
EASI 
 
DLQI 
 
Assessments of Health-Related Quality of Life:  
 
 
Dermatology Life Quality Index will be assessed by the subject at Day 1, and Weeks 2, 4 8, 
 
16, and 24 upon arrival at the site before any other procedures or assessments are performed.  
The DLQI is a self-administered, 10-item questionnaire measuring the impact of skin disease on 
subjects' quality of life based on recall over the past week. Domains include symptoms, feelings, daily 
activities, leisure, work, personal relationships, and treatment. Possible responses for each of the 10 
items include: not at all, a little, a lot, and very much. Each question is scored on a scale of 0 to 3 with a 
total range of 0 to 30.11  
 
 
 
 


Page 18 of 23 
 
 
 
 
 
 
DERMATOLOGY LIFE QUALITY INDEX 
 
 
 
 
 
 
 
 
 
 
 
 
 DLQI  
Hospital No: 
 
 
 
 
Date: 
 
 
 
 
 
 
Name:  
 
 
 
 
 
 
 
 
Score: 
Address: 
 
 
 
 
Diagnosis: 
 
 
 
 
 
 
The aim of this questionnaire is to measure how much your skin problem has affected your life OVER THE LAST 
WEEK.  Please tick one box for each question. 
 
1. 
Over the last week, how itchy, sore,  
 
 
Very much 
 
 
painful or stinging has your skin    
 
 
A lot 
 
 
 
been?   
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
 
2. 
Over the last week, how embarrassed 
 
 
Very much 
 
 
or self conscious have you been because   
 
A lot 
 
 
 
of your skin? 
 
  
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
 
3. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin interfered with you going 
 
  
 
A lot 
 
 
 
shopping or looking after your home or   
 
A little  
 
 
garden?        
 
 
 
 
 
Not at all 
 
Not relevant  
 
4. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin influenced the clothes  
 
 
 
A lot 
 
 
 
you wear? 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant  
 
5. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin affected any social or  
 
 
 
A lot 
 
 
 
leisure activities? 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant  
 
6. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin made it difficult for   
 
 
 
A lot 
 
 
 
you to do any sport? 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant  
 
7. 
Over the last week, has your skin prevented 
 
Yes 
 
 
 
you from working or studying?  
 
 
No 
 
 
Not relevant  
 
 
 
If "No", over the last week how much has   
 
A lot 
 
 
 
your skin been a problem at  
 
 
 
A little  
 
 
work or studying? 
 
 
 
 
Not at all 
 
 
8. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin created problems with your   
 
 
A lot 
 
 
 
partner or any of your close friends 
 
 
A little  
 
 
or relatives?  
 
 
 
 
 
Not at all 
 
Not relevant  
 
9. 
Over the last week, how much has your  
 
 
Very much 
 
 
skin caused any sexual   
 
 
 
A lot 
 
 
 
difficulties? 
 
 
 
 
 
A little  
 
 
 
 
 
 
 
 
 
Not at all 
 
Not relevant  


Page 19 of 23 
 
 
10. 
Over the last week, how much of a  
 
 
Very much 
 
 
problem has the treatment for your 
 
 
A lot 
 
 
 
skin been, for example by making  
 
 
A little  
 
 
your home messy, or by taking up time?   
 
Not at all 
 
Not relevant  
Please check you have answered EVERY question. Thank you.  
AY Finlay, GK Khan, April 1992 www.dermatology.org.uk, this must not be copied without the permission of the authors. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 20 of 23 
 
IGA 
 
 
 


Page 21 of 23 
 
EASI 
 
 
 


Page 22 of 23 
 
NRS-Pruritis 
 
 
 
 


Page 23 of 23 
 
References 
 
1.  
Zane LT, Chanda S, Jarnagin K, Nelson DB, Spelman L, Gold LS. Crisaborole and its potential role in 
treating atopic dermatitis: overview of early clinical studies. Immunotherapy. 2016;8(8):853-866. 
doi:10.2217/imt-2016-0023 
2.  
Dong C, Virtucio C, Zemska O, et al. Treatment of Skin Inflammation with Benzoxaborole 
Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with 
Skin Inflammation and Skin Architecture Changes. J Pharmacol Exp Ther. 2016;358(3):413-422. 
doi:10.1124/jpet.116.232819 
3.  
Bäumer W, Hoppmann J, Rundfeldt C, Kietzmann M. Highly selective phosphodiesterase 4 inhibitors for 
the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007;6(1):17-26. 
http://www.ncbi.nlm.nih.gov/pubmed/17352685. Accessed January 16, 2019. 
4.  
Samrao A, Berry TM, Goreshi R, Simpson EL. A Pilot Study of an Oral Phosphodiesterase Inhibitor 
(Apremilast) for Atopic Dermatitis in Adults. Arch Dermatol. 2012;148(8):890-897. 
doi:10.1001/archdermatol.2012.812 
5.  
Papp KA, Bissonnette R, Gooderham M, et al. Treatment of plaque psoriasis with an ointment 
formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial. BMC 
Dermatol. 2016;16(1):15. doi:10.1186/s12895-016-0051-4 
6.  
Paul C, Cather J, Gooderham M, et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 
inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized 
controlled trial (ESTEEM 2). Br J Dermatol. 2015;173(6):1387-1399. doi:10.1111/bjd.14164 
7.  
Kavanaugh A, Mease PJ, Gomez-Reino JJ, et al. Treatment of psoriatic arthritis in a phase 3 randomised, 
placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 
2014;73(6):1020-1026. doi:10.1136/annrheumdis-2013-205056 
8.  
Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in 
patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial 
(Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad 
Dermatol. 2015;73(1):37-49. doi:10.1016/j.jaad.2015.03.049 
9.  
Futamura M, Leshem YA, Thomas KS, Nankervis H, Williams HC, Simpson EL. A systematic review of 
Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many options, no standards. J Am 
Acad Dermatol. 2016;74(2):288-294. doi:10.1016/j.jaad.2015.09.062 
10.  
Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index 
(EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 
2001;10(1):11-18. http://www.ncbi.nlm.nih.gov/pubmed/11168575. Accessed January 16, 2019. 
11.  
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)--a simple practical measure for routine 
clinical use. Clin Exp Dermatol. 1994;19(3):210-216. http://www.ncbi.nlm.nih.gov/pubmed/8033378. 
Accessed November 8, 2018. 
12.  
Validation of the peak pruritus numerical rating scale: Results from clinical studies of dupilumab in adult 
patients with moderate-to-severe atopic dermatitis. J Am Acad Dermatol. 2017;76(6):AB278. 
doi:10.1016/j.jaad.2017.04.1082 
 

SAP_003.pdf: 
 
 
 
 
 
 
 
 
 
PROTOCOL 
 
 
 
 
 
Study Title: 
Apremilast 30 mg BID combined with 
Dupilumab for the Treatment of Recalcitrant 
Moderate-to-Severe Atopic Dermatitis 
 
Study Drug: 
Oral Apremilast 30 mg BID 
 
 
 
Sponsor: 
 
 
 
 
David Rosmarin, MD 
Tufts Medical Center 
Department of Dermatology 
800 Washington Street, Box 114 
Boston, MA  02111 
Phone: (617) 636-7462 
 
 
 
 
 
 
Fax: (617) 636-9169 
E-mail: drosmarin@tuftsmedicalcenter.org 
 
 
NCT:  
 
 
 
 
NCT04306965 
 
 
    
 
 
 
Version and Date:  
 
            Version June 2, 2021 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Methods 
 
 
Sample size: We will screen up to 20 patients to ensure that 16 patients complete the study. 
 
 
 
General statistical Methods: A clinical response to apremilast for the purposes of this 
study will be defined as an Investigator Global Assessment score of 0 (clear) or 1 (almost 
clear). The end points of the study will be assessed at Week 16. A period of 16 weeks 
was chosen, as this was the time frame utilized for primary endpoint reporting in the 
ESTEEM clinical program.6,8 An additional 8 weeks of study drug will be provided to 
assess enhanced clinical benefit with continued use at 24 weeks. A rate of incompletion 
and/or drop out of subjects has been factored in to assure great than 16 patients will 
complete the study. 
 
The analysis will be primarily descriptive. Mean, standard deviation, median, minimum, 
maximum, and 95% confidence interval for mean will be provided for continuous 
variables. Changes and percent changes from pre-treatment to on-treatment time points 
will be calculated for continuous efficacy points. Graphical displays of changes over time 
may be presented for key outcomes. Counts, percentages, and 95% confidence intervals 
will be provided for categorical variables. Subgroup analyses, such as gender 
stratification and stratification based on baseline treatment regimens, will be performed to 
identify a patient population that achieves the most benefit.  
 
Efficacy analyses will only use data from participants who complete at least 16 weeks of study 
treatment in order to evaluate the primary endpoint.