Pilot Study Evaluating the Efficacy of a Topical PDE4 Inhibitor for Morphea
Phase: PHASE2
Conditions: Morphea
Sponsor: Duke University

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CONFIDENTIAL 
 
 
Pilot Study Evaluating the Efficacy of a Topical PDE4 Inhibitor for Morphea 
NCT03351114 
 
 
Version: August 3, 2018 
 
 
Confidentiality Statement 
The information contained within is not to be disclosed in any way without the  
prior permission of the Principal Investigator.   
 
 
Sponsor: 
 
PI – Duke Department of Dermatology 
Funding Source: 
Pfizer (unrestricted grant) 
Protocol Source: 
PI – Duke Department of Dermatology 
Duke IRB#: 
 
Proo00086947 
 
 
Principal Investigators: 
Adela Rambi G. Cardones, MD 
 
 
 
 
 
Department of Dermatology 
 
 
 
 
 
Duke University Medical Center 
 
 
 
 
 
Durham, NC  27710 
 
 
 
 
 
Voice: 919-684-3110 
 
 
 
 
 
Fax: 919-681-9594 
 
 
 
 
 
E-mail: adela.cardones@dm.duke.edu 
 
 
Co-Investigators: 
 
Russell Hall, MD Department of Dermatology 
 
 
                     
         Sarah Blanchard, MD Department of Dermatology 
 
 
 
 
 
 
 
 
Data Management and Clinical Trial Support:                                      
 
 
 
 
 
Kim Scoggins, Department of Dermatology 
 
 
 
 
 
Statistician: 
 
 
Cindy Green, PhD 
 
 
 
 
 
 
 
 

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Abbreviations 
 
cAMP                           Cyclic adenosine monophosphate 
CTCAE                        Common Terminology Criteria for Adverse Events  
DIET                            Dyspigmentation, Induration, Erythema, and Telangiectasias 
ERK                             Extracellular signal-regulated kinase 
hCG                             Human chorionic gonadotropin 
HRQOL                        Health-related quality of life  
LoSCAT                       Localized Scleroderma Cutaneous Assessment Tool 
MAPK                          Mitogen-activated protein kinase  
PDE-4                          Phosphodiesterase-4 
SDRC                          Skin Disease Research Center (SDRC)  
TGFβ                           Transforming growth factor beta 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
TITLE PAGE ................................................................................................................... 1 
ABBREVIATIONS .......................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................. 3 
1. Protocol Title ……………………...................................................................... 4 
2. Purpose of Study ………………………………………………………………….. 4 
3. Background & Significance ............................................................................. 4 
4. Design & Procedures ...................................................................................... 4 
5. Selection of Subjects ……………………………………………………………… 8  
6. Subject Recruitment & Compensation …………………………….……………. 8                                
7. Consent Process ..………………………………………………………………… 9 
8. Subject’s Capacity to Give Legally Effective Consent ………………………… 9 
9.  Study Interventions ………………………………………………………………. 9 
10. Risk/Benefit Assessment and Safety Considerations ….…..……………….. 9 
11. Costs to the Subject …………………………………………………………….. 9 
12. Data Analysis & Statistical Considerations …………………………………… 9 
13. Data & Safety Monitoring ………………………………………………………. 10 
14. Privacy, Data Storage & Confidentiality ………………………………………. 11 
REFERENCES............................................................................................................... 12 
 
 
 
 
 
 
 
 
 
 

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1. Protocol Title:  
Pilot Study Evaluating the Efficacy of a Topical PDE4 Inhibitor for Morphea 
 
2. Purpose of the Study:  
To determine the clinical efficacy of crisaborole 2% ointment in the treatment of 
morphea. Specifically, to: 
a. Compare the difference in dermal thickness and fibrosis as measured by histology 
at baseline and after 12 weeks of crisaborole 2% ointment, applied 2 times a day. 
b. Compare changes in physician and patient reported outcomes at baseline, 4, 8 
and 12 weeks of treatment. 
 
 
3. Background & Significance:  
Morphea is an autoimmune fibrosing skin disorder of still unknown etiology. It can be 
associated with significant morbidity, and effective topical and systemic therapies are still 
lacking. cAMP is known have an anti-fibrotic effect in skin models as well as other 
organs. It is therefore not surprising that phosphodiesterase-4(PDE4), which degrades 
cAMP, has been implicated in the pathogenesis in both animal and human studies. 
Preclinical studies have suggested that PDE4 inhibition may attenuate the oxidative 
processes that mediate fibrosis1.  Systemic PDE4 inhibitors demonstrated anti-fibrotic 
effects in multiple murine skin fibrosis models, including the bleomycin-induced 
skin fibrosis models, the topoisomerase I mouse model and in murine sclerodermatous 
chronic graft-versus-host disease2. This anti-fibrotic effect was mediated though the 
blockage of cytokines and other immune mediated mechanisms. Dermal fibroblasts and 
myofibroblasts in an inflammatory disease such as psoriasis have increased expression 
of PDE43. Furthermore, PDE4 inhibition reduced TGFβ mediated fibroblast migration 
and myofibroblast transformation3. 
 
PDE4 facilitates proinflammatory signals by degrading cAMP in inflammatory cells, 
smooth muscle cells, and keratinocytes. In mouse models, the anti-fibrotic effect of 
PDE4 inhibition was mediated though the blockage of cytokines and other immune 
mediated mechanisms2. Keratinocytes play an active part in the modulation of 
inflammation in a variety of cutaneous inflammatory and immune disorders. Our group 
has a particular interest in the role of the keratinocyte mediated inflammation and 
biology4. Cross talk exists between cAMP and the RAS/RAF/mitogen-activated protein 
kinase (MAPK) and extracellular signal-regulated kinase (MEK)/ERK pathway5. 
MEK/ERK has been implicated in the development of fibrosis, and inhibition of this 
pathway interferes with the profibrotic response to TGFβ6.  
 
 
4. Design & Procedures:  
 
A Phase 2, pilot, proof-of-concept, open label, single arm prospective study to assess 
the safety, tolerability and efficacy of using crisaborole 2% ointment for adult morphea. 
We will recruit 20 adult (>=18 years of age) patients with morphea.  
 
Patients will be recruited from the Duke University Dermatology Autoimmune Disease 
Clinic. In addition, patients will also be recruited from the entire Duke System, and from 
community and academic dermatology practices.  
 

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Patients will be identified by their physician, nurse, or other member of their clinical care 
team. Upon notification by the primary team, the study team will approach patients to 
discuss the study, treatment protocol, associated procedures and obtain informed 
consent. Patients who are referred from outside of Duke will have to obtain a Duke 
Medical Record Number (MRN).  
 
Treatment: 
 
Patients will be asked to apply crisaborole 2% ointment, twice daily, on affected plaques 
for 12 weeks.  
 
Medication will be provided free of charge by Pfizer, as part of the grant that is funding 
this study. These will be dispensed by the study group at baseline and during the 
subsequent clinic visits.  
 
Skin punch biopsy of sentinel plaque: 
 
A sentinel plaque will be selected at baseline. A 4 mm skin punch biopsy will be 
performed at baseline and at 12 weeks, on the same affected plaque. 
 
If a biopsy has been previously taken of the affected plaque and is available for review, 
this will be used as the baseline biopsy. Patients who drop out of the study because of 
progression of their disease or adverse effects will undergo a skin punch biopsy at the 
time of drop out.  
 
Histologic and genomic assessment of skin biopsy specimen: 
 
Each biopsy specimen will be bisected. Half will be formalin fixed and sent for histologic 
evaluation. Histologic assessment will be performed by an experienced academic  
dermatopathologist, who will be blinded to the study design. This will be performed 
within the Duke Dermatology Skin Disease Research Center (SDRC).   
 
Dermal thickness will be measured and compared before and at the end of treatment. 
 
The other half will undergo processing for Nanostring gene expression analysis. 
Specimens will be sent to the Nanostring Core Facility at the University of North Carolina 
(UNC) , de-identified except for study subject number. Gene expression analysis is 
included for future research purposes only. A Material Transfer Agreement will be 
completed and executed between Duke and UNC. MTA will be fully executed and 
uploaded into eIRB prior to any samples being sent outside of Duke. 
 
The Lineberger Cancer Center Translational Genomics Laboratory (TGL) at UNC 
provides an assortment of analysis services employing the NanostringTM nCounter 
platform. These include gene expression, miRNA expression and miRNA gene 
expression copy number variation analysis, single gene expression, incRNA expression, 
Chip-String and RNA-Protein profiling. NanostringTM supplies custom and off-the-shelf 
assays for various groups of target genes including immunology, inflammation, and pan 
cancer panels offering pathway, immune and progression profiling. TGL maintains 2 
nCounter Prep Stations which can process 12 post-hybridization samples every 3 hours. 
A generation 2 nCounter digital analyzer can sequentially scan up to 6 cartridges of 12 
samples each with a maximum resolution scan requiring approximately 5 hours per 

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cartridge. Data is provided to the client electronically for analysis using the NSolver v. 
3.0 software provided by NanostringTM. LCCC Bioinformatics can also provide Nano 
NanostringTM string analysis services. TGL employs 4 trained specialists experienced in 
assorted types of NanostringTM assays. 
 
All sample information and metrics are recorded and maintained in the gPATH Lab 
Information Management System (LIMS) designed and maintained by LCCC 
Bioinformatics. 
 
To distinguish gene expression profiles in a sample enriched for keratinocytes, the 
epidermis and dermis will be separated using a previously described protocol that allows 
for high quality RNA extraction7. Total RNA will be isolated from epidermal and dermal 
portions of each biopsy specimen. RNA will be hybridized to a custom made kit based 
on the nCounter Human Kinase Gene Expression Code Kit (which includes 519 color-
barcoded human kinase genes) with additional genes that screen for innate and 
adaptive immune response. After washing and cleaning, the sample cartridges will be 
read in the nCounter SPRINT analyzer which allows automated data collection for up to 
24 samples in one day.  
 
Skin sections from the unaffected individuals will be used as control. These are obtained 
from an IRB exempt protocol that allows us to utilize normal skin from unidentified, 
healthy donors (Pro00012656, Access to anonymous and de-identified samples).  
 
Genes that show more than 3-fold differences between lesional and non-lesional or 
normal skin, and between baseline and at 12 weeks, will be analyzed using gene 
function-based analysis tools such as GeneSpring, and grouped into the categories of 
cell signaling, structure, cell cycle, survival, and inflammation, as described in our 
previous studies4,8.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Retention of data and samples for future research: 
 
With subject agreement, subject samples and data obtained during this research study 
will be retained for future research under previously established bio and data 
repositories. This retention of samples will require separate subject consent to 
Pro00006230 and Pro00006313. 
 
Clinical assessment 

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Patients will have a clinical assessment at baseline and at weeks 4, 8 and 12. After 
week 12, patients who need further treatment will undergo standard of care treatment as 
determined by their primary dermatologist. An optional post treatment follow-up will be 
performed at week 20.  
 
Physician and patient reported assessment and skin imaging will be performed at 
baseline, week 4, 8 and 12, and at week 20. Photography will also be performed at 
baseline and week 12.  
 
Physician assessment will utilize two previously described and validated scoring metrics. 
The sentinel plaque will be evaluated using Dyspigmentation, Induration, Erythema, and 
Telangiectasias (DIET) score9. Overall disease severity will be evaluated using the 
Localized Scleroderma Cutaneous Assessment Tool (LoSCAT)10.    
 
Health-related quality of life (HRQOL) will be measured using Skindex-2911 which has 
previously been applied to morphea12, and has a pruritus component.  
 
Photographs will be taken using a standardized clinic camera. 
 
B-Mode ultrasonographic imaging will be utilized to measure dermal thickness of the 
sentinel plaque at baseline, week 4, 8 and 12 and post-treatment at week 20.  
 
 
 
 
Summary of Clinical Trial Design 
 
  
Baseline 
Week 4 
Week 8 
Week 
12 
Week 
16 
Week 
20 
Crisaborole 2% ointment 
twice daily 
x 
x 
x 
x 
  
  
Clinic visit 
x 
x 
x 
x 
  
x 
LoSCAT scoring 
x 
x 
x 
x 
  
x 
DIET scoring 
x 
x 
x 
x 
  
x 
Skin punch biopsy 
x 
  
  
x 
  
Urine HCG 
x 
x 
x 
x 
  
  
Skindex 29 
x 
x 
x 
x 
  
x 
Skin imaging (ultrasound) 
x 
x 
x 
x 
  
x 
Photography 
x 
  
  
x 
  
x 
 
 
 
Primary outcome measure is the change in dermal thickness on skin biopsy at 12 
weeks. 
 
 
Secondary outcome measures are the following: 
• 
Change in DIET score of sentinel plaque at 4, 8 and 12 weeks. 

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• 
Change in LoSCAT score at 4, 8 and 12 weeks. 
• 
Skindex-29 at 4, 8 and 12 weeks.  
• 
Change in dermal thickness of sentinel plaque by ultrasonography at 4, 8 and 12 
weeks  
 
 
5.  Selection of Subjects: 
 
Inclusion criteria 
Subjects eligible for inclusion in this study must fulfill all of the following criteria: 
1. 
>= 18 years of age 
2. 
Clinical diagnosis of morphea. 
3. 
<20% Total body surface area involvement. 
4. 
Does not require systemic immunosuppressive therapy for morphea. 
5. 
No changes (additions, subtractions, or dose modifications) in 
immunosuppressive systemic therapy 2 months prior to starting the study 
(hydroxychloroquine, methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, 
cyclophosphamide, prednisone >=10 mg PO daily). 
6. 
No immunomodulating topical therapy (topical steroids or topical calcineurin 
inhibitor), and no topical vitamin D analogue, 2 weeks prior to starting study. 
7. 
No allergy to crisaborole or vehicle.  
8. 
No known renal disease 
9. 
Able to give informed consent. 
 
 
Exclusion Criteria 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. 
1. 
Clinical diagnosis of depression or history of suicidal ideation. 
2. 
Pregnant or breastfeeding women, with pregnant women being defined as the 
state of a female after conception until the termination of gestation, confirmed by a 
positive urine human chorionic gonadotropin (hCG) laboratory test. Women with a 
positive urine hCG at any time during the study will be withdrawn from the study.  
.  
 
6. Subject Recruitment & Compensation: 
 
Patients will be recruited from the Duke Dermatology Outpatient Clinic, including patients 
referred from Rheumatology for evaluation of morphea. We may also contact 
dermatologists in the community (within North Carolina), UNC Dermatology, Wake Forest 
Dermatology and the Durham VA Medical Center, via email and letter, to make them 
aware of our study so they can refer patients. Prior to any recruiting outside the Duke 
Derm Autoimmune clinics, we will seek approval for any flyers that are used in recruitment 
and provide a phone script for those who respond to flyers.  
  
Patients will be given compensation to cover travel expenses as part of their 
participation in the study, amounting to $50 per visit, or a maximum of $250. A gift card 
worth $50 will be given at baseline, week 4, week 8 and week 12. A final $50 gift card 
will be given at the optional week 20 visit, should they choose to participate in it.  

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7.  Consent Process – see Section 14 of the e-IRB submission form. 
 
8.  Subject’s Capacity to Give Legally Effective Consent: 
Subjects must be able to provide consent. Legal representatives will not be used.  
 
9.  Study Interventions: 
Subjects will be asked to apply crisaborole 2% ointment, twice daily, on affected plaques 
for 12 weeks. 
 
10. Risk/Benefit Assessment and Safety Considerations: 
If a subject agrees to take part in this study, there may not be a direct medical benefit to 
them. The subject’s morphea may improve from using the investigational drug in this 
study. It is also possible that a subject’s condition will not improve on the investigational 
drug. 
 
The pharmacokinetics of crisaborole as a topical medication have previously been 
studied13. Crisaborole is metabolized to inactive metabolites upon absorption, making it 
both a safe option for therapy even in relatively extensive disease. There was minimal 
systemic effect of crisaborole ointment when applied twice daily for 28 days, over up to 
35% body surface area, in children 2-17 years or age. Long term studies in adults and 
children with mild to moderate atopic dermatitis for as long as 48 weeks have also 
shown a low frequency of side effects14. The most frequently reported treatment-related 
AEs (overall, 10.2%) were worsening of pre-existing atopic dermatitis (3.1%), 
application-site pain (2.3%), and application-site infection (1.2%). The FDA monograph 
of crisaborole does not state any requirement for monitoring.  
 
The risks for obtaining skin biopsy samples include a mild amount of pain, bruising, 
bleeding, or infection at the site of the puncture. Subjects will be instructed in proper 
wound care to minimize these risks. Subjects may experience scarring at the site of 
biopsy.   
 
 
11. Costs to the Subject: 
There will be no additional costs to the subjects as a result of being in this study. However, 
routine medical care for their disease will be charged to them or their insurance company.  
 
12. Data Analysis & Statistical Considerations: 
We will aim to recruit 20 patients in the study. We anticipate to see a 30% decrease in 
dermal thickness at 12 weeks compared to baseline, using histologic evaluation of skin 
punch biopsy specimens.  Using measurements of dermal thickness that we obtained 
from our archived morphea skin biopsies, we estimated that we need 11 patients to 
detect 30% change in dermal thickness with a power of 0.80 and an alpha of 0.05. The 
goal to recruit 20 patients allows for possible drop-outs, while still allowing us to perform 
statistically significant analysis.  

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Women and minority volunteers will be encouraged to enroll, but no formal subgroup 
accrual goals are planned.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. 
 
 
 
 
 
 
 
Months 1-6 
Months 7-12 
Months 13-18 
Months 19-24 
Subject recruitment (1-2 patients per month), clinical and objective assessment, 
collection of biopsies 
Genomic profiling, data 
interpretation and 
analysis, and paper 
writing. 
 
 
13. Data & Safety Monitoring:  
Subjects will be assigned unique study numbers. The data related to this study will be 
kept in locked files and an electronic password protected database maintained by the 
Department of Dermatology research offices. Only unique study numbers but not DUMC 
history numbers will be supplied as subject IDs for data maintenance and statistical 
analysis purposes to comply with HIPAA regulations. This study will have routine 
auditing consistent with Duke Clinical Research Institute and NIH oversights. Subject 
confidentiality will be maintained. 
 

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All samples will be stored and maintained through the conclusion of the study and then 
destroyed, unless the subjects agree (and separately consent) to the Samples and Data 
being included in the Duke Autoimmune Serum Tissue Bank (Pro00006313) and Duke 
Immune Mediated Skin Disease Database (Pro00006230).  
 
This clinical research study will be monitored both internally by the PI and externally by 
the Duke University Medical Center in accord with their NIH- approved “Institutional 
Protocol Monitoring Procedures and Guidelines for NIH-Sponsored Research Involving 
Human Subjects.” 
 
14. Privacy, Data Storage & Confidentiality – see Section 12 of the e-IRB 
submission form. 
 
 

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Milara J, Morcillo E, Monleon D, Tenor H, Cortijo J. Roflumilast Prevents the 
Metabolic Effects of Bleomycin-Induced Fibrosis in a Murine Model. PLoS One. 
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2. 
Maier C, Ramming A, Bergmann C, et al. Inhibition of phosphodiesterase 4 (PDE4) 
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macrophages. Ann Rheum Dis. 2017. 
3. 
Schafer PH, Truzzi F, Parton A, et al. Phosphodiesterase 4 in inflammatory 
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Zhang X, Luo S, Wu J, et al. KIND1 Loss Sensitizes Keratinocytes to UV-Induced 
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Dytoc M, Wat H, Cheung-Lee M, Sawyer D, Ackerman T, Fiorillo L. Evaluation of 
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13. Zane LT, Kircik L, Call R, et al. Crisaborole Topical Ointment, 2% in Patients Ages 
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