Conditions: Necrobiosis Lipoidica
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 12
Healthy volunteers: no

Brief summary:
This is an open-label study that will evaluate the safety of PCS499 for the treatment of necrobiosis lipoidica (NL) and will inform the design of future studies. Approximately 12 NL patients (6-9 patients without ulceration and 3-6 patients with ulceration) who also meet other inclusion/exclusion criteria will be enrolled in the study. The primary objective of this study is to evaluate the safety and tolerability profile of PCS499 in patients with Necrobiosis Lipoidica.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: PCS499
Intervention descriptions: intervention 1: PCS499 900mg twice a day with food

Protocol document:
Prot_000.pdf: 
Protocol PCS499-NL01 
Date:  02 November 2018 
CONFIDENTIAL 
1 
1.
TITLE PAGE
PCS499 
PHASE 2 PROTOCOL 
PCS499-NL01 
An Open-Label Study to Evaluate the Safety and Tolerability of PCS499 for the 
treatment of Necrobiosis Lipoidica 
VERSION 2.0 DATE:  02 November 2018 
The Sponsor is Processa Pharmaceuticals, Inc. 
7380 Coca Cola Drive, Suite 106 
Hanover, MD 21076 
Any and all information presented in this document shall be treated as 
confidential and remain the exclusive property of Processa Pharmaceuticals.  
The use of such confidential information should be restricted to the intended 
recipient for the agreed purpose and must not be disclosed, published, or 
otherwise communicated to any unauthorized persons, for any reasons, in any 
form whatsoever without the prior written consent of Processa Pharmaceuticals, 
its affiliates, or authorized representatives. 
NCT03698864




Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
3 
3. 
STUDY CONTACT 
Clinical Study Leaders 
Address and Telephone Number 
Melissa Vrabel 
Project Leader 
Integrium, LLC® 
14351 Myford Road, Suite A 
Tustin, CA 92780 
(Tel) 714 210 6654 
(Fax) 714-210-6654 
(email) melissa.vrabel@integrium.com 
Carmen Margaritescu, MD 
Medical Director 
 
Integrium, LLC® 
14351 Myford Road, Suite A 
Tustin, CA 92780 
(Tel) 714 210 6665 
(Fax) 714-617-2368 
(email) carmen.margaritescu@integrium.com 
Maya Das 
Vice President, Clinical Research  
Processa Pharmaceuticals 
7380 Coca Cola Drive, Suite 106 
Hanover, MD  21076 
(Tel) 240-812-1750   
(Fax) 443-288-4420 
(e-mail) mdas@processapharmaceuticals.com 
Mary Nyberg 
Sr. Director, Clinical Operations 
 
Processa Pharmaceuticals 
7380 Coca Cola Drive, Suite 106 
Hanover, MD  21076 
(Tel) 443-341-7073 
(Fax) 443-288-4420 
(e-mail) mnyberg@processapharmaceuticals.com 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
4 
4. 
SYNOPSIS 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
Title of Study: An Open-Label Study to Evaluate the Safety and Tolerability of PCS499 for 
the treatment of Necrobiosis Lipoidica  
Study center(s): Approximately 4 centers in the US 
Studied period (years):  
Estimated date first patient enrolls:  To Be Determined 
Estimated date last patient enrolls:  To Be Determined 
Estimated date last patient completes 1 year of treatment:  To Be 
Determined  
Phase of  
development: 2 
OBJECTIVES: 
Primary Objective: 
To evaluate the safety and tolerability profile of PCS499 in patients with Necrobiosis 
Lipoidica 
 
 
Exploratory Objectives: 
To evaluate the efficacy of PCS499 on reducing clinical findings related to Necrobiosis 
Lipoidica  
To assess the pharmacodynamic activity of PCS499 on immunologic and inflammatory 
biomarkers 
 
Methodology:   
This is an open-label study that will evaluate the safety of PCS499 for the treatment of 
necrobiosis lipoidica (NL) and will inform the design of future studies.  Based on previous 
experience with PCS499, a 1200 mg daily dose administered as 600 mg BID was well-
tolerated in a study of patients with diabetic nephropathy, but had limited efficacy.  A recent 
Phase 1 study in healthy volunteers found that daily doses of 1800 mg administered as 900 
mg BID or 600 mg TID of PCS499 were safe and well tolerated.       
The study will consist of a 6 month treatment period followed by a 6 month extension period.   
Approximately 12 NL patients (6-9 patients without ulceration and 3-6 patients with 
ulceration) who also meet other inclusion/exclusion criteria will be enrolled in the study.  
Patients will be administered PCS499 900 mg BID.  Primary safety and exploratory efficacy 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
5 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
analysis will be performed after the last patient completes the 6-month visit. Patients will 
have the option to continue dosing in an extension period for up to an additional 6 months.   
All patients will take PCS499 300 mg BID with food for 1 week.  Beginning at Week 2, 
patients will commence administration of twice daily dosing of three PCS499 300 mg tablets 
(900 mg BID) with food.  Patients will continue at their assigned dose for the remainder of 
the study.   
During the dosing period, if a patient receiving PCS499 900 mg BID experiences 
unacceptable toxicity (i.e., non-transient, moderate to severe limitation in activity) that is 
deemed by the Investigator to be related to study drug, his/her dose will be changed to 
PCS499 600 mg TID with food at the discretion of the Investigator in consultation with the 
Medical Monitor.  If this dose is not tolerated, the dose will be further reduced to PCS499 
600 mg BID with food at the discretion of the Investigator in consultation with the Medical 
Monitor.  If 4 out of the first 6 patients dosed in this study require dose modification or 
discontinue from the study due to a drug-related adverse event within 1 month of dosing, 
consideration will be made to change the starting dose to 600 mg TID with food for all 
subsequent patients.  Efficacy and safety data will be collected at regular intervals throughout 
the course of the study.   
An analysis will be conducted to assess safety and exploratory efficacy after the last patient 
completes the 6-month visit.  A final analysis of patients enrolled in the study will be 
conducted after the last patient completes the 12-month visit.  
 
Number of patients (planned):  
• Total number enrolled into this open label study:  ~12 NL patients  
− 6-9 without ulcerations and 3-6 with ulcerations 
Diagnosis and Main criteria for Eligibility: 
Inclusion criteria: 
1. Male or female patients age 18 to 80 years of age, inclusive, at Screening. 
2. Biopsy-confirmed diagnosis of NL.  Biopsies of continually active lesions performed 
outside of this clinical study will need to be reviewed and the diagnosis confirmed by 
the study pathologist.  For patients with no previous history of biopsy, no biopsy 
within the previous 5 years, a biopsy that is not confirmed to be NL, or newly active 
lesion, a biopsy to confirm a diagnosis of NL will be performed at the Screening visit.   


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
6 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
3. Reference NL lesion with a score of 2 or greater on the IGA:NL Activity scale AND 
surface area with minimum size of 10 cm2.  If more than one lesion is present, the 
reference lesion area is the lesion with the highest disease severity. 
4. Women of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at Baseline before dosing. 
5. Women of childbearing potential must use one of the following acceptable methods 
of contraception throughout the study: oral contraceptive medication, intrauterine 
device (IUD), hormonal implants, injectable contraceptive medications, double-
barrier methods, or tubal ligation. 
6. Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months 
and increased follicle-stimulating hormone [FSH] > 40 mIU/mL. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening) or who have 
undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy 
testing. 
7. Male patients must be willing to use appropriate contraceptive measures and refrain 
from sexual activity with any female who is pregnant or lactating. 
8. Patient must be willing and able to swallow whole tablets. 
9. Patient must be willing and able to comply with study procedures. 
10. Patient must be willing and able to provide signed, informed consent. 
Exclusion criteria: 
1. Current or previous (within 4 weeks of Baseline) treatment with: 
a. Oral, topical, or intralesional corticosteroids; 
b. Systemic pentoxifylline, theophylline, or cilostazol 
c. Oral or topical retinoid; 
d. Other systemic or topical immunosuppressant drugs, including but not limited to 
calcineurin inhibitors (e.g., tacrolimus), thalidomide, apremilast, anti-malarials 
(e.g., hydroxychloroquine, chloroquine), cyclosporine, mycophenolate mofetil, 
azathioprine, methotrexate, etc.   
2. Current or previous (within 12 weeks of Baseline) treatment with any biologic 
therapy (e.g., adalimumab, etanercept, infliximab, anakinra, etc.).  
3. Phototherapy/photochemotherapy (NBUVB, UVB, PUVA) within 6 weeks prior to 
Baseline. 
4. Skin grafting, or other surgical procedure (other than debridement) within 6 weeks 
prior to Baseline. 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
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Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
5. History of drug allergy, including but not limited to pentoxifylline or other xanthine 
derivatives, or other allergy, which in the opinion of the Investigator, contraindicates 
participation. 
6. Anticipated concurrent use of a strong CYP1A2 inhibiting drug, including but not 
limited to cimetidine and/or fluvoxamine, during the course of the study (after 
Screening). 
7. Fever (>38°C), or chronic, persistent, or recurring infection(s) at Screening or 
Baseline. 
8. Any infection requiring oral antimicrobial therapy within 2 weeks prior to Baseline 
and/or any infection requiring parenteral antibiotics or hospitalization within 12 
weeks prior to Baseline.  Any treatment for such infections must have been completed 
and the infection cured for at least 2 weeks prior to Baseline. 
9. History of sarcoidosis, pyoderma gangrenosum, or any other disorder (in the 
judgment of the Investigator) that would interfere with the evaluation of NL or 
require protocol prohibited medication.    
10. History of any life threatening infection or sepsis within 12 months of Baseline. 
11. Clinically significant cardiac disease including but not limited to unstable angina, 
acute myocardial infarction within 6 months of Baseline, and arrhythmia requiring 
therapy. 
12. Patient has QTc interval ≥ 480 milliseconds on Screening ECG; a second Screening 
ECG may be done at investigator’s discretion but the average of the two QTc 
screening intervals must not be ≥ 480 milliseconds. 
13. History of cerebral hemorrhage, cerebrovascular accident, transient ischemic attack, 
gastrointestinal bleeding, or retinal hemorrhage within 6 months of Baseline. 
14. Patient has active or history of neoplastic disease (except for adequately treated non-
invasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the cervix) 
within the past 5 years prior to Baseline. 
15. Presence of clinically significant medical condition(s) including but not limited to: 
renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, 
neurological, psychiatric, substance abuse, and/or any other clinically significant 
disease or disorder, which in the opinion of the Investigator (by its nature or by being 
inadequately controlled), may put the patient at risk due to participation in the study, 
influence the results of the study, and/or affect the patient’s ability to complete the 
study. 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
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Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
16. History of or current diagnosis of active tuberculosis (TB); undergoing treatment for 
latent TB infection (LTBI); untreated LTBI (as determined by documented results 
within 3 months of the Screening Visit of a positive TB skin test with purified protein 
derivative with induration >= 5 millimeter (mm), a positive QuantiFERON-TB test or 
positive or borderline T-SPOT [Elispot] test); or positive TB test at Screening. 
Subjects with documented completion of appropriate LTBI treatment would not be 
excluded and are not required to be tested. 
17. Vaccination with live or live-attenuated virus vaccine within 1 month prior to 
Baseline. 
18. The results of the following laboratory tests performed at the central laboratory at 
Screening meet any of the criteria below: 
a. Hemoglobin < 8.0 g/dL (International System of Units (SI): < 80 g/L); 
b. White blood cells < 3.0 x 10^3 cells/mm^3 (SI: < 3.0 x 10^9 cells/L); 
c. Neutrophils < 1.0 x 10^3 cells/mm^3 (SI: < 1.0 x 10^9 cells/L); 
d. Lymphocytes < 0.5 x 10^3 cells/mm^3 (SI: < 0.5 x 10^9 cells/L); 
e. Platelets < 100 x 10^3 cells/mm^3 (SI: < 100 x 10^9 cells/L) 
f. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or 
alkaline phosphatase (ALP) ≥ 2 x upper limit of normal (ULN); 
g. Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with 
Gilbert's disease and this is clearly documented; 
h. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 based on the 
Modification of Diet in Renal Disease (MDRD) formula. 
i. Positive HIV serology  
j. Evidence of active Hepatitis B Virus (HBV) infection  
k. Evidence of active Hepatitis C Virus (HCV) infection 
19. Women who are pregnant or breastfeeding. 
20. Patient unwilling or unable to swallow tablets whole. 
21. Any other medical condition, serious intercurrent illness, or extenuating circumstance 
that, in the opinion of the Investigator, would preclude participation in the study. 
22. Use of any investigational product within 30 days prior to Baseline or currently 
enrolled in another study that involves clinical investigations. 
Investigational product, dosage and mode of administration  
Patients will take tablets twice daily by mouth with food.   


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
9 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
 
 
Group 
Dosage Forms 
PCS499 900 mg BID 
3 x PCS499 300 mg tablets  
Criteria for Evaluation: 
Safety: 
• Adverse Events (AEs) (by type, severity, and relatedness) at each visit. 
• Changes in safety clinical laboratory testing and vital signs at each visit. 
• Changes in electrocardiograms (ECGs) at Months 1, 3, 6, 9, and 12. 
Exploratory Efficacy: 
• Proportion of patients with scores of clear or almost clear (0 or 1) of the reference 
lesion on the Investigator Global Assessment: NL (IGA:NL) Activity Scale at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 1 point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 2 point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12 
• Proportion of patients with ≥ 1 point decrease in the Color score on the 
Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Physician Global Assessment (PGA) score at Months 1, 
2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on Investigator measurement at Months 1, 2, 3, 4, 
5, 6, 9, and 12. 
• Percent change from Baseline in total lesion(s) surface area of 
inflammation/erythema based on Investigator measurement at Months 1, 2, 3, 4, 
5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on photograph at Months 1, 2, 3, 4, 5, 6, 9, and 12. 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
10 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
• Change from Baseline in Dermatology Quality of Life Index (DLQI) score at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change form Baseline in Skindex-29 score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Patient Global Assessment (PtGA) visual analog scale 
(VAS) score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to obtaining scores of clear or almost clear (0 or 1) of reference lesion on 
the IGA:NL Activity scale. 
• Incidence of new ulceration (defined as a site with no previous ulceration) at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to new ulceration. 
Patients with ulceration at Baseline only: 
• Proportion of patients with ≥ 1 point decrease in the Ulcer score on the 
Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference ulcer surface area based on 
Investigator measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Percent change from Baseline in total ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Percent change from Baseline in reference ulcer surface area based on photograph 
at Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Incidence of complete wound closure of reference ulcer (defined as skin re-
epithelialization without draining or dressing requirements confirmed at two 
consecutive study visits at least 2 weeks apart) at Months 2, 3, 4, 5, 6, 9, and 12. 
• Time to complete wound closure of reference ulcer. 
• Incidence of recurrence of reference ulcer after complete wound closure at 
Months 3, 4, 5, 6, 9, and 12. 
• Time to recurrence of reference ulcer after complete wound closure. 
• Change from Baseline in reference ulcer volume based on 3D scanning at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
 
 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
11 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
Exploratory Serum Biomarkers:  
• Change from baseline in TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and MCP-1 at 
Months 1, 3, 6, 9 and 12. 
• Change from baseline in C-peptide levels at Months 1, 3, 6, 9 and 12.  
 
STATISTICAL ANALYSES: 
Analysis Populations: 
Patients will be analyzed by assigned treatment group.  Analyses will be performed based on 
observed data, and missing values will not be imputed unless otherwise stated. 
• Safety Population:  Defined as all patients enrolled in the study who received at 
least 1 dose of treatment.  
• Efficacy Population (Modified Intent to Treat (mITT)):  Defined as all patients 
enrolled in the study who received at least 1 dose of treatment and has at least 1 
post-baseline efficacy assessment.    
• Per-Protocol Population:  Defined as a subset of the Efficacy Population who did 
not have a major protocol violation as defined in the Statistical Analysis Plan. 
• Biomarker Population:  Defined as all patients enrolled in the study who received 
at least 1 dose of treatment, participated in biomarker evaluations, and have 
appropriate samples available for analysis.    
Timing of Analyses: 
All endpoints will be analyzed after the last patient completes the 3-month visit and the 6- 
month visit (primary).  A final lock of the database and the final analyses will occur after the 
last patient completes the 12-month visit. 
Patient Characteristics: 
Baseline demographics and disease characteristics will be presented for each treatment group 
by descriptive statistics as well as for the combined active groups. All descriptive summary 
statistics of continuous variables will include: n, mean, median, standard deviation, minimum 
and maximum. All descriptive summaries presenting frequencies and incidences will include 
n, % and N, where N is the total number of patients with recorded values in the 
corresponding group.  Patient completion status and exposure outcomes will be similarly 
presented.   
 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
12 
Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
Safety Analyses: 
The safety analyses will be performed using the Safety Population and include adverse 
events, changes in physical exam findings, vital signs, and clinical laboratory values.   
Adverse events will be coded using the current version of the Medical Dictionary for 
Regulatory Activities (MedDRA version 21.0 or higher).  The number and percent of patients 
reporting at least one adverse event will be summarized by System Organ Class (SOC) and 
Preferred Term (PT) and presented by dose level, severity, relationship to study drug, amount 
of drug exposure, and time. Each patient will contribute only once (i.e., first occurrence) to 
each of the incidence rates, regardless of the number of occurrences. For reporting of adverse 
event severity in patients with more than one occurrence of the same adverse event, the 
patient will only be reported once based on the highest severity of the adverse event 
observed. Patients who have a serious adverse event (SAE) or who discontinue the study due 
to an adverse event deemed to be related to study drug will be described in patient narratives.   
Vital signs, clinical laboratory, and ECG results will also be presented and summarized by 
dose level and summarized by descriptive statistics with change from Baseline values 
calculated.  All safety data collected in the clinical database, including physical exam 
findings and abnormal ECG results, will be presented in data listings.   
Efficacy Analyses: 
Efficacy analyses will be performed using the Efficacy (mITT) Population.  Efficacy 
endpoints will be summarized by descriptive statistics for each treatment group and by 
ulceration status. All descriptive summary statistics of continuous variables will include: n, 
mean, median, standard deviation, minimum and maximum. All descriptive summaries 
presenting frequencies and incidences will include n, % and N, where N is the total number 
of patients with recorded values in the corresponding group.  Graphical representations will 
be presented, if appropriate.  Efficacy data will also be presented in listings to assess changes 
within patients over time.   
Exploratory Analyses: 
Depending on the extent of the data, additional exploratory analyses may be performed to 
characterize relationships among variables, such as correlations among variables and 
trending, as well as further sub-group analyses, such as based on diabetic status and study 
completion status.  Additional sensitivity analyses may include comparisons between 
observed values and imputed values for missing data using different methods (e.g., multiple 
imputation, last observation carried forward (LOCF).       
 
 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
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Name of Sponsor/Company: Processa Pharmaceuticals, Inc. 
Name of Investigational Product: PCS499 
Name of Active Ingredient: PCS499 
Biomarker Analyses: 
Analyses will be performed using the Biomarker Population.  Biomarkers will be evaluated 
to assess changes within patients over time.  Additional exploratory analyses may be 
performed depending on the extent of the data using appropriate statistical methods. 
 
SAMPLE SIZE CALCULATION: 
As this is a pilot study, no formal sample size calculation was performed. 
 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
14 
5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
INVESTIGATOR PROTOCOL AGREEMENT .........................................................2 
3. 
STUDY CONTACT .....................................................................................................3 
4. 
SYNOPSIS ...................................................................................................................4 
5. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............14 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF TABLES .........................................................................................................................18 
LIST OF FIGURES .......................................................................................................................19 
6. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
7. 
INTRODUCTION ......................................................................................................23 
7.1. 
Background Information .............................................................................................23 
7.2. 
Preclinical Data ...........................................................................................................23 
7.3. 
Clinical Data Summary ...............................................................................................24 
7.3.1. 
Previous Phase 1 and 2 Studies ..................................................................................24 
7.4. 
Dose Rationale ............................................................................................................25 
7.5. 
Study Rationale ...........................................................................................................25 
8. 
STUDY OBJECTIVES AND PURPOSE ..................................................................27 
8.1. 
Objectives ...................................................................................................................27 
9. 
INVESTIGATIONAL PLAN .....................................................................................28 
9.1. 
Overall Study Design and Plan: Description ..............................................................28 
9.2. 
Detailed Description of Study Visits ..........................................................................28 
9.2.1. 
Screening Visit (Day -28 to Day -1, Clinic Visit) ......................................................28 
9.2.2. 
Open-Label Study .......................................................................................................29 
9.2.2.1. 
Day 0 (Baseline Visit) ................................................................................................29 
9.2.2.2. 
Day 7 and Day 14 (Phone Checks, +/- 1 day) ............................................................30 
9.2.2.3. 
Day 28/Month 1 (Clinic Visit, +/- 3 days) ..................................................................30 
9.2.2.4. 
Day 60/Month 2 (Clinic Visit, +/- 7 days) ..................................................................31 
9.2.2.5. 
Day 90/Month 3 (Clinic Visit, +/- 7 days) ..................................................................32 
9.2.2.6. 
Day 120/Month 4 (Clinic Visit, +/- 7 days) ................................................................32 


Protocol PCS499-NL01 
 
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15 
9.2.2.7. 
Day 150/Month 5 (Clinic Visit, +/- 7 days) ................................................................33 
9.2.2.8. 
Day 180/Month 6 (Clinic Visit, +/- 7 days) ................................................................34 
9.2.3. 
Extension Period .........................................................................................................34 
9.2.3.1. 
Day 270/Month 9 (Clinic Visit, +/- 10 days) ..............................................................34 
9.2.3.2. 
Day 360/Month 12 (Clinic Visit, +/- 10 days) ............................................................35 
9.2.3.3. 
Early Discontinuation from Study Drug (Clinic Visit)...............................................36 
9.2.3.4. 
Unscheduled Visits .....................................................................................................37 
9.2.4. 
Schedule of Events .....................................................................................................37 
9.3. 
Number of Subjects ....................................................................................................40 
9.4. 
Treatment Assignment ................................................................................................40 
10. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................41 
10.1. 
Patient Inclusion Criteria ............................................................................................41 
10.2. 
Patient Exclusion Criteria ...........................................................................................41 
10.3. 
Patient Withdrawal Criteria ........................................................................................43 
11. 
TREATMENT OF PATIENTS ..................................................................................45 
11.1. 
Description of Study Drug ..........................................................................................45 
11.2. 
Concomitant Medications ...........................................................................................45 
11.3. 
Treatment Compliance ................................................................................................46 
11.4. 
Randomization and Blinding ......................................................................................46 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................47 
12.1. 
Study Drug ..................................................................................................................47 
12.2. 
Study Drug Packaging and Labeling ..........................................................................47 
12.3. 
Study Drug Storage .....................................................................................................47 
12.4. 
Study Drug Preparation ..............................................................................................47 
12.5. 
Administration ............................................................................................................47 
12.6. 
Study Drug Accountability .........................................................................................48 
12.7. 
Study Drug Handling and Disposal ............................................................................48 
13. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ...................49 
14. 
ASSESSMENT OF EXPLORATORY EFFICACY ..................................................50 
14.1. 
Exploratory Efficacy Variables ..................................................................................50 
14.1.1. 
Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) ...........................50 
14.1.2. 
Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) ............................................51 
14.1.3. 
Physician Global Assessment (PGA) .........................................................................52 


Protocol PCS499-NL01 
 
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16 
14.1.4. 
Lesion/ulcer surface area ............................................................................................52 
14.1.5. 
Dermatology Quality of Life Index (DLQI) ...............................................................52 
14.1.6. 
Skindex-29 ..................................................................................................................52 
14.1.7. 
Patient Global Assessm/ent (PtGA) ............................................................................53 
14.1.8. 
Exploratory Efficacy Variables in Ulcerated Patients ................................................53 
14.1.8.1. 
Closure of reference ulcer ...........................................................................................53 
14.1.8.2. 
Ulcer volume ..............................................................................................................53 
14.2. 
Biomarkers ..................................................................................................................53 
15. 
ASSESSMENT OF SAFETY .....................................................................................54 
15.1. 
Safety Parameters .......................................................................................................54 
15.1.1. 
Vital Signs, Height, Weight, and Body Mass Index ...................................................54 
15.1.2. 
Physical Examination .................................................................................................54 
15.1.3. 
Electrocardiogram .......................................................................................................54 
15.1.4. 
Clinical Laboratory Assessments ...............................................................................54 
15.1.4.1. 
Pregnancy Testing ......................................................................................................54 
15.1.5. 
Concomitant Medications ...........................................................................................54 
15.2. 
Adverse Events and Reporting Procedures .................................................................55 
15.2.1. 
Adverse Event Definition and Collection ...................................................................55 
15.2.2. 
Categorizing Adverse Events in Relation to Study Phase ..........................................55 
15.2.3. 
Assigning Severity to Adverse Events .......................................................................56 
15.2.4. 
Serious Adverse Event Definition and Collection ......................................................56 
16. 
ENDPOINTS ..............................................................................................................58 
16.1. 
Primary Safety Endpoints ...........................................................................................58 
16.2. 
Exploratory Efficacy Endpoints .................................................................................58 
16.3. 
Exploratory Serum Biomarkers ..................................................................................59 
17. 
STATISTICAL METHODOLOGY ...........................................................................60 
17.1. 
Sample Size Determination ........................................................................................60 
17.2. 
General Statistical Methods ........................................................................................60 
17.3. 
Analysis Populations ..................................................................................................60 
17.4. 
Patient Characteristics ................................................................................................60 
17.5. 
Safety Analysis ...........................................................................................................60 
17.5.1. 
Adverse Events ...........................................................................................................60 
17.5.2. 
Other Safety Analyses ................................................................................................61 


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17.6. 
Efficacy Analysis ........................................................................................................61 
17.7. 
Biomarkers ..................................................................................................................61 
17.8. 
Exploratory Associations among Outcomes ...............................................................61 
18. 
SAMPLE COLLECTION ..........................................................................................62 
18.1. 
Biomarker Sample Collection .....................................................................................62 
18.2. 
Biomarker Sample Storage and Shipping ...................................................................62 
19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................63 
19.1. 
Study Monitoring ........................................................................................................63 
19.2. 
Sponsor’s Responsibility ............................................................................................63 
19.3. 
Audits and Inspections ................................................................................................63 
19.4. 
Institutional Review Board (IRB) ...............................................................................64 
19.5. 
Criteria for Study Termination ...................................................................................64 
19.5.1. 
Sponsor Termination ..................................................................................................64 
19.5.2. 
Patient Discontinuation ...............................................................................................64 
20. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
21. 
ETHICS ......................................................................................................................66 
21.1. 
Ethics Review .............................................................................................................66 
21.2. 
Ethical Conduct of the Study ......................................................................................67 
21.3. 
Written Informed Consent ..........................................................................................67 
22. 
DATA HANDLING AND RECORDKEEPING .......................................................69 
22.1. 
Data Collection ...........................................................................................................69 
22.2. 
Case Report Form Completion ...................................................................................69 
22.3. 
Database Management, Data Clarification, and Quality Assurance ...........................69 
22.4. 
Inspection of Records/Source Documents ..................................................................70 
22.5. 
Retention of Records ..................................................................................................71 
23. 
CONFIDENTIALITY, AMENDMENTS, AND PUBLICATIONS..........................72 
23.1. 
Subject Data Protection ..............................................................................................72 
23.2. 
Study Protocol Amendments ......................................................................................73 
23.3. 
Publication ..................................................................................................................73 
24. 
REFERENCES ...........................................................................................................74 
APPENDIX A. LABORATORY ASSESSMENTS ...................................................................76 
APPENDIX B. LIST OF BIOMARKERS ..................................................................................77 
APPENDIX C. SCALES (DLQI AND SKINDEX-29) ..............................................................78 


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LIST OF TABLES 
Table 1: 
Abbreviations and Special Terms ...............................................................................20 
Table 2: 
Schedule of Events (Study PCS499-NL01) ................................................................38 
Table 3: 
IGA:NL Activity .........................................................................................................50 
Table 4: 
IGA:NL Damage ........................................................................................................50 
Table 5: 
NLCUS: Color/Inflammation .....................................................................................51 
Table 6: 
NLCUS: Induration ....................................................................................................51 
Table 7: 
NLCUS: Ulcer ............................................................................................................52 
 


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LIST OF FIGURES 
Figure 1: 
Structural Formula for PCS499 ..................................................................................45 
 


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6. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and special terms are used in this study protocol. 
Table 1: 
Abbreviations and Special Terms 
Abbreviation or Special term 
Explanation 
3D 
Three dimensional 
AE  
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
AUC  
Area under the concentration-time curve 
BID 
Twice a day 
BP 
Blood pressure 
Con med 
Concomitant medications 
CFR 
Code of Federal Regulations 
CKD 
Chronic kidney disease 
CRF 
Case report form 
CRO 
Clinical research organization  
CYP 
Cytochrome P-450 
DLQI 
Dermatology Quality of Life Index 
ECG/EKG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HbA1c 
Glycosylated hemoglobin 
HBV 
Hepatitis B virus 
HCV  
Hepatitis C virus  
HIV 
Human immunodeficiency virus 
HPMC 
hydroxypropyl-methylcellulose 
HRQL 
Health related quality of life 


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Abbreviation or Special term 
Explanation 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGA:NL 
Investigator Global Assessment: Necrobiosis Lipoidica 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
LTBI 
Latent tuberculosis infection 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD formula 
Modification of Diet in Renal Disease formula 
mITT 
Modified Intent to Treat 
NBUVB 
Narrow Band Ultraviolet B therapy 
NL  
Necrobiosis Lipoidica 
NLCUS 
Necrobiosis Lipoidica Color and Ulcer Scale 
PCS499 
(S)-1-(4,4,6,6,6-pentadeutero-5-hydroxyhexyl)-3,7-
dimethyl-1H-purine-2,6(3H,7H)-dione. 
PGA 
Physicians Global Assessment 
PIS 
Patient Information Sheet(s) 
PHI 
Protected Health Information 
PT 
Preferred Term 
PtGA 
Patient Global Assessment 
PTX 
Pentoxifylline 
PTX-M1 
M1 metabolite of pentoxifylline: 1-((S)-5-
hydroxyhexyl)-3,7-dimethylxanthine (Metabolite of 
PTX) 
PTX-M2 
M2 metabolite of pentoxifylline 
PUVA 
Photodynamic chemotherapy 
SAE 
Serious adverse event 


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Abbreviation or Special term 
Explanation 
SDV 
Source document verification 
SOC 
System Organ Class 
SOP 
Standard operating procedure 
TB 
Tuberculosis 
TGF-β 
Transforming growth factor beta 
TID 
Three times a day 
TNF 
Tumor necrosis factor 
TORO 
Transfer of Regulatory Obligations 
United States 
US 
ULN 
Upper Limit of Normal 
UVA/UVB 
Ultraviolet A /Ultraviolet B phototherapy 
VAS 
Visual Analog Scale 
VS 
Vital Signs 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 


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7. 
INTRODUCTION 
7.1. 
Background Information 
Necrobiosis lipoidica (NL) is a rare, idiopathic granulomatous disease involving collagen 
degradation.  It is a chronic, disfiguring skin condition that often develops on the pretibial region 
of the lower extremities but can also occur on other areas including the face, scalp, forearm, and 
trunk.  NL usually presents initially as red papules that enlarge to form patches or plaques with 
an atrophic yellow center.  Although more commonly found in diabetic patients, non-diabetic 
patients can also develop NL and the progression of the disease is not correlated with glycemic 
control.  It is estimated that approximately 0.3% of the diabetic population has NL and that 
between 11-65% of the NL patients are diabetic (Muller, 1966; O'Toole, 1999).  NL also occurs 
predominantly in women (3:1 female-to-male ratio). Ulceration occurs in approximately 30% of 
patients, which can lead to more severe complications, such as deep tissue infections that can 
threaten life of the limb (Muller, 1966; Erfurt-Berge, 2015). Rare cases of squamous cell 
carcinoma in the NL region have also been reported.  
The earliest observed changes in NL involve small vessel vascular inflammation, progressing to 
larger vessel vasculitis, and collagen degeneration with septal fibrosis and fibrotic replacement 
of fat lobules (Muller, 1966). Interstitial and palisaded granulomas involving the dermis and 
subcutaneous tissues are usually present. Granulomas are composed primarily of histiocytes 
(macrophages) with lymphocytes and plasma cells.  Palisaded histiocytes can be found near 
necrobiotic areas (especially in diabetics) with deposition of extracellular fat.  Although the 
pathophysiology of NL is still unclear, various potential mechanisms for development and 
progression of NL have been proposed.  Immune-complex deposition in blood vessels, abnormal 
collagen deposition/degradation and impaired neutrophil migration have all been suggested as 
possible causes of granuloma and necrobiotic collagen seen in the disease (Ullman, 1977; 
Oikarinen, 1987; Markey, 1988; Gange, 1979).  Considering the strong association between NL 
and diabetics, diabetic microangiopathy (deposition of glycoprotein in blood vessels) has also 
been suggested to play an important role in the pathogenesis (Reid, 2013).   
7.2. 
Preclinical Data 
PCS499 is a methylxanthine derivative that is structurally identical to the pentoxifylline M1 
metabolite (PTX-M1), except that several key hydrogen atoms have been replaced with 
deuterium.  Pentoxifylline is the active ingredient in Trental® which is approved in the US for 
the treatment of intermittent claudication on the basis of occlusive arterial disease of the limbs.  
The extended release (ER) formulation of Trental was originally approved for use in Europe in 
1972 and US FDA approval for the treatment of intermittent claudication due to chronic 
occlusive arterial disease of the limbs was granted in 1984.  Metabolically, PTX and PTX-M1 
are known to interconvert in erythrocytes and liver by carbonyl reductase and CYP enzymes and 
are subsequently metabolized to hydroxy, carboxy and demethylated metabolites (PTX-M2, 
PTX-M3, PTX-M4, PTX-M6 and PTX M7) as well as the terminal metabolite, M5 by various 
CYP enzymes and possibly carboxylase (Hinze, 1972; Lillibridge, 1996; Lee, 1997; Shin, 1998; 
Nicklasson, 2002; Peterson, 2004; Wyska, 2007).  
PCS499 has a complex mechanism of action including anti-inflammatory, immunomodulatory, 
hemorheological and antifibrotic effects that potentially could benefit NL patients.  PCS499 has 


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slightly more potent anti-inflammatory/immunosuppressive activities than PTX in inhibiting 
proinflammatory cytokines (TNF-α and IFN-γ) and neutrophil activation that drive granuloma 
formation and other inflammatory/autoimmune mechanisms underlying the pathogenesis of NL.    
In addition, PTX and PTX-M1 have in vitro hemorheological properties that increase red blood 
cell deformability and decrease platelet aggregation.  These data suggested that PCS499 
potentially could moderate hypoxia and platelet aggregation/coagulation associated with 
microangiopathy and antibody-mediated vasculitis in NL.  Furthermore, PCS499 and PTX have 
similar activities in inhibiting in vitro the secretion of TGF-β, the master regulator of fibrosis, 
which could potentially modulate the fibrosis and increased collagen crossing linking in 
basement membranes in NL lesions. 
Thus, PCS499 may benefit NL patients based on its slightly more potent inhibition of pro-
inflammatory cytokines/chemoattractants and neutrophil activation that induce inflammation and 
granuloma formation, as well as its promoting effect on red blood cell deformability and platelet 
deaggregation, which can improve microcirculatory flow and hypoxia in NL lesions, plus its 
inhibitory effect on TGF-β which reduce fibrosis and other collagen abnormalities.  
In terms of toxicology findings, there was no evidence of genetic toxicity in vitro or in vivo. 
PCS499 did not inhibit any of the major CYP450 isotypes in human liver microsomes; it 
exhibited low plasma protein binding and was permeable in CaCO-2 cells. The oral 
bioavailability of PCS499 was 37% in rats, and 62% and 25% in male and female dogs, 
respectively.  
PCS499 was well-tolerated in single- and repeat-dose toxicity studies at dose levels that are 
above the anticipated human dose levels. Overall, none of preclinical results preclude the 
administration of PCS499 to humans and its development for the treatment of NL.   
Full details regarding the preclinical program for PCS499 are provided in the Investigational 
Brochure (IB). 
7.3. 
Clinical Data Summary 
7.3.1. 
Previous Phase 1 and 2 Studies 
PCS499 was previously being developed for the treatment of diabetic nephropathy. Six clinical 
trials with PCS499 have been completed including 4 studies in healthy volunteers and 2 studies 
in patients with chronic kidney disease (CKD). 
Four Phase 1 clinical trials in healthy adult volunteers have been completed evaluating tablet 
formulations, different dose regimens and administration of PCS499 with and without food. 
PCS499 tablets provide for a controlled release of the drug over an extended period of time after 
dosing. The maximum concentration (Cmax)  and area under the concentration vs time curve 
(AUC) of PCS499 increased approximately in proportion to dose across the range of tolerated 
doses.  Single daily doses up to 2400 mg have been administered to healthy subjects and were 
well tolerated up to 1800 mg. A daily dose of 1800 mg administered as 900 mg BID or 600 mg 
TID in a multiple dose healthy volunteer study was also well tolerated.  In healthy volunteers 
administered 900 mg BID or 600 mg TID, the most common adverse events were nausea and 
headache.      


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Trials in patients with CKD include a single Phase 1 study and a Phase 2, 48-week double-blind 
into 48-week open-label clinical trial in CKD patients with Type 2 diabetes.  During the Phase 2 
double-blind study, treatment with PCS499 was generally well tolerated. Gastrointestinal (GI) 
events were reported more frequently in the PCS499 arm. Nausea was the most commonly 
reported event in the PCS499 arm, with 12 (13.5%) PCS499 vs 5 (5.7%) placebo patients 
reporting the event. Influenza was reported in 9 (10.1%) PCS499 and 1 (1.1%) placebo patients, 
and peripheral oedema reported in 9 (10.1%) PCS499 and 4 (4.5%) placebo patients. 
Hypertension was reported in a greater proportion of placebo patients, with 6 (6.7%) PCS499 
and 12 (13.6%) placebo patients experiencing the event. However, as only 6 patients required 
dose reduction, and only 4 patients were unable to tolerate PCS499 due to a GI event (and were 
forced to discontinue treatment), the 600 mg BID dosing regimen, following an initial 2 weeks of 
once daily (QD) dosing, appeared to be satisfactorily tolerated in this patient population.  
Clinical safety data obtained to date in the 5 completed, Phase I clinical studies and the Phase 2 
study indicate that PCS499 is well tolerated. There have been no serious adverse events (SAEs) 
that were considered by the Investigators to be related to study treatment. Further information 
regarding previous clinical studies can be found in the Investigator Brochure.    
7.4. 
Dose Rationale 
Previously, single oral doses of up to 1800 mg have been shown to be safe and well tolerated in a 
Phase 1 study with healthy volunteers.   
PCS499 has been previously administered to CKD patients.  Multiple doses of 600 mg QD for 2 
weeks followed by 600 mg BID for an additional 2 weeks were administered to Stage 3 CKD 
patients. No significant AEs were observed in this study. Also, in a Phase 2 study (CP.505.2001), 
PCS499 was administered at a dose of 600 mg BID for up to 2 years in diabetic nephropathy 
patients. From the studies conducted to date, although tolerable, higher daily doses may be 
needed to further maximize the effects from PCS499.   
A recent study (PCS499.1005) was performed to identify a formulation with target product 
profile characteristics of a delayed time to maximum concentration (Tmax), lower Cmax, and 
increased AUC.  The PK and safety profile of the selected formulation was then assessed in a 
multiple dose study with a maximum daily dose of 1800 mg administered as 900 mg BID or 600 
mg TID.  Both the 900 mg BID and 600 mg TID dosing regimens were well-tolerated in healthy 
volunteers, although the 900 mg dose resulted in higher AUC and Cmax than the 600 mg dose.  
While the sample size was small with large variations among patients, an association may exist 
in certain subjects between the presence of AEs and a rapid drug absorption rate and higher 
maximum plasma concentrations.   
Therefore, as the 900 mg BID dosing regimen of PCS499 results in a higher AUC and is 
generally well tolerated, this regimen was selected for this study.  However, if a patient 
administered 900 mg BID has unacceptable toxicity, the dosing regimen will be changed to 600 
mg TID.   
7.5. 
Study Rationale 
No approved therapies exist for NL.  Current treatment approaches are based on empirical 
evidence, but generally produce unsatisfactory results.  These include corticosteroids (topical, 


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intralesional, and systemic), topical calcineurin inhibitors, anti-platelet agents, various 
immunosuppressants (chloroquine, thalidomide, TNF-α blockers, etc.), UV phototherapy, and 
skin grafting. For ulcerated lesions, wound care involving moisture control, infection control, 
conservative debridement, and compression therapy is employed. Spontaneous resolution has 
been reported in 13-19% of patients after 6-12 years (Muller, 1966).  
Clinically, multiple case reports have been published suggesting benefit from the use of 
pentoxifylline (PTX) in NL patients, possibly related to its vascular and anti-inflammatory 
effects (Littler, 1987; Noz, 1993; Basaria, 2003; Wee, 2017). PCS499 is an analog of 
pentoxifylline that provides an exposure profile of active molecules more favorable to inhibiting 
the secretion of TNF-α, IFN-γ, and other pro-inflammatory cytokines. Furthermore, PCS499 has 
been well tolerated in Phase 1 studies at higher doses, which may be due to the flatter slope in 
achieving maximum plasma concentrations (Cmax) of active metabolites, which would be 
consistent with published reports that equate a higher rate of adverse events with a rapid drug 
absorption rate and higher maximum plasma concentrations for PTX (Cleary, 1999).  Thus, 
PCS499 may benefit NL patients based on its enhanced inhibition of cytokines (TNF-α, IFN-γ) 
that induce inflammation and granuloma formation as well as its effect on red blood cell 
deformability and promotion of platelet deaggregation, which can improve microcirculatory 
flow.  Furthermore, higher doses of PCS499 can be administered with resulting higher exposures 
of active molecules with no observed increase in adverse effects.   
 
 


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8. 
STUDY OBJECTIVES AND PURPOSE 
8.1. 
Objectives 
 
Primary Objective: 
• To evaluate the safety and tolerability profile of PCS499 in patients with Necrobiosis 
Lipoidica 
 
 
Exploratory Objectives: 
• To evaluate the efficacy of PCS499 on reducing clinical findings related to 
Necrobiosis Lipoidica  
• To assess the pharmacodynamic activity of PCS499 on immunologic and 
inflammatory biomarkers 
 


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9. 
INVESTIGATIONAL PLAN 
9.1. 
Overall Study Design and Plan: Description 
This is an open-label study that will evaluate the safety of PCS499 for the treatment of 
necrobiosis lipoidica (NL) and will inform the design of future studies.   
The study will consist of a 6 month treatment period followed by a 6 month extension period.   
Approximately 12 NL patients (6-9 patients without ulceration and 3-6 patients with ulceration) 
who also meet other inclusion/exclusion criteria will be enrolled in the study.  Patients will be 
administered PCS499 900 mg BID.  Primary safety and exploratory efficacy analysis will be 
performed after the last patient completes the 6-month visit. Patients will have the option to 
continue dosing in an extension period for up to an additional 6 months.   
All patients will take PCS499 300 mg BID with food for 1 week.  Beginning at Week 2, patients 
will commence administration of twice daily dosing of three PCS499 300 mg tablets (900 mg 
BID) with food.  Patients will continue at their assigned dose for the remainder of the study.   
During the dosing period, if a patient receiving PCS499 900 mg BID experiences unacceptable 
toxicity (i.e., non-transient, moderate to severe limitation in activity) that is deemed by the 
Investigator to be related to study drug, his/her dose will be changed to PCS499 600 mg TID 
with food at the discretion of the Investigator in consultation with the Medical Monitor.  If this 
dose is not tolerated, the dose will be further reduced to PCS499 600 mg BID with food at the 
discretion of the Investigator in consultation with the Medical Monitor.   If 4 out of the first 6 
patients dosed in this study require dose modification or discontinue from the study due to a 
drug-related adverse event within 1 month of dosing, consideration will be made to change the 
starting dose to 600 mg TID with food for all subsequent patients.  Efficacy and safety data will 
be collected at regular intervals throughout the course of the study.   
An analysis will be conducted to assess safety and exploratory efficacy after the last patient 
completes the 6-month visit.  A final analysis of patients enrolled in the study will be conducted 
after the last patient completes the 12-month visit.  
9.2. 
Detailed Description of Study Visits 
When assessments occur at the same visit, the order of assessments will be vital signs collection, 
12-lead ECG then blood collection. 
9.2.1. 
Screening Visit (Day -28 to Day -1, Clinic Visit) 
The Screening visit will include: 
• Patient informed consent, to be reviewed and signed by the patient.   
• Review of demographics 
• Review of medical history   
• Review of Inclusion/Exclusion Criteria 
• Concomitant medications taken in the last 30 days prior to Screening visit will be 
recorded. 


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• Vital Signs (BP, heart rate, respiratory rate and temperature) as well as height and 
weight for body mass index measurements will be assessed.  
• A physical exam will be performed 
• 12-lead ECG 
• Blood and urine will be collected for safety testing 
• HIV, hepatitis panel and QuantiFERON TB test  
• Serum blood collection for pregnancy for women of child bearing potential 
(WOCBP) 
• Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• Skin biopsy  
o Note: A skin biopsy is required if the patient has no previous history of 
biopsy, no biopsy within the previous 5 years, a biopsy that is not confirmed 
to be NL, or newly active lesion 
• Study Drug instructions will be explained 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced as a result of screening procedures 
• Any concomitant medications administered for adverse events or tolerability issues as 
a result of screening procedures will be solicited (if applicable) 
 
9.2.2. 
Open-Label Study 
Patients who satisfy the eligibility criteria will be enrolled into an approximately 12 month 
treatment period in which they will receive open-label PCS499, titrated from 300 mg twice daily 
(BID) for 1 week followed by 900 mg twice daily (BID) for the remainder of the study to 
determine safety and tolerability.     
9.2.2.1. 
Day 0 (Baseline Visit) 
Patients will begin the dosing of open-label PCS499 according to their dosing instructions.  
There is no study visit on Day 1.  However, any adverse events the patients experience after their 
first dose should be reported at the next study contact (Phone Check in on Day 7). 
• Review of Inclusion/Exclusion criteria 
• Review of medical history and concomitant medications 
• Vital signs  
• Physical exam 


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• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c and PT, aPTT 
and INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Patient will be given the first kit of study medication 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced during baseline visit procedures 
• Any concomitant medications administered for adverse events or tolerability issues 
during baseline visit procedures will be solicited (if applicable) 
 
9.2.2.2. 
Day 7 and Day 14 (Phone Checks, +/- 1 day) 
The site will call the patient on Day 7 and Day 14 to assess for any adverse events or tolerability 
issues the patient may have experienced since starting dosing.  A review of systems will be 
discussed and any changes in concomitant medications will also be solicited. 
• If a patient reports satisfactory tolerability to study medication on the Day 7 Safety 
Check-in, they will be instructed to increase their morning dose to 3 tablets and their 
evening dose to 3 tablets. 
• If a patient reports tolerability issues, an additional week of dosing with the morning 
dose of 1 tablet and evening dose of 1 tablet may be performed. 
• Patients who are unable to tolerate even the single tablet after 2 weeks of dosing are 
to be discontinued from the study. 
9.2.2.3. 
Day 28/Month 1 (Clinic Visit, +/- 3 days) 
The following will be performed at this clinic visit: 
• Vital signs 


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• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including PT, aPTT and INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• Patient will be given a new kit of study medication   
9.2.2.4. 
Day 60/Month 2 (Clinic Visit, +/- 7 days) 
The following will be performed at this clinic visit: 
• Vital signs 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/wound 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• Blood and urine will be collected for safety testing (including PT, aPTT and INR) 


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• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• Patient will be given a new kit of study medication   
9.2.2.5. 
Day 90/Month 3 (Clinic Visit, +/- 7 days) 
The following will be performed at this clinic visit: 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c, PT, aPTT and 
INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• Patient will be given a new kit of study medication     
9.2.2.6. 
Day 120/Month 4 (Clinic Visit, +/- 7 days) 
The following will be performed at this clinic visit: 
• Vital signs 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
CONFIDENTIAL  
 
33 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• Blood and urine will be collected for safety testing (including PT, aPTT, and INR) 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• Patient will be given a new kit of study medication   
9.2.2.7. 
Day 150/Month 5 (Clinic Visit, +/- 7 days) 
The following will be performed at this clinic visit: 
• Vital signs 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• Blood and urine will be collected for safety testing (including PT, aPTT and INR) 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   


Protocol PCS499-NL01 
 
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34 
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• Patient will be given a new kit of study medication   
9.2.2.8. 
Day 180/Month 6 (Clinic Visit, +/- 7 days) 
The following will be performed at this clinic visit: 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c, PT, aPTT and 
INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• If the patient chooses to continue into the Extension Period, the patient will be given a 
new kit of study medication     
 
9.2.3. 
Extension Period 
9.2.3.1. 
Day 270/Month 9 (Clinic Visit, +/- 10 days) 
The following will be performed at this clinic visit: 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
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35 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c, PT, aPTT and 
INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
• The patient will be given a new kit of study medication     
9.2.3.2. 
Day 360/Month 12 (Clinic Visit, +/- 10 days) 
The following will be performed at this clinic visit: 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  


Protocol PCS499-NL01 
 
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36 
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c, PT, aPTT and 
INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
 
9.2.3.3. 
Early Discontinuation from Study Drug (Clinic Visit) 
If a patient discontinues study drug prior to study termination, the patient will return to the clinic 
for an Early Discontinuation from Study Drug assessment, which will include: 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• Photograph/3D scan of lesion(s)/ulcer 
• The following scales will be performed:  
− Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL), 
− Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS), 
− Physician Global Assessment (PGA), 
− Skindex-29,  
− Dermatology Quality of Life Index (DLQI),  
− Patient Global Assessment (PtGA) 
• 12-lead ECG 
• Blood and urine will be collected for safety testing (including HbA1c, PT, aPTT and 
INR) 
• Blood will be collected for biomarkers 
• A urine pregnancy test will be performed on all WOCBP 
• Assessment of any adverse events or tolerability issues the patient may have 
experienced since the last visit   


Protocol PCS499-NL01 
 
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37 
• Any changes in concomitant medications will also be solicited 
• Drug accountability will be performed 
 
9.2.3.4. 
Unscheduled Visits 
All attempts should be made to keep a patient on the study schedule.  Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, follow-up on adverse events or 
for other reasons, as warranted.  Procedures that may be performed at the Unscheduled visit are 
as follows: 
• Vital signs 
• Physical exam 
• Skin/ulcer exam 
• 12-lead ECG 
• Blood and/or urine collection for safety testing.  
 
9.2.4. 
Schedule of Events 
Table 2 provides detail on the schedule of assessments.  


Protocol PCS499-NL01 
 
Date:  02 November 2018 
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Table 2: 
Schedule of Events (Study PCS499-NL01)  
Procedure 
Screening 
(-28 to -1 
days) 
Dosing 
Visit 2 
Day 0 
(Baseline 
Visit) 
Visit 3 
Week 1 
Day 7 
(±1 day) 
Visit 4 
Week 2 
Day 14 
(±1 day) 
Visit 5 
Month 1 
Day 28 
(±3 days) 
Visit 6 
Month 2 
Day 60 
(±7 days) 
Visit 7 
Month 3 
Day 90  
(±7 days) 
Visit 8 
Month 4 
Day 120 
(±7 days) 
Visit 9 
Month 5 
Day 150 
(±7 days) 
Visit 10 
Month 6 
Day 180 
 (±7 days) 
Extension Period 
Visit 11 
Month 9 
Day 270 
 (±10 days) 
Visit 12 
Month 
12/ET 
Day 360 
 (±10 
days) 
PI/informed 
consent 
• 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
information 
• 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
• 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
• 
• 
 
 
 
 
 
 
 
 
 
 
Screening 
Laboratory 
Testing (Hep 
B/C, HIV, TB) 
• 
 
 
 
 
 
 
 
 
 
 
 
Skin biopsy* 
•* 
 
 
 
 
 
 
 
 
 
 
 
Medications 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Vital signs 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Physical exam 
• 
• 
 
 
 
 
• 
 
 
• 
• 
• 
Skin/ulcer 
exam 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Photograph/ 
3D scan 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
IGA:NL 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
NLCUS 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
PGA 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 


Protocol PCS499-NL01 
 
Date:  02 November 2018 
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39 
*If no previous history of biopsy, no biopsy within the previous 5 years, a biopsy that is not confirmed to be NL, or newly active lesion. 
**For WOCBP:  Serum β-HCG at Screening; Urine pregnancy test at subsequent visits. 
*** Additional hematology (PT, aPTT and INR) will be tested at every visit except Screening.  HbA1c will be tested at Day 0 and Months 3, 6, 9 and 
12. 
 
DLQI 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Skindex-29 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
PtGA 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Safety check-
in 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
Laboratory 
testing*** 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Blood for 
biomarkers 
 
• 
 
 
• 
 
• 
 
 
• 
• 
• 
Pregnancy 
test** 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
ECG 
• 
• 
 
 
• 
 
• 
 
 
• 
• 
• 
Adverse 
Events 
• 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Drug 
Accountability 
 
 
 
 
• 
• 
• 
• 
• 
• 
• 
• 
Study Drug 
Dispensed 
 
• 
 
 
• 
• 
• 
• 
• 
• 
• 
 
Study Drug 
Instructions 
• 
• 
 
 
 
 
 
 
 
 
 
 


Protocol PCS499-NL01 
 
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40 
 
 
9.3. 
Number of Subjects 
The number of subjects estimated for this study is ~12 patients (6-9 patients without ulceration 
and 3-6 patients with ulceration) with Necrobiosis Lipoidica. 
9.4. 
Treatment Assignment 
This is an open label study where the ~12 patients with Necrobiosis Lipoidica will receive 
PCS499 900mg BID (3 x 300mg tablets) with food.   


Protocol PCS499-NL01 
 
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41 
 
 
10. 
SELECTION AND WITHDRAWAL OF PATIENTS 
This section describes the inclusion and exclusion criteria for entry into the study, as well as 
patient withdrawal criteria for patients who are enrolled into the study.  Any exceptions to these 
inclusion or exclusion criteria for eligibility require approval of the Medical Monitor in advance. 
10.1. 
Patient Inclusion Criteria 
To participate in the study, patients must meet all the following inclusion criteria at screening: 
1. Male or female patients age 18 to 80 years of age, inclusive, at Screening. 
2. Biopsy-confirmed diagnosis of NL.  Biopsies of continually active lesions performed 
outside of this clinical study will need to be reviewed and the diagnosis confirmed by the 
study pathologist.  For patients with no previous history of biopsy, no biopsy within the 
previous 5 years, a biopsy that is not confirmed to be NL, or newly active lesion, a biopsy 
to confirm a diagnosis of NL will be performed at the Screening visit.   
3. Reference NL lesion with a score of 2 or greater on the IGA:NL Activity scale AND 
surface area with minimum size of 10 cm2.  If more than one lesion is present, the 
reference lesion area is the lesion with the highest disease severity. 
4. Women of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at Baseline before dosing. 
5. Women of childbearing potential must use one of the following acceptable methods of 
contraception throughout the study: oral contraceptive medication, intrauterine device 
(IUD), hormonal implants, injectable contraceptive medications, double-barrier methods, 
or tubal ligation. 
6. Females who are postmenopausal (age-related amenorrhea >= 12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL. If necessary to confirm 
postmenopausal status, an FSH will be drawn at Screening) or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. 
7. Male patients must be willing to use appropriate contraceptive measures and refrain from 
sexual activity with any female who is pregnant or lactating. 
8. Patient must be willing and able to swallow whole tablets. 
9. Patient must be willing and able to comply with study procedures. 
10. Patient must be willing and able to provide signed, informed consent. 
 
10.2. 
Patient Exclusion Criteria 
Patients will not be eligible for entry into this study if they meet any of the following exclusion 
criteria: 
1. Current or previous (within 4 weeks of Baseline) treatment with: 
a. Oral, topical, or intralesional corticosteroids; 


Protocol PCS499-NL01 
 
Date: 02 November 2018 
 
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42 
 
 
b. Systemic pentoxifylline, theophylline, or cilostazol 
c. Oral or topical retinoid; 
d. Other systemic or topical immunosuppressant drugs, including but not limited to 
calcineurin inhibitors (e.g., tacrolimus), thalidomide, apremilast, anti-malarials (e.g., 
hydroxychloroquine, chloroquine), cyclosporine, mycophenolate mofetil, 
azathioprine, methotrexate, etc.   
2. Current or previous (within 12 weeks of Baseline) treatment with any biologic therapy 
(e.g., adalimumab, etanercept, infliximab, anakinra, etc.).  
3. Phototherapy/photochemotherapy (NBUVB, UVB, PUVA) within 6 weeks prior to 
Baseline 
4. Skin grafting, or other surgical procedure (other than debridement) within 6 weeks prior 
to Baseline. 
5. History of drug allergy, including but not limited to pentoxifylline or other xanthine 
derivatives, or other allergy, which in the opinion of the Investigator, contraindicates 
participation. 
6. Anticipated concurrent use of a strong CYP1A2 inhibiting drug, including but not limited 
to cimetidine and/or fluvoxamine, during the course of the study (after Screening). 
7. Fever (>38°C), or chronic, persistent, or recurring infection(s) at Screening or Baseline. 
8. Any infection requiring oral antimicrobial therapy within 2 weeks prior to Baseline or 
any infection requiring parenteral antibiotics or hospitalization within 12 weeks prior to 
Baseline.  Any treatment for such infections must have been completed and the infection 
cured for at least 2 weeks prior to Baseline. 
9. History of sarcoidosis, pyoderma gangrenosum, or any other disorder (in the judgment of 
the Investigator) that would interfere with the evaluation of NL or require protocol 
prohibited medication.    
10. History of any life threatening infection or sepsis within 12 months of Baseline: 
11. Clinically significant cardiac disease including but not limited to unstable angina, acute 
myocardial infarction within 6 months of Baseline, and arrhythmia requiring therapy. 
12. Patient has QTc interval ≥ 480 milliseconds on Screening ECG; a second Screening ECG 
may be done at investigator’s discretion but the average of the two QTc screening 
intervals must not be ≥ 480 milliseconds. 
13. History of cerebral hemorrhage, cerebrovascular accident, transient ischemic attack, 
gastrointestinal bleeding, or retinal hemorrhage within 6 months of Baseline. 
14. Patient has active or history of neoplastic disease (except for adequately treated non-
invasive basal cell and/or squamous cell carcinoma or carcinoma in situ of the cervix) 
within the past 5 years prior to Baseline. 
15. Presence of clinically significant medical condition(s) including but not limited to: renal, 
hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, 
neurological, psychiatric, substance abuse, and/or any other clinically significant disease 


Protocol PCS499-NL01 
 
Date: 02 November 2018 
 
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43 
 
 
or disorder, which in the opinion of the Investigator (by its nature or by being 
inadequately controlled), may put the patient at risk due to participation in the study, 
influence the results of the study, and/or affect the patient’s ability to complete the study. 
16. History of or current diagnosis of active tuberculosis (TB); undergoing treatment for 
latent TB infection (LTBI); untreated LTBI (as determined by documented results within 
3 months of the Screening Visit of a positive TB skin test with purified protein derivative 
with induration >= 5 millimeter (mm), or a positive QuantiFERON-TB test or positive or 
borderline T-Spot [Elispot] test); or positive TB test at Screening. Subjects with 
documented completion of  appropriate LTBI treatment would not be excluded and are 
not required to be tested. 
17. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Baseline. 
18. The results of the following laboratory tests performed at the central laboratory at 
Screening meet any of the criteria below: 
a. Hemoglobin < 8.0 g/dL (International System of Units (SI): < 80 g/L); 
b. White blood cells < 3.0 x 10^3 cells/mm^3 (SI: < 3.0 x 10^9 cells/L); 
c. Neutrophils < 1.0 x 10^3 cells/mm^3 (SI: < 1.0 x 10^9 cells/L); 
d. Lymphocytes < 0.5 x 10^3 cells/mm^3 (SI: < 0.5 x 10^9 cells/L); 
e. Platelets < 100 x 10^3 cells/mm^3 (SI: < 100 x 10^9 cells/L) 
f. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or alkaline 
phosphatase (ALP) ≥ 2 x upper limit of normal (ULN); 
g. Total bilirubin level ≥ 2 x ULN unless the individual has been diagnosed with 
Gilbert's disease and this is clearly documented; 
h. Estimated glomerular filtration rate < 40 mL/min/1.73 m^2 based on the Modification 
of Diet in Renal Disease (MDRD) formula. 
i. Positive HIV serology  
j. Evidence of active Hepatitis B Virus (HBV) infection  
k. Evidence of active Hepatitis C Virus (HCV) infection 
19. Women who are pregnant or breastfeeding. 
20. Patient unwilling or unable to swallow tablets whole. 
21. Any other medical condition, serious intercurrent illness, or extenuating circumstance 
that, in the opinion of the Investigator, would preclude participation in the study. 
22. Use of any investigational product within 30 days prior to Baseline or currently enrolled 
in another study that involves clinical investigations. 
10.3. 
Patient Withdrawal Criteria 
The intent of this study is to follow all subjects until study termination unless the subject 
withdraws consent.  Patients will be informed that they have the right to withdraw from the study 


Protocol PCS499-NL01 
 
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44 
 
 
at any time for any reason without prejudice to their medical care.  The Investigator also has the 
right to withdraw patients from the study if it is in their best interest.  Patients may be withdrawn 
from the study if they: 
• Have entered the study in violation of the protocol 
• Require use of a prohibited concomitant medication 
• Experience an AE that warrants premature withdrawal 
All treated patients should be followed according to the Schedule of Assessments.  All patients, 
even those who are withdrawn prematurely, should have all evaluations for the Month 12/ET 
Visit performed, if possible.  All procedures required should be documented in the electronic 
case report form (eCRF).  For all patients who withdraw prematurely, the Investigator will 
indicate one of the following reasons for withdrawal on the eCRF: 
• Adverse event (AE) 
• Death 
• Protocol violation 
• Lost to follow-up 
• Patient’s decision 
• Other (reason to be specified by the Investigator) 
In case of patients’ withdrawal from the study due to an AE, such patients will be closely 
monitored until the resolution or stabilization of the AE.  The Investigator should document the 
reason for withdrawal in the source documentation and eCRF.  
If a patient withdraws participation from the trial early, early withdrawal should be documented 
by the Investigator (or designee) in the appropriate eCRF pages and source documents when 
confirmed. 


Protocol PCS499-NL01 
 
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45 
 
 
11. 
TREATMENT OF PATIENTS 
11.1. 
Description of Study Drug 
PCS499 is a stable, optically active, white-crystalline solid with the chemical name (S)-1-
(4,4,6,6,6-pentadeutero-5-hydroxyhexyl)-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione.  The 
structural formula is provided in Figure 1 . 
Figure 1: 
Structural Formula for PCS499 
 
The molecular formula is C13H15D5N4O3.    
The dosage form is a white tablet containing 300 mg of PCS499.  The inactive ingredients are 
hydroxypropylmethylcellulose (HPMC), silicon dioxide, and magnesium stearate. 
11.2. 
Concomitant Medications 
At the discretion of the Investigator, over-the-counter (OTC) medications will be allowed for the 
management of a self-limiting indication (e.g., acetaminophen for headache).  The use of 
concomitant OTC medications, including OTC herbals, must be approved by the Investigator 
before administration.  All prescription medications must be approved by the Investigator 
throughout the active treatment period.    
With the exception of PCS499, investigational drugs are not to be taken during the study.   
IMPORTANT:  Patients should be instructed to consult with the Investigator before taking 
any new medication or changing medications and/or dosing regimens throughout the study.   
Drugs that are known to be strong inhibitors of CYP1A2 may increase exposure to the 
investigational product.  The Investigator should contact the Medical Monitor prior to (if 
possible) the initiation of a CYP1A2 inhibiting drug, such as ciprofloxacin, cimetidine, 
fluvoxamine, etc.           
  
Additional medication limitations are as follows: 
• Topical skin treatments to the affected NL area are not permitted during the study. 
• Systemic or topical immunosuppressive therapy, including but not limited to 
corticosteroids (excluding intraarticular injections, inhaled or nasal steroids), 
calcineurin inhibitors, thalidomide, apremilast, anti-malarials (e.g., 
hydroxychloroquine, chloroquine), cyclosporine, mycophenolate mofetil, 
azathioprine, methotrexate, and biologics (TNF-α blockers, anakinra, etc.)  are not 
permitted during the study. 


Protocol PCS499-NL01 
 
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• Oral retinoids are not permitted during the study. 
• Phototherapy (UVA/UVB) or photochemotherapy (PUVA) is not permitted during 
the study. 
• Consumption of pentoxifylline, cilostazol, or a theophylline preparation is not 
permitted during the study.  
 
11.3. 
Treatment Compliance 
Patients will be instructed to bring their bottles, whether empty or containing unused study 
medication, with them for a compliance assessment during each clinic visit.  Compliance will be 
assessed via tablet counts.   
11.4. 
Randomization and Blinding 
This is an open-label study which does not require a randomization list or blinding. 


Protocol PCS499-NL01 
 
Date: 02 November 2018 
 
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47 
 
 
12. 
STUDY DRUG MATERIALS AND MANAGEMENT 
12.1. 
Study Drug 
The test article is PCS499 modified release 300mg tablets. 
12.2. 
Study Drug Packaging and Labeling 
PCS499 tablets will be packaged in high density polyethylene bottles respectively.   
Each patient’s study medication will be packaged in a study-specific box (kit) and shipped to the 
study site by a central distribution site. 
12.3. 
Study Drug Storage  
All investigational drug supplies should be stored in a secure, locked area, under the 
responsibility of the Investigator or other authorized individual.  Study drug must be stored in the 
original packaging between 20 to 25°C (68 to 77°F), with deviations permitted between 15 to 
30°C (59 to 86°F), and protected from extreme conditions of temperature, light, and humidity.  
12.4. 
Study Drug Preparation 
There is no study drug preparation needed for this study. 
12.5. 
Administration 
All patients will take PCS499 300 mg BID with food for 1 week.  Beginning at Week 2, patients 
will commence administration of twice daily dosing of three PCS499 300 mg tablets (900 mg 
BID) with food.  Patients will continue at their assigned dose for the remainder of the study. 
Safety and tolerability will be assessed throughout study and the following steps may be taken: 
• During the dosing period, if a patient receiving PCS499 900 mg BID experiences 
unacceptable toxicity (i.e., non-transient, moderate to severe limitation in activity) 
that is deemed by the Investigator to be related to study drug, his/her dose will be 
changed to PCS499 600 mg TID with food at the discretion of the Investigator in 
consultation with the Medical Monitor.  If this dose is not tolerated, the dose will be 
further reduced to PCS499 600 mg BID with food at the discretion of the Investigator 
in consultation with the Medical Monitor.  If 4 out of the first 6 patients dosed in this 
study require dose modification or discontinue from the study due to a drug-related 
adverse event within 1 month of dosing, consideration will be made to change the 
starting dose to 600 mg TID with food for all subsequent patients.  If clinically 
indicated at any time during the study, study medication will be discontinued.  
However, patients will not be discontinued from the study due to cessation of study 
drug. 
All changes in medication administration will also be noted in the eCRF. 
Each kit will be clearly marked with dosage instructions.    
Each subject’s medication will be packaged for dispensing as described in the study manual.  


Protocol PCS499-NL01 
 
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48 
 
 
12.6. 
Study Drug Accountability 
The Investigator or designee must maintain accurate records of the receipt of all study drug, 
including date received, lot number, expiration date if applicable, amount received, condition of 
the package and the disposition of all study drug.  
Patients will be instructed to bring their bottles, whether empty or containing unused study 
medication, with them for a compliance assessment during each clinic visit.  Compliance will be 
assessed via tablet counts.  Details of study medication compliance will be recorded on the 
eCRF.  Investigational drug orders, records of receipt, dispensing records, and inventory forms 
will be examined and reconciled during and at the end of the study.  Both the investigational 
drug that was used during the course of the study, as well as any remaining unused 
investigational drug, will be accounted for on a drug accountability record provided to the 
Investigator by Processa or its designee.  In addition, a copy of all completed drug accountability 
records will be retained in the Investigators’ Study Files, with a copy sent to Processa.  The 
investigational drug will be kept in a locked area with limited access under controlled room 
temperature conditions. 
12.7. 
Study Drug Handling and Disposal 
Investigational drug orders, records of receipt, dispensing records and inventory forms will be 
examined and reconciled during and at the end of the study.  Unless otherwise directed, at the 
end of the study, all unused and partially used containers of investigational drug must be returned 
as designated by the Sponsor. 
In addition, a copy of all completed drug accountability records must be retained in the 
Investigators’ Study Files, with a copy sent to the Trial Master File.  The investigational drug 
shall be kept in a locked area with limited access under controlled room temperature conditions 
(see Section 12.3).   


Protocol PCS499-NL01 
 
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49 
 
 
13. 
Demographics and Other Baseline Characteristics 
 
Subject demographic characteristics (e.g., age, sex, and race) and baseline characteristics will be 
collected.  Relevant NL-related as well as general medical history/current medical condition data 
until the start of study treatment will be collected, such as date of diagnosis of NL, previous 
treatments for NL, other skin disease history, and diabetic status. 
 


Protocol PCS499-NL01 
 
Date: 02 November 2018 
 
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50 
 
 
14. 
ASSESSMENT OF EXPLORATORY EFFICACY 
14.1. 
Exploratory Efficacy Variables 
14.1.1. 
Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) 
The Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) is a tool that has been 
adapted to assess the presence and severity of necrobiosis lesions.  Adaptation of the scale was 
based on input from 4 dermatologists with expertise in granulomatous disorders, NL, and ulcers.  
The scale has face validity and has performed well in limited testing.  The scale scores activity 
based on features of inflammation/erythema, induration, and ulceration (Table 3) and damage 
based on features of pigmentation, scarring, and atrophy (Table 4).  Further validation of the 
scale is ongoing. 
Instructions:  Select (1) a numeric score that describes the activity and (2) a numeric score that 
describes the damage of the reference lesion*.  (*Reference lesion is the most severely affected 
lesion.) 
Table 3: 
IGA:NL Activity 
 
Score 
Definition 
Description 
0 
Clear 
No inflammation, induration or ulceration , but residual damage may 
be present. 
1 
Almost Clear Minimal inflammation (faint erythema); essentially flat with possible 
trace induration; no ulceration present. 
2 
Mild 
Mild inflammation (pink color) and/or slight induration; no ulceration 
present. 
3 
Moderate 
Marked inflammation (dark pink, yellow-orange color) and/or 
moderate induration; no ulceration present. 
4 
Severe 
Intense inflammation (red or orange color) and/or severe induration 
and/or 1-2 shallow ulcerations present, but underlying structures 
(muscle, bone) NOT visible. 
5 
Very Severe 
Very intense inflammation (bright red/purple or deep orange color) 
and/or very severe induration and/or any deep ulceration present with 
underlying structures (muscle, bone) visible and/or more than 2 
ulcerations. 
 
Table 4: 
IGA:NL Damage 
Score 
Definition 
Description 
0 
Absent 
None 


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Score 
Definition 
Description 
1 
Dyspigmentation 
Post-inflammatory hypo- or hyper- pigmentation 
2 
Scarring 
Post-inflammatory scarring, including atrophic plaques 
  
14.1.2. 
Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) 
A tool called the Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) is also under 
development that separately assesses the color and ulcer of NL lesions.  This tool includes 
domains to separately assess the color/inflammation (Table 5) and induration (Table 6) of NL 
lesions and the extent of ulceration, if present (Table 7).  The scale was developed among 4 
dermatologists with expertise in granulomatous disorders, NL, and ulcers, and has face validity 
and has performed well in limited pre-clinical testing.  Further validation of the scale is ongoing. 
Instructions:  Select (1) a numeric score that describes the color and (2) a numeric score that 
describes the ulceration status of the reference lesion*.  (*Reference lesion is the most severely 
affected lesion.) 
Table 5: 
NLCUS: Color/Inflammation 
Score 
Color/Inflammation 
0 
None 
1 
Minimal inflammation (faint erythema) 
2 
Mild inflammation (pink) 
3 
Marked inflammation (dark pink/red, orange) 
4 
Intense inflammation (bright red/purple, deep orange) 
 
Table 6: 
NLCUS: Induration 
Score 
Induration 
0 
None 
1 
Essentially flat with possible trace induration 
2 
Slight but definite induration 
3 
Moderate induration 
4 
Severe induration  


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Table 7: 
NLCUS: Ulcer 
Score 
Ulcer 
0 
None 
1 
1-2 shallow ulcerations, but underlying structures (muscle, bone) NOT visible. 
2 
Any deep ulceration with underlying structures (muscle, bone) visible and/or 
more than 2 ulcerations 
14.1.3. 
Physician Global Assessment (PGA) 
The physician’s global assessment will be performed using a 10 cm VAS ranging from “none” to 
“extreme activity”, after the question “Based on your assessment of the disease activity, draw a 
vertical mark (|) through the horizontal line for the level of disease activity that is present today.”  
14.1.4. 
Lesion/ulcer surface area 
Surface area of the lesions(s)/ulcer will be measured by the Investigator and by photography.  
Lesion surface area is defined as the surface area of the lesion with active 
inflammation/erythema.  The total lesion surface area (if more than one lesion is present), the 
reference lesion (defined as the lesion with the highest disease severity) surface area, reference 
ulcer surface area (defined as the ulcer with the highest disease severity within the reference 
lesion), and total ulcer surface area will be calculated.  The longest length and width (measured 
perpendicular to the longest length) measurements taken by the Investigator with a ruler will be 
entered into the eCRF along with an assessment of the shape of the lesion (rectangular, circular, 
triangular, or elliptical).   
Using the digital photograph/3D scan of the lesion, the Investigator will also electronically trace 
the perimeter of the reference lesion and reference ulcer (if present).  Based on the tracing, the 
surface area of the reference lesion and the surface area and volume of the reference ulcer (if 
present) will be calculated.   
14.1.5. 
Dermatology Quality of Life Index (DLQI) 
The Dermatology Quality of Life Index (DLQI) is a self-administered, standard health-related 
quality of life (HRQL) instrument used in clinical trials related to skin diseases (Both, 2007).  
The DLQI consists of 10 items and covers six domains including: symptoms and feelings, daily 
activities, leisure, work and school, personal relationships, and treatment. Scores range from 0 to 
30 with higher scores indicating poorer HRQL.   
14.1.6. 
Skindex-29 
Skindex-29 is another self-administered standard HRQL instrument that has been proposed to be 
comprehensive, but less used in clinical trials (Chren, 2012).  It includes 29-items with 3 
domains, symptoms, emotions and functioning.  Each domain is scored from 0 to 100 with 
higher scores indicating lower quality of life.  The domains can be combined and scored 
separately.  


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14.1.7. 
Patient Global Assessment (PtGA) 
The patient’s global assessment will be performed using a 10 cm VAS ranging from “very 
severe” to “not at all”, after the question “Please indicate with a vertical mark (|) on the 
horizontal line, how does your skin condition affect you today?” 
14.1.8. 
Exploratory Efficacy Variables in Ulcerated Patients 
14.1.8.1. Closure of reference ulcer 
Closure of reference ulcer is defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits 2 weeks apart. 
14.1.8.2. Ulcer volume 
Ulcer volume will be assessed using via the use of a 3D-imaging system.   
14.2. 
Biomarkers 
Selected serum biomarkers related to the potential anti-inflammatory and/or immunosuppressive 
effects of PCS499 on NL will be measured.  These include TNF-α, IFN-γ, IL-1β, IL-6, IL-12, 
IL-17 and MCP-1.   
Additionally, an association between underlying autoimmunity and the development of NL has 
been suggested based on the higher than expected prevalence of the disease in patients with Type 
1 diabetes (as compared to Type 2 diabetes) (Erfurt-Berge, 2015).  C-peptide levels will be 
measured to assess whether there is any benefit of PCS499 in maintaining natural insulin 
production. 


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15. 
ASSESSMENT OF SAFETY 
The safety parameters collected will include adverse events, vital signs, ECGs, physical 
examinations, and laboratory tests.  In addition, concomitant medications will be recorded.  
15.1. 
Safety Parameters 
15.1.1. 
Vital Signs, Height, Weight, and Body Mass Index  
Vital signs, including blood pressure, heart rate, respiratory rate, and oral temperature, will be 
measured.  Height, weight and body mass index measurements will be collected at Screening 
only. Vital signs will be performed after the patient has been seated for at least 5 minutes. 
15.1.2. 
Physical Examination  
Full physical examinations will be performed.  All abnormal findings will be documented in the 
eCRF. 
15.1.3. 
Electrocardiogram 
Standard resting 12-lead ECGs will be performed; ECGs will be performed after the patient has 
rested for at least 5 minutes. 
15.1.4. 
Clinical Laboratory Assessments 
Clinical Safety Laboratory assessments will include hematology, chemistry and urinalysis, 
coagulation, and HgbA1c.  
Screening panels will include virus serology (HIV, and hepatitis B and C).  Results must be 
available prior to dosing. 
The list of clinical laboratory assessments is included in Appendix A. 
15.1.4.1. Pregnancy Testing 
PCS499 should not be administered to pregnant women.  Effective methods of birth control must 
be used by WOCBP. 
A serum β-HCG will be performed at Visit 1 (Screening).  All WOCBP will have local urine 
pregnancy tests as indicated in the Schedule of Events (Table 2).  A positive urine pregnancy test 
requires immediate interruption of study treatment until a serum β-HCG is performed and found 
to be negative.  If positive, the subject must be discontinued from the study. 
15.1.5. 
Concomitant Medications 
Concomitant medications are defined as any medication taken by the patient during the course of 
the study following the first dose.  Prior medications are defined as any medication taken by the 
patient within 30 days of their first dose of study medication.  Prior and concomitant medications 
will be coded using the WHO Drug Dictionary.   


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15.2. 
Adverse Events and Reporting Procedures 
15.2.1. 
Adverse Event Definition and Collection 
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product whether or not considered drug-related.  Adverse events may include safety findings 
considered to be clinically significant by the Investigator, Sponsor, or Medical Monitor.  An 
adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not it is related to the medicinal product.  Reporting an adverse event does 
not necessarily reflect a conclusion by the Investigator, Sponsor or Food and Drug 
Administration (FDA) that the event is causally related to the drug. 
All adverse events should be captured and must be reported on the Adverse Event eCRF.  
Adverse events should be spontaneously reported or elicited by non-suggestive probing.  All 
adverse event reports should contain the date the adverse event occurred, a brief description of 
the event (if the event consists of a cluster of signs and symptoms, record a diagnosis rather than 
each sign and symptom), onset date, the severity, the Investigator’s assessment of the 
relationship to study drug, the study drug action taken, the outcome, date resolved, and whether 
or not the event was serious (and if so, why). 
New information regarding signs and symptoms that occurred during the Screening phase and 
prior to the day of the first study medication dose on Day 1 of study that are related to screening 
procedures should be recorded on the Adverse Event log.  Intercurrent illnesses or injuries 
should be regarded as AEs.  Abnormal results of laboratory tests or diagnostic procedures are 
considered to be AEs if the abnormality: 
• Is associated with clinical signs or symptoms 
• Is considered by the Investigator to be of clinical significance 
• Results in study withdrawal 
• Fulfills any of the criteria for an SAE, as described in this section 
• Requires intervention or further evaluation to determine the etiology of the 
abnormality and/or assess the risk to the patient 
• Requires treatment 
15.2.2. 
Categorizing Adverse Events in Relation to Study Phase 
The relationship of each adverse event must be recorded on the Adverse Event eCRF as one of 
the choices provided on the scale that follows, where the temporal sequence is defined as an 
association between administration of a drug and the observed reaction or event such that the 
drug was present prior to the reaction or event: 
The Investigator assesses the relationship between the AE and the study drug by using the 
following definitions: 


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• DEFINITELY RELATED – Onset of the event as relative to administration of the 
study drug is reasonable and there is no other cause to explain the event; or a re-
challenge (if feasible) is positive. 
• PROBABLY RELATED – Onset of the event as relative to administration of the 
study drug is reasonable and is more likely explained by the drug than by any other 
cause.    
• POSSIBLY RELATED – Onset of the event as relative to administration of the study 
drug is reasonable; however, the event could have been due to another, equally likely, 
cause. 
• UNLIKELY TO BE RELATED – Onset of the event as relative to administration of 
the study drug, is possible but another cause itself can explain the occurrence of the 
event or there are no reasonable grounds for suspecting that the product could have 
caused the event. 
• NOT RELATED – Onset of the event as relative to administration of the study drug, 
is not reasonable; or, another cause itself can explain the occurrence of the event. 
All AEs (regardless of seriousness or relationship to study drug) including those from the time of 
signing of the Informed Consent Form (ICF) through to the follow-up/early withdrawal visit are 
to be recorded in the patient’s source documents and on the corresponding page(s) in the eCRF.  
Whenever possible, symptoms, signs, and laboratory abnormalities should be grouped as a single 
syndrome or diagnosis.  The Investigator should specify the date of onset, intensity, action taken 
with respect to study drug, corrective treatment/therapy given, outcome and his/her opinion as to 
whether there is a reasonable possibility that the AE was caused by the study drug.  All 
medications administered to treat an AE must be recorded in the patient’s source documentation 
and documented in the eCRF. 
15.2.3. 
Assigning Severity to Adverse Events 
The severity of each adverse event must be recorded on the Adverse Event eCRF as one of the 
choices provided on the scale below: 
• MILD: Awareness of sign or symptom, but easily tolerated. 
• MODERATE: Discomfort enough to cause interference with usual activity. 
• SEVERE: Incapacitating with inability to work or do usual activity. 
15.2.4. 
Serious Adverse Event Definition and Collection 
An adverse event is considered a serious adverse event (SAE) if, in the view of either the 
investigator or sponsor, it includes any untoward medical occurrence at any dose that: 
• Results in death 
• Is life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 


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• Results in a significant, persistent or permanent change, impairment, damage or 
disruption in the patient's body function/structure, physical activities and/or quality of 
life. 
• Results in a congenital anomaly/birth defect 
• Is a medically important event that may jeopardize the patient or may require medical 
or surgical intervention to prevent one of the other outcomes listed above. 
The term “life threatening” in the definition of “serious” refers to an event in which the patient in 
the view of either the Investigator or Sponsor, was at risk of immediate death at the time of the 
event; it does not refer to an event that hypothetically might have caused death if it were more 
severe.  Death is an outcome of an event.  The event that resulted in death should be recorded 
and reported on the SAE form and documented in the eCRF. 
Reporting serious adverse events to the Medical Monitor requires additional detailed reports and 
follow-up, depending upon the Investigator's (or in some cases the Sponsor's) estimate of a 
causal relationship between the test agent and the adverse event(s), and whether the adverse 
event(s) is identified in nature, severity, and frequency in the Investigator's Brochure or other 
risk information supplied to the Investigator. 
In the event of a serious adverse event, the Investigator must notify the Medical Monitor 
immediately (within 24 hours).  The SAE hotline telephone and SAE fax line numbers will be 
provided to each site and will be present also on the Serious Adverse Event Worksheet.  Details 
of the serious adverse event must be documented on the Serious Adverse Event Worksheet by 
the site and faxed to the SAE fax line.  The initial report should be as complete as possible. 
Information not available at the time of the initial report (e.g., an end date for the adverse event 
or discharge summary/testing/laboratory values received after the first report), must be 
documented on a follow-up Serious Adverse Event Worksheet.  Sites must make an effort to 
obtain all hospital medical records including discharge summary confirming final diagnosis.  
All serious adverse events (SAEs) should be submitted to the Institutional Review Board (IRB) 
as per the requirements of the IRB.  The death of a patient must be immediately (within 24 hours 
of site awareness) reported to the IRB.  All serious and non-serious adverse events should be 
thoroughly documented on the Adverse Event eCRF and followed out by the Investigator until 
the event resolves or until the termination visit.  The event may be followed longer, if deemed 
necessary.  Sites must ensure that the final SAE Worksheet captures the same information as the 
Adverse Event eCRF.  For any death occurring during the trial, the medical condition that led to 
the death on the Adverse Event eCRF and also reported on the SAE Worksheet.  The “outcome” 
status should be noted as “death” in these cases of SAEs that resulted in death.  In addition, all 
SAEs that occur within 30 days after the last dose of study drug should be recorded and reported 
as noted previously. 


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16. 
ENDPOINTS 
 
16.1. 
Primary Safety Endpoints 
• Evaluation of AEs/SAEs (by type, severity, and relatedness) at each visit. 
• Changes in safety clinical laboratory testing, vital signs at each visit. 
• Changes in ECGs at Months 1, 3, 6, 9, and 12. 
 
16.2. 
Exploratory Efficacy Endpoints 
• Proportion of patients with scores of clear or almost clear (0 or 1) on the Investigator 
Global Assessment: NL (IGA:NL) Activity scale of the reference lesion at Months 1, 
2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 1 point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 2 point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12 
• Proportion of patients with ≥ 1 point decrease in the Color score on the Necrobiosis 
Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at Months 1, 2, 3, 
4, 5, 6, 9, and 12. 
• Change from Baseline in Physician Global Assessment (PGA) score at Months 1, 2, 
3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 
9, and 12. 
• Percent change from Baseline in total lesion(s) surface area of inflammation/erythema 
based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on photograph at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Dermatology Quality of Life Index (DLQI) score at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Change form Baseline in Skindex-29 score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Patient Global Assessment (PtGA) visual analog scale 
(VAS) score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to obtaining scores of clear or almost clear (0 or 1) of reference lesion on the 
IGA:NL Activity scale. 


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• Incidence of new ulceration (defined as a site with no previous ulceration) at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to new ulceration. 
 
Patients with ulceration at Baseline only: 
• Proportion of patients with ≥ 1 point decrease in the Ulcer score on the Necrobiosis 
Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at Months 1, 2, 3, 
4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Percent change from Baseline in total ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Percent change from Baseline in reference ulcer surface area based on photograph at 
Months 1, 2, 3, 4, 5, 6, 9, and 12.  
• Incidence of complete wound closure of reference ulcer (defined as skin re-
epithelialization without draining or dressing requirements confirmed at two 
consecutive study visits at least 2 weeks apart) at Months 2, 3, 4, 5, 6, 9, and 12. 
• Time to complete wound closure of reference ulcer. 
• Incidence of recurrence of reference ulcer after complete wound closure at Months 3, 
4, 5, 6, 9, and 12. 
• Time to recurrence of reference ulcer after complete wound closure. 
• Change from Baseline in reference ulcer volume based on 3D scanning at Months 1, 
2, 3, 4, 5, 6, 9, and 12. 
 
16.3. 
Exploratory Serum Biomarkers 
• Change from baseline in TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17 and MCP-1 at 
Months 1, 3, 6, 9 and 12. 
• Change from baseline in C-peptide levels at Months 1, 3, 6, 9 and 12. 
 
 


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17. 
STATISTICAL METHODOLOGY 
All endpoints will be analyzed after the last patient completes the 3-month visit and the 6- month 
visit (primary).  A final lock of the database and the final analyses will occur after the last patient 
completes the 12-month visit. 
17.1. 
Sample Size Determination 
As this is a pilot study, no formal sample size calculation was performed. 
17.2. 
General Statistical Methods 
Patients will be analyzed by assigned treatment group.  Analyses will be performed based on 
observed data, and missing values will not be imputed unless otherwise stated. 
17.3. 
Analysis Populations 
Safety Population:  Defined as all patients enrolled in the study who received at least 1 dose of 
treatment.  
Efficacy Population (Modified Intent to Treat (mITT)):  Defined as all patients enrolled in the 
study who received at least 1 dose of treatment and has at least 1 post-baseline efficacy 
assessment.    
Per-Protocol Population:  Defined as a subset of the Efficacy Population who did not have a 
major protocol violation as defined in the Statistical Analysis Plan. 
Biomarker Population:  Defined as all patients enrolled in the study who received at least 1 dose 
of treatment, participated in biomarker evaluations, and have appropriate samples available for 
analysis.    
17.4. 
Patient Characteristics 
Baseline demographics and disease characteristics will be presented by descriptive statistics. All 
descriptive summary statistics of continuous variables will include: n, mean, median, standard 
deviation, minimum and maximum. All descriptive summaries presenting frequencies and 
incidences will include n, % and N, where N is the total number of patients with recorded values 
in the corresponding group.  Patient completion status and exposure outcomes will be similarly 
presented.   
17.5. 
Safety Analysis 
 
The safety analyses will be performed using the Safety Population and include adverse events, 
changes in physical exam findings, vital signs, clinical laboratory values, and ECG results. 
17.5.1. 
Adverse Events 
Adverse events will be coded using the current version of the Medical Dictionary for Regulatory 
Activities (MedDRA version 21.0 or higher).  The number and percent of patients reporting at 
least one adverse event will be summarized by System Organ Class (SOC) and Preferred Term 
(PT) and presented by dose level, severity, relationship to study drug, amount of drug exposure, 


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and time. Each patient will contribute only once (i.e., first occurrence) to each of the incidence 
rates, regardless of the number of occurrences. For reporting of adverse event severity in patients 
with more than one occurrence of the same adverse event, the patient will only be reported once 
based on the highest severity of the adverse event observed. Patients who have a serious adverse 
event (SAE) or who discontinue the study due to an adverse event deemed to be related to study 
drug will be described in patient narratives.    
17.5.2. 
Other Safety Analyses 
Vital signs, clinical laboratory, and ECG results will also be presented and summarized by dose 
level and summarized by descriptive statistics with change from Baseline values calculated.  All 
safety data collected in the clinical database, including physical exam findings and abnormal 
ECG results, will be presented in data listings. 
17.6. 
Efficacy Analysis 
Efficacy analyses will be performed using the Efficacy (mITT) Population.  Efficacy endpoints 
will be summarized by descriptive statistics for each treatment group and by ulceration status. 
All descriptive summary statistics of continuous variables will include: n, mean, median, 
standard deviation, minimum and maximum. All descriptive summaries presenting frequencies 
and incidences will include n, % and N, where N is the total number of patients with recorded 
values in the corresponding group.  Graphical representations will be presented, if appropriate.  
Efficacy data will also be presented in listings to assess changes within patients over time.   
17.7. 
Biomarkers 
Analyses will be performed using the Biomarker Population.  Biomarkers will be evaluated to 
assess changes within patients over time.  Additional exploratory analyses may be performed 
depending on the extent of the data using appropriate statistical methods. 
17.8. 
Exploratory Associations among Outcomes 
Depending on the extent of the data, additional exploratory analyses may be performed to 
characterize relationships among variables, such as correlations among variables and trending, as 
well as further sub-group analyses, such as based on diabetic status and study completion status.  
Additional sensitivity analyses may include comparisons between observed values and imputed 
values for missing data using different methods (e.g., multiple imputation, LOCF).       


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18. 
SAMPLE COLLECTION 
18.1. 
Biomarker Sample Collection 
Plasma and urine samples for all of these analytes will be collected as per the Schedule of Events 
(Table 2).  
Additional instructions for sample preparation, labeling, storage and shipment will be provided 
in a separate lab manual. 
18.2. 
Biomarker Sample Storage and Shipping 
Instructions for sample preparation, storage, and shipping schedule and further instructions will 
be provided in a separate lab manual. 


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19. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
19.1. 
Study Monitoring 
At regular intervals during the study, the site will be contacted through monitoring visits, letters, 
and telephone calls by a representative to review study progress, Investigator and subject 
compliance with study protocol requirements, and any emergent problems.  During monitoring 
visits, the following points will be reviewed in accordance with all applicable regulatory 
requirements and standard operating procedures (SOPs):  original medical records and other 
source documents, the Investigator site file, screening logs, subject informed consent, subject 
recruitment and follow-up, SAE documentation and reporting, documentation and reporting of 
endpoints, study drug allocation, subject compliance with the study drug regimen, study drug 
accountability, concomitant therapy use, and quality of data.  In addition, other required 
regulatory documents will be reviewed, including but not limited to:  IRB/IEC composition and 
correspondence, laboratory certification(s), delegation of authority, and Investigator and study 
personnel curricula vitae. 
19.2. 
Sponsor’s Responsibility 
Processa Pharmaceuticals or its designee is responsible for the following: 
1. Selecting qualified Investigators 
2. Providing Investigators with the information they need to properly conduct an 
investigation 
3. Ensuring proper monitoring of the investigation 
4. Ensuring that the applicable regulatory authorities, and all participating Investigators 
are properly informed of significant new information regarding AEs or risks 
associated with the medication being studied 
As the sponsor, Processa Pharmaceuticals has delegated some responsibilities to external vendors 
and Contract Research Organizations (CROs).  These will be detailed in a Transfer of Regulatory 
Obligations (TORO) per Processa SOPs. 
19.3. 
Audits and Inspections 
Processa Pharmaceuticals (or representative) may conduct audits at the study site(s).  Audits will 
include, but are not limited to:  drug supply, presence of required documents, the informed 
consent process, laboratory specimen processing, and comparison of eCRFs with source 
documents.  The Investigator agrees to cooperate with audits conducted at a reasonable time and 
in a reasonable manner. 
Regulatory authorities worldwide may also audit the Investigator during or after the study.  The 
Investigator should contact Processa Pharmaceuticals immediately if this occurs, and must fully 
cooperate with the audits conducted at a reasonable time in a reasonable manner. 
The Investigator is required to make all study documentation promptly available for inspection, 
review or audit at the study site upon request by sponsor, its representatives, or any appropriate 
regulatory agencies. 


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19.4. 
Institutional Review Board (IRB) 
Some centers in this study may utilize a central IRB that meets the requirements of 21 CFR Part 
56.  Those centers not using the central IRB will use their local institutional review board as 
applicable.   
19.5. 
Criteria for Study Termination 
19.5.1. 
Sponsor Termination 
If Processa Pharmaceuticals, Inc., their Study Representative (e.g., Contract Research 
Organization), or the Investigator discovers conditions arising during the study which indicate 
that the clinical investigation should be halted, the study must be terminated after appropriate 
consultation between the Study Sponsor, Agent and Investigator.  Conditions that may warrant 
termination include, but are not limited to:  
• The discovery of an unexpected, significant, or unacceptable risk to the patients 
enrolled in the study. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence to protocol requirements, or; 
• A decision on the part of Processa Pharmaceuticals, Inc. to suspend or discontinue 
development of the drug. 
19.5.2. 
Patient Discontinuation 
If a patient is discontinued from the study prematurely, the Investigator must select a reason for 
discontinuation on the termination page (End of Study Phase Status) eCRF.  In addition, every 
effort should be made to complete the assessments listed under the early termination study visit.  
Patients withdrawn from the study will be considered evaluable for analysis. 
A patient may be removed from the study for the following medical or administrative reasons: 
• Adverse Event: If a patient experiences an adverse event that the patient finds 
unacceptable or that, in the judgment of the Principal Investigator, Processa 
Pharmaceuticals, Inc., or the Medical Monitor presents an unacceptable consequence 
or risk to the patient, the patient may be discontinued from further participation in the 
study. 
• Administrative Discontinuation: After consultation with the Sponsor or Medical 
Monitor, a patient may be discontinued from the study for failure to comply with 
protocol requirements.  All instances of noncompliance must be documented in the 
eCRF. 
• Refusal of Treatment: If for any reason the patient refuses treatment during the study, 
the patient shall be discontinued from the study and the reasons for refusal 
documented on the eCRF.  Reasonable efforts shall be made to monitor the patient for 
adverse events following such discontinuation.  Such efforts shall be documented on 
the eCRF. 


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20. 
QUALITY CONTROL AND QUALITY ASSURANCE 
A quality control and quality assurance plan, addressing aspects of the trial that may affect data 
integrity or the protection of human subjects, may be instituted for this study.  All audit findings 
will be summarized and placed on file with appropriate documentation of response/resolution. 


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21. 
ETHICS 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and the Investigator abide by 
Good Clinical Practice (GCP), including but not limited to Title 21 Code of Federal Regulations 
(CFR) Parts 50, 56, and 312 and the International Conference on Harmonisation (ICH) 
guidelines and directives.  Compliance with these regulations also constitutes compliance with 
the ethical principles described in the current revision of the Declaration of Helsinki, Tokyo 
2004, Korea 2008 and applicable local regulatory requirements and law. 
Copies of these materials are available from Processa Pharmaceuticals and the CRO designee by 
request.  The purpose of these regulations, legal obligations, and guidances is to define the 
standards and principles for the proper conduct of clinical trials that have been developed by the 
medical, scientific, and regulatory communities.  They are not intended to impede or restrict 
clinical research. 
The ethical standards defined within GCP are intended to ensure that: 
1. Human subjects are provided with an adequate understanding of the possible risks of 
their participation in the study, and that they have a free choice to participate or not. 
2. The study is conducted with diligence and in conformance with the protocol in such a 
way as to protect subject safety and ensure the integrity of the findings. 
3. The potential benefits of the research justify the risks. 
The Investigator is responsible for protecting the rights, safety, and welfare of subjects under 
his/her care, and for the control of the medications under investigation. 
The Principal Investigator will ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study drug, and their study-
related duties and functions.  The Investigator will maintain a list of sub-Investigators and other 
appropriately qualified persons to whom he or she has delegated significant study-related duties.  
Individuals ineligible to conduct or work on clinical studies, including those ineligible as a result 
of debarment under the Generic Drug Enforcement Act of 1992, will not be allowed to conduct 
or work on studies sponsored by Processa Pharmaceuticals.  The Investigator is required to 
immediately disclose to Processa Pharmaceuticals in writing, if any person involved in the 
conduct of the study is debarred pursuant to a hearing by US FDA under this anti-fraud law, or if 
any proceeding for debarment is pending, or is (to the best of the Investigator’s knowledge) 
threatened.  
The rest of this section of the protocol describes in more detail the specific GCP-defined 
responsibilities the Investigator assumes by agreeing to participate in this study. 
21.1. 
Ethics Review 
The Investigator (or designee) must submit this study protocol, the Processa Pharmaceuticals 
approved informed consent form (ICF), patient information sheets (PISs), subject recruitment 
materials, and other appropriate documents to the appropriate IRB or IEC, and following review 
of the submitted materials is required to forward to Processa Pharmaceuticals (or designee) a 


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copy of the written and dated approval/favorable opinion signed by the IRB Chairman, along 
with a list of the IRB/IEC composition. 
The approval/favorable opinion should clearly state the trial (study number, protocol title, and 
version number), the documents reviewed (Protocol, ICF, IB, etc.) and the date of the review.  
The study will not commence at the study site until Processa Pharmaceuticals has received a 
copy of this written and dated approval/favorable opinion. 
During the trial, any amendment to the protocol and the ICF (as appropriate) should be submitted 
to the IRB/IEC.  The IRB/IEC should also be informed of any event likely to affect the safety of 
subjects or the continued conduct of the trial, in particular any change in safety.  Additionally, all 
updates to the IB will be sent to the IRB/IEC.  A progress report will be sent to the IRB/IEC and 
the protocol will be reviewed annually or more frequently, as required by IRB/IEC or local 
regulations. 
The Investigator will notify the IRB/IEC of the conclusion of the clinical study within 1 month 
of completion or termination of the study.  The final report sent to the IRB/IEC will also be sent 
to Processa Pharmaceuticals, along with the completed eCRFs and all necessary regulatory 
documents, thereby fulfilling the Investigator’s regulatory responsibility. 
The Investigator will maintain a copy of all correspondence with the IRB/IEC, including copies 
of approved documents.  The Investigator will also maintain a copy of the IRB/IEC membership 
list, including members’ occupation and qualifications (or a statement confirming compliance 
with GCP requirements for committee composition).  An IRB or IEC General Assurance 
Number may be accepted in lieu of a membership roster. 
21.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with GCP as delineated by Title 21 CFR Parts 50, 
56, and 312, and the ICH guidelines and directives.  Participating Investigators, including 
members of the Committees and National Coordinators, will receive compensation for their time 
but will receive no financial profit from their activities related to the trial.  
Before the first subject is enrolled in the study, all ethical, regulatory, and legal requirements 
must be met. 
An Investigator participating in this study is required to maintain complete and accurate study 
documentation in compliance with current GCP standards and all applicable local regulations 
related to the conduct of a clinical study. 
21.3. 
Written Informed Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations.  Written informed consent must be obtained from all subjects participating in a 
clinical study conducted by Processa Pharmaceuticals. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject.  The subject 
must be given sufficient time to consider whether to participate in the study.  


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A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
of a subject’s informed consent must also be documented in the subject’s source documentation 
prior to any testing under this protocol, including screening tests and assessments.  
Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Processa Pharmaceuticals to use and disclose patient health information (PHI) in compliance 
with local law.  
The original signed consent form will be retained with the study records. 


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22. 
DATA HANDLING AND RECORDKEEPING 
22.1. 
Data Collection 
Electronic Case Report Forms (eCRFs) will be provided to the study site by Processa or its 
designee.  All protocol-required information collected during the study must be recorded by the 
Investigator or designated representative in the source documentation for the study.  The source 
documentation will then be used to enter the protocol required information onto the eCRF.  The 
Investigator may authorize other persons to make entries in the eCRF, provided that the names, 
positions, signatures and initials of these persons are supplied in a delegation of authority log 
actively maintained at the site and reviewed by the Study Monitor.  The Investigator or 
designated representative should enter source document data for enrolled patients into the eCRF 
as soon as possible once the information has been collected.  All changes to data will be 
collected electronically through a computerized system for electronic data capture.  Changes or 
corrections to electronic case report forms will be documented by use of audit trails and include 
identification of the person making a change or correction, and will be time/date stamped.  The 
eCRF for each patient will be checked against source documents by the Study Monitor.  eCRFs 
will be stored on an appropriate storage media at the Investigator's site and the data management 
center. 
Prior to the start of the study, the Principal Investigator will complete a Delegation of Authority 
form (Site Signature and Delegation Log), showing the signatures and handwritten initials of all 
individuals and the delegation of responsibilities, such as identifying those individuals who are 
authorized to make or change entries on eCRFs. 
22.2. 
Case Report Form Completion 
Data within the eCRF will be monitored by the Clinical Research Associate according to a 
Clinical Monitoring Plan.  Queries will be generated based on discrepancies found while 
monitoring.  Site personnel will review and respond to these queries appropriately.  Additionally, 
CRO and Processa Pharmaceuticals may periodically perform aggregate data reviews, which 
could result in queries being generated for site personnel resolution.  The final, completed eCRF 
for each subject must be electronically signed and dated by the Principal Investigator to signify 
that the Principal Investigator has reviewed the eCRF and certifies it to be complete and 
accurate. 
22.3. 
Database Management, Data Clarification, and Quality Assurance 
A designated CRO will be responsible for data management.  Data Management will develop a 
Data Management Plan document and provide it to Processa Pharmaceuticals for approval.  The 
DMP document will define all activities in the data collection and cleaning process.  The detailed 
DMP will be based on the protocol, work scope, contract, analysis plans, data-flows, eCRFs, data 
cleaning procedures, other supporting documents, and data management standards and practices. 
Programmed data validation edit checks will be run to check for database completeness and 
consistency, and queries will be generated upon data entry or via review by a Clinical Data 
Manager after entry.  The sites will respond to the data queries in a timely manner. 


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Concurrent medications entered into the database will be coded using a WHO Anatomical 
Therapeutic Chemical dictionary.  Coexistent diseases and AEs will be coded using MedDRA. 
Quality control procedures will be conducted prior to database lock according to the designated 
CRO SOPs. 
When the database has been declared to be complete and accurate, it will be locked.  Any 
changes to the database after that time will only be made by joint written agreement between 
Processa Pharmaceuticals, the Trial Statistician, the Data Manager, and the Quality Assurance 
Auditor according to designated CRO SOPs. 
22.4. 
Inspection of Records/Source Documents 
According to the ICH guidelines for GCP, the sponsor or designee must verify data entered in 
the eCRF entries against the source documents, except for the pre-identified source data directly 
documented in the eCRF (if applicable).  The ICF will include a statement by which the subject 
allows the sponsor’s duly authorized personnel, the IRB/IEC, and the regulatory authorities to 
have direct access to source data that supports the data in the eCRF (e.g., subject’s medical file, 
appointment books, and original laboratory records).  These personnel, bound by professional 
secrecy, must keep confidential all personal medical information. 
The objective of source document verification (SDV) is to comply with GCP and international 
regulatory requirements and to reduce the risks of fraud.  Source document verification means 
ensuring that the source documents are an accurate and verifiable reflection of the subject’s 
participation in the study and that all relevant information that is recorded in the source 
document is accurately entered into the eCRF. 
Where source documents serve as the basis for deriving data for the trial, SDV should ensure that 
these documents are correctly labeled and filed and that the data derived from them are correct. 
All source documents pertaining to this study will be maintained by the Investigator and made 
available for inspection by authorized persons.  If electronic progress notes and other electronic 
source documents are not Title 21 CFR Part 11 compliant, they are not considered a valid source 
for this study.  All progress notes must be dated and signed by the Investigator or 
sub-Investigator at the time of the visit.  Processa Pharmaceuticals reserves the right to terminate 
the study for refusal of the Investigator to supply original source documentation for this clinical 
study. 
The Investigator will note in a source independent from the eCRF the following information: 
1. Information to confirm that the subject exists (e.g., initials, date of birth, sex) 
2. Confirmation that the subject satisfies the inclusion/exclusion criteria 
3. Confirmation that the subject is taking part in the clinical trial 
4. Confirmation of the informed consent process 
5. Visit dates and documentation of protocol assessments and procedures 
6. Information concerning all AEs 
7. Details of concomitant and investigational medications 


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Source document verification is not a substitute for clinical trial monitoring, the purpose of 
which is to ensure that the protocol has been followed correctly, the eCRF has been fully and 
accurately completed, SDV has been carried out, and the study timelines and enrollment goals 
and requirements have been met. 
22.5. 
Retention of Records 
The Investigator must maintain all study documentation as confidential, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator must retain the study documents at least 2 years after the approval of a 
marketing application/new drug application for the indication investigated or at least 2 years 
have elapsed since the formal discontinuation of clinical development of the investigational 
product (e.g., the Investigational New Drug application is withdrawn).  These documents should 
be retained for a longer period, however, if required by the applicable regulatory requirements or 
by an agreement with Processa Pharmaceuticals. 
The Investigator must notify Processa Pharmaceuticals prior to destroying any study essential 
documents. 
If the Investigator can no longer ensure archiving, he/she shall inform Processa Pharmaceuticals.  
The relevant records shall be transferred to a mutually agreed upon designee.   


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23. 
CONFIDENTIALITY, AMENDMENTS, AND PUBLICATIONS 
All information disclosed or provided by Processa Pharmaceuticals (or designee) or produced 
during the trial including, but not limited to, the protocol, the eCRFs, the IB, and the results 
obtained during the course of the trial (if applicable), are confidential.  The Investigator or any 
person under his/her authority agrees to undertake to keep confidential and not to disclose the 
information to any third party without the prior written approval of Processa Pharmaceuticals. 
However, submission of this protocol and any other necessary documentation to the IRB/IEC is 
expressly permitted, the IRB/IEC members having the same obligation of confidentiality. 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without written prior permission 
from Processa Pharmaceuticals.  However, authorized regulatory officials and sponsor personnel 
(or designee) will be allowed full access to inspect and copy the records.  The copied and 
inspected records will remain at the site and will not be transmitted or removed from the site.  
All study drug, subject bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by Processa Pharmaceuticals 
and responsible ethics committee(s) or regulatory authorities. 
Photographs from this study may be used for the further development of clinical tools to evaluate 
the disease activity in patients with Necrobiosis Lipoidica (e.g. the IGA:NL scale and the 
NLCUS).  If photographs are used, they will only include unidentifiable images, meaning that 
the patient will not be able to be identified from these photographs. 
Subjects will be identified only by unique subject numbers in eCRFs.  Their full names may, 
however, be made known to a regulatory agency or other authorized officials in the event of 
inspections.  Documents containing the full name or other personally identifiable information of 
the subject are to remain at the site.  This information will not be transferred to Processa 
Pharmaceuticals nor be contained in regulatory filings.  In the event of inspections by authorized 
agencies, this subject identification may be disclosed. 
23.1. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., PHI authorization in North 
America).  
The subject will not be identified by name in the eCRF or in any study reports and these reports 
will be used for research purposes only.  Processa Pharmaceuticals, its partner(s) and 
designee(s), and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential.  
Processa Pharmaceuticals will protect individual subject information to the fullest extent possible 
during this trial.  At no time will a subject become identified in any publication or presentation.  
However, the subject may have to become identified in the event of a regulatory authority audit 
or inspection in order to verify the accuracy of the data.  Access to subject information is at the 
discretion of Processa Pharmaceuticals and cannot occur prior to database lock or other specified 
events as determined solely by the discretion of Processa Pharmaceuticals. 


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23.2. 
Study Protocol Amendments 
The Investigator will not make any changes to this protocol without prior written consent from 
Processa Pharmaceuticals and subsequent approval by the IRB/IEC.  Any permanent change to 
the protocol, whether it is an overall change or a change for specific study center(s), must be 
handled as a protocol amendment.  Any amendment to the protocol that appears necessary as the 
study progresses will be fully discussed by the Investigator(s) and Processa Pharmaceuticals.  If 
agreement is reached regarding the need for an amendment, it will be written by Processa 
Pharmaceuticals.  The written amendment must be submitted to the chairman of the IRB/IEC 
identified with this responsibility.  Except for administrative amendments, Investigators must 
await IRB/IEC approval of protocol amendments before implementing the change(s).  
Administrative amendments are defined as having no effect on the safety of the research 
subjects, scope of the investigation, or quality of the trial.  However, a protocol change intended 
to eliminate an apparent immediate hazard to subjects should be implemented immediately, and 
the IRB/IEC notified within 5 days.  Processa Pharmaceuticals will ensure submission of any 
protocol amendments to the appropriate regulatory agencies. 
When, in the judgment of the chairman of the local IRB/IEC, the Investigators, and/or Processa 
Pharmaceuticals, the amendment to the protocol substantially alters the study design and/or 
increases the potential risk to the subject, the currently approved written ICF will require similar 
modification.  In such cases, the Investigator will obtain repeat informed consent from subjects 
enrolled in the study before expecting continued participation. 
23.3. 
Publication 
All information concerning the product as well as any information such as clinical indications for 
the study drugs, their formula, their formulation, methods of manufacture and other scientific 
data relating to it, that have been provided by Processa Pharmaceuticals or designee, and are 
unpublished, are confidential and must remain the sole property of Processa Pharmaceuticals.  
The Investigator will agree to use the information only for the purposes of carrying out this study 
and for no other purpose unless prior written permission from Processa Pharmaceuticals is 
obtained.  Processa Pharmaceuticals has full ownership of the eCRFs completed as part of the 
study. 
By signing the study protocol, the Investigator agrees that the results of the study may be used 
for the purposes of national and international registration, publication, and information for 
medical and pharmaceutical professionals by Processa Pharmaceuticals.  If necessary, the 
authorities will be notified of the Investigator’s name, address, qualifications, and extent of 
involvement. 
Processa Pharmaceuticals or designee will prepare a final report on the study.  The Investigator 
may not publish or present any information on this study without first presenting the information 
to Processa Pharmaceuticals for review. 
 
 
 


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24. 
REFERENCES 
1. Basaria S, Braga-Basaria M. Necrobiosis lipoidica diabeticorum: response to 
pentoxiphylline. J Endocrinol Invest. 2003;26(10):1037-40. 
2. 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. 
3. Chren M-M. The Skindex Instruments to Measure the Effects of Skin Disease on Quality 
of Life. Dermatologic Clinics. 2012;30(2):231-236. 
4. Cleary JD, Evans PC, Hikal AH, Chapman SW. Administration of crushed extended-
release pentoxifylline tablets: bioavailability and adverse effects. Am J Health Syst 
Pharm 1999;56:1529-1534. 
5. Erfurt-Berge C, Dissemond J, Schwede K, et al.  Updated results of 100 patients on 
clinical features and therapeutic options in necrobiosis lipoidica in a retrospective 
multicentre study.  Eur J Dermatol 2015;25:595-601. 
6. Gange RW, Black MM, Carrington P.  Defective neutrophil migration in granuloma 
annulare, necrobiosis lipoidica, and sarcoidosis.  Arch Dermatol. 1979;115(1):32-5. 
7. Hinze HJ. [Pharmacokinetics of 3,7-dimethyl-1-(5-oxo-hexyl)-xanthine (BL 191) in 
man]. Arzneimittelforschung. 1972;22(9):1492-5. German. 
8. Lee SH, Slattery JT. Cytochrome P450 isozymes involved in lisofylline metabolism to 
pentoxifylline in human liver microsomes. Drug Metab Dispos. 1997;25(12):1354-8. 
9. Lillibridge JA, Kalhorn TF, Slattery JT.  Metabolism of lisofylline and Pentoxyfylline in 
Human Liver microsomes and cytosol.  Drug Metab & Disposition 1996;24(11):1174-
1179. 
10. Littler CM, Tschen EH. Pentoxifylline for necrobiosis lipoidica diabeticorum. J Am Acad 
Dermatol. 1987 Aug;17(2 Pt 1):314-6.  
11. Markey AC, Tidman MJ, Rowe PH, Missen GA, Macdonald DM.  Aggressive ulcerative 
necrobiosis lipoidica associated with venous insufficiency, giant-cell phlebitis and 
arteritis. Clin Exp Dermatol. 1988;13(3):183-6. 
12. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabeticorum. A clinical and 
pathological investigation of 171 cases. Arch Dermatol. 1966;93(3):272-81. 
13. Nicklasson M, Björkman S, Roth B, Jönsson M, Höglund P. Stereoselective metabolism 
of pentoxifylline in vitro and in vivo in humans. Chirality. 2002;14(8):643-52. 
14. Noz KC, Korstanje MJ, Vermeer BJ. Ulcerating necrobiosis lipoidica effectively treated 
with pentoxifylline. Clin Exp Dermatol. 1993;18(1):78-9. 
15. O’Toole EA, Kennedy U, Nolan JJ, et al.  Necrobiosis lipoidica: only a minority of 
patients have diabetes mellitus.  Br J Dermatol 1999;140:283-6. 


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16. Oikarinen A, Mörtenhumer M, Kallioinen M, Savolainen ER. Necrobiosis lipoidica: 
ultrastructural and biochemical demonstration of a collagen defect. J Invest Dermatol 
1987;88:227. 
17. Peterson TC, Peterson MR, Wornell PA, Blanchard MG, Gonzalez FJ. Role of CYP1A2 
and CYP2E1 in the pentoxifylline ciprofloxacin drug interaction. Biochem Pharmacol. 
2004;68(2):395-402. 
18. Reid SD, Ladinzinski B, Lee K, et al.  Update on necrobiosis lipoidica: a review of 
etiology, diagnosis, and treatment options.  J Am Acad Dermatol 2013;69:783-91. 
19. Shin HS, Slattery JT. CYP3A4-mediated oxidation of lisofylline to lisofylline 4,5-diol in 
human liver microsomes. J Pharm Sci. 1998;87(3):390-3. 
20. Ullman S, Dahl MV. Necrobiosis lipoidica. An immunofluorescence study. Arch 
Dermatol. 1977;113(12):1671-3. 
21. Wee E, Kelly R. Pentoxifylline: An effective therapy for necrobiosis lipoidica. Australas 
J Dermatol. 2017;58(1):65-8. 
22. Wyska E, Szymura-Oleksiak J, Pekala E, Obruśnik A. Pharmacokinetic modelling of 
pentoxifylline and lisofylline after oral and intravenous administration in mice. J Pharm 
Pharmacol 2007;59(4):495-501. 
 


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APPENDIX A. LABORATORY ASSESSMENTS 
Hematology Panel 
Clinical Chemistry  
Urinalysis 
Hemoglobin (Hgb) 
Hematocrit (Hct) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count with 
differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Total 
Neutrophils) 
Mean Corpuscle Volume (MCV) 
Mean Corpuscle Hemoglobin (MCH) 
Mean Corpuscle Hemoglobin 
Concentration (MCHC) 
Red cell Distribution Width (RDW) 
Mean Platelet Volume (MPV) 
Alanine Aminotransferase (ALT) 
Albumin 
Alkaline Phosphatase (ALP) 
Aspartate Aminotransferase (AST) 
Bicarbonate (Carbon Dioxide) 
Bilirubin, Direct 
Bilirubin, Indirect 
Bilirubin, Total 
Calcium 
Chloride 
Cholesterol, Total 
Creatinine  
eGFR   
Gamma Glutamyl Transferase (GGT) 
Glucose   
HDL 
LDL 
Magnesium 
Phosphorus 
Potassium 
Protein, Total 
Sodium 
Triglyceride 
Urea, Blood Nitrogen (BUN) 
Uric Acid 
Appearance 
Bilirubin 
Blood 
Color 
Glucose, Urine 
Ketone 
Leukocyte Esterase (LE) 
Nitrite 
pH 
Protein 
Specific Gravity 
Urobilinogen 
Additional Hematology   
Serology Screen 
Other Labs 
Prothrombin time test (PT) 
Activated partial prothrombin time test 
(aPTT) 
INR 
 
Hemoglobin A1c (HbA1c) 
 
Human Immunodeficiency Virus (HIV) 1 
and 2 antibody; confirmatory testing to be 
performed if indicated 
 
Hepatitis B surface Antigen (HBsAg) 
 
Hepatitis C virus antibody (HCV); 
confirmatory testing to be performed if 
indicated 
 
QuantiFeron Gold TB test  
Follicle Stimulating Hormone (FSH) if indicated 
 
Serum β-HCG pregnancy test (at Screening) if 
indicated 
Urine Pregnancy test (in WOCBP) 
 
C-Peptide 
 
Cytokines (TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-
17, MCP-1)  
 


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APPENDIX B. LIST OF BIOMARKERS 
• TNFα (plasma)  
• IFN-γ (plasma) 
• IL-1β (plasma)  
• IL-6 (plasma) 
• IL-12 (plasma) 
• IL-17 (plasma) 
• MCP-1 (plasma) 
• C-peptide (serum) 
 
 


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APPENDIX C. SCALES (DLQI AND SKINDEX-29) 
 
Dermatology Quality of Life Index (DLQI) 
 
 


 
 
 
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  
 
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. 


Protocol PCS499-NL01 
 
Date: 02 November 2018 
 
CONFIDENTIAL  
 
79 
 
 
 
Skindex-29 
 


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
 
 
 
 
 
 
DERMATOLOGY SURVEY 
 
 
 
 
 
This survey concerns the skin condition which has bothered you the most during the 
past four weeks.          
 
 
                                                                                                                                                                                                                   
 
 
 
 
                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
 
These questions concern your feelings over the past 4 weeks about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST FOUR WEEKS  
DO THESE STATEMENTS DESCRIBE YOU? 
___________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN         ALL THE   
 
TIME 
___________________________________________ 
 
  1. My skin hurts    .    .    .   .    .    .   .    .    .   .    .    .   .    .    .    . 
 
   1              2              3               4              5 
 
  2. My skin condition affects how well I sleep    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  3. I worry that my skin condition may be serious    .    .    .    .    . 
 
   1              2              3               4              5 
 
  4. My skin condition makes it hard to work or do hobbies    .    . 
 
   1              2              3               4              5 
 
  5. My skin condition affects my social life   .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
  6. My skin condition makes me feel depressed    .    .    .    .    .   
 
   1              2              3               4              5 
 
  7. My skin condition burns or stings    .    .    .    .    .    .    .     . 
 
   1              2              3               4              5 
 
  8. I tend to stay at home because of my skin condition    .    .    . 
 
   1              2              3               4              5 
 
  9. I worry about getting scars from my skin condition    .    .    .   
 
   1              2              3               4              5 
 
10. My skin itches    .    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
11. My skin condition affects how close I can be with those I love . 
 
   1              2              3               4              5 
 
12. I am ashamed of my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
13. I worry that my skin condition may get worse    .    .    .    .    . 
 
   1              2              3               4              5 
 
14. I tend to do things by myself because of my skin condition    . 
 
   1              2              3               4              5 
 
15. I am angry about my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
16. Water bothers my skin condition (bathing, washing hands)    . 
 
   1              2              3               4              5 
 
17. My skin condition makes showing affection difficult    .    .    . 
 
   1              2              3               4              5 
 
18. I worry about side-effects from skin medications / treatments  . 
 
   1              2              3               4              5 
 
19. My skin is irritated    .    .    .    .    .    .    .    .    .    .    .    .    .     
 
   1              2              3               4              5 
 
20. My skin condition affects my interactions with others    .    .     
 
   1              2              3               4              5 
 
Please turn to next page 
 


Skindex29 
MMChren,1996 
 
 
Skindex29 – United States/English – Original version 
Skindex29_AU2.0_eng-USori.doc 
These questions concern your feelings over the past 4 week about the skin condition that has  
bothered you the most. Check the answer that comes closest to the way you have been feeling. 
 
 
HOW OFTEN DURING THE PAST 4 WEEK  
DO THESE STATEMENTS DESCRIBE YOU? 
_____________________________________________ 
 
NEVER         RARELY      SOMETIMES       OFTEN         ALL THE  
                                                                                             TIME 
_____________________________________________ 
 
21. I am embarrassed by my skin condition    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
22. My skin condition is a problem for the people I love    .    .    .  
 
   1              2              3               4              5 
 
23. I am frustrated by my skin condition    .    .    .    .    .    .    .    .  
 
   1              2              3               4              5 
 
24. My skin is sensitive    .    .    .    .    .    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
25. My skin condition affects my desire to be with people    .    .  
 
   1              2              3               4              5 
 
26. I am humiliated by my skin condition    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
27. My skin condition bleeds    .    .    .    .    .    .    .    .    .    .    .    
 
   1              2              3               4              5 
 
28. I am annoyed by my skin condition    .    .    .    .    .    .    .    .   
 
   1              2              3               4              5 
 
29. My skin condition interferes with my sex life    .    .    .    .    .  
 
   1              2              3               4              5 
 
30. My skin condition makes me tired    .    .    .    .    .    .    .    .    . 
 
   1              2              3               4              5 
 
 
 
 

SAP_001.pdf: 
Integrium, LLC 
Processa Pharmaceuticals, Inc. 
Version: 2.0 
PCS499-NL01 
Statistical Analysis Plan 
Page 1 of 25 
THIS DOCUMENT CONTAINS CONFIDENTIAL AND PROPRIETARY INFORMATION.   
IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
INTEGRIUM, LLC 
BIOMETRICS DEPARTMENT 
Clinical Study Protocol: PCS499-NL01 
An Open-Label Study to Evaluate the Safety and Tolerability of 
PCS499 for the treatment of Necrobiosis Lipoidica 
Statistical Analysis Plan (SAP) Documentation 
Author(s): 
Oliver Lopez, PhD 
Sponsor: 
Processa Pharmaceuticals, Inc. 
Document status: 
Version 2.0 
Dates: 
10AUG2020 
Number of pages: 
25 
NCT03698864




Integrium, LLC 
 
Processa Pharmaceuticals, Inc. 
Version: 2.0 
 
PCS499-NL01  
Statistical Analysis Plan 
 
  
 
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IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Document History 
 
Version 
Number 
Author 
Date  
Change 
1.0 
O. Lopez 
18DEC2019 
Initial version 
2.0 
O. Lopez 
10AUG2020 Updated changes and promoted document 
version to an intermediate draft between versions 
1.0 and 2.0 of this document.  
Changes include: 
- 
Update drug accountability definition for 
expected number of tablets and 
percentage of tables taken 
- 
Updated the scoring scheme for Skindex-
29 outcomes 
- 
Updated the calculations of the difference 
between dates to not include an additional 
day 
- 
Split table 14.2.01.1 into two tables, 
Lesions and Ulcers separately 
- 
Reordered table output related to lesions 
and ulcers, moving ulcers specific output 
before lesion specific output 
- 
Removed table 14.1.4.1 since data was 
not coded  
- 
Defined the derivation for QTcF as an 
additional ECG parameter to summarize 
- 
Updated table output count 
- 
Removed tables  
- 
Removed all figures  
- 
Incorporated sponsor commentary 
 


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Version: 2.0 
 
PCS499-NL01  
Statistical Analysis Plan 
 
  
 
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IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
Glossary of Abbreviations 
 
3D 
Three dimensional 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline Phosphatase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
BID 
Twice a day 
CKD 
Chronic kidney disease 
CYP 
Cytochrome P-450 
DLQI 
Dermatology Quality of Life Index 
ECG/EKG 
Electrocardiogram 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HbA1c 
Glycosylated hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HRQL 
Health related quality of life 
IB 
Investigational Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IGA:NL 
Investigator Global Assessment: Necrobiosis Lipoidica 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
LTBI 
Latent tuberculosis infection 


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Statistical Analysis Plan 
 
  
 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
formula 
Modification of Diet in Renal Disease formula 
NBUVB 
Narrow Band Ultraviolet B therapy 
NL 
Necrobiosis Lipoidica 
NLCUS 
Necrobiosis Lipoidica Color and Ulcer Scale 
PGA 
Physicians Global Assessment 
PHI 
Protected Health Information 
PtGA 
Patient Global Assessment 
SAE 
Serious adverse event 
SOC 
System Organ Class 
TB 
Tuberculosis 
TGF-β 
Transforming growth factor beta 
TID 
Three times a day 
TNF 
Tumor necrosis factor 
TORO 
Transfer of Regulatory Obligations 
ULN 
Upper Limit of Normal 
UVA/UVB 
Ultraviolet A /Ultraviolet B phototherapy 
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WOCBP 
Women of Child-Bearing Potential 


Integrium, LLC 
 
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Statistical Analysis Plan 
 
  
 
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Table of Contents 
Signature Page ............................................................................................................................ 2 
Document History ....................................................................................................................... 3 
Glossary of Abbreviations .......................................................................................................... 4 
1. 
Introduction ......................................................................................................................... 8 
1.1. 
Scope........................................................................................................................ 8 
1.2. 
Study Background/Plan ........................................................................................... 8 
1.3. 
Study Objectives ...................................................................................................... 9 
1.4. 
Study Endpoints ....................................................................................................... 9 
2. 
Detailed Statistical Methods .............................................................................................. 11 
2.1. 
General Statistical Methods ................................................................................... 11 
2.2. 
Study Populations .................................................................................................. 11 
2.3. 
Disposition of Patients ........................................................................................... 11 
2.4. 
Demographics and Patient Baseline Characteristics .............................................. 12 
2.5. 
Study Drug Accountability .................................................................................... 12 
2.6. 
Prior and Concomitant Medications ...................................................................... 12 
2.7. 
Pregnancy Test ....................................................................................................... 13 
2.8. 
Protocol Deviations ............................................................................................... 13 
2.9. 
Safety Evaluations ................................................................................................. 13 
2.9.1. Adverse Events ...................................................................................................... 13 
2.9.2. Laboratory Parameters ........................................................................................... 14 
2.9.3. Vital Signs ............................................................................................................. 14 
2.9.4. Physical Examination ............................................................................................ 14 
2.9.5. Electrocardiogram .................................................................................................. 15 
2.10. Exploratory Efficacy Analyses .............................................................................. 15 
2.10.1. Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) ...................... 15 
2.10.2. Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) ....................................... 16 
2.10.3. Physician Global Assessment (PGA) .................................................................... 16 
2.10.4. Patient Global Assessment (PtGA) ........................................................................ 16 
2.10.5. Lesion/ulcer surface area ....................................................................................... 16 
2.10.6. Dermatology Life Quality Index (DLQI) .............................................................. 17 
2.10.7. Skindex-29 ............................................................................................................. 17 
2.10.8. Variables in Ulcerated Patients .............................................................................. 18 
2.10.9. Biomarkers ............................................................................................................. 19 


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2.11. Interim Analyses .................................................................................................... 19 
2.12. Other Analyses ....................................................................................................... 19 
2.13. Sample Size and Power Considerations ................................................................ 19 
2.14. Handling Missing Data .......................................................................................... 19 
2.15. Computer Systems and Packages Used for Statistical Analyses ........................... 20 
3. 
Data Listing Shells ............................................................................................................ 21 
3.1. 
Data Listings Table of Contents ............................................................................ 21 
3.2. 
Data Listings .......................................................................................................... 22 
4. 
Summary Table and Figure Shells .................................................................................... 23 
4.1. 
Post-text Table of Contents ................................................................................... 23 
4.2. 
Summary Tables .................................................................................................... 25 
4.3. 
Post-text Figures Tables of Contents ..................................................................... 25 
4.4. 
Table Shells ........................................................................................................... 25 
 


Integrium, LLC 
 
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Statistical Analysis Plan 
 
  
 
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IT MUST NOT BE REPRODUCED OR DISCLOSED TO OTHERS WITHOUT PRIOR PERMISSION FROM INTEGRIUM, LLC. 
1. 
Introduction 
1.1. 
Scope 
This document contains detailed information to aid the production of the Clinical Study 
Report (CSR) including summary tables and listings for trial PCS499-NL01.  The contents of 
this document were reviewed by the sponsor, Processa Pharmaceuticals, Inc., and the trial 
biostatistician at Integrium. 
1.2. 
Study Background/Plan 
This is an open-label study that will evaluate the safety of PCS499 for the treatment of 
necrobiosis lipoidica (NL) and will inform the design of future studies. The study will consist 
of a 6-month treatment period followed by a 6-month extension period. The test article is 
PCS499 modified release 300mg tablets. 
 
Approximately 12 NL patients (6-9 patients without ulceration and 3-6 patients with 
ulceration) who also meet other inclusion/exclusion criteria will be enrolled in the study. 
Patients will be administered PCS499 900 mg BID. Primary safety and exploratory efficacy 
analysis will be performed after the last patient completes the 6-month visit. Patients will have 
the option to continue dosing in an extension period for up to an additional 6 months. 
 
All patients will take PCS499 300 mg BID with food for 1 week beginning at Visit 2/Day 0 
(Baseline). At the Visit3/Day 7 and Visit4/Day 14 phone Safety Check-in, patients will be 
instructed to increase their morning dose to 3 tablets and their evening dose to 3 tablets 
(PCS499 900 mg BID with food) if satisfactory tolerability to PCS499 300 mg BID is 
reported. Patients will continue at their assigned dose for the remainder of the study.  
 
During the dosing period, if a patient receiving PCS499 900 mg BID experiences 
unacceptable toxicity (i.e., non-transient, moderate to severe limitation in activity) that is 
deemed by the Investigator to be related to study drug, his/her dose will be changed to 
PCS499 600 mg TID with food at the discretion of the Investigator in consultation with the 
Medical Monitor. If this dose is not tolerated, the dose will be further reduced to PCS499 600 
mg BID with food at the discretion of the Investigator in consultation with the Medical 
Monitor. If 4 out of the first 6 patients dosed in this study require dose modification or 
discontinue from the study due to a drug-related adverse event within 1 month of dosing, 
consideration will be made to change the starting dose to 600 mg TID with food for all 
subsequent patients. If clinically indicated at any time during the study, study medication will 
be discontinued. However, patients will not be discontinued from the study due to cessation of 
study drug. Efficacy and safety data will be collected at regular intervals throughout the 
course of the study. 
 


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An analysis will be conducted to assess safety and exploratory efficacy after the last patient 
completes the 3-month visit and then again when the last patient completes the 6-month visit. 
A final analysis of patients enrolled in the study will be conducted after the last patient 
completes the 12-month visit. 
1.3. 
Study Objectives 
1.3.1. Primary Objective 
The primary objective of this study is: 
• To evaluate the safety and tolerability profile of PCS499 in patients with Necrobiosis 
Lipoidica.   
1.3.2. Secondary Objective 
There are no secondary objectives defined for this study. 
1.3.3. Exploratory Objectives 
The exploratory objectives for this study are: 
• To evaluate the efficacy of PCS499 on reducing clinical findings related to 
Necrobiosis Lipoidica. 
• To assess the pharmacodynamic activity of PCS499 on immunologic and 
inflammatory biomarkers. 
1.4. 
Study Endpoints 
1.4.1. Primary Endpoints 
The following safety parameters will be recorded at regular intervals during the study: 
• Adverse Events (AEs) (by type, severity, and relatedness) at each visit. 
• Changes in safety clinical laboratory testing and vital signs at each visit. 
• Changes in electrocardiograms (ECGs) at Months 1, 3, 6, 9, and 12. 
1.4.2. Secondary Endpoint 
There are no secondary endpoints defined for this study 
1.4.3. Exploratory Endpoints 
The exploratory endpoints are: 
• Proportion of patients with scores of clear or almost clear (0 or 1) of the reference 
lesion on the Investigator Global Assessment: NL (IGA:NL) Activity Scale at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 1-point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 2-point decrease in IGA:NL Activity score of the 
reference lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 


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• Proportion of patients with ≥ 1-point decrease in the Color score on the Necrobiosis 
Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at Months 1, 2, 3, 4, 
5, 6, 9, and 12. 
• Change from Baseline in Physician Global Assessment (PGA) score at Months 1, 2, 3, 
4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 
9, and 12. 
• Percent change from Baseline in total lesion(s) surface area of inflammation/erythema 
based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on photograph at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Dermatology Quality of Life Index (DLQI) score at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Change form Baseline in Skindex-29 score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Change from Baseline in Patient Global Assessment (PtGA) visual analog scale (VAS) 
score at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to obtaining scores of clear or almost clear (0 or 1) of reference lesion on the 
IGA:NL Activity scale. 
• Incidence of new ulceration (defined as a site with no previous ulceration) at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to new ulceration. 
 
Patients with ulceration at Baseline only: 
• Proportion of patients with ≥ 1-point decrease in the Ulcer score on the Necrobiosis 
Lipoidica Color and Ulcer Scale (NLCUS) of the reference lesion at Months 1, 2, 3, 4, 
5, 6, 9, and 12. 
• Percent change from Baseline in reference ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in total ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference ulcer surface area based on photograph at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Incidence of complete wound closure of reference ulcer (defined as skin re-
epithelialization without draining or dressing requirements confirmed at two 
consecutive study visits at least 2 weeks apart) at Months 2, 3, 4, 5, 6, 9, and 12. 
• Time to complete wound closure of reference ulcer. 
• Incidence of recurrence of reference ulcer after complete wound closure at Months 3, 
4, 5, 6, 9, and 12. 
• Time to recurrence of reference ulcer after complete wound closure. 
• Change from Baseline in reference ulcer volume based on 3D scanning at Months 1, 2, 
3, 4, 5, 6, 9, and 12. 
 


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Exploratory Serum Biomarkers: 
• Change from baseline in TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and MCP-1 at 
Months 1, 3, 6, 9 and 12. 
• Change from baseline in C-peptide levels at Months 1, 3, 6, 9 and 12. 
2. 
Detailed Statistical Methods 
2.1. 
General Statistical Methods 
The statistical analysis of the data obtained from this study will be the responsibility of the 
study biostatistician. If, after the study has begun, changes are made to the statistical analysis 
plan, these deviations will be listed in the Documentation of Statistical Decisions document, 
along with an explanation as to why they occurred. 
Continuous data will be summarized using descriptive statistics (number, mean, median, 
standard deviation, minimum, and maximum values). Categorical data will be summarized 
using frequency tables (frequency and percent). 
If at the end of the study the Efficacy Population and the Per Protocol Population include the 
same patients, then only table and figure output for the Efficacy Population will be produced. 
2.2. 
Study Populations 
Safety Population 
All patients enrolled in the study who received at least 1 dose of treatment. 
Efficacy Population (mITT) 
All patients enrolled in the study who received at least 1 dose of treatment and have at least 1 
post-baseline efficacy assessment. 
Per-Protocol Population (PP) 
All patients enrolled in the study who received at least one dose of study treatment, have at 
least 1 post-baseline efficacy assessment, and did not have a major protocol violation. 
Biomarker Population 
All patients enrolled in the study who received at least 1 dose of treatment, participated in 
biomarker evaluations, and have appropriate samples available for analysis. 
2.3. 
Disposition of Patients 
The number and percentage of patients entering, discontinuing or completing the study will be 
presented. Reasons for withdrawal pre- and post-randomization will also be summarized. 
 
 
 
 


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2.4. 
Demographics and Patient Baseline Characteristics 
Demographic data (age, sex, race, and ethnicity), baseline characteristics (age, weight, height, 
and body mass index), and general medical history will be summarized by means of 
descriptive statistics or frequency tables. 
2.5. 
Study Drug Accountability  
Treatment compliance will be assessed via tablet counts. Patients will be dispensed kits of 
study medication and dose and frequency will be recorded starting at Visit2/Day 0 (Baseline) 
and at every clinic visit starting at Month 1/Day 28 through Month 11/Day 270. The number 
of tablets returned will be captured starting at Month 1/Day 28 and repeated at every clinic 
visit through Month 12/Day 360. 
 
The actual number of tablets taken, expected number of tablets taken based on the dose and 
frequency assigned, and percentage of tablets taken will be listed and summarized by 
descriptive statistics (n, mean, median, standard deviation, minimum and maximum) by clinic 
visit and overall.  
 
The dose and frequency of dosage will be listed and summarized in frequency tables by clinic 
visit.  
 
Actual number of tablets taken will be defined as the difference between the number of tablets 
dispensed and the number of tablets returned for each clinic visit and overall. Expected 
number of tablets number of tablets will be calculated as the maximum number of tablets 
based on the number of days between dispensation and collection of study drug, and the 
expected study dose and regimen for that particular study month. The percentage of tablets 
taken will be the ratio of  actual number of tablets taken and expected number of tablets taken 
multiplied by 100.  
 
2.6. 
Prior and Concomitant Medications 
Prior and concomitant medications will be identified using the September 2018 release 
version of the World Health Organization (WHO) Drug dictionary.  
 
Concomitant medications are defined as any medication taken by the patient during the course 
of the study following the first dose.  
 
Prior medications are defined as any medication taken by the patient within 30 days of their 
first dose of study medication. 
 
Section 2.15 describes the imputation rules for partial dates. All medications will be presented 
in a data listing and summarized by frequency counts. 
 
 


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2.7. 
Pregnancy Test 
The results of the pregnancy tests will be listed separately from hematology and urinalysis 
laboratory results. A serum pregnancy test will be administered at the screening visit and urine 
pregnancy tests will be administered at subsequent visits.  
2.8. 
Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be listed 
and summarized.  
2.9. 
Safety Evaluations 
All safety summaries will be presented for the Safety Population. 
2.9.1. Adverse Events 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.1. 
AEs occurring on or before Visit 2/Day 0 (Baseline) prior to drug administration will be 
regarded as “pre-treatment” and will not be included in the treatment emergent AE 
tabulations. 
Treatment Emergent Adverse Events (TEAEs) are defined as any AE that starts or increases 
in severity after drug administration at Visit 2/Day 0 and will be summarized. 
Listings of all AEs will be provided and separately by: 
• Treatment Emergent AEs 
• AEs leading to discontinuation of study 
• Serious AEs 
An overall summary table will be provided showing the number and percentage of patients 
with any: 
• Pre-Treatment AEs 
• TEAE 
• Severe TEAE 
• Serious TEAE 
• Drug-related TEAE 
• Drug-related severe TEAE 
• Drug-related serious TEAE 
• TEAE leading to withdrawal of study drug 
• TEAE leading to change in study drug dose 
• TEAE with outcome death 
The number of reported AEs will also be shown in this summary table. 
Summary tables for the following will also be presented: 
• Summary of TEAEs by Body System and Preferred term, 


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• Summary of TEAEs by Severity, 
o If a patient has reported the same treatment emergent adverse event multiple 
times then the adverse event with the highest severity will be summarized. 
• Summary of Drug-related TEAEs, and 
• Summary of Drug-related TEAEs by Severity.  
o If a patient has reported the same drug-related treatment emergent adverse 
event multiple times, then the adverse event with the highest severity will be 
summarized. 
Inferential statistical analysis comparing the AE data between active and placebo is not 
planned. 
2.9.2. Laboratory Parameters 
Clinical Safety Laboratory assessments will include hematology, chemistry and urinalysis, 
coagulation, and HgbA1c. Screening panels will include virus serology (HIV, hepatitis B and 
C, and TB) and FSH (to confirm post-menopausal status).  
 
Observed values of continuous safety laboratory parameters and corresponding changes from 
baseline will be summarized by descriptive statistics (n, mean, median, standard deviation, 
minimum and maximum) by visit. Categorical safety laboratory parameters will be 
summarized by frequency tables.   
 
A clinically significant change from baseline (Visit 2/Day 0) will be recorded as an AE if 
deemed appropriate by the Investigator. 
 
All laboratory outcomes will be listed.  
2.9.3. Vital Signs 
Observed values of vital sign parameters (temperature, SBP/DBP, heart rate, and respiration 
rate) and corresponding changes from baseline (Visit 2/Day 0) will be listed and summarized 
by descriptive statistics (n, mean, median, standard deviation, minimum and maximum) by 
visit. 
A clinically significant change from baseline (Visit 2/Day 0) will be recorded as a TEAE if 
deemed appropriate by the Investigator. 
2.9.4. Physical Examination  
Individual physical examination findings will be listed by visit. A clinically significant change 
from Baseline (Visit 2/Day 0) will be recorded as a TEAE if deemed appropriate by the 
Investigator.  
Results of the physical examination will be listed and summarized in frequency tables by 
body system. 


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A clinically significant change from Screening will be recorded as an AE if deemed 
appropriate by the Investigator. 
2.9.5. Electrocardiogram 
Observed values of continuous ECG parameters and corresponding changes Visit 2/Day 0 will 
be summarized by descriptive statistics (n, mean, median, standard deviation, minimum and 
maximum). Results of ECG measurements will be summarized in frequency tables by visit. 
A clinically significant change from baseline (Visit 2/Day 0) will be recorded as an AE if 
deemed appropriate by the Investigator.  
 
Fridericia’s formula will be used to derive the QT correction, QTcF parameter. QTcF is 
defined as the QT interval divided by the cubed root of the RR interval (QTcF = QT / ∛RR). 
2.10. Exploratory Efficacy Analyses 
2.10.1. Investigator Global Assessment: Necrobiosis Lipoidica (IGA:NL) 
The IGA:NL will be assessed at every visit the patient visits the clinic (i.e. excluding Visit 3 
and 4).  The IGA:NL will be used to assess the presence and severity of necrobiosis lesions. 
The two scales that will be determined are Activity and Damage. Activity has a 6-point scale 
(0-5) and Damage a 3-point scale (0-2).  
 
The outcomes from this assessment will treated as categorical and will be listed and 
summarized by frequency tables. 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit. 
• Proportion of patients with scores of clear or almost clear (0 or 1) of the reference 
lesion on the Activity Scale at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 1-point decrease in Activity score of the reference lesion 
at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Proportion of patients with ≥ 2-point decrease in Activity score of the reference lesion 
at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to obtaining scores of clear or almost clear (0 or 1) of reference lesion on the 
IGA:NL Activity scale. 
Proportion of subjects with >= 1 point decrease or >=2 decrease in Activity score will be 
determined from the baseline Visit 2/Day 0. 
 
Time to obtaining scores of clear or almost clear (0 or 1) will be defined as the difference 
between the date when this outcome of interest is determined and the date of first study drug 
exposure. 
 
 


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2.10.2. Necrobiosis Lipoidica Color and Ulcer Scale (NLCUS) 
The NLCUS will be assessed starting at Visit 2/Day 0 and at every clinic visit through Month 
12. The NLCUS will be used to assess the color and ulcer of necrobiosis lesions. The three 
scales that will be determined are Color/Inflammation, Induration, and Ulcer. 
Color/Inflammation has a 5-point scale (0-4), Induration a 5-point scale (0-4), and Ulcer a 3-
point scale (0-2).  
 
The outcomes from this assessment will treated as categorical and will be listed and 
summarized by frequency tables. 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit. 
• Proportion of patients with ≥ 1-point decrease in the Color score of the reference 
lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Among patients with ulceration at Baseline only: Proportion of patients with ≥ 1-point 
decrease in the Ulcer score on the Color and Ulcer Scale (NLCUS) of the reference 
lesion at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
2.10.3. Physician Global Assessment (PGA) 
The PGA will be assessed using a 10 cm VAS ranging from “none” to “extreme activity”. The 
distance marked in centimeters from “none” to “extreme activity” and the change from 
baseline (Visit 2/Day 0) will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit.  
2.10.4. Patient Global Assessment (PtGA) 
The PtGA will be assessed using a 10 cm VAS ranging from “not at all” to “very severe”. The 
distance marked in centimeters from “not at all” to “very severe” and the change from 
baseline (Visit 2/Day 0) will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit. 
2.10.5. Lesion/ulcer surface area 
Surface area of the lesions(s)/ulcer will be measured by the Investigator and by photography. 
Continuous outcomes, separately for those measured by the Investigator and by photography, 
and changes from baseline (Visit 2/Day 0), will be listed and summarized by descriptive 
statistics (n, mean, median, standard deviation, minimum and maximum) by visit. 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit. 
• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 
9, and 12. 
• Percent change from Baseline in total lesion(s) surface area of inflammation/erythema 
based on Investigator measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 


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• Percent change from Baseline in reference lesion surface area of 
inflammation/erythema based on photograph at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit, for patients with ulceration at 
Baseline only. 
• Percent change from Baseline in reference ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in total ulcer surface area based on Investigator 
measurement at Months 1, 2, 3, 4, 5, 6, 9, and 12. 
• Percent change from Baseline in reference ulcer surface area based on photograph at 
Months 1, 2, 3, 4, 5, 6, 9, and 12. 
2.10.6. Dermatology Life Quality Index (DLQI) 
The DLQI consists of 10 items and covers six sub-scales including: symptoms and feelings, 
daily activities, leisure, work and school, personal relationships, and treatment. Scores range 
from 0 to 30 with higher scores indicating poorer health related quality of life (HRQL). 
 
Each question is scored on a four-point Likert scale (0-3) where the score of 0 can represent 
one of three possible scenarios: 
• Score of 0 can mean “Not at all”, “Not relevant”, or “Question unanswered” 
• Score of 1 means “A little” 
• Score of 2 means “A lot” 
• Score of 3 means “Very much” 
 
The DLQI is administered starting at Visit 2/Day 0 and at every clinic visit until Month 12. 
Total and sub-scale specific continuous outcomes, and the change from baseline (Visit 2/Day 
0), will be listed and summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum and maximum) by visit. 
 
The six sub-scales include the following items and have the noted maximum score 
• Symptoms and feelings includes Questions 1 and 2 with a maximum score of 6 
• Daily activities includes Questions 3 and 4 with a maximum score of 6 
• Leisure includes Questions 5 and 6 with a maximum score of 6 
• Work and school includes Question 7 with a maximum score of 3 
• Personal relationships includes Questions 8 and 9 with a maximum score of 6 
• Treatment includes Question 10 with a maximum score of 3 
2.10.7. Skindex-29 
The Skindex-29 includes 29-items with 3 domains: Symptoms, Emotions and Functioning. 
Each domain is scored from 0 to 100 with higher scores indicating a lower quality of life and 
a higher impact of the skin disease. Scoring is based on the Skindex-29 documentation and is 
done as follows: 


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• Never = 0 
• Rarely = 25 
• Sometimes = 50 
• Often = 75 
• All the time = 100 
 
The Skindex-29 is administered starting at Visit 2/Day 0 and at every clinic visit until Month 
12. Total and domain specific continuous outcomes, and the change from baseline (Visit 
2/Day 0), will be listed and summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum and maximum) by visit 
 
The three domains include the following items 
• Emotions includes Questions (10) 3, 6, 9, 12, 13, 15, 21, 23, 26, and 28 
• Symptoms includes Questions (7) 1, 7, 10, 16, 19, 24, and 27 
• Functioning includes Questions (12) 2, 4, 5, 8, 11, 14, 17, 20, 22, 25, 29, and 30 
2.10.8. Variables in Ulcerated Patients 
Closure of Reference Ulcer 
Closure of reference ulcer is defined as skin re-epithelialization without drainage or dressing 
requirements confirmed at two consecutive study visits 2 weeks apart. Time to complete 
wound closer will be defined as the difference between the date when wound closure is 
determined and the date of first dose. Time to closure will be listed and summarized by 
descriptive statistics (n, mean, median, standard deviation, minimum and maximum).  
 
Continuous outcomes for ulcers that do not close will be included in the listing output but will 
be excluded from the summary table output.  
 
Ulcer volume 
Ulcer volume will be assessed using a 3D-imaging system. Data for ulcer volume will be 
provided to Integrium by an external vendor. Continuous outcome for volume and changes 
from baseline (Visit 2/Day 0) will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum). 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit. 
• Incidence of new ulceration (defined as a site with no previous ulceration) at Months 
1, 2, 3, 4, 5, 6, 9, and 12. 
• Time to new ulceration defined as the difference between the date the new ulceration 
is reported and the date of first dose administration. 
 
The outcomes detailed below will be listed and summarized by descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) by visit, separately for patients with 
ulceration at Baseline only. 


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• Incidence of complete wound closure of reference ulcer (defined as skin re-
epithelialization without draining or dressing requirements confirmed at two 
consecutive study visits at least 2 weeks apart) at Months 2, 3, 4, 5, 6, 9, and 12. 
• Time to complete wound closure of reference ulcer. 
• Incidence of recurrence of reference ulcer after complete wound closure at Months 3, 
4, 5, 6, 9, and 12. 
• Time to recurrence of reference ulcer after complete wound closure. 
• Change from Baseline in reference ulcer volume based on 3D scanning at Months 1, 2, 
3, 4, 5, 6, 9, and 12. 
2.10.9. Biomarkers 
Blood collection for biomarker outcomes will occur at Visit 2/Day 0 and Months 1, 3, 6, 9, 
and 12. Selected serum biomarkers include TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17 and 
MCP-1. Continuous biomarker outcomes and changes from baseline (Visit 2/Day 0) will be 
listed and, whenever possible, summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum and maximum), separately for all patients and for patients with ulceration 
at Baseline only.  
 
Additionally, C-peptide levels will be measured to assess whether there is any benefit of 
PCS499 in maintaining natural insulin production. Continuous C-peptide level outcomes and 
changes from baseline (Visit 2/Day 0) will be listed and summarized by descriptive statistics 
(n, mean, median, standard deviation, minimum and maximum), for all patients and separately 
for patients with ulceration at Baseline only. 
2.11. Interim Analyses 
No interim analyses are planned.    
2.12. Other Analyses 
No other analyses are planned. 
2.13. Sample Size and Power Considerations 
This study is not powered for statistical significance. No sample size calculations were 
performed. 
2.14. Handling Missing Data 
Listings will be provided for all data. Descriptive statistics will be provided for all planned 
visits as provided on the Case Report Forms (CRFs). No imputations for missing data will be 
used in calculations.  
Visit windows will not be used in this study. Likewise, unscheduled visits will not be 
reassigned a visit number based on the visit date. 


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Dates related to the medications will be imputed using the rules below in an effort to 
categorize them properly into the summary tables.  
Imputing partial or missing start dates: 
• If the year is unknown, then the start date will not be imputed. The date will remain 
missing. 
• If the month is unknown, impute the month as January. 
• If the day is unknown, impute the day as ‘01’. 
Impute partial or missing stop dates: 
• If the year is unknown, then the stop date will not be imputed. The date will remain 
missing. 
• If the month is unknown, impute the month as December. 
• If the day is unknown, impute the day to be the last day of the month. 
If an imputed stop date is greater than the date of study completion/discontinuation date of the 
study, then the imputed stop date will be set equal to the date of completion/discontinuation 
date.  
The imputed dates will be stored in the analysis datasets along with the original dates as 
recorded by the sites.  
2.15. Computer Systems and Packages Used for Statistical Analyses 
SAS® version 9.4 on the Microsoft Server 2008 R2 64-bit platform will be used for all 
analyses.  All computations will be performed using SAS®.  The exact form of the various 
algorithms will be the SAS® defaults.  The output from any SAS® procedure will be used in 
the tables using SAS® macros. 


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3. 
Data Listing Shells 
3.1. 
Data Listings Table of Contents 
The following post-text listings will be generated. 
Listing Number 
Listing Title 
16.2.1 
Patient Completion / Discontinuation 
16.2.2 
Protocol Deviations 
16.2.3 
Population Definitions 
16.2.4.1 
Demographics and Baseline Characteristics 
16.2.4.2 
Patient Eligibility and Informed Consent 
16.2.4.3 
Medical/Surgical/Procedural History 
16.2.4.4 
Necrobiosis Lipoidica History 
16.2.4.5.1 
Reference Lesion History 
16.2.4.5.2 
Reference Ulcer History  
16.2.4.6 
Non-drug Treatment History 
16.2.4.7 
Prior and Concomitant Medications 
16.2.4.9 
Safety Check In 
16.2.5 
Treatment Compliance 
16.2.6.1.1 
Reference Lesion Measurement Results 
16.2.6.1.2 
Reference Ulcer Measurement Results 
16.2.6.1.3 
Additional Lesion and Ulcer Reporting Results 
16.2.6.2.1 
Investigator Global Assessment: Necrobiosis Lipoidica Reference Lesion 
(IGA:NL) Results 
16.2.6.2.2 
Color and Ulcer Scale Reference Lesion (NLCUS) Results 
16.2.6.2.3 
Global Assessment Results 
16.2.6.3.1 
Dermatology Life Quality Index Results 
16.2.6.3.2 
Skindex-29 - Dermatology Survey Results 
16.2.6.4 
Biomarkers 
16.2.6.5 
Reference Lesion and Ulcer Photography 
16.2.7.1 
Adverse Events 
16.2.7.2 
Adverse Events Leading to Discontinuation of Study 
16.2.7.3 
Serious Adverse Events 


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Listing Number 
Listing Title 
16.2.8.1 
Safety Laboratory Results - Hematology 
16.2.8.2 
Safety Laboratory Results - Chemistry 
16.2.8.3 
Safety Laboratory Results - Urinalysis 
16.2.8.4 
Safety Laboratory Results - Infectious Serology 
16.2.9.1 
Vital Sign Results 
16.2.9.2 
Physical Examination Results 
16.2.9.3 
Electrocardiogram Results 
 
3.2. 
Data Listings 
All patients and all data will be presented in the listings. The listings will be sorted by patient 
number. All listings will contain the patient number and the treatment. 
There are currently 34 listings that are planned to be generated. The 34 listings are broken 
down as follows: 18 Standard Unique, 0 Standard Repeat 16 Non-Standard Unique and 0 
Non-Standard Repeat. 
 


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4. 
Summary Table and Figure Shells 
4.1. 
Post-text Table of Contents 
The following post-text tables will be generated. 
Table Number 
Table Title 
14.1.1.1 
Summary of Patient Disposition – Modified Intention-to-Treat Population  
14.1.1.2 
Summary of Patient Disposition – Safety Population  
14.1.1.3 
Summary of Patient Disposition – Per Protocol Population  
14.1.2.1 
Summary of Demographics and Baseline Characteristics – Modified Intention-to-
Treat Population  
14.1.2.2 
Summary of Demographics and Baseline Characteristics – Safety Population  
14.1.2.3 
Summary of Demographics and Baseline Characteristics – Per Protocol 
Population  
14.1.3.1 
Summary of Medical/Surgical/Procedural History – Safety Population  
14.1.3.2 
Necrobiosis Lipoidica History – Safety Population  
14.1.3.3 
Necrobiosis Lipoidica Reference Lesion and Ulcer History – Safety Population  
14.1.4.1 
Summary of Prior Medications – Safety Population  
14.1.4.2 
Summary of Concomitant Medications – Safety Population  
14.1.5.1 
Summary of Treatment Compliance – Modified Intention-to-Treat Population  
14.1.5.2 
Summary of Treatment Compliance – Safety Population  
14.1.5.3 
Summary of Treatment Compliance – Per Protocol Population  
14.2.01.1.1 
Summary of Reference Ulcer Measurement Results – Modified Intention-to-
Treat Population 
14.2.01.1.2 
Summary of Reference Lesion Measurement Results – Modified Intention-to-
Treat Population 
14.2.01.2 
Summary of Reference Lesion and Ulcer Measurement Results – Per Protocol 
Population 
14.2.02.1 
Summary of Reference Ulcer Measurement Results -External Data – Modified 
Intention-to-Treat Population 
14.2.02.2 
Summary of Reference Ulcer Measurement Results -External Data – Per 
Protocol Population 
14.2.03.1 
Summary of Variables in Ulcerated Patients – Modified Intention-to-Treat 
Population 
14.2.03.2 
Summary of Variables in Ulcerated Patients – Per Protocol Population 


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Table Number 
Table Title 
14.2.04.1 
Summary of Reference Lesion Measurement Results - External Data – Modified 
Intention-to-Treat Population 
14.2.04.2 
Summary of Reference Lesion Measurement Results -External Data – Per 
Protocol Population 
14.2.05.1 
Summary of Investigator Global Assessment: Necrobiosis Lipoidica Reference 
Lesion (IGA:NL) Results – Modified Intention-to-Treat Population  
14.2.05.2 
Summary of Investigator Global Assessment: Necrobiosis Lipoidica Reference 
Lesion (IGA:NL) Results – Per Protocol Population  
14.2.06.1 
Summary of Color and Ulcer Scale Reference Lesion (NLCUS) Results – 
Modified Intention-to-Treat Population  
14.2.06.2 
Summary of Color and Ulcer Scale Reference Lesion (NLCUS) Results – Per 
Protocol Population  
14.2.07.1 
Summary of Global Assessment Results – Modified Intention-to-Treat 
Population  
14.2.07.2 
Summary of Global Assessment Results – Per Protocol Population  
14.2.08.1 
Summary of Dermatology Life Quality Index Results – Modified Intention-to-
Treat Population  
14.2.08.2 
Summary of Dermatology Life Quality Index Results – Per Protocol Population  
14.2.09.1 
Summary of Skindex-29 - Dermatology Survey Results – Modified Intention-to-
Treat Population  
14.2.09.2 
Summary of Skindex-29 - Dermatology Survey Results – Per Protocol 
Population  
14.2.10 
Summary of Biomarker Results – Biomarker Population  
14.3.1.1 
Overall Summary of Adverse Events – Safety Population  
14.3.1.2 
Summary of Treatment Emergent Adverse Events by Body System and Preferred 
Term – Safety Population  
14.3.1.3 
Summary of Treatment Emergent Adverse Events by Body System, Preferred 
Term and Severity – Safety Population  
14.3.1.4 
Summary of Treatment Emergent Adverse Events by Body System, Preferred 
Term and Relationship to Study Medication – Safety Population  
14.3.1.5 
Summary of Adverse Events Leading to Study Discontinuation – Safety 
Population  
14.3.1.6 
Summary of Serious Adverse Events – Safety Population  
14.3.5.1 
Summary of Laboratory Results - Hematology – Safety Population  
14.3.5.2 
Summary of Laboratory Results - Chemistry – Safety Population  


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Table Number 
Table Title 
14.3.5.3 
Summary of Laboratory Results - Urinalysis – Safety Population  
14.3.6.1 
Summary of Vital Signs Results – Safety Population 
14.3.6.2 
Summary of Electrocardiogram Results – Safety Population  
4.2. 
Summary Tables 
There are currently 45 tables that are planned to be generated. The 45 tables are broken down 
as follows: 16 Standard Unique, 4 Standard Repeat, 15 Non-Standard Unique and 10 Non-
Standard Repeat. 
4.3. 
Post-text Figures Tables of Contents 
There are no figures planned for this study. 
4.4. 
Table Shells 
The table shells can be found in a separate file. The following number of decimal places will 
be used when presenting summary statistics: 
• N to 0 decimal places 
• Minimum and maximum to the same number of decimal places as recorded in the raw 
data. 
• Means and medians, and confidence intervals to 1 more decimal place than is recorded in 
the raw data. Standard deviations to 2 more decimal places than is recorded in the raw 
data. 
• Percentages to 1 decimal place. 
 
The precision may be changed for individual endpoints as needed.