Clinical Protocol for Administration of Topical Pentoxifylline Gel on Behcet's Disease Oral Ulcers
Phase: PHASE2
Conditions: Behçet Disease Affecting Oral Mucosa
Sponsor: Ipekyolu Ilac Ltd. Sti

 
1
CLINICAL PROTOCOL 
Clinical Protocol for Administration of Topical 
Pentoxifylline Gel on Behçet’s Disease Oral Ulcers 
 
 
 
 
Principal Investigator: Dr. Gülen Hatemi 
Sponsor: İpekyolu İlaç Ltd. Şti. (Silk Road Therapeutics) 
Pre-IND Number: P140375 
Protocol Version: 04 
Unique Protocol ID: P140375V04 
Ethics Committee Approval Date: 21 February 2019 
 
 
21 February 2019 
 
 
 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 2
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................ 3 
PROTOCOL SUMMARY ........................................................................... 3 
LIST OF ABBREVIATIONS ...................................................................... 3 
INTRODUCTION ........................................................................................ 5 
RATIONALE AND TARGET POPULATION ......................................... 6 
PURPOSE ..................................................................................................... 6 
STUDY DESIGN .......................................................................................... 7 
STUDY TREATMENT .............................................................................. 10 
STUDY POPULATION ............................................................................. 11 
PATIENT SAFETY ................................................................................... 12 
STUDY PROCEDURES ............................................................................ 14 
Recruitment .................................................................................................................. 14 
Enrollment Visit Procedures ...................................................................................... 15 
Phone Visit Procedures ............................................................................................... 17 
Home Visit Procedures ................................................................................................ 17 
Clinic Visit Procedures ................................................................................................ 18 
End of Study Visit Procedures ................................................................................... 19 
Post Dosing Procedures ............................................................................................... 20 
Schedule of Activities .................................................................................................. 21 
STATISTICAL CONSIDERATIONS ...................................................... 22 
REFERENCES ........................................................................................... 23 
INVESTIGATOR AGREEMENT ............................................................ 25 
APPENDICES ............................................................................................ 26 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 3
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), applicable United States (US) Code of 
Federal Regulations (CFR). The Principal Investigator (PI) will assure that no deviation 
from, or changes to the protocol will take place without prior agreement from the 
Investigational New Drug (IND) sponsor, and documented approval from the Ethics 
Committee (EC), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human 
Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the EC for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the EC before the 
changes are implemented to the study.  All changes to the consent form will be EC 
approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent 
form. 
PROTOCOL SUMMARY 
 
Although Behçet’s Disease (BD) has no FDA-approved therapies, numerous clinical 
reports suggest that oral ulcers of BD may resolve when treated with systemic ingested 
PTX. We here propose to investigate the therapeutic potential of PTX dissolved in muco-
adherent formulation and directly applied to the oral lesions. This 60 patient, open label, 
proof of concept trial is designed to meet regulatory requirements for safety concerns 
while at the same time exploring the potential efficacy and clinical utility of this product. 
While topical PTX can never cure BD, the results of this trial may support its use in 
ameliorating the morbidity of these ulcers. 
LIST OF ABBREVIATIONS 
Abbreviation or Specialist Term Explanation 
AE 
Adverse Event 
AIDS 
Acquired Immune Deficiency Syndrome 
BD 
Behçet’s Disease 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CYP1A2 
Cytochrome P450 1A2 
EC 
Ethics Committee 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 4
Abbreviation or Specialist Term Explanation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HLA 
Human Leukocyte Antigen 
ICH 
 
International Conference on Harmonisation of 
Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug 
PI 
Principal Investigator 
POC 
Proof of Concept 
PTX 
Pentoxifylline 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
TNF 
Tumor Necrosis Factor 
US 
United States 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 5
INTRODUCTION 
 
Silk Road Therapeutics (İpekyolu İlaç Ltd. Şti.) is developing topical intraoral 
application of Pentoxifylline (PTX), for treatment of oral ulcers in Behçet’s Disease 
patients. 
Disease Background 
Behçet’s Disease (BD) is a complex, chronic, relapsing, multi-system inflammatory 
disorder that is characterized by oral ulcers, genital ulcers, ocular lesions and skin lesions. 
BD is usually a diagnosis of exclusion for which international diagnostic criteria have 
been developed (ISG, 1990, Hatemi et al., 2018). A genetic/immunologic basis for the 
disorder is suggested by its association with human leukocyte antigen HLA-B51, which 
occurs in around 60% of BD patients (Yazici, 1980, Gul, 2007, Kose, 2012, Alpsoy, 
2016, Yazici et al., 2018). There is a concentrated prevalence of BD along the Silk Road, 
an ancient trading route extending from Japan to Turkey, with Turkey having the highest 
prevalence of BD (Azizlerli et al., 2003). There are reports of clinical responsiveness to 
immune modulatory agents (Sakane et al., 1999, Saenz et al., 2000, Hatemi et al., 2015, 
Alpsoy, 2016,). 
Investigational Product Background Information 
Since 1999, ingested (p.o.) PTX has been FDA-licensed for the treatment of intermittent 
claudication.  The presumed mechanism of action is a rheological effect (i.e. an alteration 
in blood viscosity) of the drug, which enhances circulation. However, PTX also has well-
documented anti-TNF and other anti-inflammatory actions (Aviado et al., 1984, Zabel, et 
al., 1993, Entzian et al., 1997, González-Espinoza et al., 2012, Green et al., 2012, Jull et 
al., 2012).  Case series have suggested that ingested, systemic PTX may be beneficial for 
BD (Brenner, 1987, Yasui et al., 1996, Hisamatsu et al., 2001, Oliveira-Soares et al, 
2002, Thornhill et al., 2007, Appenzeller et al., 2011, Jull et al., 2012, Ahmadi et al., 
2016). For direct application on oral ulcers, a compounded formulation of PTX, applied 
topically, direct application of PTX on oral ulcers offers an opportunity for higher 
localized therapeutic concentrations, however, this has never been formally investigated 
in human clinical trials. 
Non-Clinical Studies 
A rich literature of PTX in wound healing exists. For detailed discussion of animal 
studies, see the investigator’s brochure. 
Clinical Studies 
PTX has a well-defined adverse event profile derived from 50 years of experience in the 
marketplace and thousands of participants in clinical trials for various indications 
(Aviado, 1984, Jull et al., 2012, Salhiyyah, et al, 2015). In a 2015 Cochrane review of 
clinical trials utilizing PTX treatment for intermittent claudication, analyzed 24 trials 
conducted to test the safety and efficacy of PTX among 3,777 participants. The authors 
concluded that PTX was shown to be generally well tolerated. The most commonly 
reported side effects were of gastrointestinal symptoms such as nausea (Salhiyyah et al, 
2015). Additionally, a 2012 Cochrane review of clinical trials utilizing PTX for treatment 
venous leg ulcers analyzed 12 trials conducted to test the safety and efficacy of PTX with 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 6
864 participants. Again, most reported adverse effects were gastrointestinal (Jull et al., 
2012). We anticipate our topical application of PTX will have fewer adverse effects while 
at the same time increasing local therapeutic concentrations.  
Risks/Benefit Assessment 
The risks of PTX are well characterized and previously reported adverse events were 
primarily gastrointestinal. We expect fewer GI symptoms to result from our topical 
application. Benefits of PTX to BD patients were previously reported as noted above. We 
anticipate these benefits can be optimized by a topical application, but require a 
controlled trial to test that hypothesis. 
RATIONALE AND TARGET POPULATION 
 
The most common symptom of BD is recurrent oral ulcers, which profoundly affects 
patients’ quality of life. The oral ulceration in BD is indistinguishable from recurrent 
aphthous stomatitis, they arise in crops as discrete, multiple aphthous ulcers, they are 
usually painful, persist for an average of two weeks, and subside without scarring (Saenz 
et al., 2000, Alpsoy, 2007, Taylor et al., 2014,). There is no cure or FDA-approved 
therapies for BD and the treatment of recurrent oral ulcers that are associated with BD is 
palliative (Taylor et al., 2014). We hypothesize that application of topical PTX will 
accelerate the healing of these lesions in a clinically meaningful way, and further 
hypothesize that topical PTX can become a valuable adjunct to any other systemic 
therapy for BD. 
PURPOSE 
 
Behçet’s Clinic at Cerrahpaşa Medical Faculty at the University of Istanbul has a long 
history of supportive care for BD patients and is recognized as the world leader in this 
regard. By comparing patients receiving colchicine as part of supportive care to those 
who also receive topical PTX in addition to colchicine as part of supportive care, we seek 
to prove the concept that topical PTX may have clinical value. Additionally, we seek to 
demonstrate the safety and practicality of using topical PTX in BD patients. 
Objectives 
The overall objective is to measure the effects of PTX on speed of oral ulcer healing over 
time. 
Primary Objectives 
The primary objective is to measure the efficacy of daily dosing of topical PTX gel on 
speed of oral ulcer healing of BD patients. 
Secondary Objectives 
The secondary objective is to assess the safety and tolerability of daily dosing of topical 
PTX gel on BD patients. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 7
Endpoints 
This proof of concept trial will explore a number of efficacy endpoints including: 
 
• Measurement of the index ulcer at enrollment 
• Total number of ulcers 
• Patient reported outcome pain scores (see Appendix) 
• BD Quality of Life assessment (See Appendix) 
• BD Activity Index (See Appendix) 
 
In addition, pharmacovigilance for adverse events (AEs) will focus on already known and 
published PTX AEs as well as any experiences of local irritation that would be unique to 
this route of administration. 
STUDY DESIGN 
Overview of Study Design 
We plan to enroll 60 patients with active oral ulcers of BD into an open label trial to 
determine the effects of topical PTX on healing duration of BD oral ulcers. This initial 
proof-of-concept trial will be conducted under US IND and with Turkish government and 
institutional permissions obtained for a single study site in Istanbul. We choose Turkey 
because in that country both the clinical expertise and the prevalent patients are sufficient 
to permit enrollment at a single center. We believe that a single enrollment center will 
provide us the greatest control over adherence to study protocols and eliminate inter-rater 
variability in endpoint assessments. However, we envision that a subsequent, 
registrational/pivotal trial will be conducted at multiple sites in both Turkey and the US.  
 
Patients who are eligible for study entry (see inclusion/exclusion criteria below) will be 
randomized into two groups: 
 
• Colchicine therapy as part of supportive care routinely offered in Behcet’s Clinic-
Istanbul 
OR 
• Colchicine therapy as part of supportive care as above with the addition of topical 
PTX 
 
According to the EULAR 2018 recommended guidelines of Behcet’s Disease (Hatemi et 
al., 2018), the first line of therapy to be used as standard therapy against recurring oral 
ulcers is colchicine. However, a significant portion of the patients undergoing colchicine 
therapy does not have sufficient response and require subsequent immune modulatory 
therapy. The goal of this study is to determine the effectiveness of PTX gel on oral ulcers. 
If the PTX gel therapy provides a sufficient response in patients, these patients might not 
need to undergo immune modulatory therapies. 
 
For all patients in either group, we will collect an oral photograph, the size and location 
of the largest oral ulcer, number of ulcers, quality of life and BD activity assessments, 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 8
pain scores, and concomitant medications. This data will be collected either in person or 
by telephone for the following two weeks. Additionally, adverse event experiences will 
be solicited. Data analyses will be exploratory comparisons of differences in safety and 
efficacy endpoints between BD patients who did and did not receive topical PTX. 
Stopping Criteria 
Any adverse events, which occur among study subjects, will be reported to the study’s PI, 
who will have authority to terminate enrollment for any patient. Additionally, in the event 
that any serious unexpected adverse event should occur among patients treated with 
topical PTX, the study’s PI will have the authority to suspend enrollment of any future 
patients and cease treatment of any patients currently enrolled. Additionally, 30 days after 
the final dose, patients will be contacted to assure otherwise unrecorded adverse events 
have occurred. 
Rationale for Study Design 
While we acknowledge that an open label trial is not most methodologically robust 
because it may embrace placebo effect biases, evaluator biases, and patient reporting 
biases (among others), this design was favored by US regulatory authorities for several 
practical and safety-driven reasons. Remembering that this is a new drug product applied 
via a new route of administration to a new study population, open label design allows the 
clinician to know if study subjects are so exposed. Furthermore, an initial validation that 
this therapy is non-inferior to current practice is a reasonable precautionary first step. 
Rationale for Dose Selection 
Patients on topical PTX will be given 1 tube containing 1,000mg of PTX in a single day 
20 ml dosage to be applied no fewer than four times per day with complete consumption 
of the entire tube each day. All digitally-accessible ulcers are to be treated. The rationale 
for this dose is based on the experience with p.o. PTX treatment. 
Our dosing strategy is designed to maximize lesional concentrations of PTX through a 
minimum of four times daily applications of our drug. As, systemic gastrointestinal 
absorption is possible due to accidental swallowing, we will limit our total daily dosing 
for this topical preparation to no greater than the recommended dose for the licensed, 
intentionally ingested product. For our proposed formulation of 5% PTX, we calculate 
that dose to be no more than 20 grams of individually packaged drug applied four times 
or more daily with the goal of applying 1 package per day. Consequently, this yields a 
total maximal dose of 1,000 mg of active pharmacologic agent. This is slightly less than 
the total recommended dose of 1,200mg p.o. PTX. 
The rationale for a topical formulation of PTX directly applied to BD oral ulcers is due to 
the potential therapeutic value of PTX in BD as suggested by some studies in 
combination with a potential improvement in PTX delivery via a topical oral formulation, 
which should maximize local concentrations of PTX to affected mucosal sites while 
minimizing adverse events that would otherwise occur from systemic PTX exposure.  

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 9
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all 
phases of the study including the last visit shown in the Schedule of Activities (SoA). If 
topical PTX therapy was shown to be effective during the study, Silk Road Therapeutics 
will make every effort to get these participants access to topical PTX therapy. 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 10
STUDY TREATMENT 
Study Treatment Administration 
Study Treatment Description 
PTX is a topical gel for intraoral application on the area of the oral ulcers. 
Dosing and Administration 
Our drug product requires digital application directly to accessible oral lesions. Hence, 
the drug administrator should wash their hands thoroughly before application, and put 
topical PTX gel liberally on the oral ulcer areas 
Preparation/Handling/Storage/Accountability 
Topical PTX gel will be supplied in tubes containing the daily dose of 20 ml of drug 
product. 
Acquisition and accountability 
Each patient in the treatment group will receive 14 days supply of topical PTX consisting 
of 14 tubes. Patients will be asked to present all used and unused tubes at every in person 
visit with study personnel. All used and unused tubes will be collected upon study 
completion. 
Formulation, Appearance, Packaging, and Labeling 
Study treatment will be a formulation of 5% hypromellose, 5% PTX, 1.3% of 
polyethylene oxide, 0.8% of methylparaben, 0.8% of propylparaben. 20 ml topical gel 
containing 1,000mg of PTX will be packaged in a light-opaque plastic tube. Please see 
the sample label in Appendix. 
Product Storage and Stability 
Product needs to be stored between 10°C and 30°C within the original packaging. Lots 
will be released subsequent to affirmation from stability testing that demonstrates 
acceptable stability and bioburden results. Our stability studies are currently ongoing, and 
in previous studies the stability of PTX in a topical cream formulation was confirmed for 
at least 62 days when stored in white opaque ointment jars at room temperature (Gupta, 
2012). 
Measure to Minimize Bias: Randomization 
While neither placebo effect nor evaluator biases can be completely eliminated in the 
context of the open label trial, other potential biases will be mitigated by randomization. 
For example, because of our randomization strategy, we expect disease severity, co-
morbidities, concomitant medications and other potential confounder, both known and 
unknown, to be equally represented in treatment and control groups. 
Study Treatment Compliance 
Treatment compliance will be monitored by daily phone calls and tube collections. 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 11
STUDY POPULATION 
Number of Subjects 
60 
Inclusion Criteria 
• Meets the International Study Group criteria for BD (ISG, 1990). 
• Presents with at least one active lesions accessible to measurement, the largest of 
which is to be designated as the index ulcer 
• Index oral ulcer to be assessed should be in the easily accessible areas of the oral 
mucosa, and the oral ulcer first began within 48 hrs prior to enrollment 
• Adult (>18 years) male or a non-pregnant, non-lactating female. 
• Has signed an Ethics Committee (EC) approved subject consent form. 
• Has completed all screening procedures satisfactorily, is deemed to be an 
acceptable subject and is otherwise eligible for entry into the study. 
• Is willing and able to comply with the protocol. 
• Is being treated with colchicine. 
Exclusion Criteria 
• Has a severe, acute, or chronic systemic disease other than BD such as congestive 
heart failure, hepatic failure, renal failure, systemic lupus erythematosus, Stevens-
Johnson syndrome, ulcerative colitis, cancer, leukemia, diabetes, AIDS, or any 
other condition for which they are immune-compromised. 
• Has received PTX in any form over the previous 60 days prior to enrollment. 
• Is under active treatment for dental conditions, such that multiple dental office 
visits would be required during the study period, or presents with oral conditions 
which are not thought to be related to BD and in the judgment of a qualified 
dentist, will require treatment during the study period. 
• Is suffering from any medical condition other than Behçet’s Disease known to 
cause oral ulcerations, such as erosive lichen planus, benign mucous membrane 
pemphigoid, Systemic Lupus Erythematous, Crohn’s disease, Reiter’s syndrome, 
or AIDS. Has an eating disorder and/or psychiatric illness requiring treatment. 
Has a history of, or is currently exhibiting, any disease or condition, which, in the 
opinion of the principal investigator, would place the subject at increased risk 
during study therapy. Has any abnormality in hematological or biochemical 
variable, which, in the opinion of the principal investigator, would place the 
subject at increased risk during study therapy. 
• Has experienced recent cerebral and/or retinal hemorrhage or in patients who 
have previously exhibited intolerance to this product or methylxanthines such as 
caffeine, theophylline, and theobromine. 
• Is receiving immune suppressing or modulating therapy (e.g., apremilast) or 
topical corticosteroids within 2 weeks prior to enrollment. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 12
• Has concomitant administration of strong CYP1A2 inhibitors (including e.g. 
ciprofloxacin or fluvoxamine) and other drugs that may increase the exposure to 
PTX.  
• Is not being treated with colchicine. 
Strategies for Recruitment and Retention 
• The total duration of recruitment for the study will be approximately 4 months. 
• We anticipate accruing a mean of 6 patients per week for 10 weeks. 
• We anticipate to provide resources to a crew, from the rich history of the Behçet’s 
Clinic at Cerrahpaşa Medical Faculty at the University of Istanbul 
• The primary recruitment venue will be the Behçet’s Clinic at Cerrahpaşa Medical 
Faculty at the University of Istanbul. 
• All BD patients who attend the clinic weekly (100 per week) will be invited to 
enroll in a study upon their next outbreak of new oral ulcers. 
• Additionally, patients known to the clinic to have regular intermittent-continuous 
oral ulcers will be directly contacted and invited to enter the study upon their next 
outbreak of new oral ulcers. 
• Every effort will be made to accommodate the study subject’s schedules and 
enhance subject retention. For example, at home visits, phone calls to collect data 
in lieu of direct visits and other accommodations will be made to assure the 
highest retention feasible. 
• In order to enhance subject retention, subjects will be compensated for their 
travel/food and work loss costs during visit attendance. 
Recruitment Definitions 
• Screen Failure- Subjects whom the informed consent is obtained and do not 
proceed to study treatment (e.g. does not meet the entry criteria). Screening data 
will be documented on the study specific Screening Log. Reasons for screen 
failure will be documented in the subject’s source documents and on the 
Screening Log. 
• Enrolled- Subjects who pass all screening evaluations and are randomized to 
supportive care or supportive care in addition to study treatment. 
• Treated- Subjects who are enrolled and receive at least one dose of randomized 
study treatment. 
• Treatment Discontinuation- Subjects who receive randomized study treatment but 
fail to complete treatment through 2 weeks or hospital discharge. 
• Study Discontinuation- Subjects who complete randomized study treatment, but 
not the follow-up visit. 
• Completed Subject- Subjects who complete treatment and the follow-up visit.  
PATIENT SAFETY 
 
We have the following plan for mitigating risk to research subjects:  

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 13
• direct examination of the oral mucosa to detect and control any local irritant 
effects 
• intensive pharmacovigillance at each clinical contact that occurs no less than 
every 48hrs throughout the treatment period 
 
Local Irritation 
Because this will be one of the first carefully controlled trials of topically administered 
PTX, we will closely monitor the possible occurrence of any local oral mucosal irritation 
in study subjects. 
By design, this study will require in-person examination of the oral mucosa no less than 
every 48 hrs through two weeks of study duration.  At the time of in-person 
examinations, both ulcer-healing metrics and safety monitoring will be conducted.  We 
posit that this very frequent, in-person pharmacovigillance is a superior means to ensure 
patient safety than any animal proxy might provide. 
Intensive Pharmacovigillance 
Additionally, targeted surveillance will be made for adverse events that were previously 
noted to occur in PTX treatments. Study subjects will be asked, no less frequently than 
every 48 hours, whether they have experienced any of these symptoms already 
documented for systemic PTX. 
 
Adverse events will be categorized as serious or non-serious, expected or unexpected in 
accordance with ICH document. Rather than recapitulate the basis of this categorization, 
it is attached here as an appendix. All serious and all unexpected adverse events will be 
immediately reported to the study’s PI. 
 
Study Treatment Discontinuation and Subject Discontinuation and 
Withdrawal 
As stipulated by the Informed Consent, study subjects are entitled to withdraw from the 
study at any time. Additionally, as previously noted in this document, the study’s PI may 
withdraw the study subject or terminate the study entirely for bona fide medical reasons. 
 
In the absence of a medical contraindication or significant protocol violation, Principal 
Investigator will make every effort to keep subject in the study. The reason for a 
premature subject withdrawal should be selected from the following standard categories: 
 
• Adverse Event- clinical or laboratory events that in the judgment of the PI require 
discontinuation of study medication in the best interests of the subject. 
• Death- death of the subject whether study related or not. 
• Lost to follow-up- the subject did not return for follow-up visit(s) following the 
completion of study treatment and hospital discharge despite attempts to contact 
the subject to maintain scheduled appointments. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 14
• Protocol Non-compliance- the subject’s participation in the study failed to meet 
protocol requirements, which had a direct impact on subject safety and evaluation 
of the subject’s data. The violation necessitated termination from the study. 
• Subject meets withdrawal criteria- subject’s condition meets the criteria for the 
withdrawal from the study. 
Withdrawal Criteria 
Subjects will be withdrawn from the study if the subject meets any of the following 
criteria after the initiation of study treatment. 
• Allergic reaction to the topical PTX gel. 
Withdrawal Procedures 
All subjects who are withdrawn from the study will have a post dosing assessment 
completed. 
Pre and Post Enrollment Restrictions 
Two weeks prior to the start of the clinical trial do not use any drug that might interact 
with PTX. For example, avoid strong CYP1A2 inhibitors (including e.g. ciprofloxacin or 
fluvoxamine) and other drugs that may increase the exposure to PTX. Please see the 
exclusion criteria for more details about PTX risk factors. 
Pre and Post Enrollment Recommendations 
While not a formal restriction, the subjects should avoid eating/drinking within 1 hr after 
application of topical PTX gel. 
Subjects should not use any other topical cream or gel other than topical PTX during the 
clinical trial. For example, topical corticosteroids should not be utilized during the 
clinical trial. 
STUDY PROCEDURES 
Recruitment  
A description of the study’s objectives-to assess the clinical utility of topical PTX for oral 
lesions- will be presented orally and with a written handout weekly to all patients in the 
Behçet’s Clinic. Interested patient will contact the study nurse upon fresh outbreaks of 
oral lesions. 
 
Additionally, phone screening will be conducted in order to determine potential study 
subjects that are most likely to participate in the study. The clinical site coordinator will 
prepare a list of potential subjects from the database of the Behçet’s Clinic at Cerrahpaşa 
Medical Faculty at the University of Istanbul, and contact potential subjects and ask if 
they are interested in participating in this study. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 15
Study Information Script 
Study information script will be prepared that will contain the important details that need 
to be communicated to the potential study subject including the following: 
• The purpose of this study is to determine the effect of topical PTX gel on BD oral 
ulcer healing. 
• Previous studies suggest beneficial effects of oral PTX on ulcer healing and in 
treatment of BD, this study will use the same drug in a gel form to be applied 
inside your mouth onto the area of the BD oral ulcer. 
• If the potential subject is interested in participating in this study, determine the 
study eligibility of the potential subject. 
Study Eligibility Determination 
• Potential study subject should be suffering from recent BD oral ulcers, and he/she 
has favorable opinion on trying to participate in a clinical trial for potential 
treatment.  
• Please see the study population for more detailed information on 
inclusion/exclusion criteria. 
• If the potential subject is not eligible for this study, ask him/her if he/she has any 
information on potential subjects who would be interested to participate in this 
study. 
Study Expectations and Duration 
• Subject is expected to participate in all the clinic/at home/phone visits, which is 
estimated to take 2 weeks of treatment with daily follow-up via clinic/at home or 
a phone visit. 
Record of Eligibility and Reason of Eligibility 
Clinical trial coordinator will record the reason of eligibility of the subject. 
Patient Agreement to Visit within 48hrs of Ulcer Emergence 
• Potential study subject should be communicated the importance of noting the time 
of oral ulcer emergence as soon as he/she realizes it, and visiting the clinic within 
48hrs of oral ulcer emergence. 
• Potential study subject should be informed to contact the clinical site coordinator 
in order to ensure timely scheduling of clinic visit. 
• Potential study subject should be reminded that his/her transportation/food cost 
will be compensated upon visit attendance. 
• Potential study subject should be asked if he/she has any information on potential 
subjects who would be interested to participate in this study. 
Enrollment Visit Procedures 
Subjects who meet the enrollment criteria will be randomized. Computer generated table 
of random numbers will be utilized in randomization to two groups: 
 
• Colchicine therapy as part of supportive care routinely offered in Behcet’s Clinic-
Istanbul 
OR 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 16
• Colchicine therapy as part of supportive care routinely offered in Behcet’s Clinic-
Istanbul as above with the addition of topical PTX 
 
The investigational drug will be dispensed to the second group: 
• 14 tubes of topical PTX gel will be given to the patient on the baseline visit. 
• The instructions on how to administer the topical PTX gel will be explained to the 
patient and demonstrated by administering the first tube of topical PTX gel in the 
clinic. 
Informed Consent Form 
The subject will provide written informed consent using the current version of the Ethics 
Committee approved informed consent form. 
 
The Principal Investigator (PI) and other site personnel as assigned by the PI will be 
responsible for obtaining informed consent after the study has been explained to the 
subjects, and all of the subject’s questions are answered. The original signed consent 
form will be filed in the subject’s records in accordance with institutional policy and a 
copy will be provided to the subject. The consent process will be documented in the 
subject’s source documents and the Informed Consent Log supplied for the study. 
 
Written informed consent must be obtained prior to performing any study related 
procedures. 
 
If a protocol amendment requires revision to the informed consent form, the revised 
Ethics Committee approved form must be used to obtain and document re-consent from 
the subject.  
History and Baseline Characteristics 
The following history and demographic data will be collected: 
Age, sex, race, ongoing medical conditions, concomitant medications. 
Physical Examination 
Because these patients are already enrolled in the Behcet’s Clinic-Istanbul-Cerrahpasa, 
no additional physical examinations are required for the study. However, at each in-
person clinical encounter, the study nurse will collect vital signs (temperature, pulse, 
respiration, blood pressure) and if significantly divergent from normal, inform the study’s 
PI. 
Patient Ulcer Documentation 
The clinician will assess the current state of Behçet’s Disease on the patient. The 
following will be documented on the CRF: 
• The total number of visible oral ulcers 
• The noted time of oral ulcer emergences obtained from the patient 
• The recently emerged oral ulcer will be determined and designated as the index 
ulcer by the clinician. The index ulcer will be measured with the pre-determined 
measuring device, and documented by imaging the index ulcer by photography 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 17
along with the measuring device that will serve as a constant measure for accurate 
size determination. 
Quality of Life 
Behçet’s Disease Quality of Life Measure Form and Behçet’s Disease Current Activity 
Form will be filled out with the help of the clinician. 
Pain Assessment 
Patient reported outcome pain scores will be assessed using the numerical rating system 
(see Appendix). 
Phone Visit Procedures 
Phone visits will be performed daily on days that the patient is not having a visit at home 
or in the clinic. 
Adverse Events Assessment 
At each clinical encounter, both in person and in telephone, patients will be queried about 
adverse events already known to occur with PTX treatment. Additionally, at each patient 
in-person encounter, patients will be examined for local irritation. Any unexpected 
medical events will also be collected and if serious as per ICH guidelines, will be 
reported immediately to study’s PI. 
List of Concomitant Medications 
Patient’s list of concomitant medications will be recorded.  
Resolution of Existing Conditions or Prior Events 
Patient will be asked about the state of the existing conditions and/or prior events since 
the last visit. The current state of these conditions/events will be recorded. 
Pain Assessment 
Patient reported outcome pain scores will be assessed using the numerical rating system 
(see Appendix). 
Adherence  
Patient’s adherence to topical PTX gel will be assessed and recorded. 
Home Visit Procedures 
Vital Signs 
Vital signs will be recorded. 
Adverse Events Assessment 
At each clinical encounter, both in person and in telephone, patients will be queried about 
adverse events already known to occur with PTX treatment. Additionally, at each patient 
in-person encounter, patients will be examined for local irritation. Any unexpected 
medical events will also be collected and if serious as per ICH guidelines, will be 
reported immediately to study’s PI. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 18
List of Concomitant Medications 
Patient’s list of concomitant medications will be recorded.  
New or Emerging Events 
New or emerging events since the last visit will be recorded. 
Resolution or Change of Any Events 
Patient will be asked about the state of the existing conditions and/or prior events since 
the last visit. The current state of these conditions/events will be recorded 
Picture of Ulcer 
The index ulcer will be documented by photography along with the measuring device that 
will serve as a constant measure for accurate size determination. 
Measurement of Ulcer and Ulcer Count 
The index ulcer will be measured with the pre-determined measuring device, and the area 
of the index ulcer will be recorded along with the total ulcer count. 
Pain Assessment 
Patient reported outcome pain scores will be assessed using the numerical rating system 
(see Appendix). 
Adherence 
Patient’s adherence to topical PTX gel will be assessed and recorded. 
Clinic Visit Procedures 
Vital Signs 
Vital signs will be recorded. 
Adverse Events Assessment 
At each clinical encounter, both in person and in telephone, patients will be queried about 
adverse events already known to occur with PTX treatment. Additionally, at each patient 
in-person encounter, patients will be examined for local irritation. Any unexpected 
medical events will also be collected and if serious as per ICH guidelines, will be 
reported immediately to study’s PI. 
List of Concomitant Medications 
Patient’s list of concomitant medications will be recorded.  
New or Emerging Events 
New or emerging events since the last visit will be recorded. 
Resolution or Change of Any Events 
Patient will be asked about the state of the existing conditions and/or prior events since 
the last visit. The current state of these conditions/events will be recorded 
Picture of Ulcer 
The index ulcer will be documented by photography along with the measuring device that 
will serve as a constant measure for accurate size determination. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 19
Measurement of Ulcer and Ulcer Count 
The index ulcer will be measured with the pre-determined measuring device, and the area 
of the index ulcer will be recorded along with the total ulcer count. 
Pain Assessment 
Patient reported outcome pain scores will be assessed using the numerical rating system 
(see Appendix). 
Adherence 
Patient’s adherence to topical PTX gel will be assessed and recorded. 
End of Study Visit Procedures 
Vital Signs 
Vital signs will be recorded. 
Adverse Events Assessment 
At each clinical encounter, both in person and in telephone, patients will be queried about 
adverse events already known to occur with PTX treatment. Additionally, at each patient 
in-person encounter, patients will be examined for local irritation. Any unexpected 
medical events will also be collected and if serious as per ICH guidelines, will be 
reported immediately to study’s PI. 
List of Concomitant Medications 
Patient’s list of concomitant medications will be recorded.  
New or Emerging Events 
New or emerging events since the last visit will be recorded. 
Resolution or Change of Any Events 
Patient will be asked about the state of the existing conditions and/or prior events since 
the last visit. The current state of these conditions/events will be recorded 
Picture of Ulcer 
The index ulcer will be documented by photography along with the measuring device that 
will serve as a constant measure for accurate size determination. 
Measurements of Ulcer and Ulcer Count 
The index ulcer will be measured with the pre-determined measuring device, and the area 
of the index ulcer will be recorded along with the total ulcer count. 
Pain Assessment 
Patient reported outcome pain scores will be assessed using the numerical rating system 
(see Appendix). 
Quality of Life 
Behçet’s Disease Quality of Life Measure Form and Behçet’s Disease Current Activity 
Form will be filled out with the help of the clinician. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 20
Adherence 
Patient’s adherence to topical PTX gel will be assessed and recorded. 
Collection of Used/Unused Tubes 
The used and unused tubes of topical PTX gel will be collected from the patient. Patient’s 
adherence to the daily drug dosage recommendation will be assessed from the tube 
content. 
Post Dosing Procedures 
As noted above, all patients on study drug will be contacted 30 days following the final 
dose to assess if there are any additional adverse events. This assessment can be 
performed using the aforementioned phone visit procedures. In the case of any adverse 
events, patients will be followed up until the resolution of the adverse event (or up to 
maximum of 30 days after the day of adverse event emergence), and in the case the 
adverse event does not resolve, PI will be informed of this issue. 
 
 
 
 

Schedule of Activities (SoA) 
 
The enrollment and the end of study visits will be performed in the clinic. If the visits in between the enrollment and the end of study visits (Visits #2,3,5,6) 
cannot be performed in the clinic, the patients can be visited at their home as part of a home visit. Face-to-face visits (clinic and home visits) should not be more 
than 48 hours apart. One exception to this schedule would be if the following 48hr visit is scheduled on a weekend, the time difference between the visits could 
be increased to 72hrs to accommodate a weekday schedule. Phone visits will be performed on the days that there are no face-to-face visits.  
 
Procedure 
Screening 
Enrollment Visit 
 
 
Tel. 
1 
Visit 
2* 
Tel. 
2 
Visit 
3* 
Tel. 
3 
Tel. 
4 
Visit 
4 
Tel. 
5 
Visit 
5* 
Tel. 
6 
Visit 
6* 
Tel. 
7 
Tel. 
8 
End of Study Visit 
7 
Follow Up Visit 
Day 45 
Visit Number: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Determination of Study Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Explanation of Study Expectations 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agreement to Visit within 48hrs of Ulcer Emergence 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Vital Signs 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Quality of Life Form 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
Current Activity Form 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
X 
Identification of Index Ulcer 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Measurement of Index Ulcer 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Imaging of Index Ulcer 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Total Ulcer Count 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Pain Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resolution of Any Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Check for Drug Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Drug Adherence 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of Used/Unused Tubes 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
*: Visits 2, 3, 5 and 6 can be a home visit if  clinic visit is not possible or feasible for patients. 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 22
STATISTICAL CONSIDERATIONS 
 
As noted above, this proof of concept trial aims to better define the primary endpoints for 
a future, pivotal, registrational trial.  Given our early stage in drug development, we can, 
a priori, anticipate post hoc analyses of this trial that will enable refinement in the design 
and statistical analysis of that future trial.  Our “registrational endpoint development” 
begins with three metrics: diameter of largest ulcer at enrollment, total number of ulcers 
and pain scores as measures followed over time.   
We are preparing a survival analysis plan that compares the diminution in largest ulcer 
size over time.  This endpoint is fundamental to our “proof of concept” because it directly 
measures, on one particular lesion, the healing effects of PTX compared to the standard 
of care. 
Total ulcer number is a more problematic metric because our topical intervention is not 
expected to affect the development of new ulcers, only to accelerate the healing of 
existing ulcers.  Regardless, total number of ulcers will be collected at each visit because 
it is a reasonable measure of the patient’s overall BD control.  
Lastly, pain scores suffer from all the subjectivity inherent to that individualized 
experience. As above, pain likewise may be altered by the “noise” of new ulcers, which 
this intervention is not expected to affect.  Still, measuring pain offers an opportunity to 
correlate simple measurements of mucosal disruption with the patient’s fundamental 
disease experience. 
As this is a proof of concept study, and the methodology is likely to be modified, the the 
details regarding the statistical considerations are not yet finalized. 
In the event of the discovery of missing, repeated, unused or spurious data, these will be 
corrected as soon as possible. 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 23
REFERENCES 
Ahmadi M, Khalili H. Potential benefits of pentoxifylline on wound healing. Expert Rev 
Clin Pharmacol. 2016;9(1):129-42. doi: 10.1586/17512433.2016.1109443.  Epub 2015 
Nov 11. Review. PubMed PMID: 26558813. 
Appenzeller S, Hazel E. Pentoxifylline for the treatment of anterior uveitis in Behcet's 
disease: possible alternative for TNF blockers. Rheumatol Int. 2011 Nov;31(11):1511-3. 
doi: 10.1007/s00296-009-1305-9. Epub 2009 Dec 16. Review. PubMed PMID: 
20013266. 
Alpsoy E, Zouboulis CC, Ehrlich GE. Mucocutaneous lesions of Behcet's disease. Yonsei 
Med J. 2007 Aug 31;48(4):573-85. Review. PubMed PMID: 17722228; PubMed Central 
PMCID: PMC2628050.  
Aviado DM, Porter JM. Pentoxifylline: a new drug for the treatment of intermittent 
claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse 
effects. Pharmacotherapy. 1984 Nov-Dec;4(6):297-307. Review. PubMed PMID: 
6393073.  
Brenner MA. Nonhealing venous stasis ulcers. Pentoxifylline as adjunctive therapy. J Am 
Podiatr Med Assoc. 1987 Nov;77(11):586-8. PubMed PMID: 3443913.  
Entzian P, Schlaak M, Seitzer U, Acil Y, Ernst M, Zabel P. Pentoxifylline inhibits the 
fibrogenic activity of pleural effusions and transforming growth factor-beta. Mediators 
Inflamm. 1997;6(2):119-26. PubMed PMID: 18472845; PubMed Central PMCID: 
PMC2365858.  
González-Espinoza L, Rojas-Campos E, Medina-Pérez M, Peña-Quintero P, Gómez-
Navarro B, Cueto-Manzano AM. Pentoxifylline decreases serum levels of tumor necrosis 
factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a 
randomized double-blind, controlled clinical trial. Nephrol Dial Transplant. 2012 
May;27(5):2023-8. doi: 10.1093/ndt/gfr579. Epub 2011 Oct 3. PubMed PMID: 
21968012.  
Green LA, Kim C, Gupta SK, Rajashekhar G, Rehman J, Clauss M. Pentoxifylline 
reduces tumor necrosis factor-α and HIV-induced vascular endothelial activation.  AIDS 
Res Hum Retroviruses. 2012 Oct;28(10):1207-15. Epub 2012 May 8. PubMed PMID: 
22463742; PubMed Central PMCID: PMC3448099.  
Gul A. Standard and novel therapeutic approaches to Behçet's disease. Drugs. 
2007;67(14):2013-22. Review. PubMed PMID: 17883285.  
Hatemi G, Christensen R, Bang D, Bodaghi B, Celik AF, Fortune F, Gaudric J, Gul A, 
Kötter I, Leccese P, Mahr A, Moots R, Ozguler Y, Richter J, Saadoun D, Salvarani C, 
Scuderi F, Sfikakis PP, Siva A, Stanford M, Tugal-Tutkun I, West R,  Yurdakul S, 
Olivieri I, Yazici H. 2018 update of the EULAR recommendations for the management 
of Behçet's syndrome. Ann Rheum Dis. 2018 Jun;77(6):808-818. doi:  
10.1136/annrheumdis-2018-213225. Epub 2018 Apr 6. PubMed PMID: 29625968.  
Hatemi G, Melikoglu M, Tunc R, Korkmaz C, Turgut Ozturk B, Mat C, Merkel PA, 
Calamia KT, Liu Z, Pineda L, Stevens RM, Yazici H, Yazici Y. Apremilast for Behçet's 
syndrome--a phase 2, placebo-controlled study. N Engl J Med. 2015 Apr 
16;372(16):1510-8. doi: 10.1056/NEJMoa1408684. PubMed PMID: 25875256. 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 24
Hisamatsu T, Kishikawa H, Fukuya H, Matsuoka K, Mizuno Y, Nishida J. Combination 
therapy including pentoxifylline for entero-Behçet's disease. Bull Tokyo Dent Coll. 2001 
Aug;42(3):169-76. PubMed PMID: 11806151. 
Jull AB, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. 
Cochrane Database Syst Rev. 2012 Dec 12;12:CD001733. doi: 
10.1002/14651858.CD001733.pub3. Review. PubMed PMID: 23235582. 
Oliveira-Soares R, Freitas JP, Sousa Ramalho P, Guerra Rodrigo F. Treatment with 
pentoxifylline in Behçet's disease. J Eur Acad Dermatol Venereol. 2002 Mar;16(2):181-2. 
PubMed PMID: 12046834. 
Saenz A, Ausejo M, Shea B, Wells G, Welch V, Tugwell P. Pharmacotherapy for 
Behcet's syndrome. Cochrane Database Syst Rev. 2000;(2):CD001084. Review. PubMed  
PMID: 10796413. 
Taylor J, Glenny AM, Walsh T, Brocklehurst P, Riley P, Gorodkin R, Pemberton MN. 
Interventions for the management of oral ulcers in Behçet's disease. Cochrane Database 
Syst Rev. 2014 Sep 25;(9):CD011018. doi: 10.1002/14651858.CD011018.pub2. Review. 
PubMed PMID: 25254615. 
Thornhill MH, Baccaglini L, Theaker E, Pemberton MN. A randomized, double-blind, 
placebo-controlled trial of pentoxifylline for the treatment of recurrent aphthous 
stomatitis. Arch Dermatol. 2007 Apr;143(4):463-70. Erratum in: Arch Dermatol. 2007 
Jun;143(6):716. PubMed PMID: 17438178.  
Yasui K, Ohta K, Kobayashi M, Aizawa T, Komiyama A. Successful treatment of Behçet 
disease with pentoxifylline. Ann Intern Med. 1996 May 15;124(10):891-3. PubMed 
PMID: 8610918. 
Yazici H, Tuzun Y, Pazarli H, Yalcin B, Yurdakul S, Muftuoglu A. The combined  use of 
HLA-B5 and the pathergy test as diagnostic markers of Behçet's disease in  Turkey. J 
Rheumatol. 1980 Mar-Apr;7(2):206-10. PubMed PMID: 7373623.  
Yazici H, Seyahi E, Hatemi G, Yazici Y. Behçet syndrome: a contemporary view.  Nat 
Rev Rheumatol. 2018 Feb;14(2):107-119. doi: 10.1038/nrrheum.2017.208. Epub 2018 
Jan 3. Review. Erratum in: Nat Rev Rheumatol. 2018 Jan 24;14 (2):119. PubMed PMID: 
29296024. 
Zabel P, Schade FU, Schlaak M. Inhibition of endogenous TNF formation by 
pentoxifylline. Immunobiology. 1993 Apr;187(3-5):447-63. Review. PubMed PMID: 
8330908.  
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 25
INVESTIGATOR AGREEMENT 
 
I have reviewed the protocol entitled “ “ and agree that it contains all the information 
necessary to conduct the study as required. I will conduct the trial in accordance with the 
principles of ICH Good Clinical Practice and Declaration of Helsinki. 
 
I will obtain written informed consent from each prospective trial subject prior to 
conducting any protocol-specified procedures. The consent form used will have the 
approval of the local EC. 
 
I will maintain adequate source documents and record all observations, treatments, 
procedures pertinent to trial subjects in their medical records. I will complete the case 
report form supplied by Silk Road Therapeutics. I will ensure that my facilities and 
records will be available for inspection by representatives of Silk Road Therapeutics, the 
EC, or local regulatory authorities.  
 
I will notify Silk Road Therapeutics, or its designated representative, within 24 hours of 
any serious adverse events. Following this notification, a written report describing the 
serious adverse event will be provided to Silk Road Therapeutics, or its designated 
representative, as soon as possible, but no later than three days following the initial 
notification. 
 
My signature below indicates that my participation in this clinical study presents no 
conflict of interest for me or my sub-investigators participating in the study. 
 
 
 
 
 
 
Investigator’s Name (Print): 
 
 
 
 
Investigator’s Signature: 
 
 
 
 
Date: 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 26
APPENDICES 
BD Quality of Life Assessment 
 
 

 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 27
BD Current Disease Activity Form 
 
 

BEHÇET'S DISEASE CURRENT
ACTIVITY FORM 2006
Name:
M/F
PATIENT'S PERCEPTION OF DISEASE ACTIVITY
HEADACHE, MOUTH ULCERS, GENITAL ULCERS, SKIN LESIONS, JOINT INVOLVEMENT AND
GASTROINTESTINAL SYMPTOMS
EYE INVOLVEMENT
Date:
Sex:
Centre:
Telephone
Date of birth:
Country:
Clinician:
Address:
All scoring depends on the symptoms present over the 4 weeks prior to assessment.
Only clinical features that the clinician feels are due to Behçet's Disease should be scored.
(Ask the patient the following question:)
"Thinking about your Behçet's disease only, which of 
these faces expresses how you have been feeling over 
the last four weeks? ''(Tick one face)
Ask the patient the following questions and fill in the related boxes "Over the past 4 weeks have you had?"
(please tick one box per line)     
not at all
Present 
for up to 4 
weeks
Headache
Mouth Ulceration
Genital Ulceration
Erythema 
Skin Pustules
Joints - Arthralgia
Joints - Arthritis
Nausea/vomiting/abdominal pain 
Diarrhoea+altered/frank blood per rectum
(Ask questions below)
(please circle)
Right Eye
Left Eye
"Over the last 4 weeks have you 
had?"
a red eye
No
Yes
No
Yes
a painful eye
No
Yes
No
Yes
blurred or reduced vision
No
Yes
No
Yes
If any of the above is present: "Is this new"?
No
Yes
(circle the correct answer)
 
  

CLINICIAN'S OVERALL PERCEPTION OF DISEASE ACTIVITY
BEHÇET'S DISEASE ACTIVITY INDEX
SCORE
0      1
2      3
4      5
6      7
8      9
10     11
12
0      3
5      7
8      9
10    11   12    13
15     17
20
NERVOUS SYSTEM INVOLVEMENT (include intracranial vascular disease)
New Symptoms in nervous system and major vessel involvement are defined as those not previously 
documented or reported by the patient
(Ask questions below)
Over the last 4 weeks have you had any of the following?
please circle
tick if new
blackouts
No
Yes
difficulty with speech
No
Yes
difficulty with hearing
No
Yes
blurring of/double vision
No
Yes
weakness/loss of feeling of face
No
Yes
weakness/loss of feeling of arm
No
Yes
weakness/loss of feeling of leg
No
Yes
memory loss
No
Yes
loss of balance
No
Yes
Is there any evidence of new active nervous system involvement?
No
Yes
MAJOR VESSEL INVOLVEMENT(exclude intracranial vascular disease)
(Ask question below)
"Over the last 4 weeks have you had any of the following?"
please circle
tick if new
had chest pain
No
Yes
had breathlessness
No
Yes
coughed up blood
No
Yes
had pain/swelling/discolouration of the face
No
Yes
had pain/swelling/discolouration of the arm
No
Yes
had pain/swelling/discolouration of the leg
No
Yes
Is there evidence of new active major vessel inflammation?
No
Yes
Tick one face that expresses how  you feel the patient’s 
disease has been over the last 4 weeks. 
Add up all the scores which are highlighted in blue (front page items, one tick = score of 1 on index, all other items 
score 'yes' = 1.  You should now have a score out of 12 which is the patient's Behçet’s Disease Activity Index Score. 
            
Patients index score
Transformed index score 
on interval scale    
 
  

06.03.06
©University of Leeds UK
Explanation to doctor completing the form;
1.  Use your clinical judgment recording only those features you believe are due to Behcet's disease.
2.  Please explain to the patient the meaning of the words used, if necessary.
3.  If there is pain in a joint (whether or not there is swelling etc) score 'arthralgia'.
4.  If there is swelling or inflammation of a joint score 'arthritis'.  Thus you can score 'arthralgia' and 'arthritis'.
5.  The form concerns the impairments relating to Disease Activity.  It is produced by Rasch analysis and
is psychometrically robust.  It is not measuring the impact of the disease activity.

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 28
Patient Reported Outcome Pain Score 
 
 
 

Patient Reported Outcome Pain Score Assessment 
Patient Reported Outcome Pain Score Assessment  
 
The subject can select the numerical value corresponding to her/his pain score. For more 
information, please consult the clinician. 
 
 
Pain score during eating: 
 
 
 
Pain score during drinking: 
 
 
 
Pain score during speaking: 
 
 
 
Pain score during dental care: 
 
 
 
General pain score due to oral ulcers: 
 
 
 
 

 
 
Topical PTX Gel for Behçet’s Disease 
 
 
 
 29
Sample Label