Photodynamic Therapy-Induced Immune Modulation: Part III
Phase: PHASE1
Conditions: Actinic Keratosis, Photodynamic Therapy
Sponsor: Wright State University

 
 
 
Title: Photodynamic Therapy-Induced Immune Modulation: Part III 
NCT#: NCT03643744 
Document Date: 21Apr2021 

 
 
 
 
 
 
 
 
 
 
Photodynamic Therapy-Induced Immune 
Modulation: PART III 
 
PI: Jeffrey B. Travers, M.D., Ph.D. 
 
Department of Pharmacology & Toxicology 
Department of Dermatology 
Staff Physician, Dayton VAMC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Inclusion/Exclusion Criteria 
4.0 
Enrollment 
5.0 
Study Procedures/compensation 
6.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk to 
Participants or Others 
7.0 
Study Withdrawal/Discontinuation 
8.0 
Statistical Considerations 
9.0 
Privacy/Confidentiality Issues 
10.0 Quality Control 
11.0 Follow-up and Record Retention 
12.0 COVID-19 Safety Plan 
13.0 References 
14.0 Abbreviations 
 

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1.0 
Background 
 
This study is Part III of the Photodynamic Therapy-Induced Immune Modulation 
research. Part III is designed as a double-blinded proof of concept of feasibility study to 
define if the immunosuppression associated with photodynamic therapy (PDT) can be 
blocked by treatment with cyclo-oxygenase-2 (COX-2) inhibitor celecoxib in comparison 
to placebo.  PDT consists of application of the photosensitizer 5-aminolevulenic acid 
followed by treatment with a blue light.  PDT is used to treat pre-cancerous actinic 
keratosis on large areas of skin [1].  These studies are a continuation of ongoing studies 
that indicate that the lipid mediator platelet-activating factor (PAF) is generated in skin 
following PDT, and that PDT suppresses the immune system.  Our hypothesis is that 
PDT-generated PAF results in the immunosuppression associated with PDT.   
Therefore, we propose that a treatment to block that immunosuppression could protect 
the patient undergoing PDT. Unfortunately, blockers of the PAF system are not currently 
commercially available. However our research studies using mice indicate that PAF- and 
PDT-induced immunosuppression is blocked by treatment with COX-2 inhibitors (2,3). 
We would like to conduct this research study as a proof of concept.  
 
This double-blinded placebo-controlled study will test if a seven day treatment with COX-
2 inhibitor celecoxib (200mg BID) following PDT will 1) block PDT-induced 
immunosuppression, and 2) enhance the effectiveness of PDT as measured by 
decreased numbers of actinic keratosis at 6 months and 12 months following PDT in 
comparison to placebo treated.  This protocol will recruit subjects undergoing PDT or 
control subjects (not undergoing PDT) at Department of Dermatology at Boonshoft 
School of Medicine at Wright State University where the PI is Chair of Pharmacology & 
Toxicology, with joint appointment in the WSU Department of Dermatology.  These 
studies are temporarily funded by WSU Department of Pharmacology and Toxicology. 
 
Please note that this study will recruit both subjects who are planning to undergo PDT as 
a part of their management of their actinic keratosis and normal control subjects.  This 
study will compare the effects of celecoxib vs placebo on the immune effects and 
effectiveness of PDT.  This study also assesses if celecoxib alone modulates immune 
responses in control subjects.  Thus, there will be 4 groups:  PDT + Celecoxib, PDT + 
placebo, Control + Celecoxib and Control + placebo. We plan to randomize the subjects 
and one of the study personnel (coordinators who will not have any contact with subjects 
except for making up the medicines will be unblinded).  These studies take advantage of 
the large numbers of patients undergoing PDT at WSU.   
These studies include: 
• 
Research subjects (those who receive PDT therapy) 
o Skin testing with intradermal Candida and Trichophyton antigens 
on two separate occasions. 
o Reporting a pain scale of 0-10 
o Urine collection (7 samples) 
o laboratory serum collection (2 venipunctures) 
o PDT-conducted for clinical reasons 
o 7 days of Celecoxib 200mg 2x per day or placebo 
o Follow up visits months 6 and 12 to assess actinic keratosis in 
treated areas. 
 
• 
Control subjects 

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o Skin testing with intradermal Candida and Trichophyton antigens 
on two separate occasions. 
o Urine collection (7 samples) 
o Laboratory serum collection (2 venipunctures) 
o 7 days of celecoxib 200mg 2 x per day or placebo. 
  
 
2.0 Rationale and Specific Aims  PART III 
 
This protocol is designed to address multiple questions that have arisen since we have 
discovered 
that 
1) 
PDT 
in 
mice 
generates 
PAF 
and 
related 
oxidized 
glycerophosphocholines (ox-GPCs); and that 2) PDT suppressed systemic immunity 
against the allergen DNFB (dinitrofluorobenzene) in wild-type but not PAF-R-knockout 
mice [3]; and 3) the literature indicates that PDT induces localized immunosuppression 
[4]; and 4) our ongoing studies that PDT of human subjects results in PAF agonists in 
their skin; and finally, 5) our ongoing studies that PDT of human subjects results in 
immunosuppression.  
 
To test immunosuppression in humans, we plan two strategies.  The first strategy will 
test skin testing against Candida and Trichophyton antigens, before and after PDT 
treatment. 
 
We can also measure immune responses by taking peripheral blood mononuclear cells 
(PBMCs) from blood of subjects before/after PDT and incubate them with candida and 
trichophyton  as well as other common antigens, to see if can measure an immune 
response (by measuring gamma-interferon by EIA).  We can also measure levels of 
immunosuppressive T cells (Tregulatory cells) in the blood as well as the Treg-
associated cytokine interleukin-10 (IL-10).  Previously, we have demonstrated that when 
PAF is made, increased Tregs and IL-10 can be found in the mice.    Again, our studies 
have demonstrated in mice that COX-2 inhibitors can block immunosuppression 
associated with PDT, and PAF agonists [2,3,4]. 
 
This study will also collect urine specimens from the PDT-treated subjects (before and 
after PDT) to test them for COX-2 metabolites and reactive-oxygen-associated markers 
(isoprostanes).  We will also test urines in control subjects treated with celecoxib vs 
placebo.    
 
We hypothesize that these studies will demonstrate the following: 
1.  PDT will result in immunosuppression (as measured by increased IL-10 in serum, 
and lymphocyte assays, as well as diminished candida/trichophyton skin testing). 
2.  PDT will result in increased COX metabolites and isoprostanes in urine. 
3. Short-term Celecoxib treatment at commonly used dosages following PDT will inhibit 
the PDT-induced immunosuppression in comparison to placebo treatment. 
4. Short-term Celecoxib treatment following PDT will block the increased COX 
metabolites in urine, but will have no effect on the isoprostanes. 
5.  Subjects undergoing PDT treated with celecoxib will exhibit decreased levels of 
erythema and decreased pain/tenderness in comparison to placebo control. 
6.  PDT will be more effective (as measured by less actinic keratosis in the PDT-treated 
areas at 6 and 12 mo following PDT) in those subjects who underwent Celecoxib 
treatment compared to placebo treatment. 
7.  Control (non-PDT) subjects will not experience any differences in immune responses 
in those treated with celecoxib versus placebo treatment.    

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This proof of concept study is valuable as it may form the basis of future studies to test if 
cyclooxygenase inhibitors can block PDT-mediated systemic immunosuppression, and 
potentially improve the long-term outcomes of PDT.    
 
3.0 Inclusion/Exclusion Criteria 
 
Inclusion Criteria for control subjects 
• 
Adult age 45 or older 
• 
Caucasion (Fair skin, Fitzpatrick types I and II) 
• 
Ability to understand and consent to the instructions of the study 
• 
Have access to stable transportation 
 
Inclusion Criteria for study subjects 
• 
 WSU dermatologist has prescribed PDT for the treatment of actinic damage 
(Presence of precancerous actinic keratoses whose treatment necessitates PDT 
with the BLU-U).  
• 
Undergoing PDT on greater than 5% body surface area: face and scalp, face and 
dorsal surface of arms, face and chest, face and back, or dorsal surface of arms 
alone, chest alone, or back alone. 
• 
Caucasian (Fair skin, Fitzpatrick types I and II) 
• 
Adult-age 45 or older 
• 
Ability to understand the informed consent and comply with instructions and have 
stable transportation. 
 
 
Exclusion Criteria for all subjects 
• 
PDT on less than 5% body surface area (eg, forehead) 
• 
Present treatment with corticosteroids or Non-steroidal anti-inflammatory drugs 
(e.g., cyclooxygenase inhibitors) within past 2 months (except low-dose 81 mg 
aspirin). 
• 
On antioxidant supplements (e.g., vitamin C) for past 2 months 
• 
Tanning bed use within last 3 months 
• 
PDT treatments within last 3 months 
• 
Significant health issues that could affect your immune system (e.g., uncontrolled 
Diabetes Mellitus, Rheumatoid arthritis, skin rashes, psoriasis) that could 
interfere with testing 
• 
Pregnant or nursing  
• 
No immunosuppression, and on no immunosuppressive medications or NSAIDS 
within past 30 days (except low-dose [81 mg daily] aspirin). 
• 
No signficant underlying diseases that could potentially interfere with the immune 
assays or cardiac or renal or liver problems. 
• 
History of blood clot or hypercoagulable state or GI bleed/ulceration. 
 
 
All subjects will be asked the screening questions below as part of the 
inclusion/exclusion criteria: 
• 
Are you 45 years old or older? 
• 
Do you regularly use tanning beds? 

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• 
Are you being treated for anything that requires UV-treatments? 
• 
Have you had any diseases that got worse when you went in the sun? 
• 
Are you using topical or oral anti-inflammatory doses of NSAIDS or steroid? 
• 
Have you ever had any abnormal reactions or allergies to NSAIDS? 
• 
Are you taking any medications that warn you to stay out of the sun? 
• 
Have you ever had a reaction to medications that were applied to your skin? 
• 
Do you have severe sugar diabetes, heart problems or liver problems or other 
health problems that affect your immune system? 
• 
Have you had significant sun exposure or sunburn within the last 2 weeks? 
Tanning bed exposure in the past 3 months? 
• 
Have you had PDT in past 3 months? 
• 
Have you ever had a blood clot or other bleeding issues? 
• 
Have you ever had a stomach ulcer or bleeding from GI tract? 
• 
Are you pregnant or nursing? 
 
4.0 
Enrollment 
 
Subjects who will be undergoing PDT for actinic keratoses and controls will be recruited 
from the Dermatology clinics at WSU. Control subjects may also be recruited from other 
sites or other practices. The potential subjects will be told by their physician about the 
study. They will be reminded that this study will in no way benefit them directly and that 
their participation is only voluntary, and if they choose not to participate it will not impact 
their care or the interest of their providers in their case.  In addition, advertising flyers 
placed in the Wright State Department of Dermatology clinics will be used to seek PDT 
subjects and control subjects.    The flyers will require subjects who are interested in 
participating in the study to contact the PI, or the research office.  The PI, or study team 
member, will meet with the potential subjects. The PI will determine enrollment status 
based on the inclusion and exclusion criteria.  Each subject will be given all of the 
procedures and risks in writing and a signed informed consent statement will be 
obtained from each subject prior to enrollment in the study. The subjects will also be 
informed of the need to avoid sun exposure or tanning bed use for 3 months prior to 
PDT or during the study.    
 
5.0 Study Procedures 
 
Outlines of testing for PDT-treated subjects.  Please note that the Controls (see 
picture on page 9) will undergo all procedures EXCEPT the PDT.  Controls also 
will not have actinic keratosis counted/mapped and will not be following up to 
have actinic keratosis mapped at 6 and 12 months. 
 

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DAY -2.  Consent, Skin testing, Venipuncture  
• 
Informed consent.  Explanation of the study, listing of all the required dates to 
return to the clinic for the study, and a signed informed consent will be obtained 
• 
Intended PDT treatment site will be noted, photographed and recorded 
• 
Actinic keratosis mapping.  Numbers of AKs will be counted and mapped on a 
diagram to allow us a base recording for future comparisons 
• 
Venipuncture.  20ml of blood will be drawn by routine phlebotomy. 
• 
Intradermal skin testing application.  An area on inner (volar) arm where planned 
PDT will not be taking place will be photographed, and intradermal injections of 
0.1 ml standardized solutions of commercially available Candida and 
Trichophyton protein antigens, or saline will be intradermally injected into skin to 
form small wheals.  The area will be photographed. 
 
DAY 0.  Read skin testing results, Urine specimen, PDT, Start celecoxib or placebo 
• 
Intradermal skin testing reading.  The skin reactions to the Candida and 
Trichophyton antigens will be visualized, photographed, and the size of the 
reactions measured using calipers. 
• 
Urine specimens.  Urine Sample will be obtained, and 6 sterile pre-labelled urine 
cups will be provided to the subject for home urine collection along with an 
orange opaque biohazard bag to store the samples in the freezer until they are 
returned to the research site.  
• 
Photodynamic Therapy (PDT).  PDT is a standard treatment at the WSU 
Department of Dermatology clinics and approximately 75-80 procedures are 
performed annually.  PDT is being conducted for clinical reasons and will 
therefore be submitted to the patient/patient’s insurance as routine care. 
Patients sign a separate informed consent for the PDT therapy and the PDT 
will follow standard clinical guidelines. Control subjects will not undergo the PDT 
treatment. 
• 
Celecoxib.  The subjects in the study arms which receive Celecoxib will be 
provided #14 capsules of 200mg celecoxib or 14 placebo capsules and 
instructed to take 1 capsule in the morning and 1 capsule in the evening.  They 
will be instructed to start the medication the same day (2 doses) and take as 
prescribed for a total of seven days.  The subjects will be provided a 7 day pill 
dispenser with AM/PM components for their use.  Funds from the study budget 

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will pay for the prescription so that there will not be a cost to the subjects.  The 
dose of celecoxib was similar to that used long-term in previously reported 
studies where subjects were treated with celecoxib 200mg BID for ~ 1 year.  This 
is a dose and time frame that based upon our murine studies, should inhibit PAF-
induced immunosuppression.  
 
DAY 1-5 Urine Home Collection  
At night (~8 h post-PDT) on the day of PDT treatment, and days 1-5 First 
morning urine samples will be obtained in the sterile cups provided to the subject, 
each placed in the biohazard bag and stored in the freezer.   The subject will 
bring the urine samples back to the research clinic at day 7 study visit.  Subjects 
will be asked to fill out a Urine Collection Record form. Also, they will rate the 
pain associated with the PDT treatment on the Skin Pain Visual Analogue Scale 
(VAS). The scale will be 0 (no skin pain) to 10 (severe skin pain). 
 
DAY 7. Return of urine samples, Repeat skin testing to control and PDT-treated 
sites, Venipuncture. 
• 
Urine samples returned to the research site from research subjects 
• 
Subjects will bring empty pill dispensers. 
• 
Intradermal skin testing application.  An area on opposite inner (volar) arm where 
PDT did not take place, as well as a PDT-treated site (extensor arms, scalp, etc) 
will be photographed, and intradermal injections of 0.1 ml standardized solutions 
of commercially available Candida or Trichophyton protein antigens, or saline will 
be intradermally injected into skin to form small wheals.  The areas will be 
photographed. 
• 
Reporting amount of pain.  The 0-10 pain scale will be used again to query the 
subject as to amount of discomfort in the PDT-treated sites.  
• 
Venipuncture.  20ml of blood will be drawn by routine phlebotomy. 
 
 
DAY 9.  Read skin testing results 
• 
Intradermal skin testing reading.  The skin reactions to the Candida and 
Trichophyton antigens will be visualized, photographed, and the size of the 
reactions measured using calipers. 
 
6 months and 12 months. 
The subjects who were treated with PDT will be seen when they return to the 
dermatology clinic for their routine follow up care. We will use a body map to record the 
current numbers and sites where they have the precancerous AK lesions.  Their current 
numbers and sites will be compared to the numbers and locations of their AKs pre-
treatment with PDT obtained at visit Day 0. This comparison will help to define 
effectiveness of the therapy.  This information will become part of their medical record. 
 
 
 
 
 
 
 
 

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CONTROL SUBJECTS 
 
 
 
DAY 0.  Consent, Skin testing, Venipuncture, Urine specimen  
• 
Informed consent.  Explanation of the study, listing of all the required dates to 
return to the clinic for the study, and a signed informed consent will be obtained 
• 
Venipuncture.  20ml of blood will be drawn by routine phlebotomy. 
• 
Intradermal skin testing application.  An area on inner (volar) arm will be 
photographed, and intradermal injections of 0.1 ml standardized solutions of 
commercially available Candida or Trichophyton protein antigens, or saline will 
be intradermally injected into skin to form small wheals.  The area will be 
photographed. 
• 
Urine specimens.  Urine Sample will be obtained, and 6 sterile pre-labelled urine 
cups will be provided to the subject for home urine collection along with an 
orange opaque biohazard bag to store the samples in the freezer until they are 
returned to the research site.  
 
DAY 2.  Read skin testing results, Start celecoxib or placebo 
• 
Intradermal skin testing reading.  The skin reactions to the Candida and 
Trichophyton antigens will be visualized, photographed, and the size of the 
reactions measured using calipers. 
• 
Celecoxib.  The subjects in the study arms which receive Celecoxib will be 
provided #14 capsules of 200mg celecoxib or 14 placebo capsules and 
instructed to take 1 capsule in the morning and 1 capsule in the evening.  They 
will be instructed to start the medication the same day (2 doses) and take as 
prescribed for a total of seven days.  The subjects will be provided a 7 day pill 
dispenser with AM/PM components for their use.  Funds from the study budget 
will pay for the prescription so that there will not be a cost to the subjects.  The 
dose of celecoxib was similar to that used long-term in previously reported 
studies where subjects were treated with celecoxib 200mg BID for ~ 1 year.  This 
is a dose and time frame that based upon our murine studies, should inhibit PAF-
induced immunosuppression. 
 
DAY 9. Repeat skin testing, Venipuncture. 
• 
Subjects will bring empty pill dispensers. 

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9 
 
• 
Intradermal skin testing application.  An area on opposite inner (volar) arm where 
previous skin testing did not take place will be photographed, and intradermal 
injections of 0.1 ml standardized solutions of commercially available Candida or 
Trichophyton protein antigens, or saline will be intradermally injected into skin to 
form small wheals.  The areas will be photographed. 
• 
Venipuncture.  20ml of blood will be drawn by routine phlebotomy. 
 
DAY 11.  Read skin testing results 
• 
Intradermal skin testing reading.  The skin reactions to the Candida and 
Trichophyton antigens will be visualized, photographed, and the size of the 
reactions measured using calipers. 
 
Compensation.   
The subjects will be compensated for involvement in the study.  
Research subjects require more visits and procedures than control subjects.  
 
Breakdown for each event is as follows: 
 
Consent 
 
 
 
$20.00   
PDT ($20), Control ($20) 
Venipuncture  
 
 
$10.00   
PDT ($20), Control ($20) 
Urine collection 
 
 
$5.00    
PDT ($35), Control ($35) 
Skin testing APPLICATION  
$15.00   
PDT ($45), Control ($45) 
Skin testing READING 
 
$20.00   
PDT ($40), Control ($40) 
Bonus for completing study   
$65.00   
PDT ($65), Control ($65) 
Follow up visits at 6 and 12 months $25.00   
PDT ($50)  
 
Hence the research (PDT) subjects may receive up to $ 275.00 and the control subjects 
up to $225.00.  
 
There is no cost for parking at the Wright State Physician’s Building.  Compensation is 
based upon completed study procedures and overall study completion. Since completion 
of study procedures are critical to the study findings if a subject cannot come to their 
scheduled visit (and cannot be quickly rescheduled) they will be removed from the study.  
Another subject will be enrolled in their place. Our goal is to enroll 48 subjects who 
complete the study.  
 
6.0  Reporting of Adverse Events or Unanticipated Problems involving Risk to 
       Participants or Others 
  
 
 
Risks of the study are as follows: 
 
1. Photodynamic therapy.  The risks to PDT are explained to the patient at the time 
of therapy decision and obtaining the informed consent for that standard of care 
procedure. 
PLEASE 
NOTE 
THAT 
PDT 
TREATMENT 
IS 
ALREADY 
RECOMMENDED FOR THE TREATMENT OF THE SUBJECT.  THEY WILL BE 
SIGNING A SEPARATE INFORMED CONSENT FOR THE TREAMTENT AND 
THEY/THEIR INSURANCE AS APPROPRIATE WILL BE BILLED FOR THE 
TREATMENT.   
2. Photography - the risk of photography is the possible loss of confidentiality.  
Pictures will not be of recognizable body parts or markings. Photos will be 

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labeled with the study number and a code that does not identify the subject.  
Photos will not include any identifying information. 
3. Urine samples/non-invasive skin measurement with calipers.  There are no risks 
to these. 
4. Intradermal skin testing.  These procedures are used in dermatology and allergy 
to define the ability of a host to respond to the allergen of interest.  The majority 
of individuals will test positive to Candida protein antigens, and approximately 
50% of individuals test positive for antigens from the common dermatophyte 
fungus Trichophyton (which causes skin infections like “athlete’s feet”).  The side 
effects are localized skin inflammation and rash and occasionally can be painful.  
Very rarely an individual can have a systemic reaction.  If we do note that the 
subject’s first skin testing results in exaggerated reactions, then the subject will 
not undergo further testing with this antigen. 
5. Celecoxib  Celecoxib is a commonly used NSAID, which is COX-2 specific.  It 
was designed to have anti-inflammatory effects but have minimal side effects 
such as gastric distress, etc.  There have been multiple studies examining the 
long-term effects of celecoxib 200mg BID.  In particular, there was a published 
multicenter trial that indicated that long-term celecoxib was effective for 
diminishing the incidence of non-melanoma skin cancers [7].  It should be noted 
that in these studies the incidence of side effects of the celecoxib was similar to 
placebo.  Long-term use of COX-2-selective inhibitors have been associated with 
increased cardiovascular events due to a pro-coagulant effect [6].  However, this 
is not associated with short-term use.  There is a slight risk of GI bleeding.  
These effects will be minimized as we will recruit subjects with no history of GI 
ulceration/bleeding/blood clots. 
6. There is also the potential risk of loss of confidentiality, but this will be minimized  
 
as photos of the PDT- and treated sites will not allow the person to be 
 
identified, and will not expose buttocks/genitals.   Samples   will be labeled with 
 
numeric numbers  --III-001, III-002, III-003 etc. and the   study number (XXXX). 
Example III-001-XXXX.  
 
Risks of exaggerated PDT-related sunburn will be minimalized as subjects will be 
queried about abnormal reactions to sun or artificial sources of light, as well as if they 
are taking any medicine which is potentially photosensitizing.   
 
Adverse Event and Serious Adverse Event Collection and Reporting 
Information related to any adverse event will be collected at every study visit. The NCI-
CTCAE (Common Terminology Criteria for Adverse Events) volume 4.03 published June 
14, 2010 will be utilized for definition, grading scale and ‘study relatedness’ criteria of the 
event. Dr. Travers will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study 
intervention. 
 
An adverse event (AE) means any untoward medical occurrence in a subject associated 
with the use of an intervention that does not necessarily have a causal relationship with 
the intervention. It can be any unfavorable and unintended sign (including abnormal 
laboratory findings), symptom or disease temporally associated with the investigation, 
whether or not considered intervention-related. 
 

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An unanticipated problem can be any unexpected, related or possibly related to the 
intervention, and increases risk to participants or others more than was previously 
known. All three must be true to have an unexpected problem. Each unanticipated 
problem is assessed as to the impact on subject safety. 
 
A serious adverse event (SAE) is any AE that results in one of the following outcomes: 
• 
Death 
• 
Life threatening 
• 
Requires hospitalization or prolonged hospitalization 
• 
A congenital anomaly/birth defect 
• 
Persistent or significant disability/incapacity 
• 
Requires intervention to prevent permanent impairment or damage 
 
All reports will simultaneously be submitted to NIAMS, through KAI. This will include: 
• 
Safety reports and meeting deliberations, including findings of adverse events 
and any comments, minutes, or recommendations resulting from the review of 
these periodic reports or meetings. 
• 
Expedited reporting, including SAEs and unanticipated problems, along with the 
independent assessment of such events, as appropriate, should be reported in 
an expedited manner. 
Each AE will be accompanied with the severity grade. The grades are as follows: 
• 
Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
• 
Grade 2 Moderate: minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*. 
• 
Grade 3 Hospitalization: hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL**. 
• 
Grade 4 Life-threatening consequences: urgent intervention indicated. 
• 
Grade 5 Death 
 
*Activities of Daily Living (ADL) refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, etc. 
 
Grade 1 Mild and Grade 2 Moderate represent AEs that will be recorded at the time of 
occurrence and reported to DSMB at the next semi-annual meeting. DSMB meeting 
documents will be forwarded to the local IRB, as well as to the NIAMS, through KAI. 
 
Grade 3 – Grade 5 are considered SAEs. Serious adverse events include death, are life 
threatening, requires hospitalization or prolonged hospitalization, a congenital 
anomaly/birth defect, results in persistent or significant disability/incapacity, or require 
intervention to prevent permanent impairment or damage. All SAEs will be reported to 
the local IRB, the DSMB, and to NIAMS through KAI within 48 hours. 
 
In addition to severity grade, each AE will have the relationship to the study intervention 
assessed by Dr. Travers. The degree of certainty about causality will be graded using 
the categories below. 
• 
Related – The AE is known to occur with the study intervention, there is a 
reasonable possibility that the study intervention caused the AE. 

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• 
Not Related – There is not a reasonable possibility that the administration of the 
study intervention caused the event. 
 
Data Monitoring Plan 
Dr. Travers will be the individual responsible for monitoring the safety environment of the 
participants.  He will establish a Data and Safety Monitoring Board (DSMB) to assist in 
the safety oversight of this trial. Dermatology chair and board-certified dermatologists, 
Julian Trevino, MD, and Max Rubin, MD, will also serve on the DSMB. Also, Dr. R. 
Michael Johnson, MD, FACS, a board-certified plastic surgeon will serve on the DSMB. 
The DSMB will review the results of this study on a semi-annual basis and provide the 
Institutional Review Board (IRB) with a copy of that review report. Dr. Travers is not part 
of the DSMB as he is the PI for the trial. 
 
In the event of adverse outcome (e.g., exaggerated skin reaction to skin testing antigen), 
this will be treated appropriately (with no physician cost from Dr Travers, though a 
pharmacy fee could be incurred if any prescription agents needed) and will be noted and 
reported to the DSMB for their review.  Moreover, if any SAE or unanticipated events 
occur, these will also be reported to NIAMS within 48 hours.  Non-serious AEs will be 
reported to the DSMB semi-annually versus immediately.     
 
Dr. Travers is an experienced (~20 years) board-certified dermatologist who would be 
experienced in dealing with any potential adverse events should one arise.  More 
importantly, Dr. Travers’  role as a PI is to monitor the following: 1) ensuring that only 
subjects who meet the eligibility criteria are enrolled; 2) the informed consent process 
will be conducted appropriately and all subjects consented before proceeding with any 
study procedures; 3) Data will be collected and analyzed as outlined in the protocol; 4) 
Privacy and confidentiality of the subjects will be maintained; 5) Documentation of 
dropouts; 6) Documentation and reporting of all adverse events.     
He will be assisted by study coordinator Elizabeth Cates, who will assist with non-
invasive components of the study.  Another study coordinator (Amy Williams) will be in 
charge of dispensing the celecoxib vs placebo and will serve as unblinded personnel.   
 
7.0 Study Withdrawal/Discontinuation 
 
Participants will be instructed that taking part in this study is voluntary and they may 
choose not to take part or may leave the study at any time.  Emphasis will be stressed to 
the participants that leaving the study will not result in any penalty or loss of benefits that 
they are entitled.  
 
8.0 Statistical Considerations 
 
Statistical support will be provided by Dr. Genxin Li from WSU who will be collaborating 
with the PI.  There are numerous outcomes in this study.  They include: 1) levels of 
isoprostanes and PGE2 in urine before/after PDT; 2) Skin immune reactions; 3) T cell 
reactions; 4) numbers of actinic keratosis in the PDT-treated areas at 6 and 12 months.  
Moreover, these will be compared to control subjects control sites/pre-PDT as well as 
treatment with celecoxib/no celecoxib.  Outcomes will be analyzed using McNemar’s 
Test comparing the PDT-treated vs non-PDT treated area and celecoxib vs no celecoxib 
exposure. Secondary outcomes will be analyzed similarly using McNemar’s tests for 
binary outcomes and paired t-tests for numeric outcomes.  Exact and/or non-parametric 
methods will be considered if standard test assumptions are not met.  

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The sample size of 12 per group for PDT + celecoxib, PDT placebo, control + celecoxib 
and control placebo. Use of 12 allows reasonable discrimination for pilot studies 
(Pharmaceut. Stat. 4:287-291, 2005 [7]).  Once we have obtained preliminary data from 
these subjects and controls, we will have Dr. Li perform power analysis to define if more 
subjects are needed, and submit a new/amended study if appropriate. 
 
9.0 Privacy/Confidentiality Issues 
 
There is also the potential risk of loss of confidentiality, but this will be minimized as 
photos of the will not allow the person to be identified, and will only expose a small areas 
of buttocks and will not show any breasts/genitals. All conversations and procedures will 
take place in Wright State Physician’s building in the dermatology clinic in a private 
examining room.  The data will be kept in the locked office of the PI.  Samples and 
pictures from subjects will be coded by numbers as outlined above.  Photos will not be of 
recognizable body parts or markings.   
 
10.0 
Quality Control 
 
Quality control (QC) procedures will be done on all regulatory documents, research 
subject records and original source documentation. Any missing data will be 
communicated to the PI and coordinators for resolution. 
 
Following written Standard Operating Procedures (SOPs), the Clinical Research 
Operations Manager will verify that the trial is conducted, documented, and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), and applicable regulatory requirements. 
 
The investigational site will keep records of all original source data. If requested, the site 
will provide access to original source documents to applicable regulatory agencies. 
 
11.0 Follow-up and Record Retention 
 
The duration of the study is expected to be 4 years from the first enrolled subject, and 
the duration of record retention will be 10 years.  After this time, records will be archived.  
We do not plan to biobank any samples. 
 
12.0 
COVID-19 Safety Plan 
 
All subjects are phone screened for COVID-19 symptoms the day before their 
appointment. When they arrive for their appointment they are instructed to call the 
research office prior to entering the building. Subjects are permitted to enter the building 
once research staff are ready to bring them back to the patient area. Everyone is 
required to wear masks when entering the building and have their temperature taken. 
Masks are provided to subjects who do not have one. 
 
The research staff are required to wear masks and check for symptoms prior to reporting 
to work. 
 

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Patient room and equipment are cleaned and disinfected according to health authority 
guidance. During the research visit, subjects and research staff need to maintain the 
appropriate social distancing requirement when procedures are not being performed. 
 
In regards to contact tracing, the research office keeps track of all appointments on a 
calendar to remember who has been in the office. These appointments have the 
subject’s contact information such as full names, phone numbers, email addresses and 
approximate appointment length. Should subjects need to contact the research office, a 
copy of the informed consent with the office’s contact information is listed on the first 
page. 
 
13.0 References 
 
1. Matthews YJ. Damian DL. Topical photodynamic therapy is immunosuppressive in 
humans. British Journal of Dermatology. 162(3):637-41, 2010. 
 
2.  Zhang Q. Yao Y. Konger RL. Sinn AL. Cai S. Pollok KE. Travers JB. UVB radiation-
mediated inhibition of contact hypersensitivity reactions is dependent on the platelet-
activating factor system. Journal of Investigative Dermatology. 128(7):1780-7, 2008. 
 
3.  Ferracini M. Sahu RP. Harrison KA. Waeiss RA. Murphy RC. Jancar S. Konger RL. 
Travers JB.  Topical photodynamic therapy induces systemic immunosuppression via 
generation of platelet-activating factor agonists.  Journal of Investigative 
Dermatology.135:321-23, 2015. 
 
4.  Ullrich SE. Photoimmunology. Mutation Research. 571:185-205, 2005. 
 
5.  Elmets CA, Viner JL, Pentland AP et al.,  Chemoprevention of nonmelanoma skin 
cancer with celecoxib:  a randomized, double-blind placebo-controlled trial.  Journal of 
the National Cancer Institute 102:1835-44, 2010.   
 
6.  Patrono, C.  Cardiovascular effects of cyclooxygenase inhibitors: a mechanistic and 
clinical perspective.  British Journal of Clinical Pharmacology 82:957-64, 2016. 
 
7.   Julious, SA.  Sample size of 12 per group rule of thumb for a pilot study.  
Pharmaceutical  Statistics. 4:287-291, 2005. 
 
14.0 Abbreviations. 
 
AE; Adverse Event 
ALA; aminolevulinic acid 
BSA; Body surface area 
DNCB; dinitrochlorobenzene 
EIA; enzyme-linked immunoabsorbant assay 
NSAIDs; non-steroidal anti-inflammatory drugs 
Ox-GPCs; oxidized glycerophosphocholines 
PDT; photodynamic therapy  
PAF; platelet-activating factor 
PGE2; prostaglandin E2 
QC; Quality control 

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SAE; Serious Adverse Event 
WSP; Wright state physician’s building 
WSU; Wright state university