Photodynamic Therapy (PDT) With Levulan and Blue Light for the Treatment of Actinic Cheilitis
Phase: PHASE4
Conditions: Actinic Cheilitis
Sponsor: Dartmouth-Hitchcock Medical Center



 
 
 
Photodynamic Therapy with Levulan and Blue Light for 
the Treatment of Actinic Cheilitis 
 
SPONSOR 
Department of Dermatology 
at Dartmouth-Hitchcock 
Medical Center 
  
DRAFT VERSION: 
DATE FINAL: 
1.0 
10.14.14 
  
 

 
 
 
 
2
1. PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Principal Investigator: 
M. Shane Chapman, MD 
 
 
 
 
 
 
 
Signature of Principle Investigator 
 
Date 
 
Printed Name of Principle 
Investigator 
 
 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/EC procedures, the Declaration of Helsinki, ICH Good Clinical 
Practices guidelines, and the applicable parts of the United States Code of 
Federal Regulations or local regulations governing the conduct of clinical 
studies. 
 
 



TABLE OF CONTENTS 
1.
Principle Investigator Signature Page  
 
 
 
 
2 
2.
Study Personnel   
 
 
 
 
 
 
5 
3.
Protocol Synopsis  
 
 
 
 
 
 
6 
4.
Schedule of Assessments  
 
 
 
 
 
10 
5.
Introduction & Rationale   
 
 
 
 
 
12 
6.
Study Objective 
 
 
 
 
 
 
 
12 
6.1 Hypothesis 
 
 
 
 
 
 
 
12 
7.
Research Design & Methods 
 
 
 
 
 
12 
7.1 Subject Recruitment  
 
 
 
 
 
13 
7.2 Screening & Eligibility  
 
 
 
 
 
13 
 
7.2.1 Inclusion Criteria 
 
 
 
 
 
13 
 
7.2.2 Exclusion Criteria 
 
 
 
 
 
13 
7.3 Visit Schedule & Assessments 
 
 
 
 
14 
7.4 Duration of Treatment 
 
 
 
 
 
15 
7.5 Risk to Subjects 
 
 
 
 
 
 
15 
7.6 Discontinuation of Study Drug 
 
 
 
 
16 
8.
Treatment & Blue Light Parameters 
 
 
 
  
16 
8.1 Pre-Exposure Skin Care 
 
 
 
 
 
16 
8.2 Investigational Medication 
 
 
 
 
 
16 
 
8.2.1 Supplier   
 
 
 
 
 
 
16 
 
8.2.2 Receipt & Storage of Study Treatment  
 
 
16 
 
8.2.3 Accountability 
 
 
 
 
 
 
17 
 
8.2.4 Handling & Disposal of Drug 
 
 
 
 
17 
8.3 Light Treatment  
 
 
 
 
 
 
17 
8.3.1 Blue Light Treatment 
 
 
 
 
 
17 
8.3.2 Supplier  
 
 
 
 
 
 
17 
8.4 Post-Exposure Skin Care 
 
 
 
 
 
17 
9.
Clinical Assessments  
 
 
 
 
 
 
18 
9.1 Demographic Information 
 
 
 
 
 
18 
9.2 Physician Performed Assessments 
 
 
 
 
18 
 
9.2.1 Efficacy Assessments  
 
 
 
 
 
18 
 
9.2.2 Pre & Post-Treatment Safety Assessments 
 
 
18 

 
 
 
 
4
9.3 Patient Performed Assessments 
 
 
 
 
19 
 
9.3.1 Subject Global Assessment 
 
 
 
 
20 
 
9.3.2 Pre & Post-Treatment Pain Assessment 
 
 
20 
 
9.3.3 Dermatology Life Quality Index  
 
 
 
20 
 
9.3.4 Two-Day Post-Treatment Telephone Follow-Up Visit   
23 
10. 
Assessment of Adverse Events  
 
 
 
 
 
24 
10.1 Methods & Timing of Safety Assessments  
 
 
25 
10.2 Recording & Reporting of Adverse Events   
 
 
25 
 
10.2.1 Adverse Events  
 
 
 
 
 
25 
 
10.2.2 Serious Adverse Events 
 
 
 
 
25 
 
10.2.3 Classification of Severity  
 
 
 
 
26 
 
10.2.4 Classification of Relationship/Causality of AE/SAE  
 
to Study Drug  
 
 
 
 
 
 
27 
 
10.2.5 Report of Adverse Events to the IRB 
 
 
 
27 
 
10.2.6 Pregnancy 
 
 
 
 
 
 
27 
  
11. 
Protocol Amendments/Deviations  
 
 
 
 
28 
 
11.1 Protocol Amendments  
 
 
 
 
 
28 
 
11.2 Protocol Deviations  
 
 
 
 
 
28 
12. 
Quality Control & Quality Assurance  
 
 
 
 
28 
 
12.1 Analyses & Reporting  
 
 
 
 
 
28 
 
12.2 Investigator Responsibilities  
 
 
 
 
28 
 
12.3 Audits & Inspections  
 
 
 
 
 
28 
13. 
Regulatory Considerations  
 
 
 
 
 
29 
 
13.1 Informed Consent  
 
 
 
 
 
 
29 
 
13.2 Study Records Requirement  
 
 
 
 
29 
14. 
References  
 
 
 
 
 
 
 
31 
15. 
Abbreviations  
 
 
 
 
 
 
 
32 
 
 

 
 
 
 
5
2. STUDY PERSONNEL  
Financial Supporter:  
Section of Dermatology / DUSA 
Pharmaceuticals Inc. 
Study Location: 
Dartmouth Hitchcock Medical Center 
18 Old Etna Road 
Lebanon, NH, 03756  
Phone: (603) 625-0151 
Fax: (603) 625-6212 
Principle Investigator:  
Michael Shane Chapman, MD 
Sub-Investigators: 
Joan Paul, MD, MPH 
Pamela Gangar, MD 
 
 
 

 
 
 
 
6
3.  PROTOCOL SYNOPSIS 
Title 
Photodynamic therapy with Levulan and blue light for the 
treatment of actinic cheilitis 
Protocol Number  1.0 
Study Medication  Levulan Kerastick containing 20% aminolevulinic acid HCL (ALA) 
(DUSA Pharmacueticals) 
Study Device  
BLU-U Blue Light Photodynamic Therapy (PDT) Illuminator  
Omnilux revive2TM 
Study Objectives  
 
To evaluate the safety and efficacy of PDT with blue light and 
topical Levulan in the treatment of actinic cheilitis 
Study Design  
 
This is a single center, investigator initiated, nonrandomized, open-
label, proof of concept study of PDT with blue light and topical 
Levulan in the treatment of actinic cheilitis 
Inclusion Criteria 
• 
Must be able to understand and voluntarily sign an 
informed consent form 
• 
Must be male or female ≥ 18 years of age at the time of 
consent 
• 
Must be able to adhere to the study visit schedule and 
other protocol requirements 
• 
Must have a diagnosis of actinic cheilitis by 
histopathological evaluation of biopsy specimen or clinical 
presentation 
Exclusion Criteria 
• 
Inability to provide voluntarily consent or mentally 
incompetent 
• 
No active herpes labialis lesions 
• 
Subjects with any condition which places the subject at 
unacceptable risk if he/she were to participate in the study, 
or confounds the ability to interpret data from the study 
• 
Subjects with any other skin condition that might affect the 
evaluation of the study disease 
• 
Pregnant or breastfeeding female subjects 

 
 
 
 
7
• 
Subjects who have used any investigational medication 
within one month prior to study entry 
• 
Subjects who have been previously exposed to PDT and/or 
topical Levulan therapy  
• 
Subjects who have used local therapy (e.g. cryotherapy) or 
topical treatment (e.g. 5% fluorouracil) within three months 
of study entry 
• 
Subjects who have used an oral photosensitizing drug (e.g. 
Declomycin) within six months of study entry 
• 
Subjects who are currently using photosensitizing agents 
(e.g. thiazides, tetracyclines, fluoroquinolones, 
phenothiazines, and sulfonamides) because of the risk of 
augmented photosensitivity 
• 
Subjects who are frequently exposed to ultraviolet radiation 
(e.g. lifeguards, construction workers, frequent sunbed 
users, etc.) 
• 
Subjects with a history of cutaneous photosensitization, 
porphyria, hypersensitivity to porphyrins, or 
photodermatosis 
• 
Subjects with a known hypersensitivity to ALA 
• 
Subjects who are immunocompromised 
Study Procedures 
The study will consist of a screening visit, up to three scheduled 
treatments, and two scheduled office visits.  There can be a three-
day window period for each scheduled visit in order to 
accommodate the subject’s schedule and unforeseen scheduling 
conflicts.  
1. Visit 1 (Screening):  Subjects can be screened for the study 
up to two weeks before Visit 2 (Baseline).  During screening, 
the study will be reviewed, written informed consent 
obtained, and eligibility confirmed.  If applicable, the 
washout from prohibited medications or treatments will be 
determined at this visit. 

 
 
 
 
8
2. Visit 2 (Baseline):  Following signed, written informed 
consent and confirmation of eligibility, all subjects will have 
their lips photographed.  Medical history, dermatologic 
exam, urine pregnancy test (if applicable), review of 
concomitant medications, clinical evaluations, and 
tolerability assessments will be performed at this visit.  
Study medication application to clean skin will be followed 
by a ninety minute incubation period under occlusion.  
Subsequently, patients will be exposed to blue light therapy 
for 16 minutes and 40 seconds.  Post-therapy assessments 
will be performed afterwards, as well as education on 
appropriate sun protection methods. 
3. Visits 3-4:  Subjects will return every six weeks for up to two 
additional treatments.  Treatment will be discontinued once 
the patient has achieved clinical clearance.  Tolerability 
assessments, study medication application, blue light 
therapy, post-therapy assessments, and photographs will 
be performed.  
4. Visit 5-6 (End of Study):  Subjects will return 12 and 24 
weeks after the last treatment for clinical evaluations, 
tolerability assessments, and photographs. 
Study 
Measurements 
Primary efficacy will be assessed by the investigator for the 
following: 
• 
Clearance will be estimated clinically as minimal (0%-25%), 
mild (26%-50%), moderate (51%-75%), good (76%-99%), or 
complete (100%). 
• 
Results will also be evaluated by comparing photographs 
before and immediately after treatments, and 12 and 24 
weeks after the last treatment. 
Secondary endpoints will include the following: 
• 
Subject reported pain during and after blue light 
illumination using a Visual Analogue Scale (VAS) from 0 (no 
pain) to 10 (worst pain imaginable). 

 
 
 
 
9
• 
Percent of patients with adverse events. 
Safety will be assessed by the investigator as follows: 
• 
Local Skin Reactions:  Assessment of swelling, 
vesiculation/pustulation, erosion/ulceration, erythema, 
flaking/scaling, and crusting using a five-point ordinal scale 
(0: none to 4: severe) will be conducted after each 
treatment visit.  The presence or absence of 
hyperpigmentation in the treatment area will also be 
documented after each treatment visit.  
• 
Subjects will be asked to rate their pain using a VAS both 
during and after blue light treatment.  
• 
PDT Reactions:  Other than those specified under local skin 
reactions. 
• 
Adverse Events:  Evaluation of any reported local or 
systemic events outside the treatment area and other than 
those specified under local skin reactions.  
Study Endpoints 
Primary Endpoints:  
• 
Clearance will be estimated as a percentage improvement 
from baseline. 
Secondary Endpoints:  
• 
Tolerability of treatment and tabulation of reported local 
and systemic adverse events.  
Study Duration  
24 to 36 weeks 
Total Sample Size 
20 

 
 
Page 10 of 32 
 
4.0 SCHEDULE OF ASSESSMENTS 
 
Treatment Phase  
Observational 
Follow-up Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
 
5 
6 
End of Study/ 
Early 
Termination 
Visit 
Week(s) 
-2-0 
weeks 
day 0 
6 
weeks 
12 
weeks 
24 
weeks 
36 weeks 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X 
X  
 
 
 
 
Concomitant  
Medications 
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
 
 
 
X 
Treatments 
 
X 
X 
X 
 
 
Physician Efficacy 
Assessments  
Comparison of 
photographs 
 
X 
X 
X 
X 
X 
Investigator Global 
Assessment 
 
X 
X 
X 
X 
X 
Subject Efficacy 
Assessments  
Subject Global 
Assessment of 
Improvement 
 
X 
X 
X 
X 
X 
DLQI 
 
X 
X 
X 
X 
X 
Physician Safety 
Assessments  

 
 
Page 11 of 32 
 
 
Treatment Phase  
Observational 
Follow-up Phase 
Visit Number 
1 
Screening 
2 
Baseline 
3 
4 
 
5 
6 
End of Study/ 
Early 
Termination 
Visit 
Week(s) 
-2-0 
weeks 
day 0 
6 
weeks 
12 
weeks 
24 
weeks 
36 weeks 
Swelling, 
Vesiculation, 
Erosion, Erythema, 
Flaking, Crusting 
 
X 
X 
X 
X 
X 
Hyperpigmentatio
n 
 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
Pregnancy Testingd 
X 
X 
 
 
 
X 
Subject Safety 
Assessments  
Redness, swelling, 
and dryness 
 
X 
X 
X 
X 
X 
Pain (VAS Scale) 
 
X 
X 
X 
X 
X 
Photographs  
 
X 
X 
X 
X 
X 

 
 
Page 12 of 32 
 
5. INTRODUCTION & RATIONALE  
Actinic cheilitis is a common precancerous malformation of the lower lip caused by UV 
radiation. Conventional therapies, such as cryotherapy, topical 5-fluorouracil, Imiquimod, 
chemical peels, electrodessication, laser ablation, and vermilionectomy are oftentimes 
successful in the majority of patients. However, these treatments may be expensive, 
time-consuming, associated with noncompliance, have a high recurrence rate, require 
local or general anesthesia, and offer risk of unaesthetic scars. There are also numerous 
adverse side effects associated with the aforementioned treatments; therefore, 
alternative treatments for the treatment of actinic cheilitis are essential.   
 
In the literature, several reports have shown photodynamic therapy (PDT) to be 
efficacious in the treatment of actinic cheilitis. Of note, patients in these case 
reports/series received therapeutic benefit with relatively few PDT treatments, which 
were associated with minimal cutaneous side effects.1-2 PDT is based on the combined 
use of photosensitizers and photoradiation. Topically applied δ-aminolevulinic acid (ALA) 
is theorized to be taken up by premalignant cells. Upon irradiation with a light source, 
photoactivated porphyrins produce singlet oxygen and other potent oxidizers, resulting 
in cell death.3 Unfortunately, controlled clinical trials assessing the efficacy of PDT for 
actinic cheilitis are lacking. As PDT does not appear to have any systemic side effects, if 
proven efficacious, PDT could be one of the safest treatment options for actinic cheilitis. 
 
6. STUDY OBJECTIVE  
To evaluate the safety and efficacy of PDT with blue light and topical Levulan 
(aminolevulinic acid) in the treatment of actinic cheilitis. 
 
6.1 HYPOTHESIS 
The use of PDT with blue light and topical Levulan treatment will reduce the number of 
actinic cheilitis lesions.  
 
7. RESEARCH DESIGN & METHODS  
This is a single center, investigator initiated, nonrandomized, open-label, proof of 
concept study of PDT with blue light and topical Levulan in the treatment of actinic 
cheilitis. 

 
 
Page 13 of 32 
 
 
7.1 SUBJECT RECRUITMENT  
Patients with a diagnosis of actinic cheilitis who have been seen at the outpatient 
dermatology clinic at Dartmouth Hitchcock Medical Center will be contacted by 
telephone by study coordinator(s), investigator(s), or designee in order to recruit study 
participants after discussing the study in detail.   
 
7.2 SCREENING & ELIGIBILITY 
Male and female subjects ≥ 18 years of age with a diagnosis of actinic cheilitis will be 
asked to participate in this study after the objectives, methods, and potential hazards of 
the study have been fully explained, and they have signed the informed consent form. 
The Principle Investigator will be responsible for keeping a record of all subjects who 
sign an informed consent form for entry into this study. A total of 20 subjects will be 
enrolled in this study.   
 
7.2.1 INCLUSION CRITERIA  
• 
Must be able to understand and voluntarily sign an informed consent form 
• 
Must be male or female ≥ 18 years of age at the time of consent 
• 
Must be able to adhere to the study visit schedule and other protocol 
requirements 
• 
Must have a diagnosis of actinic cheilitis by histopathological evaluation of 
biopsy specimen or clinical presentation 
 
7.2.2 EXCLUSION CRITERIA 
• 
Inability to provide voluntarily consent or mentally incompetent 
• 
No active herpes labialis lesions 
• 
Subjects with any condition which places the subject at unacceptable risk if 
he/she were to participate in the study, or confounds the ability to interpret data 
from the study 
• 
Subjects with any other skin condition that might affect the evaluation of the 
study disease 
• 
Pregnant or breastfeeding female subjects 

 
 
Page 14 of 32 
 
• 
Subjects who have used any investigational medication within one month prior 
to study entry 
• 
Subjects who have been previously exposed to PDT and/or topical Levulan 
therapy  
• 
Subjects who have used local therapy (e.g. cryotherapy) or topical treatment (e.g. 
5% fluorouracil) within three months of study entry 
• 
Subjects who have used an oral photosensitizing drug (e.g. Declomycin) within 
six months of study entry 
• 
Subjects who are currently using photosensitizing agents (e.g. thiazides, 
tetracyclines, fluoroquinolones, phenothiazines, and sulfonamides) because of 
the risk of augmented photosensitivity 
• 
Subjects who are frequently exposed to ultraviolet radiation (e.g. lifeguards, 
construction workers, frequent sunbed users, etc.) 
• 
Subjects with a history of cutaneous photosensitization, porphyria, 
hypersensitivity to porphyrins, or photodermatosis 
• 
Subjects with a known hypersensitivity to δ-aminolevulinic acid 
• 
Subjects who are immunocompromised 
 
7.3 VISIT SCHEDULE & ASSESSMENTS  
The study will consist of a screening visit, up to three scheduled treatments, and two 
scheduled office visits.  There can be a three-day window period for each scheduled visit 
in order to accommodate the subject’s schedule and unforeseen scheduling conflicts.  
1. Visit 1 (Screening):  Subjects can be screened for the study up to two weeks 
before Visit 2 (Baseline).  During screening, the study will be reviewed, written 
informed consent obtained, and eligibility confirmed.  If applicable, the washout 
from prohibited medications or treatments will be determined at this visit. 
2. Visit 2 (Baseline):  Following signed, written informed consent and confirmation 
of eligibility, all subjects will have their lips photographed.  Medical history, 
dermatologic exam, urine pregnancy test (if applicable), review of concomitant 
medications, clinical evaluations, and tolerability assessments will be performed 
at this visit.  Study medication application to clean skin will be followed by a 
ninety minute incubation period under occlusion.  Subsequently, patients will be 
exposed to blue light therapy for 16 minutes and 40 seconds.  Post-therapy 

 
 
Page 15 of 32 
 
assessments will be performed afterwards, as well as education on appropriate 
sun protection methods. 
3. Visits 3-4:  Subjects will return every six weeks for up to two additional 
treatments.  Treatment will be discontinued once the patient has achieved clinical 
clearance.  Tolerability assessments, study medication application, blue light 
therapy, post-therapy assessments, and photographs will be performed.  
4. Visit 5-6 (End of Study):  Subjects will return 12 and 24 weeks after the last 
treatment for clinical evaluations, tolerability assessments, and photographs. 
 
7.4 DURATION OF TREATMENT  
After the screening visit, subjects will receive in-office treatments every six weeks for 12 
weeks for up to a total of 3 treatments.  Treatment will be discontinued once the patient 
has achieved clinical clearance.  Each subject will then be followed for 24 weeks after the 
last treatment visit. In total, each subject will be part of the study for approximately 36 
weeks.   
 
7.5 RISK TO SUBJECTS 
PDT often invokes a transient local skin reaction, including increased erythema, edema, 
and/or scaling. These symptoms typically dissapate after one to two weeks, and are 
usually well tolerated if strict sun protection and avoidance are heeded; however, certain 
patients may have a more significant adverse response to PDT, especially if they are 
taking concomitant photosensitizing drugs (i.e. doxycycline, topical/oral retinoids, etc.). It 
is therefore of uptmost importance that patients who are currently using 
photosensitizing agents or frequently exposed to ultraviolet radiiation are exclused from 
study participation in order to minimize the risk of adverse events.  
 
No patient identifying information will be documented on any of the research materials, 
except for the informed consent paperwork and the Subject ID Key (see Section 9.1). 
Only the study investigators and assigned research personel will know the identity of 
each study subject, but they will not disclose this information unless necessitated by the 
law. The informed consent paperwork and all of the study research materials (i.e. 
demographic questionnaires, data collection sheets, etc.) will be held in a secure and 

 
 
Page 16 of 32 
 
confidential file for at least three years after the conclusion of this study, in accordance 
with the rules put in place by the IRB. 
 
7.6 DISCONTINUATION OF STUDY TREATMENT  
The following events are considered sufficient reasons for considering the 
discontinuation of a subject from the study:  
• 
An adverse event (AE) that in the judgement of the investigator may cause severe 
or permanent harm 
• 
Subject withdraws consent 
• 
Subject lost to follow-up 
• 
Death 
• 
Protocol violation 
 
8. TREATMENT & BLUE LIGHT PARAMETERS  
8.1 PRE-EXPOSURE SKIN CARE  
Subjects will wash their face with CeraVe Facial Cleanser prior to study treatment.  
Subsequently, the mixed contents of Kerastick (see section 8.2) will be applied topically 
with gloves to the designated target treatment area. After an incubation period of ninety 
minutes, subjects will wash their face again with CeraVe Facial Cleanser.  
 
8.2 INVESTIGATIONAL MEDICATION 
Kerastick is the dosage form of Levulan, which consists of a low-density polyethylene 
tube with two glass ampules and a sponge applicator tip covered with a protective 
cardboard sleeve and cap. Each Levulan Kerastick applicator contains one ampule 
containing 354 mg of aminolevulinic acid HCL (ALA) and one ampule of 1.5 mL of 
vehicle. Upon mixing both ampules, the concentration of ALA becomes 20%. 
 
8.2.1 SUPPLIER 
Levulan Kerastick will be supplied by DUSA pharmaceuticals, Inc.  
 
8.2.2 RECEIPT & STORAGE OF STUDY DRUG  

 
 
Page 17 of 32 
 
The Principle Investigator or designee is responsible for taking inventory of each 
shipment of study drug received. All investigational drug will be stored in a locked, safe 
area to prevent unauthorized access at the Heater Road clinic at Dartmouth Hitchcock 
Medical Center. The study drug will be stored as directed on the package insert.  
 
8.2.3 ACCOUNTABILITY  
The Principle Investigator or designee is responsible for keeping a record of all 
investigational drug that is dispensed during the study.  
 
8.2.4 HANDLING & DISPOSAL OF DRUG  
Any unused product will be documented, discarded, and need not be returned to DUSA 
pharmaceuticals, Inc. If any study drug is lost or damaged, its disposition will be 
documented in the subject’s source documents.  
 
8.3 LIGHT TREATMENT 
8.3.1 BLUE LIGHT TREATMENT  
Blue light will be administered to the lips using the BLU-U blue light (417 nm) PDT 
illuminator. The prescribed treatment time will be 16 minutes and 40 seconds, which will 
result in a total light dose of approximately 10 J/cm2 delivered at 10 mW/cm2.  Light 
exposure will be controlled with a timer. The investigator, subject, and anyone else in the 
light treatment room will wear appropriate protective eyewear at all times.  
 
8.3.2 SUPPLIER  
The BLU-U light and Omnilux revive2TM device is available at the dermatology clinic at 
Dartmouth Hitchcock Medical Center. 
 
8.4 POST-EXPOSURE SKIN CARE  
Subjects will be given verbal and written post-treatment instructions to clean treatment 
sites with warm water and CeraVe Facial Cleanser, and to apply topical petrolatum 
ointment until any weeping or crusting has subsided. Subjects will also apply chapstick 
with sun protection. All subjects will be instructed to avoid direct sun exposure and to 
apply a sun block with at least a sun protection factor (SPF) of 30 (Neutrogena SPF 100) 
for at least 48 hours after each treatment.  

 
 
Page 18 of 32 
 
 
9. CLINICAL ASSESSMENTS   
Efficacy and safety assessments during the treatment phase of the study will be done at 
the intervals specified in Section 4. The same investigator should complete the 
evaluations for a given subject throughout the study; however, if the assigned 
investigator is not available, another investigator with overlapping experience with the 
subject can complete the evaluation.  
 
9.1 DEMOGRAPHIC INFORMATION  
After signing the informed consent paperwork, each subject will be given a short 
questionnaire regarding their personal demographic information (i.e. gender, age, race, 
ethnicity, highest educational degree, annual income, marital status). Each subject will be 
assigned a Subject ID number (1-20), which will be documented on each of their study 
materials.  
 
9.2 PHYSICIAN PERFORMED ASSESSMENTS  
9.2.1 EFFICACY ASSESSMENTS  
Primary efficacy will be assessed by the investigator for clearance from baseline (Visit 2) 
to the end of study (Visit 6; week 36).  Clearance will be estimated clinically as minimal 
(0%-25%), mild (26%-50%), moderate (51%-75%), good (76%-99%), or complete (100%).  
Clinical photographs will also be taken at Visit 2 to 6. Care will be taken to avoid 
including any identifying landmarks, such as characteristic tattoos, birthmarks, etc. 
 
9.2.2 PRE & POST-TREATMENT SAFETY ASSESSMENTS  
A study physician will complete post-treatment assessments based upon visual 
observation of swelling, vesiculation/pustulation, erosion/ulceration, erythema, 
flaking/scaling, and crusting. The assessment will be based upon the scaling system 
below: 
 
Swelling 
 
Grade 0: not present 
Grade 1: slight, lesion specific edema 
Grade 2: palpable edema extending beyond individual lesions 

 
 
Page 19 of 32 
 
Grade 3: confluent or visible edema 
Grade 4: marked swelling, very easily noticeable from a 
distance  
Vesiculation/Pustulation 
 
Grade 0: not present 
Grade 1: only vesicles  
Grade 2: <50% pustules with or without vesicles 
Grade 3: > 50%, but <75% pustules with or without vesicles 
Grade 4: >75% pustules with or without vesicles  
Erosion/Ulceration 
 
Grade 0: not present 
Grade 1: lesion specific erosion 
Grade 2: erosion extending beyond individual lesions 
Grade 3: erosion >50%  
Grade 4: black eschar or ulceration 
Erythema 
 
Grade 0: not present 
Grade 1: slightly pink <50% 
Grade 2: pink or light red >50% 
Grade 3: red 50-75% 
Grade 4: severe redness, >75%, very easily noticeable from a 
distance 
Flaking/Scaling 
 
Grade 0: not present 
Grade 1: isolated scale, specific to lesions 
Grade 2: scale <50% 
Grade 3: scale >50%, but <75% 
Grade 4: scale >75%, very easily noticeable from a distance 
Crusting 
 
Grade 0: not present 
Grade 1: isolated crusting 
Grade 2: crusting <50% 
Grade 3: crusting >50% 
Grade 4: crusting >75%, very easily noticeable from a distance 
 
 
9.3 PATIENT PERFORMED ASSESSMENTS  
Subjective pre-treatment evaluations will be assessed based on the Subjective Global 
Assessment. Subjects will be instructed to circle their response.  

 
 
Page 20 of 32 
 
 
9.3.1 SUBJECT GLOBAL ASSESSMENT  
The subject global assessment of improvement will be performed during every visit 
(except baseline) to assess the subject’s impression of their overall improvement as 
compared to baseline. The subject global assessment scale is defined as follows: 
 
9.3.2 PRE & POST-TREATMENT PAIN ASSESSMENT  
Subjects will be asked to describe their pain prior to the application of topical Levulan 
and immediately after blue or red light illumination using a Visual Analogue Scale (VAS) 
from 0 to 10, 0 indicating no pain and 10 indicating the worst possible pain.  Pain will be 
assessed at each treatment visit.  
 
 
 
 
 
  
  
      0          
 
 
 
 
 
 
 
 
     10 
 
 
9.3.3 DERMATOLOGY LIFE QUALITY INDEX 
Subjects will be asked to complete the Dermatological Life Quality Index (DLQI) at every 
scheduled visit except for screening. These questionnaires should be completed by the 
subject before any other procedures or assessments are performed. If the subject is 
physically unable to complete the questionnaires, study personnel/staff may assist 
Excellent improvement 
My lip lesions are completely (100%) gone, except for 
possibly some residual color change 
Marked improvement 
My lip lesions are greatly (~75%) improved  
Moderate improvement 
My lip lesions are definitely (~50%) improved  
Mild improvement 
My lip lesions are somewhat (~25%) improved  
No improvement 
My lip lesions are not (0%) improved  
Worst Possible 
Pain 
No Pain 

 
 
Page 21 of 32 
 
him/her. Relatives and friends of the subject may not under any circumstances assist the 
subject with the questionnaire. The subject will initial and date his/her entries in the 
designated area of the Case Report Form (CRF) for each questionnaire.  The CRF will 
serve as the source documentation for this study. The DLQI questionnaire is as follows: 
 
Dermatological Life Quality Index 
The aim of this questionnaire is to measure how much your skin problem has affected 
your life OVER THE LAST WEEK.  Please check one response for each question. 
 
Question 
Response 
1. Over the last week, how itchy, sore, painful, or stinging has 
your skin been? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
2. Over the last week, how embarrassed or self-conscious have 
you been because of your skin? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
3. Over the last week, how much has your skin interfered with 
you going shopping or looking after your home or garden? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
4. Over the last week, how much has your skin influenced the 
clothes you wear? 
□ 1. Very much 

 
 
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□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
5. Over the last week, how much has your skin affected any 
social or leisure activities? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
6. Over the last week, how much has your skin made it difficult 
for you to do any sport? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
7. Over the last week, has your skin prevented you from 
working or studying? 
  
  
  
  
If “No”, over the last week how much has your skin been a 
□ 1. Yes 
□ 2. No 
□ 3. Not relevant 
  
  
□ 1. A lot 

 
 
Page 23 of 32 
 
problem at work or studying? 
□ 2.A little 
□ 3. Not at all 
8. Over the last week, how much has your skin created problems 
with your partner or any of your close friends or relatives? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
9. Over the last week, how much has your skin caused any 
sexual difficulties? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
10. Over the last week, how much of a problem has the 
treatment for your skin been, for example by making your 
home messy or by taking up time? 
□ 1. Very much 
□ 2. A lot 
□ 3. A little 
□ 4. Not at all 
□ 5. Not relevant 
 
 
9.3.4 TWO-DAY POST-TREATMENT TELEPHONE FOLLOW-UP VISIT  
Patients will be asked to rate redness, swelling, and dryness on the scale below. The 
scales will be read to the patient over the phone.  
 
Redness  
 
Grade 0: None 
Grade 1: Minimal redness, only a little noticeable 

 
 
Page 24 of 32 
 
Grade 2: Mild redness, easily noticeable and involving less than 1/3 
of the face 
Grade 3: Moderate redness, easily noticeable and involving between 
1/3 and 2/3 of the face 
Grade 4: Severe redness, very easily noticeable from a distance,  
and involving over 2/3 of the face  
 Swelling 
 
Grade 0: None 
Grade 1: Minimal swelling, only a little noticeable 
Grade 2: Mild swelling, easily noticeable and involving less than1/3 
of the face 
Grade 3: Moderate swelling, easily noticeable and involving  
between 1/3 and 2/3 of the face 
Grade 4: Severe swelling, very easily noticeable from a distance,  
and involving over 2/3 of the face  
Dryness of Skin 
 
Grade 0: None 
Grade 1: Minimal dry skin, only a little noticeable 
Grade 2: Mild dry skin, easily noticeable and involving less than  
1/3 of the face 
Grade 3: Moderate dry skin, easily noticeable and involving  
between 1/3 and 2/3 of the face 
Grade 4: Severe dry skin, very easily noticeable from a distance,  
and involving over 2/3 of the face 
 
Additionally the subject will be asked the open-ended question, “Have you had any 
problems since leaving our office after your last appointment?” The study coordinator 
will then record each subject’s response in the appropriate source document.  
 
10. ASSESSMENT OF ADVERSE EVENTS  
Safety precautions, such as the use of highly experienced investigators, frequent office 
visits, and close monitoring of clinical and laboratory findings (pregnancy tests) have 
been implemented in the protocol and are specified in the Schedule of Assessments (see 
Section 4). All unexpected physical examination findings will be captured as Adverse 
Events (AEs) when deemed medically significant by the investigator. Potential events that 
are anticipated post-treatment include erythema and pain. Other, less frequent potential 
events associated with any dermatological PDT include bleeding, crusting, numbness, 
itching, blistering and dryness, all of which tend to be transient.   
 
A qualified physician associated with the study will be available to assess clinical signs 
and symptoms that may be indicative of an AE. Any clinical sign or symptom that was 
not present at baseline and are not included in the expected side effect profile of PDT 
will be recorded as an AE. AEs may be reported spontaneously by the patient or elicited 

 
 
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through open (non-leading) questioning during each visit and up until the end of the 
period of observation (week 36; Visit 6). 
 
10.1 METHODS & TIMING OF SAFETY ASSESSMENTS  
Adverse events (AEs) will be assessed at every visit. Subjects who have an AE will be 
monitored with relevant clinical assessments and laboratory tests, as determined by the 
investigator. Every attempt will be made to obtain the resolution dates for ongoing AEs.  
 
Physical exams will be performed as per the Schedule of Assessments. Any clinically 
significant physical exam abnormalities will be documented as an AE. Pregnancy testing 
for females of child bearing potential (FCBP) will be done at screening, baseline, and at 
week 36. The FCBP will consist of a urine pregnancy test for -hCG with a sensitivity of at 
least 50 mIU/ml.  
 
10.2 RECORDING & REPORTING OF ADVERSE EVENTS  
10.2.1 ADVERSE EVENTS 
An AE is any noxious, unintended, or untoward medical occurrence that may appear or 
worsen in a subject during the course of a study. An AE may be a new concurrent illness, 
a worsening concomitant illness, an injury, or any concomitant impairment of the 
subject’s health, including laboratory test values (as specified by the criteria below), 
regardless of etiology. Any medical condition that was present prior to study treatment 
and remains unchanged or improved should not be recorded as an AE. If there is a 
worsening of an established medical condition (aside from the expected treatment side 
effects), this should be considered an AE. Individual signs and symptoms of an AE should 
be recorded on the AE page of the subject’s source documents. All AEs will be recorded 
by the investigator(s) from the time the informed consent form is signed through the 
end of the designated follow-up period (week 36; Visit 6).  
 
10.2.2 SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE which: 
• 
Results in death 
• 
Is life-threatening (i.e. in the opinion of the investigator, the subject is at 
immediate risk of death from the AE) 

 
 
Page 26 of 32 
 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization 
• 
Results in persistent or significant disability/incapacity (a substantial disruption of 
the subject’s ability to conduct normal life functions) 
• 
Results in a congenital anomaly/birth defect 
• 
Constitutes an important medical event 
 
Important medical events are defined as those occurrences that may not be immediately 
life threatening or result in death, hospitalization, or disability, but may jeopardize the 
subject’s health or require medical or surgical intervention to prevent one of the other 
outcomes listed previously. Medical and scientific judgment should be exercised in 
deciding whether such an AE should be considered serious. 
 
Events not considered to be an SAE are hospitalizations occurring under the following 
circumstances:  
• 
Hospitalizations planned before entry into the clinical study 
• 
Hospitalizations for elective treatment of a condition unrelated to the 
studied indication or its treatment  
• 
Hospitalizations that occur on an emergency, outpatient basis and do not 
result in admission (unless fulfilling the criteria under serious adverse 
event)  
• 
Hospitalizations that are part of the normal treatment or monitoring of 
the studied indication and not associated with any deterioration in the 
condition  
 
If an AE is considered serious, both the AE pages of the CRF and the SAE Report Form 
must be completed. For each SAE, the investigator will provide information on severity, 
start and stop dates, relationship to study drug, action taken regarding study treatment, 
and outcome.  
 
10.2.3 CLASSIFICATION OF SEVERITY   
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
 

 
 
Page 27 of 32 
 
Mild 
 
 
The adverse event is transient and easily tolerated. 
Moderate
 
 
The adverse event causes the patient discomfort and interrupts the patient’s 
usual activities. 
Severe 
 
  
The adverse event causes considerable interference with the patient’s usual 
activities and may be incapacitating or life-threatening. 
 
10.2.4 CLASSIFICATION OF RELATIONSHIP/CAUSALITY OF AE/SAE  
TO STUDY DRUG  
The investigator must determine the relationship between the administration of study 
drug and the occurrence of an AE/SAE as not suspected or suspected as defined below: 
 
Not suspected: 
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship unlikely or 
remote, or other medications, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the 
observed event. 
Suspected: 
The temporal relationship of the adverse event to study drug 
administration makes a causal relationship possible, and 
other medications, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the 
observed event. 
 
10.2.5 REPORT OF ADVERSE EVENTS TO THE INSTITUTIONAL REVIEW 
BOARD  
The Principle Investigator is required to notify the Institutional Review Board (IRB) of a 
serious adverse events according to institutional policy.   
 
10.2.6 PREGNANCIES  
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless 
of age) of a female subject or the female partner of a male subject occurring while the 

 
 
Page 28 of 32 
 
subject is in the study are considered immediately reportable events. Study treatments 
will be stopped immediately if this occurs.  
 
11. PROTOCOL AMENDMENTS/DEVIATIONS  
11.1 PROTOCOL AMENDMENTS  
Any amendment to this protocol must be agreed to by the Principle Investigator and 
reviewed by DUSA Pharmaceuticals, Inc. Written verification of Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval will be obtained before any 
amendment is implemented. Written signed approval from the IRB/IEC should refer 
specifically to the investigator, protocol number and title, and mention any applicable 
amendment numbers. Amendments that are administrative in nature do not require 
IRB/IEC approval, but will be submitted to the IRB/IEC for information purposes. 
 
11.2 PROTOCOL DEVIATIONS  
When an emergency occurs that requires a deviation from the protocol for a subject, a 
deviation will be made only for that subject. A decision will be made as soon as possible 
to determine whether or not the aforementioned subject is to continue in the study. The 
subject’s medical records will completely describe and explain the protocol deviation. In 
addition, the Principle Investigator will notify the IRB/IEC in writing of a protocol 
deviation. Non-emergency, minor deviations from the protocol will be permitted with 
approval of the Principal Investigator.  
 
12. QUALITY CONTROL & QUALITY ASSURANCE  
12.1 ANALYSES & REPORTING  
After all 20 patients have completed the 36-week clinical trial, the Section of Biostatistics 
and Epidemiology at Dartmouth Medical School will help facilitate data analysis, 
interpretation, and presentation for future publication.   
 
12.2 INVESTIGATOR RESPONSIBILITIES  
The investigator(s) will follow the principles of good clinical practice (GCP) and conduct 
the study in accordance with the principles of the Declaration of Helsinki. 
 
12.3 AUDITS & INSPECTIONS  

 
 
Page 29 of 32 
 
The Principle Investigator is required to permit direct access to the facilities where the 
study took place, source documents, CRFs and applicable supporting records of subject 
participation for audits and inspections by the IRBs/IECs and regulatory authorities (i.e. 
FDA). The investigator will make every effort to be available for audits and/or 
inspections.  
 
13. REGULATORY CONSIDERATIONS  
13.1 INFORMED CONSENT  
Documentation that informed consent occurred prior to a subject’s entry into the study 
and of the informed consent process should be recorded in the subject’s source 
documents. The original consent form signed and dated by the subject and the person 
consenting the subject must be maintained in the Principle Investigator’s study files. A 
copy of the informed consent form will be given to the subject. 
 
13.2 STUDY RECORDS REQUIREMENTS  
The Principle Investigator must ensure that the records and documents pertaining to the 
conduct of the study and the distribution of the study drug be retained by the 
investigator for as long as needed to comply with national regulations (generally two-
three years after discontinuing clinical development). The Principle Investigator agrees to 
adhere to the document/records retention procedures by signing the protocol. The 
following are examples of pertinent records and documents: 
• 
Copies of CRFs and source documents  
• 
Hospital records  
• 
Clinical and office charts  
• 
Laboratory notes  
• 
Memoranda  
• 
Subject’s evaluation checklists  
• 
Pharmacy dispensing records  
• 
Recorded data from automated instruments  
• 
Copies or transcriptions certified after verification as being accurate copies  
• 
Microfiches  
• 
Photographic negatives, microfilm, or magnetic media 
• 
Subject files  

 
 
Page 30 of 32 
 
• 
Records kept at the pharmacy, laboratory, and medico-technical departments 
involved in the clinical study 
• 
Documents regarding subject treatment and study drug accountability 
• 
Original signed informed consent forms  
 
 
 

 
 
Page 31 of 32 
 
14. REFERENCES  
1.  Ribeiro, C. F., Souza, F. H. D. M. D., Jordão, J. M., Haendchen, L. C., Mesquita, L., Schmitt, 
J. V., & Faucz, L. L. (2012). Photodynamic therapy in actinic cheilitis: clinical and 
anatomopathological evaluation of 19 patients. Anais brasileiros de dermatologia, 87(3), 418-423. 
 
2.  Zaiac, M., & Clement, A. (2011). Treatment of actinic cheilitis by photodynamic therapy with 5-
aminolevulinic acid and blue light activation. Journal of drugs in dermatology: JDD, 10(11), 1240-
1245. 
 
3.  Akimoto, M., Maeda, K., Omi, T., Nishimura, T., & Miyakawa, M. (2010). Photodynamic 
Therapy in the Dermatological Field and Enhanced Cutaneous Absorption of Photosensitizer. 
Session 2A7, 314. 
 
 
 
 
 
 
 
 

 
 
Page 32 of 32 
 
15. ABBREVIATIONS  
AE: Adverse Events 
ALA: Aminolevulinic Acid 
CRF: Case Report Form 
DLQI: Dermatological Life Quality Index 
FCBP: Females of Child Bearing Potential 
GCP: Good Clinical Practice 
IEC: Independent Ethics Committee 
IRB: Institutional Review Board 
PDT: Photodynamic Therapy 
SAE: Severe Adverse Events 
SPF: Sun Protection Factor  
VAS: Visual Analogue Scale