Clinical trial NCT03322293
Conditions: Actinic Keratoses
Keywords: Actinic Keratoses photodynamic therapy aminolevulinic acid precancerous skin lesion
Sponsor: University of California, San Francisco
Start date: 2017-12-01; Completion date: 2019-07-01
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, single-blind controlled trial with parallel group design to determine whether daylight photodynamic therapy (PDT) affords a reduction in treatment symptoms of pain, burning, and pruritus as measured by 1) symptom level during the treatment period and 2) pain at the end of treatment exposure.

Detailed description:
Actinic keratoses (AK) are common precancerous skin lesions that arise on sun-damaged skin. Treatment is aimed at preventing progression to cutaneous squamous cell carcinoma (SCC). First-line therapy for clinically apparent lesions includes cryotherapy and curettage; and field therapy options are topical 5-fluorouracil, imiquimod, ingenol mebutate, and photodynamic therapy (PDT). PDT involves the topical application of aminolevulinic acid (ALA), or one of its derivatives, as a photosensitizing agent. In response, rapidly proliferating, dysplastic cells preferentially accumulate protoporphyrin IX (PpIX). When PpIX is activated by blue or red light, singlet oxygen species are produced, resulting in cell death. PDT is beneficial due to its brief treatment course and efficacy in clearing AK. However, its main drawbacks are the adverse effects of pain, burning, pruritus, erythema, crusting, and inflammation associated with treatment. While conventional PDT uses red or blue artificial light to activate a high concentration of accumulated protoporphyrins, daylight PDT uses natural daylight to activate lower levels of protoporphyrins in a continuous manner. Daylight PDT, when compared with conventional PDT, has been associated with significantly less pain while achieving comparable efficacy for the treatment of AK. Daylight PDT is also more cost-effective and reduces the amount of time spent in clinic. Previous randomized studies comparing daylight PDT with conventional PDT have largely used methyl-aminolevulinate as the photosensitizer, have been intra-individual comparative studies, and have been performed in Nordic countries. Because the effective light dose from natural daylight depends on geographic location and seasonal and weather changes, randomized trials in different geographic and environmental conditions are of interest. The proposed randomized clinical trial investigates the tolerability and efficacy of daylight ALA-PDT for the treatment of AK in San Francisco for the first time; subjects will be randomized to various treatment arms, as opposed to previous split-face and intra-individual studies.

Arms: arm 1: This is considered the standard of care arm for photodynamic therapy for the treatment of actinic keratosis. This treatment arm includes: Acetone preparation, ALA topical application, 1 hour incubation, 16 minutes 40 seconds (16:40) BLU-U exposure, application of sunscreen.

Drug intervention: Aminolevulinic acid HCl (ALA) topical solution 20% Device: BLU-U blue light phototherapy illuminator arm 2: This treatment arm combines standard of care BLU-U exposure and daylight exposure. This treatment arm includes: Acetone preparation, ALA topical application, 15 minute incubation, 16:40 BLU-U exposure, application of sunscreen, 45 minute daylight exposure.

Drug intervention: Aminolevulinic acid HCl (ALA) topical solution 20% Device: BLU-U blue light phototherapy illuminator arm 3: This is the experimental arm. This treatment arm includes: Acetone preparation, ALA topical application, 15 minute incubation, application of sunscreen, 1 hour daylight exposure.

Drug intervention: Aminolevulinic acid HCl (ALA) topical solution 20% Device: none
Interventions: intervention 1: Aminolevulinic Acid Topical 20% Topical Solution intervention 2: BLU-U blue light phototherapy illuminator
Intervention descriptions: intervention 1: PDT involves the topical application of aminolevulinic acid (ALA), or one of its derivatives, as a photosensitizing agent. Subjects will receive ALA in all treatment arms (A, B, and C). intervention 2: Depending on the treatment arm, subjects will either receive BLU-U exposure or not. Treatment arms A and B have BLU-U exposure and treatment arm C does not.

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Research Protocol 
Tolerability and efficacy of daylight aminolevulinic-acid-photodynamic therapy (ALA-PDT) 
compared with conventional ALA-PDT for treatment of actinic keratosis on the face or scalp 
Protocol Number: 
Version 1.0 
Version Date: 
March 13th, 2017 
Investigational Product: 
Aminolevulinic acid HCl topical solution 20% (Levulan 
Kerastick) 
IND Number: 
 
Development Phase: 
Not applicable 
Sponsor: 
Investigator Initiated Protocol 
Funding Organization: 
Sun Pharmaceutical Industries Ltd 
Principal Investigator: 
Name: Sarah Arron, MD, PhD 
 
Telephone: 415-353-9684 
 
Fax: 415-353-7838 
 
E-mail: Sarah.Arron@ucsf.edu 
 
 
Approval: 
 
 
 
PI Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive use of 
investigators of this product and is subject to recall at any time.  The information in this document 
may not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.   


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Sun Pharmaceutical Industries Ltd. with complete and timely information, as 
outlined in the protocol.  It is understood that all information pertaining to the study will 
be held strictly confidential and that this confidentiality requirement applies to all study 
staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain 
the procedures required to carry out the study in accordance with accepted GCP principles 
and to abide by the terms of this protocol. 
 
Protocol Number:  1.0 
 
Protocol Title:  Tolerability and efficacy of daylight aminolevulinic-acid-photodynamic 
therapy (ALA-PDT) compared with conventional ALA-PDT for treatment of actinic 
keratosis on the face or scalp 
 
Protocol Date:  March 13th, 2017 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number 
 


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TABLE OF CONTENTS 
 
1 
BACKGROUND ................................................................................................................. 11 
      1.1     Overview of Clinical and Non-Clinical Studies .......................................................... 11 
2 
STUDY RATIONALE ........................................................................................................ 11 
2.1 
Risk / Benefit Assessment ........................................................................................... 12 
3 
STUDY OBJECTIVES ....................................................................................................... 12 
3.1 
Primary Objective ....................................................................................................... 12 
3.2 
Secondary Objectives .................................................................................................. 12 
4 
STUDY DESIGN ................................................................................................................. 13 
4.1 
Study Overview ........................................................................................................... 13 
5 
CRITERIA FOR EVALUATION ..................................................................................... 13 
5.1 
Primary Efficacy Endpoint .......................................................................................... 13 
5.2 
Secondary Efficacy Endpoints .................................................................................... 13 
5.3 
Safety Evaluations ....................................................................................................... 14 
6 
SUBJECT SELECTION .................................................................................................... 14 
6.1 
Study Population ......................................................................................................... 14 
6.2 
Inclusion Criteria ......................................................................................................... 144 
6.3 
Exclusion Criteria ....................................................................................................... 14 
7 
CONCURRENT MEDICATIONS .................................................................................... 15 
7.1 
Allowed Medications and Treatments......................................................................... 15 
      7.2    Prohibited Medications and Treatments ……………………………………...............15 
8 
STUDY TREATMENTS .................................................................................................... 15 
8.1 
Method of Assigning Subjects to Treatment Groups .................................................. 15 
8.2 
Blinding ....................................................................................................................... 15 
8.3 
Formulation of Test and Control Products .................................................................. 15 
8.4 
Supply of Study Drug at the Site ................................................................................. 156 
8.5 
Study Drug Accountability ......................................................................................... 177 
8.6 
Measures of Treatment Compliance ........................................................................... 17 
9 
STUDY PROCEDURES AND GUIDELINES ................................................................. 18 
9.1 
Clinical Assessments ................................................................................................... 18 
      9.2     Clinical Laboratory Measurements…………………………………………..............19 
10 EVALUATIONS BY VISIT ............................................................................................... 19 
10.1 Visit 1 (Screening, Day -29 to 1) ................................................................................ 19 
10.2 Visit 2 (Day 1)  ............................................................................................................ 20 
10.3 Visit 3 (Day 3, telephone) ........................................................................................... 21 
10.4 Visit 4 (Day 8) ............................................................................................................. 21 
10.5 Visit 5 (Day 15, telephone) ......................................................................................... 21 
      10.6   Visit 6 (Day 29) ……………………………………………………………...............21 
10.7   Visit 7 (Day 84)……………………………………………………………………...22 


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10.8 Early Withdrawal Visit ............................................................................................... 22 
11 ADVERSE EVENT REPORTING AND DOCUMENTATION .................................... 22 
11.1 Adverse Events ........................................................................................................... 22 
11.2 Serious Adverse EVENT (SAE) ................................................................................. 24 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS................................... 24 
      12.1   Early Discontinuation of Study Drug ……………………………………..................24 
12.2 Withdrawal of Subjects from the Study ...................................................................... 245 
12.3 Replacement of Subjects ............................................................................................. 25 
13 PROTOCOL VIOLATIONS ............................................................................................. 25 
14 DATA SAFETY MONITORING  ..................................................................................... 26 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................... 26 
15.1 Data Sets Analyzed ..................................................................................................... 26 
15.2 Demographic and Baseline Characteristics ................................................................. 26 
15.3 Analysis of Primary Endpoint ..................................................................................... 26 
15.4 Analysis of Secondary Endpoints ............................................................................... 27 
15.5 Interim Analysis .......................................................................................................... 27 
15.6 Sample Size and Randomization ................................................................................. 27 
16 DATA COLLECTION, RETENTION AND MONITORING ....................................... 27 
16.1 Data Collection Instruments ........................................................................................ 27 
16.2 Data Management Procedures ..................................................................................... 28 
16.3 Data Quality Control and Reporting ........................................................................... 28 
16.4 Archival of Data .......................................................................................................... 28 
16.5 Availability and Retention of Investigational Records ............................................... 28 
16.6 Subject Confidentiality................................................................................................ 29 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................. 29 
17.1 Protocol Amendments ................................................................................................. 29 
17.2 Institutional Review Boards and Independent Ethics Committees ............................. 29 
17.3 Informed Consent Form .............................................................................................. 30 
17.4 Publications ................................................................................................................. 30 
17.5 Investigator Responsibilities ....................................................................................... 30 
APPENDIX I. SCHEDULE OF STUDY VISIT...…………………………………………. 32 
APPENDIX II. TREATMENT PROTOCOL……………………………………………… 32 
APPENDIX III. TIMING OF SYMPTOM ASSESSMENT…………………………..........33 
APPENDIX IV. UNIVERSAL PAIN ASSESSMENT TOOL………………………...........33 
APPENDIX V. LOCAL SKIN RESPONSE ASSESSMENT……………………………....34 
APPENDIX VI. SKINDEX-16………………………………………………………..............35 
APPENDIX VII. REFERENCES..…………………………………………………………...36 


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LIST OF ABBREVIATIONS 
AE 
AK 
ALA 
adverse event 
actinic keratosis 
aminolevulinic acid  
BLU-U 
blue light phototherapy illuminator 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
HCl 
Good Clinical Practice 
Hydrochloride  
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
LSR 
PDT 
PpIX 
Institutional Review Board 
Local skin reaction 
photodynamic therapy 
protoporphyrin IX 
PI 
Principal Investigator 
SAE 
SCC 
serious adverse event 
squamous cell carcinoma 


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PROTOCOL SYNOPSIS 
TITLE 
Tolerability and efficacy of daylight aminolevulinic-acid-photodynamic 
therapy (ALA-PDT) compared with conventional ALA-PDT for 
treatment of actinic keratosis on the face or scalp 
 
SPONSOR 
Investigator Initiated Protocol 
FUNDING 
ORGANIZATION 
Sun Pharmaceutical Industries Ltd 
NUMBER OF SITES 
1 
RATIONALE 
Actinic keratoses (AK) are common precancerous skin lesions that 
arise on sun-damaged skin. Treatment is aimed at preventing 
progression to cutaneous squamous cell carcinoma (SCC). First-line 
therapy for clinically apparent lesions includes cryotherapy and 
curettage; and field therapy options are topical 5-fluorouracil, 
imiquimod, ingenol mebutate, and photodynamic therapy (PDT). PDT 
involves the topical application of aminolevulinic acid (ALA), or one 
of its derivatives, as a photosensitizing agent. In response, rapidly 
proliferating, dysplastic cells preferentially accumulate 
protoporphyrin IX (PpIX). When PpIX is activated by blue or red 
light, singlet oxygen species are produced, resulting in cell death. 
PDT is beneficial due to its brief treatment course and efficacy in 
clearing AK. However, its main drawbacks are the adverse effects of 
pain, burning, pruritus, erythema, crusting, and inflammation 
associated with treatment. While conventional PDT uses red or blue 
artificial light to activate a high concentration of accumulated 
protoporphyrins, daylight PDT uses natural daylight to activate lower 
levels of protoporphyrins in a continuous manner. Daylight PDT, 
when compared with conventional PDT, has been associated with 
significantly less pain while achieving comparable effiacy for the 
treatment of AK. Daylight PDT is also more cost-effective and 
reduces the amount of time spent in clinic. Previous randomized 
studies comparing daylight PDT with conventional PDT have largely 
used methyl-aminolevulinate as the photosensitizer, have been intra-
individual comparative studies, and have been performed in Nordic 
countries. Because the effective light dose from natural daylight 
depends on geographic location and seasonal and weather changes, 
randomized trials in different geographic and environmental 
conditions are of interest. The proposed randomized clinical trial 
investigates the tolerability and efficacy of daylight ALA-PDT for the 
treatment of AK in San Francisco for the first time; subjects will be 
randomized to various treatment arms, as opposed to previous split-
face and intra-individual studies.  


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STUDY DESIGN 
Randomized (1:1:1), single-blind controlled trial with parallel group 
design 
PRIMARY 
OBJECTIVE 
To determine whether daylight PDT affords a reduction in treatment 
symptoms of pain, burning, and pruritus as measured by 1) symptom 
level during the treatment period and 2) pain at the end of treatment 
exposure. 
SECONDARY 
OBJECTIVES 
To determine efficacy in clearance of AK at 12 weeks as measured by 
1) Reduction in number of AKs and 2) Proportion of patients with 
partial and complete clearance of AKs. 
To determine whether daylight PDT affords a reduction in local skin 
reaction to treatment. 
To determine whether daylight PDT enables a faster resolution of pain 
and local skin response during the follow-up period. 
NUMBER OF 
SUBJECTS 
30; 10 in each treatment arm 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
• Adults at least 18 years old. 
• Subjects must be able to read, sign, and understand the 
informed consent 
• Subjects have at least 4 and no more than 20 clinically typical, 
visible actinic keratoses in the target treatment area on the face 
or scalp.   
• Subject must be willing to forego any other treatments for AK 
in the treatment area on the face or scalp, during the study 
period, and for 14 days prior to screening; including 
cryotherapy, topical 5-fluorouracil, imiquimod, and ingenol 
mebutate. 
• Subjects who have previously received PDT must undergo at 
least an 8-week washout period prior to enrollment in study. 
• Subject must be willing and able to participate in the study and 
to comply with all study requirements including concomitant 
medication and other treatment restrictions, and telephone 
interview. 
• If subject is a female of childbearing potential she must have a 
negative urine pregnancy test result prior to study treatment 
initiation and must agree to use an approved method of birth 
control while enrolled in the study. Women who are pregnant, 
lactating, or planning to become pregnant during the study 


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period are excluded from the study. 
Exclusion Criteria: 
• Subjects with any dermatologic disease in the treatment area 
that may be exacerbated by the treatment proposed or that 
might impair the evaluation of AKs. 
• Subjects who are currently participating in another clinical 
study or have completed another clinical study with an 
investigational drug or device on the study area within 30 days 
prior to study treatment initiation. 
• 
Subjects with any medical condition that, in the opinion of the 
investigator, makes the patient unsuitable for the trial. 
 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Study medication—Aminolevulinic acid HCl topical solution 20% 
(Levulan Kerastick) 
Study device—BLU-U blue light phototherapy illuminator 
After preparation of the treatment area with acetone, one stick of 
Levulan (containing 354 mg ALA HCl) will be topically applied to 
the treatment area (face or scalp).  Subjects will be randomized to one 
of three treatment arms to receive BLU-U exposure and/or daylight 
exposure. Treatment arms are as follows:  
A. Conventional arm: Acetone preparation, ALA topical 
application, 1hour incubation, 16 minutes 40 seconds (16:40) 
BLU-U exposure, application of sunscreen. 
B. Combination arm: Acetone preparation, ALA topical 
application, 15 minute incubation, 16:40 BLU-U exposure, 
application of sunscreen, 45 minute daylight exposure. 
C. Daylight arm: Acetone preparation, ALA topical application, 
15 minute incubation, application of sunscreen, 1 hour 
daylight exposure. 
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 115 days. 
Screening:  up to 30 days 
Treatment: 1 day  
Follow-up:  84 days 
The total duration of the study is expected to be 16 months.  
Approximately 12 months for subject enrollment and 4 months for 
treatment and final subject follow-up. 


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CONCOMMITANT 
MEDICATIONS 
Allowed: Bland topical emollients such as Eucerin, Cetaphil. 
Prohibited: Any topical prescription medication on the treatment area 
during the study. 
EVALUATIONS 
 
PRIMARY ENDPOINT 
Primary objective is to determine whether daylight PDT affords a 
reduction in treatment symptoms of pain, stinging/burning, and 
itching/pruritus.   
Primary endpoints will be: 
 1) peak symptom level and composite score during the treatment 
period  
 2) symptom level and composite score at the end of treatment 
exposure.  
SECONDARY 
ENDPOINTS 
1) To determine efficacy in clearance of AK at 12 weeks:  
A. percent reduction in number of AKs from baseline to 12 weeks 
B. proportion of subjects with complete and partial clearance of 
AKs as described above 
2) To determine whether daylight PDT affords, at end of treatment, a 
reduction in composite local skin reaction 
3) To determine whether daylight PDT has a faster resolution of 
composite treatment symptoms and local skin response during  
days 8, 29, and 84. 
 
STATISTICS 
Primary Analysis Plan 
Symptom level over time during the treatment period will be graphed 
for visualization along the three axes of pain, stinging/burning, and 
itching/pruritus as well as a composite symptom score. Peak symptom 
level during the treatment period and pain at the end of treatment 
exposure will be compared between the conventional treatment arm 
(A), the combination treatment arm B), and the daylight treatment arm 
(C), with unpaired t-tests. 
 
Percent reduction in the number of actinic keratoses and proportions 
of patients with partial and complete clearance of actinic keratoses 
will be presented descriptively and visualized as histograms.  We will 
compare the percent reduction in the number of AKs and the 
proportions of patients with clearance between the conventional 
treatment arm (A) and the combination treatment arm B), and between 
the conventional treatment arm (A) and the daylight treatment arm 
(C), using unpaired t-tests.  
 


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All analyses will be based on the intent-to-treat (ITT) population. In 
the ITT population, patients will be counted in the treatment group 
upon randomization, regardless of receiving any dose of study 
medication. For efficacy analysis, all missing values due to patient 
early termination from the study will be imputed using last 
observation carried forward (LOCF) method, as appropriate. For each 
patient, the Baseline values will be defined as those values recorded at 
Day 1 prior to dosing. Patients who are lost-to-follow-up after 
Baseline will be included to the ITT population carrying forward their 
Baseline values.  
 
Rationale for Number 
of Subjects 
This is a small descriptive study. With ten subjects in each group, we 
will be powered to detect a 1.25-point difference in pain (pain scale 1-
10) with a two-sided alpha of 0.05 and a power of 0.8. 
 
 
 


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1 
BACKGROUND 
Photodynamic therapy (PDT) is one field therapy option for the treatment of actinic 
keratosis (AK). PDT involves the topical application of aminolevulinic acid (ALA), or 
one of its derivatives, as a photosensitizing agent. In response, rapidly proliferating, 
dysplastic cells preferentially accumulate protoporphyrin IX (PpIX). When PpIX is 
activated by blue or red light, singlet oxygen species are produced, resulting in cell death. 
PDT is beneficial due to its brief treatment course, ease of patient compliance, and 
efficacy in clearing AK. However, its main drawbacks are the adverse effects of pain, 
burning, pruritus, erythema, crusting, and inflammation associated with treatment. 
Daylight PDT, when compared with conventional PDT, has been associated with 
significantly less pain while achieving comparable efficacy for the treatment of AK in 
randomized trials from Nordic countries and Australia.1-2 
1.1   Overview of Clinical and Non-Clinical Studies 
Randomized trials, mostly from Nordic countries (Denmark, Norway, Sweden, Finland) 1, 
3-10 and one from Australia,2 have supported the use of daylight PDT for the treatment of 
AK. One case series from the United States documented the Southern California 
experience with daylight PDT.11 PDT has been associated with significantly less pain 
compared with conventional PDT, while maintaining efficacy comparable to that of 
conventional PDT for treatment of AK.1,2,11 Post-treatment cosmesis with daylight PDT 
has been excellent.11 The effective dose of sunlight required for AK clearance by daylight 
PDT is unclear. Effective light dose from natural sunlight has been shown to be highly 
variable based on geographic location, weather, and time of year.12-13 
2 
STUDY RATIONALE 
Actinic keratoses (AK) are common precancerous skin lesions that arise on sun-damaged 
skin. Treatment is aimed at preventing progression to cutaneous squamous cell carcinoma 
(SCC). First-line therapy for clinically apparent lesions includes cryotherapy and 
curettage; and field therapy options are topical 5-fluorouracil, imiquimod, ingenol 
mebutate, and photodynamic therapy (PDT). PDT involves the topical application of 
aminolevulinic acid (ALA), or one of its derivatives, as a photosensitizing agent. In 
response, rapidly proliferating, dysplastic cells preferentially accumulate protoporphyrin 
IX (PpIX). When PpIX is activated by blue or red light, singlet oxygen species are 
produced, resulting in cell death. PDT is beneficial due to its brief treatment course and 
efficacy in clearing AK. However, its main drawbacks are the adverse effects of pain, 
burning, pruritus, erythema, crusting, and inflammation associated with treatment. While 
conventional PDT uses red or blue artificial light to activate a high concentration of 
accumulated protoporphyrins, daylight PDT uses natural daylight to activate lower levels 
of protoporphyrins in a continuous manner. Daylight PDT, when compared with 
conventional PDT, has been associated with significantly less pain while achieving 
comparable efficacy for the treatment of AK. Daylight PDT is also more cost-effective 
and reduces the amount of time spent in clinic. Previous randomized studies comparing 
daylight PDT with conventional PDT have largely used methyl-aminolevulinate as the 
photosensitizer, have been intra-individual comparative studies, and have been performed 


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in Nordic countries. Because the effective light dose from natural daylight depends on 
geographic location and seasonal and weather changes, randomized trials in different 
geographic and environmental conditions are of interest. The proposed randomized 
clinical trial investigates the tolerability and efficacy of daylight ALA-PDT for the 
treatment of AK in San Francisco for the first time; subjects will be randomized to various 
treatment arms, as opposed to previous split-face and intra-individual studies.  
2.1 
Risk / Benefit Assessment 
The risks of aminolevulinic acid HCl are primarily local site reactions such as pain, 
erythema, burning, pruritus, and crusting. These typically begin on day 1 of treatment. 
Adverse reactions reported in >10% of patients treated with aminolevulinic acid were 
erythema, crusted skin, desquamation, burning, stinging, hyperpigmentation, 
hypopigmentation, pruritus, skin erosion. In 1-10% of treated patients, edema, 
dysesthesia, local flare, urticaria, localized vesiculation, drug eruption, dermal ulcer, 
scabbing, excoriation, oozing, hemorrhage, localized tenderness, or local pain were 
reported. As mucous membrane irritation and ocular injury are risks of treatment, the eyes 
and mucous membranes will be avoided. During artificial light treatment, the subject, 
health care personnel, and all present will wear appropriate eye protection; all will be 
counseled to avoid looking directly at the light source. Due to photosensitization 
associated with treatment, patients will be advised to avoid sunlight and prolonged or 
intense light that is not part of the treatment regimen for 40 hours. 
Photodynamic therapy with ALA has accepted benefits for the treatment of AK which 
outweigh the risks. Other field treatments require a longer duration of therapy and require 
patient compliance at home. Participants in this study will benefit from ALA-PDT, either 
illuminated by daylight or artificial blue light via BLU-U blue light phototherapy 
illuminator. 
 
3 
STUDY OBJECTIVES 
3.1 Primary Objective 
To determine whether daylight PDT affords a reduction in treatment symptoms of pain, 
stinging/burning, and itching/pruritus.   
3.2 
Secondary Objectives 
The secondary objects are (1) to determine efficacy in clearance of AK at 12 weeks; (2) to 
determine whether daylight PDT affords a reduction in local skin reaction to treatment; (3) 
to determine whether daylight PDT has a faster resolution of treatment symptoms and 
local skin response during the follow-up period.  
 


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4 
STUDY DESIGN 
4.1 
Study Overview 
This is a randomized (1:1:1) controlled trial with parallel group design. Thirty adult 
subjects are planned; with 10 subjects in each of three treatment arms.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  
The following medications and devices will be used:  
(1) Aminolevulinic acid HCl topical solution 20% (Levulan Kerastick) 
(2) BLU-U blue light phototherapy illuminator 
 
Three treatment arms to be compared are as follows:  
A. Conventional arm: Acetone preparation, ALA topical application, 1hour 
incubation, 16:40 BLU-U exposure, application of sunscreen. 
B. Combination arm: Acetone preparation, ALA topical application, 15 minute 
incubation, 16:40 BLU-U exposure, application of sunscreen, 45 minute daylight 
exposure. 
C. Daylight arm: Acetone preparation, ALA topical application, 15 minute 
incubation, application of sunscreen, 1 hour daylight exposure. 
Total duration of subject participation will be up to 115 days.  Total duration of the study 
is expected to be 16 months. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint will be (1) symptom level during the treatment period and 
(2) pain at the end of treatment exposure. 
With these endpoints, we will be able to determine whether daylight PDT offers a 
reduction in treatment symptoms of pain, burning, and pruritus. 
5.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are efficacy, local skin reaction to treatment, and 
symptoms and local skin response during follow-up period.  
1) Efficacy in clearance of AK at 12 weeks:  
A.  percent reduction in number of AKs from baseline to 12 weeks 
B.  proportion of subjects with complete and partial clearance of AKs as described 
above. 
2) To determine whether daylight PDT affords, at end of treatment, a reduction in 
composite local skin reaction 


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3) To determine whether daylight PDT has a faster resolution of composite treatment 
symptoms and local skin response during days 8, 29, and 84. 
5.3 
Safety Evaluations 
Evaluations include: adverse event reporting and physician evaluation. Adverse event 
reporting and physician evaluation will occur at every visit, if applicable. Telephone 
interview will occur on days 3, 15, and early termination (if applicable). Physical 
examination will occur at Screening, days 8, 29, 84, and early termination (if applicable).  
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of AK who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.   
6.2 
Inclusion Criteria 
• Adults at least 18 years old. 
• Subjects must be able to read, sign, and understand the informed consent 
• Subjects have at least 4 and no more than 20 clinically typical, visible actinic keratoses 
in the target treatment area on the face or scalp.   
• Subject must be willing to forego any other treatments for AK in the treatment area on 
the face or scalp, during the study period, and for 14 days prior to enrollment; including 
cryotherapy, topical 5-fluorouracil, imiquimod, and ingenol mebutate. 
• Subjects who have previously received PDT must undergo at least an 8-week washout 
period prior to enrollment in study. 
• Subject must be willing and able to participate in the study and to comply with all study 
requirements including concomitant medication and other treatment restrictions, and 
telephone interview. 
• If subject is a female of childbearing potential she must have a negative urine pregnancy 
test result prior to study treatment initiation and must agree to use an approved method of 
birth control while enrolled in the study. Women who are pregnant, lactating, or planning 
to become pregnant during the study period are excluded from the study. 
6.3 
Exclusion Criteria 
• Subjects with any dermatologic disease in the treatment area that may be exacerbated by 
the treatment proposed or that might impair the evaluation of AKs. 
• Subjects who are currently participating in another clinical study or have completed 
another clinical study with an investigational drug or device on the study area within 30 
days prior to study treatment initiation. 


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• Subjects with any medical condition that in the opinion of the investigator, makes the 
patient unsuitable for the trial. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
7.1 
Allowed Medications and Treatments 
Bland topical emollients such as Eucerin and Cetaphil are allowed. 
7.2 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be 
considered a protocol violation: any topical prescription medication on the treatment area 
during the study. 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Thirty eligible patients will be randomly assigned to one of three treatment arms 
(Conventional Arm, Combination Arm, Daylight Arm) in a 1:1:1 ratio using a SAS-based 
computer-generated randomization scheme developed by the study data management 
provider.  The investigator or designee will complete a randomization worksheet prior to 
Visit 1.  
8.2    Blinding 
This is a single-blinded study, as the subject cannot be blinded to treatment.  AK counts, 
local skin reaction, and ALA application will be performed by the blinded investigator. 
History, concomitant medications, randomization, light exposure, symptom assessment, 
and Skindex-16 will be administered by the unblinded study coordinator. 
8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
The active study product is Aminolevulinic acid HCl topical solution 20% (Levulan 
Kerastick), developed by Sun Pharmaceutical Industries Ltd for topical administration in 
the management of minimally to moderately-thick AK of the face or scalp. Levulan 
Kerastick consists of a plastic tube containing two sealed glass ampules and a dry 
applicator tip. One ampule contains 354 mg ALA HCl as a dry solid, and the other ampule 
holds 1.5 mL of solution vehicle containing alcohol USP (ethanol content = 48% v/v), 
water, laureth-4, isopropyl alcohol, and polyethylene glycol. Levulan Kerastick 20% 
topical solution is obtained by breaking both ampules and shaking the plastic tube to mix 
contents. 
8.3.2 
Formulation of Control Product 
Not applicable. 


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8.3.3 
Packaging and Labeling 
Aminolevulinic acid HCl topical solution 20% (Levulan Kerastick) is supplied in 
packages of six single-use plastic tubes with applicator tips. Each plastic tube contains one 
ampule of 354 mg ALA HCl as a dry solid and one ampule of 1.5 mL of solution vehicle. 
Each carton (kit) of ALA HCl topical solution 20% will be labeled with the required FDA 
warning statement, the protocol number, the name of the investigator,  patient number, 
name of sponsor, and directions for use and storage. Each tube will be labeled with the 
expiration date. 
8.4 
Supply of Study Drug at the Site 
Sun Pharmaceutical Industries Ltd will ship ALA HCl topical solution 20% (Levulan 
Kerastick) to the investigational site. The initial Levulan Kerastick shipment will be 
shipped after site activation (i.e., all required regulatory documentation has been received 
by Sun Pharmaceutical Industries Ltd and a contract has been executed.) Subsequent 
Levulan Kerastick shipments will be made after site request for resupply. 
8.4.1 
Dosage/Dosage Regimen 
Aminolevulinic acid HCl topical solution 20% (Levulan Kerastick) will be applied 
topically once by a healthcare provider on the day of treatment. One Levulan Kerastick 
will be applied to the treatment area on the face or scalp. Care will be taken to avoid the 
eyes and mouth.  
Treatment arms are as follows:  
A. Conventional arm: Acetone preparation, ALA topical application, 1 hour 
incubation, 16:40 BLU-U exposure, application of sunscreen. 
B. Combination arm: Acetone preparation, ALA topical application, 15 minute 
incubation, 16:40 BLU-U exposure, application of sunscreen, 45 minute daylight 
exposure. 
C. Daylight arm: Acetone preparation, ALA topical application, 15 minute 
incubation, application of sunscreen, 1 hour daylight exposure. 
Due to photosensitivity, subjects should avoid sunlight, tanning beds, and any prolonged 
or intense light exposure for 40 hours after application of ALA HCl, outside of the 
assigned treatment regimen. Subjects should not wash or clean their faces until all steps of 
treatment have been completed.  
8.4.2 
Dispensing 
The investigator or other training study staff will dispense ALA HCl 20% topical solution 
to be used by the study provider on treatment day. Medication will not be dispensed to the 
subjects for home use.  
8.4.3 
Administration Instructions  
Aminolevulinate acid HCl 20% topical solution (Levulan Kerastick) will be applied 
topically once by the study provider. After acetone preparation of the treatment area, 


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Levulan Kerastick will be applied to the subject’s affected areas within the treatment area. 
The treatment area will be either the face or scalp; the site will be determined at 
Screening. Prior to Levulan treatment, any hypertrophic AKs in the treatment area will be 
scraped with a curette by the study provider to remove thick scale. 
The study provider will prepare and administer Levulan Kerastick in the following 
manner: 
1. Hold Levulan Kerastick so the applicator cap is pointing up. 
2. Crush bottom ampule containing solution vehicle by applying finger pressure to 
marked location on the cardboard sleeve. 
3. Crush the top ampule containing the ALA HCl powder by applying finger pressure 
to marked location on the cardboard sleeve. To ensure both ampules are crushed, 
continue crushing the applicator downward 
4. Holding the Levulan Kerastick between the thumb and forefinger, pointing the 
applicator cap away from the face, shake the Levulan Kerastick gently for at least 
30 seconds to mix ALA HCl and solution vehicle. Do not press on end cap while 
shaking.  
5. Apply contents of one Levulan Kerastick using applicator tip to all affected areas 
within treatment area. Mouth, periorbital area, and all mucosal surfaces will be 
avoided.  
 
Depending on the assigned treatment arm, patients will receive 16 minutes, 40 seconds of 
artificial blue light on the treatment area via BLU-U blue light phototherapy illuminator 
and/or daylight exposure for the assigned duration. Light exposure will be provided by the 
unblinded study provider.  
8.4.4 
Storage 
Study drug should be stored by the study site at controlled room temperature, 15 to 30ºC (59-
86ºF). If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below 
this range, this should be reported to the designee and captured as a deviation.  
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing of study drug for each subject will 
be maintained on an ongoing basis by a member of the study site staff. 
The number of study drug dispensed for each subject will be recorded on the 
Investigational Drug Accountability Record.   
8.6 
Measures of Treatment Compliance 
Not applicable.  


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9 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at Study Days 1 (may be combined with screening), 8, 29, 84, and 
at early termination when applicable.  Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
9.1.4 
Physical Examination 
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician at Screening. Qualified staff (MD, NP, RN, and PA) 
may complete the abbreviated physical exam at all other visits.  New abnormal physical 
exam findings must be documented and will be followed by a physician or other qualified 
staff at the next scheduled visit. 
9.1.5 
Vital Signs 
Body temperature, blood pressure, pulse and respirations will be performed after resting 
for 5 minutes at Screening and at day 1. 
9.1.6 
Actinic keratosis (AK) count 
An AK count will be performed to count the lesions in the treatment area. AK count will 
be performed at Screening and at days 1, 8, 29, and 84.  
9.1.7 
Local Skin Reaction (LSR) 
Local skin reaction based on known response to PDT (Levulan package insert) will be 
graded by visual assessment on a custom 4 point scale where 0=none, 1=mild, 
2=moderate, 3=severe.  Each of the following four reactions will be graded: erythema, 
vesiculation/postulation, crusting/scabbing/erosion, and edema/swelling. A composite 


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score will be calculated (range 0-16). LSR assessment will be performed at days 1, 8, 29, 
and 84.  
9.1.8 
   Symptom assessment  
The patient symptom assessment will measure three axes: pain, stinging/burning, and 
itching/pruritus. Each of these three will be scored by patient report on a numeric scale 
(0= none, 10= worst possible). Each symptom will be scored and a composite score will 
be calculated (range 0-30). All subjects will have symptom assessments at 15, 30, 45, 60, 
and 75 minutes (Table 2). These times allow equivalent assessments relative to medication 
application regardless of treatment protocol.   
A Universal Pain Assessment Tool demonstrating the numeric scale, verbal descriptor 
scale, and activity tolerance scale will be provided to assist patients in selecting their pain 
level (Appendix IV). 
9.1.9 
Skindex-16 
Skindex-16 is used to measure quality of life in patients with skin diseases. The Skindex-
16 will be administered on Days 1, 3, 8, 15, 29, 84, and early termination (if applicable). 
9.1.10 Photography 
The investigator or trained study staff will photograph the subject’s treatment area on Day 
1, Day 8, Day 29, Day 84, and at early termination (if applicable). Prior to photographing 
the treatment area, study staff will (1) photograph a subject identification card including: 
subject’s initials, subject number, visit day and date; and (2) place a light-balanced sticker 
in the treatment area.  
9.1.11 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
9.2 
Clinical Laboratory Measurements  
9.2.1 
Pregnancy Test 
A urine pregnancy test will be obtained from female subjects who are of childbearing age 
prior to their participation in the study. 
10 EVALUATIONS BY VISIT 
All study visits will have a window +/- 3 days. 
10.1 Visit 1 (Screening, Day -29 to 1) 
1. 
Review the study with the subject (or subject’s legal representative) and obtain 
written informed consent and HIPAA authorization. 
2. 
Assign the subject a unique screening number. 


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3. 
Record demographics data. 
4. 
Record medical history, including a history of actinic keratosis, diagnosis date, and 
prior AK treatments. 
5. 
Record concomitant medications. 
6. 
Perform a complete physical examination. 
7. 
Perform and record vital signs. 
8. 
Perform urine pregnancy test in female subjects of childbearing age. 
9. 
Obtain informed consent. 
10. 
Photography of treatment area. 
11. 
Schedule subject for visit 2 in 0-29 days. 
10.2 Visit 2 (Day 1, may be combined with Screening) 
Unblinded investigator: 
1. 
Randomization to treatment arms (1:1:1). Investigator will use sequential 
envelopes with randomly prefilled treatment arms. Envelopes will be filled in 
batches of three (nine patients) to ensure even allocation between arms during the 
course of treatment. 
2.         Perform and record vital signs. 
3. 
Concomitant medications and Adverse Events review. 
 
Blinded investigator: 
4. 
Perform abbreviated physical examination. 
5. 
Perform an AK count  
6. 
Perform a pre-treatment local skin response assessment  
7. 
Curette any hypertrophic AK 
8.         Application of ALA 
 
Unblinded investigator: 
9. 
Monitor ALA incubation duration depending on treatment arm 
10. 
Light exposure (BLU-U and/or sunlight, depending on treatment arm)  
11. 
Symptom assessment. All subjects will have symptom assessments at 15, 30, 45, 
60, and 75 minutes (Table 2). 
12.        Skindex-16  
13. 
Record any Adverse Events. 
14.       Photography of treatment area. 
 
Blinded investigator: 
15. 
Perform a post-treatment local skin response assessment  


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10.3 Visit 3 (Day 3, telephone) 
1. 
Record any Adverse Events  
2. 
Symptom assessment 
3. 
Skindex-16 
10.4 Visit 4 (Day 8)  
Unblinded investigator: 
1. 
Record changes to concomitant medications. 
2. 
Record any Adverse Events 
3. 
Symptom assessment  
4. 
Record Skindex-16 
5. 
Photography of treatment area. 
 
Blinded investigator: 
6. 
Perform abbreviated physical examination. 
7. 
Perform AK count  
8. 
Record LSR  
 
10.5 Visit 5 (Day 15, telephone) 
1.    Record any Adverse Events 
2.    Symptom assessment 
3.    Skindex-16 
10.6 Visit 6 (Day 29) 
Unblinded investigator: 
1.       Record changes to concomitant medications. 
2.       Record any Adverse Events. 
3.       Symptom assessment  
4.       Skindex-16  
5.       Photography of treatment area. 
 
Blinded investigator: 
6.       Perform abbreviated physical examination 
7.       Perform an AK count (blinded investigator) 
8.       Perform a local skin response assessment (blinded investigator) 
 


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10.7 Visit 7 (Day 84) 
Unblinded investigator: 
1.       Record changes to concomitant medications. 
2.       Record any Adverse Events. 
3.       Symptom assessment  
4.       Skindex-16  
5.       Photography of treatment area. 
 
Blinded investigator: 
6.       Perform abbreviated physical examination 
7.       Perform an AK count (blinded investigator) 
8.       Perform a local skin response assessment (blinded investigator) 
 
10.8  Early Withdrawal Visit 
Unblinded investigator: 
 
1.         Record changes to concomitant medications. 
2.         Perform complete physical examination. 
3.         Record any Adverse Events.  
4.         Symptom assessment  
5. 
Record Skindex-16 
6. 
Photography of treatment area. 
 
Blinded investigator: 
 
7. 
Perform AK count  
8. 
Record LSR  
 
11 
ADVERSE EVENTS REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 


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The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the event is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse event as it occurred. 
This does not refer to an event that hypothetically might have caused 
death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 


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Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
11.2 Serious Adverse Events (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse event 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
11.2.1 Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF IRB Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB), the site investigator will report SAEs to the IRB.   
   
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject or the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation:  
Subject withdrawal of consent (or assent) 
Subject is not compliant with study procedures 


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Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
Protocol violation requiring discontinuation of study treatment 
Lost to follow-up 
Sponsor request for early termination of study 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all remaining 
scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents Refer to Section 10 for early termination procedures. 
12.2 Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject or the investigator , 
or the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Visit 7) should have an early discontinuation 
visit. Refer to Section 10 for early termination procedures.  Subjects who withdraw should 
be encouraged to come in for a final visit (and the procedures to be followed would 
include those for their next scheduled visit).   
12.3 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced.   
Subjects who withdraw from the study will not be replaced.  
 
13   PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject or investigator fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary 


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endpoint criteria.  Protocol violations for this study include, but are not limited to, the 
following: 
Failure to meet inclusion/exclusion criteria 
Use of a prohibited concomitant medication 
Failure of compliance with treatment regimen as described for assigned treatment arm 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation.  
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder. 
14 DATA SAFETY MONITORING  
Due to the scope of this study, there will be no formal Data Safety Monitoring Board 
(DSMB) or Data Monitoring Committee (DMC). This is an open-label, single-center 
study for an FDA-approved medication, and the investigator will have access to all study 
data.  
 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
All eligible patients who are enrolled in the study and receive at least one dose of the 
study drug (the Safety Population) and who have had at least one post-baseline safety 
evaluation will be included in the safety analysis. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by dose level: race, 
gender, age, height and weight.   
15.3 Analysis of Primary Endpoint 
This is a small descriptive study, with the primary tolerability endpoints:  1) peak 
symptom level and composite score during the treatment period and 2) symptom level and 
composite score at the end of treatment exposure. 
Symptom level over time during the treatment period will be graphed for visualization 
along the three axes of pain, stinging/burning, and itching/pruritus as well as a composite 
symptom score. Peak symptom level during the treatment period and pain at the end of 
treatment exposure will be compared between the conventional treatment arm (A), the 
combination treatment arm B), and the daylight treatment arm (C), with unpaired t-tests. 


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15.4 Analysis of Secondary Endpoints 
Efficacy and tolerability data will be summarized by each secondary endpoint. 
Symptom level over time during the treatment period will be graphed for visualization 
along the three axes of pain, stinging/burning, and itching/pruritus as well as a composite 
symptom score. Peak symptom level during the treatment period and pain at the end of 
treatment exposure will be compared between the conventional treatment arm (A), the 
combination treatment arm B), and the daylight treatment arm (C), with unpaired t-tests. 
Percent reduction in the number of actinic keratoses and proportions of patients with 
partial and complete clearance of actinic keratoses will be presented descriptively and 
visualized as histograms.  We will compare the percent reduction in the number of AKs 
and the proportions of patients with clearance between the conventional treatment arm (A) 
and the combination treatment arm B), and between the conventional treatment arm (A) 
and the daylight treatment arm (C), using unpaired t-tests.  
All analyses will be based on the intent-to-treat (ITT) population. In the ITT population, 
patients will be counted in the treatment group upon randomization, regardless of 
receiving any dose of study medication. For efficacy analysis, all missing values due to 
patient early termination from the study will be imputed using last observation carried 
forward (LOCF) method, as appropriate. For each patient, the Baseline values will be 
defined as those values recorded at Day 1 prior to dosing. Patients who are lost-to-follow-
up after Baseline will be included to the ITT population carrying forward their Baseline 
values. 
15.5 Interim Analysis 
Not applicable. 
15.6 Sample Size and Randomization 
This is a small descriptive study. With ten subjects in each group, we will be powered to 
detect a 1.25-point difference in pain (pain scale 1-10) with a two-sided alpha of 0.05 and 
a power of 0.8. 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.   
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific Case Report Form (eCRF) when the information 
corresponding to that visit is available.  Subjects will not be identified by name in the 
study database or on any study documents to be collected, but will be identified by a site 
number, subject number and initials. 


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If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
The data will be entered into a validated database.  The Data Management group will be 
responsible for data processing, in accordance with procedural documentation.  Database 
lock will occur once quality assurance procedures have been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database on a regular basis. 
Query reports (Data Clarification Requests) pertaining to data omissions and 
discrepancies will be forwarded to the Investigators and study monitors for resolution.  
The study database will be updated in accordance with the resolved queries.  All changes 
to the study database will be documented. 
16.4 Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with 
any updates or changes to the database.   
At critical junctures of the protocol (e.g., production of interim reports and final reports), 
data for analysis is locked and cleaned per established procedures. 
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and copies of all source documentation 
related to that subject.  The Investigator must ensure the reliability and availability of 
source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the IND 
has been discontinued.   


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16.6 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation.  
Additional subject confidentiality issues (if applicable) are covered in the Clinical Study 
Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be 
kept in a locked file cabinet and code sheets linking a patient’s name to a patient 
identification number will be stored separately in another locked file cabinet.  Clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all 
applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act 
of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the investigator.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as necessary to 
eliminate immediate safety hazards to patients.  A protocol amendment intended to 
eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards 
The protocol and consent form will be reviewed and approved by the IRB prior to study 
initiation.  Serious adverse events regardless of causality will be reported to the IRB in 
accordance with the standard operating procedures and policies of the IRB, and the 
Investigator will keep the IRB informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB.  The IRBs written unconditional approval of the study 
protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRBs unconditional approval statement will be 
transmitted by the Investigator to Sun Pharmaceutical Industries Ltd, prior to the shipment 
of study supplies to the site.  This approval must refer to the study by exact protocol title 
and number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 


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patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse events occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and submit to the IRB.  The consent form generated by the Investigator must be 
acceptable and be approved by the IRB.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations.  
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study. If a subject is unable to sign the informed consent form 
(ICF) and the HIPAA authorization, a legal representative may sign for the subject.   A 
copy of the signed consent form will be given to the subject or legal representative of the 
subject and the original will be maintained with the subject’s records. 
17.4 Publications  
The publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
17.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol, except when to protect the safety, 
rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 


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5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee. 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB all changes in the research activity and all unanticipated 
problems involving risks to subjects or others (to include amendments and IND safety 
reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312. 
 


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APPENDIX I. SCHEDULE OF STUDY VISITS 
 
Screening (Day 
-29 to Day 1) 
Day 1 (may be combined 
with screening) 
Day 3 
(telephone) 
Day 8 
Day 15 
(telephone) 
Day 29 
Day 84 
Informed consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Concomitant medications 
X 
X 
 
X 
 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
Urine Pregnancy test (if 
applicable) 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
ALA-PDT  
 
X 
 
 
 
 
 
AK count 
X 
X 
 
X 
 
X 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
Local Skin Reaction 
 
X  
(pre and post) 
 
X 
 
X 
X 
Symptom Assessment 
 
X 
X 
X 
X 
X 
X 
Skindex-16 
 
X 
X 
X 
X 
X 
X 
Photography 
 
X 
 
X 
 
X 
X 
 
APPENDIX II. TREATMENT PROTOCOL 
 


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APPENDIX III.  TIMING OF SYMPTOM ASSESSMENTS 
Min 
Symptom 
Assessment 
Conventional Arm 
Combination Arm 
Daylight Arm 
0 
Begin 1 hour Incubation 
Begin 15 minute incubation 
Begin 15 minute incubation 
5 
Incubation 
Incubation 
Incubation 
10 
Incubation 
Incubation 
Incubation 
15 
X 
Incubation 
Sunscreen, BLU-U Exposure: 
16m 40s 
Sunscreen, Daylight Exposure: 
60m 
20 
Incubation 
BLU-U 
Daylight 
25 
Incubation 
BLU-U 
Daylight 
30 
X 
Incubation 
End BLU-U, Begin Daylight 
Exposure: 60m 
Daylight 
35 
Incubation 
Daylight 
Daylight 
40 
Incubation 
Daylight 
Daylight 
45 
X 
Incubation 
Daylight 
Daylight 
50 
Incubation 
Daylight 
Daylight 
55 
Incubation 
Daylight 
Daylight 
60 
X 
BLU-U Exposure: 16m 40s 
Daylight 
Daylight 
65 
BLU-U 
Daylight 
Daylight 
70 
BLU-U 
Daylight 
Daylight 
75 
X 
End BLU-U, Sunscreen 
End Daylight 
End Daylight 
 
APPENDIX IV.  UNIVERSAL PAIN ASSESSMENT TOOL 
 
 
 
 
 
 


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APPENDIX V. LOCAL SKIN RESPONSE ASSESSMENT 


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APPENDIX VI.  SKINDEX-16 
 
 


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APPENDIX VII. REFERENCES 
1. Wiegell SR, Haedersdal M, Philipsen PA, Eriksen P, Enk CD , Wulf HC. 
Continuous activation of PpIX by daylight is as effective as and less painful than 
conventional photodynamic therapy for actinic keratoses; a randomized, controlled, 
single-blinded study. Br J Dermatol 2008; 158:740-6. 
2.  Rubel DM, Spelman L, Murrell DF, See JA, Hewitt D, Foley P et al. Daylight 
photodynamic therapy with methyl aminolevulinate cream as a convenient, 
similarly effective, nearly painless alternative to conventional photodynamic 
therapy in actinic keratosis treatment: a randomized controlled trial. Br J Dermatol 
2014;171:1164-71. 
3. Wiegell SR, Fabricius S, Gniadecka M, Stender IM, Berne B, Kroon S et al. 
Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of 
the face and scalp: a randomized multicentre study. Br J Dermatol 2012;166:1327-
32. 
4. Neittaanmaki-Perttu N, Gronroos M, Karppinen TT, Tani TT , Snellman E. Hexyl-
5-aminolaevulinate 0.2% vs. methyl-5-aminolaevulinate 16% daylight 
photodynamic therapy for treatment of actinic keratoses: results of a randomized 
double-blinded pilot trial. Br J Dermatol 2016;174:427-9. 
5. Neittaanmaki-Perttu N, Karppinen TT, Gronroos M, Tani TT , Snellman E. 
Daylight photodynamic therapy for actinic keratoses: a randomized double-blinded 
nonsponsored prospective study comparing 5-aminolaevulinic acid nanoemulsion 
(BF-200) with methyl-5-aminolaevulinate. Br J Dermatol 2014;171:1172-80. 
6. Togsverd-Bo K, Lei U, Erlendsson AM, Taudorf EH, Philipsen PA, Wulf HC et al. 
Combination of ablative fractional laser and daylight-mediated photodynamic 
therapy for actinic keratosis in organ transplant recipients - a randomized controlled 
trial. Br J Dermatol 2015;172:467-74. 
7. Wiegell SR, Fabricius S, Stender IM, Berne B, Kroon S, Andersen BL et al. A 
randomized, multicentre study of directed daylight exposure times of 1 ½  vs. 2 ½ h 
in daylight-mediated photodynamic therapy with methyl aminolaevulinate in 
patients with multiple thin actinic keratoses of the face and scalp. Br J Dermatol 
2011; 164:1083-90. 
8. Wiegell SR, Haedersdal M, Eriksen P , Wulf HC. Photodynamic therapy of actinic 
keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight 
exposure: a double-blinded randomized clinical trial. Br J Dermatol 2009; 
160:1308-14. 
9. Wiegell SR, Heydenreich J, Fabricius S , Wulf HC. Continuous ultra-low-intensity 
artificial daylight is not as effective as red LED light in photodynamic therapy of 
multiple actinic keratoses. Photodermatol Photoimmunol Photomed 2011; 27:280-5. 
10.  Wiegell SR, Lerche CM , Wulf HC. Is the thin layer of methyl aminolevulinate 
used during photodynamic therapy sufficient? Photodermatol Photoimmunol 
Photomed 2016; 32:88-92. 
11.  Lane K, Hovenic W, Ball K, Zachary CB. Daylight Photodynamic Therapy: The 
Southern California Experience. Lasers in Surgery and Medicine 2015; 47: 168-72. 


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12. Fitzmaurice S , Eisen DB. Daylight Photodynamic Therapy: What is Known and 
What is Yet to be Determined. Dermatol Surg 2016; 42:286-95. 
13.  Grinblat B, Galimberti G, Pantoja G, Sanclemente G, Lopez M, Alcala D et al. 
Feasibility of daylight-mediated photodynamic therapy for actinic keratosis 
throughout the year in Central and South America: a meteorological study. Int J 
Dermatol 2016.