Conditions: Rosacea Papulopustular Rosacea
Keywords: Rosacea Photodynamic Therapy Aminolevulinic Acid Papulopustular Rosacea Blue Light
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: yes

Brief summary:
Rosacea is a chronic inflammatory disorder that is characterized by severe flushing (transient erythema), non-transient erythema, papules, pustules, and telangiectasia. Topical therapy is not always effective in treating symptoms of rosacea. Furthermore, rapid recurrence is common following the use of systemic antibiotics, resulting in the chronic use of these medications to control the disease. Although the exact pathogenesis of rosacea is unknown, treatment for this condition has been investigated based on its similarity to acne and photodamaged skin. Case reports have shown promising results in rosacea patients treated with methyl aminolevulinate photodynamic therapy (MAL - PDT). Other than a case report which observed significant improvement of papules, pustules, erythema, and flushing following 5 - aminolevulinic acid photodynamic therapy (ALA-PDT) treatment of a patient with rosacea, the role of ALA-PDT in the treatment of rosacea has not been reported.

We have designed a pilot study investigating the efficacy of ALA-PDT in treating papulopustular rosacea. The objectives of the study are as follows:

Primary objective:

1. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules), erythema, and telangiectasia of rosacea as assessed by the Investigator's Global Assessment (IGA).
2. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules) of rosacea as assessed by the Inflammatory Lesion Investigator's Global Assessment (ILIGA).

   Secondary objectives:
3. To evaluate improvement of rosacea associated erythema as assessed by the Clinical Erythema Assessment (CEA) scale.
4. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules) of rosacea as measured by a difference in inflammatory lesion count.
5. To evaluate improvement of rosacea as assessed by the Patient Overall Assessment Scale.

Detailed description:

Arms:
arm 1: Entire face treated with 20% Aminolevulinic Acid (Levulan) and Blu-U light arm 2: Entire face treated with vehicle substance only and Blu-U light arm 3: Entire face treated with vehicle substance only

Interventions: intervention 1: Aminolevulinic acid topical solution 20% intervention 2: Blu-U Light Therapy intervention 3: Placebo vehicle only
Intervention descriptions: intervention 1: Intervention used in the experimental arm only intervention 2: Intervention used in experimental and sham arms intervention 3: Intervention only includes the placebo vehicle solution

Protocol document:
Prot_SAP_000.pdf: 
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Version Date: March 14, 2017 
 
 
Photodynamic Therapy for Papulopustular Rosacea 
 
 
 
STUDY PROTOCOL 
 
 
GWU IRB # 031416 
NCT02075671 
 
PRINCIPAL INVESTIGATOR: 
 
Alison Ehrlich, MD, MHS 
Professor and Chair of Dermatology  
George Washington University 
 
Medical Faculty Associates 
2150 Pennsylvania Avenue, NW  
Washington, DC 20037  
(202) 741-2619   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1. 
STATEMENT OF HYPOTHESIS AND OBJECTIVES 
2. 
BACKGROUND, SIGNIFICANCE, AND RATIONALE  
3. 
RESEARCH DESIGN AND METHODS 
3.1 
OVERVIEW OF DESIGN 
3.2 
SAMPLE SIZE, INCLUSION AND EXCLUSION CRITERIA 
3.3 
SCREENING PHASE 
3.4 
TREATMENT PHASE 
3.5 
STUDY COMPLETION AND WITHDRAWAL CRITERIA 
3.6 
STRENGHTS AND LIMITATIONS OF PROPOSED RESEARCH 
4. 
DATA VARIABLES, COLLECTION, AND EVALUATION 
4.1 
DATA VARIABLES 
4.2 
DATA COLLECTION 
4.3 
STATISTICAL CONSIDERATIONS 
5. 
HUMAN SUBJECTS PROTECTION 
5.1 
SUBJECT SELECTION 
5.2 
RISKS AND BENEFITS 
5.3 
CONFIDENTIALITY 
5.4 
ADVERSE EVENTS AND SAFETY MONITORING 
6. 
REFERENCES 
 
 
 
 
 


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1. STATEMENT OF HYPOTHESIS AND OBJECTIVES: 
 
Rosacea is a chronic inflammatory disorder that is characterized by severe flushing (transient 
erythema), non-transient erythema, papules, pustules, and telangiectasia. Topical therapy is not 
always effective in treating symptoms of rosacea. Furthermore, rapid recurrence is common 
following the use of systemic antibiotics, resulting in the chronic use of these medications to 
control the disease. Although the exact pathogenesis of rosacea is unknown, treatment for this 
condition has been investigated based on its similarity to acne and photodamaged skin. Case 
reports have shown promising results in rosacea patients treated with methyl aminolevulinate 
photodynamic therapy (MAL – PDT).  Other than a case report which observed significant 
improvement of papules, pustules, erythema, and flushing following 5 - aminolevulinic acid 
photodynamic therapy (ALA-PDT) treatment of a patient with rosacea, the role of ALA-PDT in 
the treatment of rosacea has not been reported.   
We have designed a pilot study investigating the efficacy of ALA-PDT in treating papulopustular 
rosacea. The objectives of the study are as follows:   
Primary objective:  
1. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules), 
erythema, and telangiectasia of rosacea as assessed by the Investigator’s Global 
Assessment (IGA).  
 
2. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules) of 
rosacea as assessed by the Inflammatory Lesion Investigator’s Global Assessment 
(ILIGA).  
 
Secondary objectives:  
3. To evaluate improvement of rosacea associated erythema as assessed by the Clinical 
Erythema Assessment (CEA) scale.  
 
4. To evaluate improvement of the inflammatory lesions (papules, pustules, nodules) of 
rosacea as measured by a difference in inflammatory lesion count.  
 
5. To evaluate improvement of rosacea as assessed by the Patient Overall Assessment 
Scale.  
 
  
2. BACKGROUND, SIGNIFICANCE, AND RATIONALE 
 
 
Rosacea  


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Rosacea is a chronic inflammatory disorder that is characterized by severe flushing (transient 
erythema), nontransient erythema, papules, pustules, and telangiectasia. It primarily affects the 
central third of the face. Secondary features of rosacea include burning or stinging, 
erythematous plaques, edema, dry appearance, peripheral locations, ocular manifestations, and 
phymatous changes.1 It has a prevalence of about 10%. The majority of patients with rosacea 
are between the ages of 30-60 years of age.2,3   
There are four subtypes of rosacea (erythematotelangiectatic, papulopustular, phymatous, and 
ocular); patients may have characteristics of more than one subtype. Although the exact 
pathogenesis of rosacea is unknown, increased blood flow, excessive sun exposure, hair follicle 
mites (Demodex folliculorum and Demodex brevis), and inflammatory mediators (neutrophils, 
macrophages, and lymphocytes) are thought to play role.3  
Treatment for rosacea consists of topical azelaic acid, sodium sulfacetamide, sulfur, topical and 
systemic metronidazole, antibiotics (erythromycin, clindamycin, tetracycline), and, in resistant 
cases, isotretinoin. The therapeutic effect of these medications on rosacea is related more 
towards their anti-inflammatory than their antibacterial actions.3, 4  
Topical therapy is not always effective in treating symptoms of rosacea. Furthermore, rapid 
recurrence is common following the use of systemic antibiotics, resulting in the chronic use of 
these medications in order to control the disease.4  Pharmacological treatment is partially 
effective in treating the papulopustular lesions of rosacea, but the treatment of erythema, 
flushing, and telangiectasia is limited and at times requires the use of lasers, including pulse-
dye laser.5   
Photodynamic Therapy 
Photodynamic therapy (PDT) has been used for various dermatological conditions. It involves 
the administration of a photosensitizer which is absorbed by target cells. Absorption occurs 
preferentially by hyperproliferative tissue compared to normal tissue. Illumination with a light 
source of a specific wavelength results in the release of reactive oxygen species within the 
target tissue and results in the phototoxic destruction of tissue and bacteria.4,6   
5 - aminolevulinic acid (ALA) and its methylated ester, methyl aminolevulinate (MAL), are two 
common photosensitizers used in PDT. Both ALA and MAL are converted to protoporphyrin IX 
(PpIX), a cytotoxic intermediate that destroys tissues through necrosis and apoptosis. ALA, 
which is activated by blue light (417 +/- 5nm), is approved by the FDA for the treatment of 
hypertrophic actinic keratoses (AKs) of the face and scalp. It has also been used off-label in 
treating acne vulgaris, photodamaged skin, sebaceous hyperplasia, and skin cancer. MAL, 
which is activated by red light, is approved by the FDA for the treatment of nonhyperkeratotic 
AKs of the face and scalp. MAL is also approved in some European countries for the treatment 
of superficial and nodular basal cell carcinoma (BCC) and Bowen’s disease.4,6  


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Both ALA and MAL – PDT have been effective in treating acne vulgaris. Studies have shown 
that PDT results in significant reductions in the number of inflammatory acne lesions.6 The role 
of PDT in the treatment of acne may be due its antibacterial properties, its ability to damage 
sebaceous glands, reduce follicular obstruction, and decrease sebum production and gland 
size.7,8 Hair follicles and sebaceous glands accumulate PpIX after administration of topical ALA. 
PpIX also accumulates more in acne lesions compared to surrounding skin. Propinobacterium 
acnes, a bacteria involved in the pathogensis of acne, produces porphyrins, a metabolic 
byproduct, which, when activated by light, results in the destruction of the bacteria.9 Topical ALA 
causes a preferential accumulation of additional porphyrins in Propinobacterium acnes, further 
enhancing the destructive effect of light.  
The mechanism of PDT in the treatment of rosacea is not completely understood. One theory is 
that rosacea is a folliculitis induced by gram-negative bacteria that are destroyed by a similar 
mechanism as Propinobacterium acnes following PDT. It is uncertain if these gram-negative 
bacteria also produce endogenous porphyrins.10 It is possible that PDT could also result in the 
destruction of Demodex follicularis. PDT has also been used in the treatment of actinic 
keratoses and photodamaged skin. Since rosacea may be induced and worsened by sunlight, 
the effect of PDT in treating rosacea could be related to its skin rejuvenating properties. The role 
of PDT in the treatment of neoplastic cells by inducing apoptosis, necrosis, and affecting the 
microvasculature could be another potential mechanism by which it treats rosacea.11  
Although the exact pathogenesis of rosacea is unknown, treatment for this condition has been 
investigated based on its similarity to acne and photodamaged skin. Since follicular 
inflammation occurs in rosacea and there is a therapeutic overlap between acne and rosacea, 
the role of PDT in the treatment of rosacea is being investigated. Nybaek et al observed clearing 
of rosacea in 3 out of 4 patients treated with MAL-PDT. They suggested that a total of two to 
three treatments with PDT may result in remissions for more than three months following 
treatment.4 Katz et al observed significant improvement of papules, pustules, erythema, and 
flushing following ALA-PDT treatment of a 45 year old female with rosacea.12  
In light of the above work we have designed a pilot study further investigating the ability of ALA-
PDT in treating papulopustular rosacea. If successful, this study could provide further evidence 
for the use of PDT in the treatment of rosacea. The results of this study may lead to the 
development of larger studies that are statistically powered to determine improvement of 
rosacea using ALA-PDT.  
3. RESEARCH DESIGN AND METHODS 
3.1 Overview of Design 
All participants will be patients that have been screened within the Department of Dermatology 
at the Medical Faculty Associates. Individuals meeting inclusion and exclusion criteria (see 
Section 3.2) will be randomized to one of three groups (groups A, B, or C); each group will 
contain 10 patients. Those in group A will have their entire face treated with 20% 5-ALA 
(Levulan® Kerastick®, Dusa Pharmaceuticals) and Blu-U light (DUSA ®). Those in group B will 


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have their entire face treated with the vehicle (Kerastick® without 5-ALA) and Blu-U light (DUSA 
®). Those in group C will have their entire face treated with the vehicle (Kerastick® without 5-
ALA) only. All patients will have their face treated with either 20% 5-ALA (Levulan® Kerastick®, 
Dusa Pharmaceuticals) or the vehicle (Kerastick® without 5-ALA), which will remain in contact 
with the skin for one hour and, for those in group A and B, subsequently irradiated with a 417nm 
blue light set at 10 J/cm2 from a Blu-U light (DUSA ®) for 16 minutes and 40 seconds. Each 
subject will receive a total of 4 treatments with a 2-3 week interval between each treatment (See 
Section 3.4). In addition, the face will be photographed and assessed by a blinded investigator 
(See Section 4). If ≥ 30% of patients in group A experience improvement in the Investigator’s 
Global Assessment Score (IGA) by at least one point (See Section 3) we will offer subjects in 
group B and group C one treatment with 20% 5-ALA (Levulan® Kerastick®, Dusa 
Pharmaceuticals) and Blu-U light (DUSA ®), which will occur 2-3 weeks after the completion of 
the blinded study period. 
 
3.2 Sample Size, Inclusion and Exclusion criteria 
We will enroll a total of 30 patients for this study. Each group (A, B, or C) will contain 10 
patients. The inclusion and exclusion criteria for the study are as follows: 
 
Inclusion Criteria:  
 
1. Ages 18-79 years 
2. Clinical diagnosis of papulopustular rosacea based on physician evaluation. Only 
patients with 3-50 papules and/or pustules, and a CEA total score ≥ 5, (See Section 
4.1.3) will be enrolled.  
3. History of failing at least one conventional treatment for rosacea (metronidazole, 
sodium sulfacetamide, tetracycline, azaleic acid) or not interested in continuous 
treatment with these agents.  
 
 
Exclusion Criteria:  
 
1. < 18 or > 79 years of age 
2. Allergy to 5 - aminolevulinic acid (ALA) or any component of the vehicle  
3. Use of topical acne or rosacea treatments (on the face) within 2 weeks prior to Treatment 1 
4. Use of systemic antibiotics within 1 month prior to Treatment 1  
5. Use of topical retinoids (on the face) within 1 month prior to Treatment 1  
6. Use of systemic retinoids, including isotretinoin, within 6 months prior to Treatment 1.  
7. Use of laser or light based rosacea treatments (on the face) within 1 month prior to 
Treatment 1 
8. Cosmetic procedures (e.g., superficial chemical peels, exfoliation or microdermabrasion of 
the face) within 2 months prior to Treatment 1 
9. Use of topical corticosteroids (on the face) 1 month prior to Treatment 1 


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10. Use of systemic corticosteroids 3 months prior to Treatment 1   
11. Known or suspected history of drug or alcohol abuse within the past 6 months as 
determined by the medical record or patient interview 
12. History of adverse reaction to light exposure  
13. History of disorder of porphyrin metabolism 
14. Scarring or infection in the area being treated  
15. Extensive facial hair that would either impair blue light exposure or interfere with lesion 
evaluation 
16. Inability to make study visits or anticipated poor compliance 
17. Pregnant females or nursing mothers. Eligible women of reproductive age will be required 
to have a negative urine pregnancy test at screening. They will also be required to be on at 
least one reliable form of effective birth control [examples: barrier method (condoms, 
diaphragm), oral, injectable, implant birth control or abstinence] during the course of this 
study and 30 days following the last treatment period. 
18. Life threatening illness that would interfere with the patient’s ability to complete the study  
19. Participation in another clinical experimental therapeutic study within 30 days of screening 
visit  
20. Any history or evidence of severe illness or any other condition that would make the 
patient, in the opinion of the investigator, unsuitable for the study.  
 
3.3 Screening Phase 
Prior to the first treatment session, potential participants will be evaluated for study eligibility. All 
other inclusion and exclusion criteria must be met prior to study entry/enrollment.  The 
screening phase will be 7-30 days prior to visit 2. If Visit 2 is unable to be scheduled within that 
window the subject will need to have the inclusion/exclusion reviewed again prior to completing 
Visit 2. 
3.4 Treatment Phase 
After the screening phase, subjects (ages 18 – 79 years) with papulopustular rosacea, will be 
randomized into one of three groups (groups A, B, or C). Each group will contain 10 patients. 
Those in group A will have their entire face treated with 20% 5-ALA (Levulan® Kerastick®, 
Dusa Pharmaceuticals) and Blu-U light (DUSA ®). Those in group B will have their entire face 
treated with the vehicle (Kerastick® without 5-ALA) and Blu-U light (DUSA ®). Those in group C 
will have their entire face treated with the vehicle (Kerastick® without 5-ALA) only. All subjects 
will have their face cleansed with acetone; each subjects face should be clean and dry prior to 
application of 20% 5-ALA (Levulan® Kerastick®, Dusa Pharmaceuticals) or vehicle (Kerastick® 
without 5-ALA).  20% 5-ALA (Levulan® Kerastick®, Dusa Pharmaceuticals) or vehicle 
(Kerastick® without 5-ALA) will be crushed and prepared for application after shaking for at 
least 3 minutes. Topical 5-ALA or vehicle will be liberally applied on skin (entire face) with extra 
pressure on lesions and allowed to remain in contact with the skin for 1 hour. Those in groups A 
and B will then have their entire face irradiated with a 417nm blue light set at 10 J/cm2 from a 
Blu-U light (DUSA ®) for 16 minutes and 40 seconds. After irradiation, the face will be washed 
with soap and water and sunscreen will be applied. Each subject will receive a total of 4 
treatments with a 2-3 week interval between each treatment session. If ≥30% of patients in 


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group A experience improvement in the Investigator’s Global Assessment Score (IGA) by at 
least one point (See Section 3) we will offer subjects in group B and group C an additional full 
face treatment with 20% 5-ALA (Levulan® Kerastick®, Dusa Pharmaceuticals) and Blu-U light 
(DUSA ®) 2-3 weeks after the completion of the blinded study period. Assessments 
(Investigator’s Global Assessment (IGA), Inflammatory Lesion Investigator’s Global Assessment 
(ILIGA), Clinical Erythema Assessment (CEA) Scale, inflammatory lesion count, and 
photographs (See Section 4.1.3)) will be performed at baseline, prior to each treatment session, 
and at study completion by a blinded investigator. A Patient Overall Assessment will be 
performed prior to every treatment visit (except week 0), and at study completion.  
3.5 Study Completion and Withdrawal Criteria 
Completion of the blinded component of the study will occur for each individual after 4 
treatments with 20% 5-ALA (Levulan® Kerastick®, Dusa Pharmaceuticals) and Blu-U light 
(DUSA ®) (group A), vehicle (Kerastick® without 5-ALA) and Blu-U light (DUSA ®) (group B), or 
vehicle (Kerastick® without 5-ALA) only (group C). Participants will have final assessments 
performed 2 months (+/- 2 weeks) after their last treatment of the blinded period, as outlined in 
Table 1. If ≥30% of patients in group A experience improvement in the Investigator’s Global 
Assessment Score (IGA) by at least one point (See Section 3) we will offer subjects in group B 
and group C an additional full face treatment with 20% 5-ALA (Levulan® Kerastick®, Dusa 
Pharmaceuticals) and Blu-U light (DUSA ®), which will occur 2-3 weeks after the completion of 
the blinded study period. 
Subjects may choose to withdraw from the study at any time and for any reason.  The principle 
and co-investigators may also withdraw any individual that develops worsening rosacea. All 
serious adverse events that are probably or definitely related to the protocol will be reported to 
the George Washington University Medical Center Institutional Review Board in accordance 
with IRB policies and procedures. 
3.6 Strength and Limitations of Proposed Research 
Strengths of the study include its relatively simple design and the potential for its completion 
within a short period of time due to the small number of participants (ten).  
Limitations of this study include the inability to conduct robust statistical analysis due to its small 
sample size.  However, the results of this project may lead to the development of larger studies 
that will have the statistical power to detect improvements.  
4. DATA VARIABLES, COLLECTION, AND EVALUATION 
4.1 Data Variables 
The following data will be evaluated in patients fulfilling inclusion and exclusion criteria and who 
agree to participate in the study.   
1. Sociodemographic Variables: Age, gender, race 


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2.   Clinical History: 
a. Rosacea history: The patient's disease and treatment history will be obtained. All past 
and current medications for rosacea will be recorded. 
b. Past medical history: All current and past medical conditions will be documented, 
allowing us to screen for the presence of any condition that, in the opinion of any of the 
investigators, would make the patient unsuitable for study inclusion.  Allergies to 
medications will also be noted. 
c. Current medications: All medications will be recorded.   
d. Social History: We will screen for the presence of any drug or alcohol abuse within 
the past 6 months as determined by the medical record or patient interview. 
 
3.   Rosacea - specific Variables: All variables described below will be assessed by the  
 
same blinded investigator at various points throughout the study.  
      a.   Investigator’s global assessment of rosacea (IGA). The IGA is a subjective 7-     
 
      point, static scoring system. Scores range from 0 to 6: 0 (clear) = no papules and/or            
 
      pustules, no residual erythema, no or mild to moderate telangiectasia; 1(minimal) =    
 
      rare papules and/or pustules, residual to mild erythema, mild to moderate          
    
 
      telangiectasia; 2 (mild) few papules and/or pustules, mild erythema, mild to moderate   
 
      telangiectasia; 3 (mild to moderate) = distinct number of papules and or/pustules;         
 
      mild to moderate erythema; mild to moderate telangiectasia; 4 (moderate) =       
   
 
      pronounced number of papules and/ or pustules, moderate erythema, mild to     
   
 
      moderate telangiectasia; 5 (moderate to severe) = many papules and/ or pustules,     
 
      occasionally with large inflamed lesions, moderate erythema, moderate   
    
   
 
      telangiectasia; 6 (severe) = numerous papules and/or pustules occasionally with  
   
 
      confluent areas of inflamed lesions; moderate or severe erythema, moderate or   
   
 
      severe telangiectasia. This assessment will be performed at baseline, prior to                 
 
      every treatment visit, and study completion. Improvement will be indicated by   
       
a decrease in the IGA score by ≥ 1 point compared to the previous assessment.   
     
      
Worsening will be indicated by an increase in the IGA score of ≥ 1 point compared to   
      
the previous assessment. 
 
 
 
b.   Inflammatory Lesion Investigator’s Global Assessment (ILIGA). The ILIGA is a  
 
      subjective 5-point measure of the overall disease severity. Scores range from 0 to 4:      
                  0 (clear) = no papules/pustules/nodules; 1 (almost clear) = 1 to 2 papules/pustules; 2     
                  (mild) = 3 to 10 papules/pustules; 3 (moderate) = 11 to 19 papules/pustules or ≤ 2   
                  nodules; 4 (severe) = ≥ 20 papules/pustules, or > 2 nodules. This assessment will be 
 
      performed at baseline, prior to every treatment visit, and study completion.        
  
 
      Improvement will be indicated by a decrease in the ILIGA score by ≥ 1 point   
 
      compared to the previous assessment. Worsening will be indicated by an increase in  
 
      the ILIGA score of ≥ 1 point compared to the previous assessment.             
 


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            c.   Clinical Erythema Assessment (CEA) scale. The CEA scale is an assessment of                                
 
        erythema. It has a score range from 0 to 4: 0 (none) = no redness; 1 (mild) = slight     
 
       pinkness; 2 (moderate) = definite redness; 3 (significant) = marked erythema; 4  
     
 
       (severe) = fiery redness. The total score is based on the evaluation of all areas of       
 
       the face (forehead, chin, right cheek, left cheek, and nose). Each of these areas will   
 
       be scored from 0-4, giving a maximum total score of 20. Improvement will be      
                   indicated by a decrease in the total CEA score by ≥ 1 point compared to the    
      
                   previous assessment. Worsening will be indicated by an increase in the total CEA      
 
       score of ≥ 1 point compared to the previous assessment.  The CEA will be   
                   performed at baseline, prior to every treatment visit, and study completion.  
 
 
 
d   Inflammatory lesion count. The number of inflammatory lesions (papules, pustules,   
 
      nodules) will be recorded at baseline, prior to every treatment visit, and      
   
         
                  at study completion. The inflammatory lesion count will be used to grade the     
                  ILIGA (See 4.1.3.a above).  
    
 
e.   Photographs: Photographs of the face will be taken at baseline, prior to every  
 
treatment visit, and at study completion. These photographs will be used by the blinded 
investigator in completing the IGA, CEA scale, and in determining the number of 
inflammatory lesions present.  
 
f.   Patient Overall Assessment Scale. Patients will assess the overall improvement of                
      their rosacea using a 4-point scale, where 1 = excellent improvement, 2 = good /    
      moderate improvement, 3 = no change, 4 = worsening. This assessment will be    
      performed prior to every treatment visit (except week 0), and at study    
                  completion. Improvement will be indicated by a decrease by ≥ 1 point compared to        
the previous assessment. Worsening will be indicated by an increase in this scale by ≥ 1 
point compared to the previous assessment.     
 
4.2 Data Collection 
All data variables will be stored in a secure database using coded identifiers in place of name.  
Most of the data will initially be recorded on approved study forms containing the participant's 
study ID code. After transfer of data into the computerized database, all paper forms will be kept 
in a secure locked cabinet within a locked office within the department.  Photographs will be stored 
with a secure electronic file and will be labeled with the participant's study ID code and date they 
were taken.  
4.3 Statistical Considerations 
 
Since this is a pilot study, we will perform only basic descriptive statistical analysis of our 
results.  Due to the small number of subjects, it is unlikely that any statistical test would have the 


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power to detect a significant difference in any of the measured variables. Instead, we will look 
for a decrease in IGA, ILIGA, and CEA scores, decrease in inflammatory lesion count, and an 
improvement in the Patient Overall Assessment Scale. The results of this project may lead to 
the development of larger studies that will have the statistical power to detect significant 
differences in these variables after treatment with 5-ALA-PDT.  
5. HUMAN SUBJECTS PROTECTION 
5.1 Subject Selection 
 
At the time of recruitment, each potential subject will be provided with an informed consent form 
to read. The potential subject will be allowed to take the consent form home to discuss its 
content with family members or friends. All individuals will be given a contact number that they 
may call to obtain answers to any questions regarding the study and their participation.  All 
subjects must sign a consent form prior to any study procedures being performed. 
Involvement of special subjects such as pregnant women, institutionalized individuals, 
prisoners, or impaired and non-competent individuals are not anticipated in this study. Eligible 
women of reproductive age will be required to be on one reliable form of effective birth control 
during the treatment period. They will also be required to have a negative urine pregnancy test 
during the screening period and prior to each treatment session for the duration of the study. 
Individuals from all racial/ethnic groups, regardless of gender, and those that are economically 
and educationally disadvantaged are eligible for this study if they meet the eligibility 
requirements. 
 
5.2 Risks and Benefits 
 
A temporary burning or stinging sensation may occur during light exposure following ALA 
application. A minority of patients may experience these symptoms after light exposure. Pruritus 
may also occur.6   
 
Patients with AKs and BCC usually experience a phototoxic reaction (edema, erythema, vesicles, 
crusting, erosions) when treated with ALA-PDT. This is an expected reaction that eventually 
results in the resolution of the treated lesions. These phototoxic reactions can be associated with 
pain, burning, and peeling and can last for up to 2 weeks.6 The severity of the phototoxic reaction 
increases with longer application times of ALA. Exposure to artificial lights or sunlight within the 
first 2 days following PDT treatment can result in a more severe phototoxic reaction. To decreases 
this risk, all subjects will have their faces washed with soap and water and will also have 
sunscreen applied following PDT treatment. Each subject will be advised to avoid sunlight or 
artificial light exposure for at least 48 hrs following PDT treatment and to also wear a wide-
brimmed hat or other protective apparel to shade the treated area from sun light or other bright 
light. 
 
Hyperpigmentation and occasionally hypopigmentation may occur following ALA-PDT treatment. 
These pigment changes usually resolve within six months. In one study, < 3% of patients treated 
with 5-ALA patch-PDT for AKs showed hypopigmentation after one year.13  Hyperpigmentation of 


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healthy skin following ALA-PDT is dependent on the dose of ALA. It usually occurs within 48-72 
hours following treatment and increases for the following two weeks. It occurs more frequently in 
individuals with psoriasis who are treated with PDT. In one study, all twenty-one subjects with 
psoriasis experienced mild to moderate hyperpigmentation of their psoriasis lesions following 
PDT. In another study, PDT resulted in hyperpigmentation of psoriasis lesions in seven out eight 
subjects. Pigmentary change occurs less frequently in patients treated with PDT for non 
melanoma skin cancer. The Scottish PDT Centre reported that 1% of 762 patients treated with 
PDT 
for 
non 
melanoma 
skin 
cancer 
developed 
pigmentary 
changes. 
Prolonged 
hyperpigmentation has been observed when treating hirsutism with PDT.6,14   
ALA-PDT for the treatment of acne has also been associated with erythema, crusting, 
discomfort/pain, and hyperpigmentation.14  In one study, skin exfoliation and postinflammatory 
hyperpigmentation was observed on the back for 1-3 months following the use of ALA – PDT (1-
4 treatment sessions) for the treatment of acne on the back of all 22 subjects.6 In another study, 
20 patients with moderate to severe acne vulgaris of the face had one side of their face treated 
with ALA-PDT and the other side treated with blue light alone. Patients experienced erythema, 
pain, stinging, peeling, pruritis, oozing, and pustules on their face. Fifty-five percent of patients 
experienced stinging and 25% experienced pain during ALA-PDT treatment. ALA-PDT resulted 
in erythema in 65% of patients, exfoliation in 70%, pruritus in 65%; these symptoms were more 
severe on acne lesions. These symptoms resolved within a few days following treatment and 
were less severe on the side of the face treated with blue light alone. Two patients experienced 
edema, crusting, and oozing and another two patients experienced transient pustular lesions on 
the side of the face treated with ALA-PDT treatment. Hyperpigmentation was observed in fifty-
five percent of patients on the side of the face treated with blue light alone and in 65% of patients 
on the side of the face treated with ALA- PDT.15  
 
Hair loss is another potential side-effect. Localized permanent hair loss, though uncommon, has 
been observed when treating BCC and Bowen’s disease.  
 
Scarring following topical PDT is very rare. Of the 762 patients treated with PDT for non melanoma 
skin cancer at the Scottish PDT Centre (See Above), only 0.8% developed mild to moderate 
scarring.6,14 
Topical PDT has a low risk of carcinogenicity. Porphyrin-like molecules have antioxidant and 
antimutagenic properties. Only two cases of skin cancer have been reported in patients receiving 
PDT. The first case involved an 82 year old male who developed melanoma on one of his skin 
sites 6 months after being treated with seven sessions of PDT, over 4 years, for actinic keratosis 
and squamous cell carcinoma. Although the development of melanoma in this case was probably 
coincidental, multiple treatments of PDT has the potential to possibly promote its development. 
The other case involved a 38 year old male who responded to ALA-PDT for the treatment of SCC 
in situ of the glans penis. He was started on topical 5-fluorouracil and was later found to have 
SCC on his penis, which was likely due to incomplete clearance and  progression of the SCC in 
situ. The potential role of PDT in causing this progression is unknown.14  


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Systemic ALA given at higher dosages than that contained in a Kerastick® has been associated 
with elevated liver enzymes. Elevated liver enzymes have not been associated with the topical 
application of ALA.  
Blue light may cause irreversible damage to the retina. Therefore, during each treatment session, 
patients will be required to wear protective goggles to decrease this risk.6  
ALA is a Category C drug. The safety of ALA during pregnancy and the risk to the unborn child 
are unknown. Therefore, we are not enrolling pregnant women in this study. Women who are 
able to have children must have a negative pregnancy test result at screen.  A repeat pregnancy 
test must be done if they miss any periods or their menstrual cycle becomes very irregular. If a 
pregnancy occurs, there may be a risk of miscarriage, birth defects or other unknown medical 
conditions.  All women must use at least one reliable form of effective birth control [example: 
barrier method (condoms, diaphragm), oral, injectable, implant birth control or abstinence] 
during the treatment period and for 30 days following the completion of this study. Treatment will 
be discontinued if a subject becomes pregnant. They will, however, continue to be observed 
through the conclusion of pregnancy. This observation will entail one telephone call visit at the 
conclusion of the first trimester, one telephone call visit at the conclusion of the second 
trimester, and one telephone call at the end of each month thereafter until the conclusion of the 
pregnancy. With the subject’s permission, any serious adverse events, abnormal lab results, or 
abnormal diagnostic test results pertaining to the subject or her developing fetus, as reported by 
the subject, will be recorded in our data base and reported to the GWU IRB in accordance to 
their policies and procedures.  
Patients may benefit from study participation by experiencing an improvement of their rosacea. It 
is still possible that their rosacea may not improve with the treatment under investigation.  
5.3 Confidentiality 
 
      All information collected as part of this study will be treated as confidential. Subject consent forms 
and data collection sheets will be stored in a locked office in the MFA Dermatology Department.  
These documents will be accessible to study investigators only. A computer database will be 
created. This database will not contain any subject identifiers. The data within the database will 
be labeled with each subject's study identification number.  Database information will be 
maintained in a password-protected file.  All the data included in this study will only be accessible 
to the investigators listed on the title page, and they will not be released for use by other 
researchers. 
 
5.4  Adverse Events and Safety Monitoring 
 
Patients will be closely monitored for any adverse events experienced during this study, as 
described in Section 5.2: Risks and Benefits.  Adverse events monitoring will be performed by 
the principal investigator during each treatment session starting at visit 3, during the blinded and 
post-treatment period of the study. Any event occurring more than two months after the final 
treatment will not be considered an adverse event. Patients will be educated as to the possible 
side effects and complications related to 5-ALA-PDT therapy, and will be instructed to notify any 


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Version Date: March 14, 2017 
 
investigator should they experience signs or symptoms of an adverse event.  Because the 
anticipated risks associated with this study are low, we feel that an independent monitoring 
board will not be necessary.   
All events that meet the Prompt Reporting Requirements (HRP-801) (including but not limited to 
new or increased risk, harm experienced by the subject, noncompliance with the federal 
regulations governing human research, and state medical board actions) will be reported to the 
GW OHR via a Problem Report and Promptly Reportable Information Form (HRP-204) within 5 
business days of knowledge of the event.  
 


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Version Date: March 14, 2017 
 
 
 
Table 1: Example Study Schedule of Events* 
Week 
Screen 
W0** 
W3 
W6 
W9 
W17*** 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
Informed Consent 
X 
 
 
 
 
 
Clinical History/ Screening Form 
X 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
IGA 
X 
X 
X 
X 
X 
X 
ILIGA 
X 
X 
X 
X 
X 
X 
CEA Scale 
X 
X 
X 
X 
X 
X 
Inflammatory Lesion Count  
X 
X 
X 
X 
X 
X 
Patient Overall Assessment Scale 
 
 
X 
X 
X 
X 
Photographs  
X 
X 
X 
X 
X 
X 
Adverse Events  
 
 
X 
X 
X 
X 
Treatment: 5-ALA-PDT (Group A);   
vehicle - PDT(Group B); vehicle (Group C)  
 
X 
X 
X 
X 
 
IGA, investigator’s global assessment; ILIGA, inflammatory lesion investigator’s global assessment; CEA, clinical erythema assessment; 5-ALA-PDT, 5 - aminolevulinic acid (ALA). *Actual schedule and time 
between treatments may vary for each subject. Each visit’s assessment and treatment day may occur 2-3 weeks after the previous treatment/assessment visit. **The first treatment will occur after the 
washout periods have been met. Re-evaluation of entry criteria will be performed at V2 when more than 30 days have passed since screening or to confirm a washout has been met. *** Final evaluation/study 
completion will occur 2 months (+/- 2 weeks) after the final treatment session of the blinded period of the study.  
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