Actinic Keratoses
Conditions
Keywords
Actinic Keratoses, photodynamic therapy, aminolevulinic acid, precancerous skin lesion
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.
Interventions
DRUGAminolevulinic Acid Topical 20% Topical Solution
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).
DEVICEBLU-U blue light phototherapy illuminator
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.
Sponsors
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Investigator)
Masking description
This is a single-blinded study, as the subject cannot be blinded to treatment. Disease assessments and aminolevulinic acid (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.
Intervention model description
Randomized (1:1:1), single-blind controlled trial with parallel group design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Treatment Symptoms | 12 weeks | Primary objective is to determine whether daylight PDT changes treatment symptoms of pain, stinging/burning, and itching/pruritus. This was measured using a visual analog scale from 0-10, with higher scores indicating worse treatment symptoms, or more pain/burning/itching. Lower scores indicate less pain, burning/stinging, and itching/pruritus. Positive numbers represent increases in symptoms and negative numbers represent decreases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in AK Lesion Count | 12 weeks | The number of actinic keratoses within the treatment area was counted both pre and post-treatment. Then, the mean percent change from baseline actinic keratosis lesion count was calculated for each treatment group. |
| Reduction of AK Counts | 12 weeks | The number of AK lesions within the treatment area was assessed both pre and post-treatment. Then, the number of participants with various levels of AK lesion reduction (100% reduction or greater than 75% reduction) was calculated for each treatment group. This outcome measures the proportion of subjects with complete (100%) and partial (greater than or equal to 75%) reduction of baseline actinic keratosis lesion counts at 12 weeks (study end). |
| Change in Local Skin Reaction From Pre-treatment to 12 Weeks Post-treatment | 12 weeks | To determine whether daylight PDT affords a reduction in local skin reaction to treatment. A Local Skin Response Assessment scale will be used to measure this outcome. The investigators will grade categories including Erythema, Flaking/Scaling, crusting, swelling, Pustulation (pustules), and Erosion, on a 0-4 scale (total maximum score of 24). A higher score indicates more erythema, flaking, crusting, etc. and therefore a more robust skin reaction. A score of 0 represents no erythema, flaking, crusting, etc. |
| Peak Pain Score at Day 8 Post-treatment | 8 days post-treatment | Pain was measured by patient report with a visual analog scale from 0-10. 0 indicates no pain and 10 indicates the maximum pain score. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A. Conventional Arm 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
Aminolevulinic Acid Topical 20% Topical Solution: 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).
BLU-U blue light phototherapy illuminator: 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. | 8 |
| B. Combination Arm 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
Aminolevulinic Acid Topical 20% Topical Solution: 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).
BLU-U blue light phototherapy illuminator: 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. | 8 |
| C. Daylight Arm 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
Aminolevulinic Acid Topical 20% Topical Solution: 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). | 8 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | B. Combination Arm | A. Conventional Arm | Total | C. Daylight Arm |
|---|---|---|---|---|
| Actinic Keratosis Count | 11.3 lesion count STANDARD_DEVIATION 3 | 12.1 lesion count STANDARD_DEVIATION 4.2 | 10.8 lesion count STANDARD_DEVIATION 4.9 | 10.3 lesion count STANDARD_DEVIATION 3.7 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 7 Participants | 21 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 3 Participants | 1 Participants |
| Age, Continuous | 77.7 years | 71.9 years | 75 years | 75.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 8 Participants | 23 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 24 Participants | 8 Participants |
| Region of Enrollment United States | 8 participants | 8 participants | 24 participants | 8 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 24 Participants | 8 Participants |
| Treatment Area Face | 6 Participants | 5 Participants | 17 Participants | 6 Participants |
| Treatment Area Scalp | 2 Participants | 3 Participants | 7 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 8 / 8 | 8 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Change in Treatment Symptoms
Primary objective is to determine whether daylight PDT changes treatment symptoms of pain, stinging/burning, and itching/pruritus. This was measured using a visual analog scale from 0-10, with higher scores indicating worse treatment symptoms, or more pain/burning/itching. Lower scores indicate less pain, burning/stinging, and itching/pruritus. Positive numbers represent increases in symptoms and negative numbers represent decreases.
Time frame: 12 weeks
Population: 24 participants enrolled in the study who underwent treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A. Conventional Arm | Change in Treatment Symptoms | 3.9 score on a scale |
| B. Combination Arm | Change in Treatment Symptoms | 0.5 score on a scale |
| C. Daylight Arm | Change in Treatment Symptoms | 0.37 score on a scale |
Secondary
Change in Local Skin Reaction From Pre-treatment to 12 Weeks Post-treatment
To determine whether daylight PDT affords a reduction in local skin reaction to treatment. A Local Skin Response Assessment scale will be used to measure this outcome. The investigators will grade categories including Erythema, Flaking/Scaling, crusting, swelling, Pustulation (pustules), and Erosion, on a 0-4 scale (total maximum score of 24). A higher score indicates more erythema, flaking, crusting, etc. and therefore a more robust skin reaction. A score of 0 represents no erythema, flaking, crusting, etc.
Time frame: 12 weeks
Population: 24 participants who underwent treatment were analyzed, with data from the 1 participant lost to follow up in Group C carried forward. 8 participants were analyzed for each subgroup, with 24 participants analyzed overall.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A. Conventional Arm | Change in Local Skin Reaction From Pre-treatment to 12 Weeks Post-treatment | 1.0 score on a scale |
| B. Combination Arm | Change in Local Skin Reaction From Pre-treatment to 12 Weeks Post-treatment | 1.25 score on a scale |
| C. Daylight Arm | Change in Local Skin Reaction From Pre-treatment to 12 Weeks Post-treatment | 1.0 score on a scale |
Secondary
Peak Pain Score at Day 8 Post-treatment
Pain was measured by patient report with a visual analog scale from 0-10. 0 indicates no pain and 10 indicates the maximum pain score.
Time frame: 8 days post-treatment
Population: 24 participants who underwent treatment were analyzed, with data from the 1 participant from Group C who was lost to follow up carried forward. 8 participants from each subgroup were analyzed, with 24 participants overall. Mean peak pain on day 8 with a 95% confidence interval for each treatment group on day 8 is reported below.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| A. Conventional Arm | Peak Pain Score at Day 8 Post-treatment | 3.5 score on a scale |
| B. Combination Arm | Peak Pain Score at Day 8 Post-treatment | 5.13 score on a scale |
| C. Daylight Arm | Peak Pain Score at Day 8 Post-treatment | 4.00 score on a scale |
Secondary
Percent Change in AK Lesion Count
The number of actinic keratoses within the treatment area was counted both pre and post-treatment. Then, the mean percent change from baseline actinic keratosis lesion count was calculated for each treatment group.
Time frame: 12 weeks
Population: 24 participants who underwent treatment were analyzed, with the data for the 1 participant in group C who was lost-to-follow up carried forward. This means that data for 8 participants in each subgroup and 24 participants overall was analyzed for this outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A. Conventional Arm | Percent Change in AK Lesion Count | 63.9 percent change | Standard Deviation 24.9 |
| B. Combination Arm | Percent Change in AK Lesion Count | 66.4 percent change | Standard Deviation 29.5 |
| C. Daylight Arm | Percent Change in AK Lesion Count | 61.8 percent change | Standard Deviation 59.9 |
Secondary
Reduction of AK Counts
The number of AK lesions within the treatment area was assessed both pre and post-treatment. Then, the number of participants with various levels of AK lesion reduction (100% reduction or greater than 75% reduction) was calculated for each treatment group. This outcome measures the proportion of subjects with complete (100%) and partial (greater than or equal to 75%) reduction of baseline actinic keratosis lesion counts at 12 weeks (study end).
Time frame: 12 weeks
Population: 24 participants who underwent treatment were analyzed, with data from the 1 participant in group C who was lost to follow up carried forward. 8 Participants were included in data analysis for each subgroup, with 24 participants included overall.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| A. Conventional Arm | Reduction of AK Counts | Partial Clearance | 2 Participants |
| A. Conventional Arm | Reduction of AK Counts | Complete Clearance | 2 Participants |
| B. Combination Arm | Reduction of AK Counts | Partial Clearance | 3 Participants |
| B. Combination Arm | Reduction of AK Counts | Complete Clearance | 2 Participants |
| C. Daylight Arm | Reduction of AK Counts | Partial Clearance | 5 Participants |
| C. Daylight Arm | Reduction of AK Counts | Complete Clearance | 2 Participants |