Maximal Use Systemic Exposure Study of Levulan Kerastick (MUSE 2)

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the potential for systemic exposure of aminolevulinic acid (ALA) and protoporphyrin IX (PpIX) when applied topically under occlusion, in a maximal use setting in patients with multiple actinic keratoses (AK) involving the upper extremities.

Official Title
-----------------
A Pharmacokinetic Study of Levulan Kerastick (Aminolevulinic Acid HCl) for Topical Solution, 20% Under Maximal Use Conditions

Conditions
-----------------
Keratosis, Actinic

Intervention / Treatment
-----------------
* Drug: Aminolevulinic Acid (ALA)
* Device: BLU-U


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 6 Grade 1/2 AKs on one upper extremity AND At least 12 Grade 1/2 AKs on the OTHER upper extremity Exclusion Criteria: Pregnancy history of cutaneous photosensitization, porphyria, hypersensitivity to porphyrins or photodermatosis lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or untreated skin cancers within the Treatment Area Body Mass Index (BMI) > 32.0 kg/m2 skin pathology or condition which could interfere with the evaluation of the test product or requires the use of interfering topical or systemic therapy significant blood loss within 60 days or donated blood/plasma within 72 hours prior to Visit 2 (Baseline) tested positive at screening for human immunodeficiency virus (HIV) or was known to be seropositive for HIV a history of lead poisoning or a history of a significant exposure to lead tested positive at screening for hepatitis B surface antigen, hepatitis C antibody or had a history of a positive result positive drug screen at Screening Screening safety labs are clinically significant in the opinion of the investigator major surgery within 30 days prior to Visit 2 (Baseline) or plans to have surgery during the study Subject is immunosuppressed currently enrolled in an investigational drug or device study has received an investigational drug or been treated with an investigational device within 30 days prior to Visit 2 (Baseline) known sensitivity to one or more of the vehicle components (ethyl alcohol, isopropyl alcohol, laureth 4, polyethylene glycol) use of the following topical preparations on the extremities to be treated: Keratolytics including urea (greater than 5%), alpha hydroxyacids [e.g.glycolic acid, lactic acid, etc. greater than 5%], salicylic acid (greater than 2%) within 2 days of initiation of treatment Cryotherapy within 2 weeks of initiation of treatment Retinoids, including tazarotene, adapalene, tretinoin, retinol, within 4 weeks of initiation of treatment Microdermabrasion, laser ablative treatments, ALA-PDT, chemical peels, 5-FU, diclofenac, imiquimod or other topical treatments for AK within 8 weeks of initiation of treatment use of systemic retinoid therapy within 6 months of initiation of treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALA<br>20% aminolevulinic acid applied via Kerastick to individual AK lesions on the upper extremities and covered with occlusive dressing for 3 hours prior to BLU-U treatment | Drug: Aminolevulinic Acid (ALA)<br>* 20% ALA applied to upper extremities for 3 hours prior to 10 J/cm2 blue light<br>* Other names: Levulan Kerastick;Device: BLU-U<br>* 10 J/cm2 of 417 nm blue light delivered at 10 mW/cm2<br>* Other names: Blue Light Photodynamic Therapy (PDT);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Baseline Corrected Plasma Concentration (Cmax) for ALA | Maximum baseline corrected plasma concentration (Cmax) for ALA over the 24 hour sampling time period. Blood samples were taken before ALA application and at 15 and 30 minutes, 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours following study medication application. | 2 days | 
| Time at Which Cmax is Attained (Tmax) for ALA | Time of the maximum baseline corrected plasma concentration for ALA measured at at 15 and 30 minutes, 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours following study medication application.If a maximum value occurred at more than one timepoint Tmax is defined as the first timepoint with this value. | 2 days | 
| AUCt | AUCt is the area under the baseline corrected plasma concentration-time profile up to the last quantifiable/non-negative plasma concentration | 0, 15, 30 minutes, and 1, 2, 4, 8, 12, 16, 24 hours post-dose | 
| The Terminal Exponential Half-life (T1/2,z) for ALA | The terminal slope was calculated by linear least squares regression of the log plasma concentration-time data. The terminal exponential half-life (T1/2,z) will be calculated as 0.693 divided by the absolute value of slope. | 2 days | 
| Maximum Baseline Corrected Plasma Concentration (Cmax) for PpIX | Maximum baseline corrected plasma concentration (Cmax) for PpIX over the 48 hour sampling time period. Blood samples were taken before ALA application and at 15 and 30 minutes, 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours following study medication application. | 2 days | 
| Time at Which Cmax is Attained (Tmax) for PpIX | Time of the maximum baseline corrected plasma concentration for PpIX measured at at 15 and 30 minutes, 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours following study medication application.If a maximum value occurred at more than one timepoint Tmax is defined as the first timepoint with this value. | 2 days | 
| AUCBL for PpIX | The area under the concentration time-curve assuming the baseline observed plasma concentration existed from time 0 to tlast. | 0, 15, 30 minutes, and 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours post-dose | 
| AUCt for PpIX | The area under the observed plasma concentration time-curve from time 0 to the last quantifiable plasma concentration. | 0, 15, 30 minutes, and 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours post-dose | 
| AUCt/AUCBL for PpIX | The ratio of AUCt to AUCBL for PpIX | 0, 15, 30 minutes, and 1, 2, 4, 8, 12, 16, 24, 36 and 48 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hyperpigmentation | HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas | Baseline | 
| Hyperpigmentation | HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas | 24 hours after PDT | 
| Hyperpigmentation | HYPERPIGMENTATION SCALE Grade 0 = No hyperpigmentation Grade 1 = Light hyperpigmentation involving small areas Grade 2 = Moderate hyperpigmentation involving small areas; light hyperpigmentation involving moderate areas Grade 3 = Moderate hyperpigmentation involving moderate sized areas; light hyperpigmentation involving large areas; small areas of marked hyperpigmentation Grade 4 = Marked hyperpigmentation involving moderate or large sized areas | Week 4 | 
| Hypopigmentation | HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas | Baseline | 
| Hypopigmentation | HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas | 24 hours after PDT | 
| Hypopigmentation | HYPOPIGMENTATION SCALE Grade 0 = No hypopigmentation Grade 1 = Light hypopigmentation involving small areas Grade 2 = Moderate hypopigmentation involving small areas; light hypopigmentation involving moderate areas Grade 3 = Moderate hypopigmentation involving moderate sized areas; light hypopigmentation involving large areas; small areas of marked hypopigmentation Grade 4 = Marked hypopigmentation involving moderate or large sized areas | Week 4 | 
| Erythema | Erythema Scale - Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema | Baseline | 
| Erythema | Erythema Scale - Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema | 5 Minutes after PDT | 
| Erythema | Erythema Scale - Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema | 24 hours after PDT | 
| Erythema | Erythema Scale - Grade 0 = None Grade 1 = Minimal - barely perceptible erythema Grade 2 = Mild - predominantly minimal erythema (pink) in the treated area with or without a few isolated areas of more intense erythema Grade 3 = Moderate - predominantly moderate erythema (red) in the treated area with or without a few isolated areas of intense erythema (bright red) Grade 4 = Severe - predominantly intense erythema (bright red) in the treated area with or without a few isolated areas of very intense (fiery red) erythema | Week 4 | 
| Edema | EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area | Baseline | 
| Edema | EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area | 5 Minutes after PDT | 
| Edema | EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area | 24 hours after PDT | 
| Edema | EDEMA SCALE Grade 0 = None Grade 1 = Minimal - scant, rare edema Grade 2 = Mild - easily seen edema, minimally palpable, involving up to 1/3 of the treatment area Grade 3 = Moderate - easily seen edema and typically palpable, involving between 1/3 to 2/3 of the treatment area Grade 4 = Severe - easily seen edema, indurated in some areas, involving over 2/3 of the treatment area | Week 4 | 
| Stinging/Burning | STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable | Baseline | 
| Stinging/Burning | STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable | Intraprocedure | 
| Stinging/Burning | STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable | 5 Minutes after photodynamic therapy | 
| Stinging/Burning | STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable | 24 hours after PDT | 
| Stinging/Burning | STINGING AND BURNING SCALE Grade 0 = None Grade 1 = Minimal, barely perceptible -tolerable and little discomfort Grade 2 = Moderate - tolerable, but causes some discomfort Grade 3 = Severe - very uncomfortable or intolerable | Week 4 | 
| Scaling and Dryness | SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling | Baseline | 
| Scaling and Dryness at Visit 4 | SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling | 24 hours after PDT | 
| Scaling and Dryness | SCALING AND DRYNESS SCALE Grade 0 = None Grade 1 = Minimal - barely perceptible desquamation Grade 2 = Mild - limited areas of fine desquamation in up to 1/3 of the treatment area Grade 3 = Moderate - fine desquamation involving 1/3 to 2/3 of the treatment area or limited areas of coarser scaling Grade 4 = Severe - coarser scaling involving more than 2/3 of the treatment area or limited areas of very coarse scaling | Week 4 | 
| OOZING/VESICULATION/CRUSTING | OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above | Baseline | 
| OOZING/VESICULATION/CRUSTING | OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above | 24 hours after PDT | 
| OOZING/VESICULATION/CRUSTING | OOZING/VESICULATION/CRUSTING Grade 0 = None Grade 1 = Minimal - a single area of oozing, vesiculation or crusting 3 mm diameter or less in size Grade 2 = Mild - two to four areas of oozing, vesiculation or crusting 3 mm diameter or less in size OR a single area larger than 3 mm diameter in size Grade 3 = Moderate - more than a single area of oozing, vesiculation or crusting larger than 3 mm diameter in size or more than four areas of 3 mm diameter or less in size Grade 4 = Severe - any degree of oozing, vesiculation or crusting greater than (3) above | Week 4 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Actinic keratosis