PEP005 Gel - Biological Effects in Actinic Keratosis Assessed by Reflectance Confocal Microscopy

Study Overview
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Brief Summary
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This trial will be conducted to explore the biological effects in the skin following treatment with PEP005 Gel, 0.05% administered for two consecutive days, assessed by reflectance confocal microscopy.

Official Title
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A Phase 1, Two-stage, Single-centre, Open Label, Within- and Between-subject Comparison Trial to Explore the Biological Effects of PEP005 (Ingenol Mebutate) Gel, 0.05%, Applied Once Daily for 2 Consecutive Days in Subjects With Actinic Keratosis on the Upper Extrem-ity. A Single-arm First Stage Followed by a Two-arm, Parallel Group, Randomized, Placebo (Vehicle) -Controlled Second Stage

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: Ingenol mebutate
* Drug: Placebo Gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects at least 18 years of age Subjects with AK lesions and subclinical AK lesions within a contiguous 25 cm2 area on the upper extremity Subjects must have a 25 cm2 area of normal skin on the inner upper arm Female subjects must be of either:• Non-childbearing potential, post-menopausal, or have a confirmed clinical history of sterility or • Childbearing potential, with a confirmed negative urine pregnancy test prior to exposure. Female subjects of childbearing potential must be willing to consent to using high effective methods of contraception Ability to follow trial instructions and likely to complete all trial requirements Obtained written informed consent prior to any trial-related procedures Exclusion Criteria: Location of the selected treatment areas:• Within 5 cm of an incompletely healed wound or infected area of the skin • Within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma(SCC) History or evidence of skin conditions other than the trial indication that would interfere with evaluation of the investigational product Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety during the course of the trial, as determined by Investigator clinical judgment Anticipated need for in-patient hospitalisation or in-patient surgery during the trial period. Current participation in any other interventional clinical trial Subjects who have received treatment with any non-marketed drug product within the last two months Previous enrolment in this clinical trial Prohibited Therapies and/or Medications 2 weeks prior to the Screening visit within 2 cm of selected treatment area:•Cosmetic or therapeutic procedures •Use of acid-containing therapeutic products • Use of topical salves or topical steroids Prohibited Therapies and/or Medications: within 4 weeks prior to the Screening visit: • Treatment with immunomodulators, cytotoxic drugs or interferon/interferon inducers,systemic medications that suppress the immune system, or with UVB Prohibited Therapies and/or Medications: within 8 weeks prior to the Screening visit: • Treatment with 5-FU, imiquimod, diclofenac, or photodynamic therapy: within 2 cm of the selected treatment areas. Use of systemic retinoids

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: PEP005 Gel 0.05%<br>active ingredient of PEP005: Ingenol mebutate | Drug: Ingenol mebutate<br>* 0.05% Ingenol mebutate Gel once daily for 2 consecutive days<br>* Other names: PEP005;|
| Placebo Comparator: Placebo Gel<br>Vehicle of PEP005 Gel | Drug: Placebo Gel<br>* Gel vehicle of PEP005<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by Reflectance Confocal Microscopy (RCM) in actinic keratosis (AK) skin.This RCM imaging technique is a relatively new non-invasive, real-time evaluation method to generate horizontal skin sections at a resolution comparable to routine histology. The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 2 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by Reflectance Confocal Microscopy (RCM) in Sub actinic keratosis (AK) skin. The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 2 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin. The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 2 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin | Baseline to Day 3 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin. The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 3 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 3 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 8 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 8 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 8 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 57 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 57 | 
| Change in Degree of Infiltration | Change from baseline in the degree of infiltration of the epidermis by inflammatory cells following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin The degree of infiltration of the epidermis by inflammatory cells will be based on inflammation/small bright cells (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. The degree of infiltration of the dermis by inflammatory cells will be based on inflammatory cells in the dermis (grading 0-3) as assessed by RCM from baseline across the trial period for the subjects receiving PEP005 Gel. | Baseline to Day 57 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin | Baseline to Day 2 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin | Baseline to Day 2 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin | Baseline to Day 2 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM(Reflectance Confocal Microscopy) in AK (actinic keratosis) skin | Baseline to Day 3 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin | Baseline to Day 3 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin | Baseline to Day 3 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin | Baseline to Day 8 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin | Baseline to Day 8 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel,0.05% as assessed by RCM (Reflectance Confocal Microscopy) in normal skin | Baseline to Day 8 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in AK (actinic keratosis) skin | Baseline to Day 57 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM (Reflectance Confocal Microscopy) in Sub AK (actinic keratosis) skin | Baseline to Day 57 | 
| Change in Degree of Necrosis | Change from baseline in the degree of necrosis in the epidermis following treatment with ingenol mebutate gel, 0.05% as assessed by RCM in normal skin | Baseline to Day 57 |