Clinical Trial of Ingenol Mebutate Gel 0.015% & 0.05% in Actinic Keratosis

A Multi-center, OPen, InvEstigator Initiated Phase IV Clinical TRial to Evaluate the Efficacy and SaFety of Ingenol Mebutate Gel 0.015% on Face and Scalp & 0.05% on Trunk and Extremities in KorEan Patient With ACtinic KeraTosis (PERFECT)

This study evaluate the efficacy and safety of ingenol mebutate gel 0.015% on face and scalp & 0.05% on trunk and extremities in Korean patient with actinic keratosis.

The mechanism of action of ingenol mebutate for actinic keratosis(AK) treatment involves a rapid induction of necrosis followed by neutrophil-mediated, antibody-dependent cellular cytotoxicity (ADCC) of residual lesion. As the ingenol mebutate infiltrates the cell membrane, it increases intracellular Ca2+ concentration which leads to mitochondrial swelling and disruption of mitochondrial membrane within hours. The release of intra-mitochondrial Ca2+ into the cytoplasm leads to depletion of adenosine triphosphate (ATP) and a rapid induction of cell death by necrosis. This process occurs within 1 hour of application, which explains why the treatment period requires only 2 or 3 days of treatment. As the next phase, the cellular necrosis is accompanied by a robust inflammatory response through the release of proinflammatory cytokines from skin cells and tumor cells undergoing necrosis. The release of these proinflammatory cytokines into the dysplastic cells mediates the process of neutrophil recruitment through paracrine signaling and activation of endothelial cells. Here, the neutrophil mediated ADCC occurs, where activated neutrophils attach to the fragment, crystallized (Fc) parts of antibodies of dysplastic cells and destroys the residual dysplastic epidermal cells. In this way, the ingenol mebutate eradicates any residual tumor cells and prevents recurrence of actinic keratosis.As described above, the rapid effect and dual mechanism of action of ingenol mebutate gel allows not only a short-course therapy (2 or 3 days of application) for the elimination of actinic keratosis but also, the benefit for eradication of any residual lesions preventing the recurrence and the progression of AK into squamous cell carcinoma (SCC).

Inclusion Criteria:

1. Male or female aged ≥ 19 years
2. Histopathologically diagnosed AK patients with at least 1 macroscopic and discrete lesion within a contiguous 25 cm2 (e.g. 5 cm x 5 cm) of treatment area
3. The treatment area including the lesion must be accessible to apply the investigational product. However, the lesions on lips, mucosa, outer ear (concha) and those around eyes are excluded.
4. Subjects who signed the written informed consent prior to perform any study-related procedures or assessments, including photographs of their treatment area for documentation and efficacy assessment.

Exclusion Criteria:

1. Hypersensitivity to any components of the investigational product
2. History or evidence of skin conditions that could interfere with evaluation of the investigational product(e.g., eczema, unstable psoriasis, xeroderma pigmentosa, inflammatory or infectious disease around the selected treatment area)
3. Unhealed wound within 5 cm, or basal cell carcinoma or squamous cell carcinoma within 10 cm from the selected treatment area.
4. Subjects who received or expected to receive any of the following pharmacotherapy and non-pharmacotherapy or procedures during the treatment and follow-up period
5. Subjects who have following disorder or abnormal laboratory result
6. Pregnant, lactating, and childbearing potential women who are unwilling to practice effective contraception; for example, oral contraceptives, hormonal methods, placement of an intrauterine device (IUD) or intrauterine system (IUS), barrier methods (i.e., condom or occlusive cap with spermicidal foam/gel/film/cream/suppository), male sterilization, and abstinence.
7. Subjects who previously underwent another clinical trial within 30 days or 5-times the half-life of previous investigational product prior to baseline (the longer period of time must be considered).
8. Other conditions by investigator's discretion to be inappropriate for this clinical study.