An Equivalence Study of Generic Ingenol Mebutate Gel 0.015% and Picato Gel 0.015% in Subjects With Actinic Keratosis

Study Overview
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Brief Summary
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The objective of this study was to evaluate the safety and therapeutic equivalence of generic ingenol mebutate gel, 0.015% to Picato gel, 0.015% by establishing the therapeutic comparability of the two active products and the superiority of the two active products over the vehicle gel in the treatment of AK on the face and scalp.

Detailed Description
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Picato® (ingenol mebutate) gel is the first and only ingenol mebutate product approved by the Food and Drug Administration (FDA) in 2012 for the topical treatment of AKs on the face and scalp (0.015% formulation) and on the trunk and extremities (0.05% formulation). The FDA approved regimen for ingenol mebutate gel, 0.015% for the treatment of AKs on the face and scalp is once-daily application of one unit dose tube for three consecutive days applied to one contiguous skin area of approximately 25 cm2 (e.g., 5 cm x 5 cm).

Official Title
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A Multicenter Randomized Doubleblind Vehicle-controlled Parallel Comparison Study to Determine Therapeutic Equivalence of Generic Ingenol Mebutate Gel 0.015% and Picato® Gel 0.015% in Subjects With Actinic Keratosis on the Face or Scalp

Conditions
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ACTINIC KERATOSIS

Intervention / Treatment
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* Drug: Ingenol Mebutate (Picato®)
* Drug: Generic Ingenol Mebutate
* Drug: Vehicle Foam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject was male or non-pregnant female 18 years of age or older. Females must have been post-menopausal, surgically sterile, or using an effective method of birth control. Women of childbearing potential (WOCBP) must have had a negative urine pregnancy test (UPT) at Visit 1/Baseline. Subject provided written informed consent. Subject had a clinical diagnosis of AK at Visit 1/Baseline with at least four, but no more than eight visible and discrete non-hyperkeratotic, non-hypertrophic AK lesions, each at least 4 mm in diameter, within a contiguous 25 cm2 treatment area (the Treatment Area) located on the face or scalp. Subject was willing and able to apply the test article as directed, comply with study instructions, and commit to all follow-up visits for the duration of the study. Subject was in good general health and free of any disease state or physical condition that might have impaired evaluation of AK lesions or which, in the investigator's opinion, exposed the subject to an unacceptable risk by study participation. Exclusion Criteria: 1. Subject was pregnant, lactating, or was planning to become pregnant during the study. Subject had a location of the selected contiguous 25 cm2 Treatment Area that (a) was within 5 cm of an incompletely healed wound or (b) was in an area containing a lesion that was previously treated with ingenol mebutate. Subject had hyperkeratotic, hypertrophic, or large mat-like AKs (e.g., AK >1 cm2 in size) within the contiguous 25 cm2 Treatment Area. Subject had more than eight AKs, independent of size, within the selected contiguous 25 cm2 Treatment Area Subject had atopic dermatitis, basal cell carcinoma, eczema, psoriasis, rosacea, squamous cell carcinoma, xeroderma pigmentosum, or any other possibly confounding skin conditions within the region of the head that contained the selected Treatment Area (i.e., face or scalp). Subject had any skin pathology or condition that, in the investigator's opinion, could have interfered with the evaluation of the test article or required the use of interfering topical, systemic, or surgical therapy. Subject was immunosuppressed (e.g., human immunodeficiency virus, systemic malignancy, graft host disease, etc.). Subject experienced an unsuccessful outcome from previous ingenol mebutate therapy (an unsuccessful outcome was defined as after a reasonable therapeutic trial with no compliance issues and the topical drug did not work). Subject used topical creams, lotions, or gels of any kind within the selected Treatment Area within one day prior to entry into the study. Subject had the need or planned to be exposed to artificial tanning devices or excessive sunlight during the study or had used artificial tanners within two weeks of Visit 1/Baseline. Subject had used any of the following topical medications on the face or scalp: Corticosteroids within two weeks of Visit 1/Baseline; Keratolytic-containing therapeutic products or medicated or irritant topical salves within two weeks of Visit 1/Baseline, including, but not limited to, alpha hydroxy acids (e.g., glycolic acid, lactic acid etc. >5%), beta hydroxy acid (salicylic acid >2%), and urea >5%; Topical retinoids (e.g., tazarotene, adapalene, tretinoin) within two weeks of Visit 1/Baseline; Light treatments (e.g., psoralen plus ultraviolet A therapy, ultraviolet B) within four weeks of Visit 1/Baseline; Photodynamic therapy within eight weeks of Visit 1/Baseline; 5-fluorouracil, diclofenac, imiquimod, or ingenol mebutate within eight weeks of Visit 1/Baseline; or Other topical therapy for actinic keratosis within 2 cm of the selected contiguous 25 cm2 Treatment Area within eight weeks of Visit 1/Baseline. Subject had cryodestruction or chemodestruction, surgical excision, curettage, dermabrasion, chemical peel, or laser resurfacing on the Treatment Area (i.e., face or scalp) within two weeks prior to Visit 1/Baseline. Subject used any of the following systemic medications: Corticosteroid therapy within one month; Interferon/interferon inducers, cytotoxic drugs, immuno-modulators, or immunosuppressive therapies within one month; Retinoid therapy within six months prior to Visit 1/Baseline. Subject had lesions suspicious for skin cancer (skin cancer not ruled out by biopsy) or untreated skin cancers within the selected contiguous 25 cm2 Treatment Area on the face or scalp. Subject was enrolled in an investigational drug or device study. Subject used an investigational drug or investigational device treatment within one month prior to Visit 1/Baseline. Subject had a history of sensitivity to any of the ingredients in the test articles (see Section 9.4.2). Subject had any condition which, in the investigator's opinion, would have made it unsafe or precluded the subject's ability to fully participate in this research study. Subject was unable to communicate or cooperate with the investigator due to language problems, poor mental development, impaired cerebral function, or physical limitations. Subject was known to be noncompliant or was unlikely to comply with the requirements of the study protocol (e.g., due to alcoholism, drug dependency, mental incapacity) in the opinion of the investigator. Subject was previously enrolled in the same study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Picato<br>Picato® (ingenol mebutate) gel, 0.15% (Leo Pharma Inc.) [Reference Listed Drug (RLD)] | Drug: Ingenol Mebutate (Picato®)<br>* Brand product<br>* Other names: RLD;|
| Experimental: Generic Ingenol Mebutate<br>Generic ingenol mebutate gel, 0.15% [Test] | Drug: Generic Ingenol Mebutate<br>* Generic formulated to have the same therapeutic effect of the brand<br>* Other names: Test;|
| Placebo Comparator: Vehicle Foam<br>Vehicle gel of the test product | Drug: Vehicle Foam<br>* It does not contain active ingredient. A placebo to test the sensitivity of the active treatments.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Clearance of AK Lesions | Treatment success (complete clearance of AK lesions) at Day 57, where complete clearance of AK lesions was defined as having no (zero) clinically visible AK lesions in the Treatment Area | 57 days |