Safety and Efficacy of Ingenol Mebutate Once Daily for 2 or 3 Consecutive Days in Subjects With Actinic Keratosis

Study Overview
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Brief Summary
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To identify the Maximum Tolerated Dose levels of ingenol mebutate gel after once daily treatment for 2 or 3 consecutive days and to evaluate efficacy of ingenol mebutate gel in different doses after once daily treatment for 2 or 3 consecutive days compared to vehicle gel

Official Title
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Safety and Efficacy of Escalating Doses of Ingenol Mebutate Once Daily for Two or Three Consecutive Days When Used on Full Face, Full Balding Scalp or Approximately 250 cm2 on the Chest in Subjects With Actinic Keratosis

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: Ingenol mebutate gel
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be competent to understand the nature of the trial and provide informed consent Part 1: Subjects with 5 to 20 clinically typical, visible and discrete AKs on the face Part 2: Subjects with 5 to 20 clinically typical, visible and discrete AKs on either the face, the balding scalp (the balding part of the scalp should be at least 25 cm2) or a contiguous area of approximately 250 cm2 on the chest Subject at least 18 years of age Female subjects must be of either: Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or, Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment, to rule out pregnancy Female subjects of childbearing potential1 must be willing to use effective contraception at trial entry and until completion Exclusion Criteria: Location of the treatment area (full face, full balding scalp or chest) within 5 cm of an incompletely healed wound, within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC Prior treatment with ingenol mebutate gel within the treatment area Lesions in the treatment areas that have: atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or, recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions History or evidence of skin conditions other than the trial indication that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum) Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the treatment areas. 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 and efficacy during the course of the trial, as determined by the investigator's clinical judgment Any abnormal laboratory tests that are medically significant and would impact the safety of the subjects or the interpretation of the trial results, as determined by the investigator's judgment Anticipated need for hospitalisation or out-patient surgery during the first 15 days after the first trial medication application. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in Prohibited Therapies or Medications Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel Presence of acute sunburn within the treatment areas Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial. Subjects previously assigned to treatment in Part 1 or rand Female subjects who are breastfeeding. In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state)

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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 was an open-label, dose escalation. Part 2 was a randomised, double-blind, parallel group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A: Ingenol mebutate gel 0.005%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Active Comparator: Part 2: Ingenol mebutate gel 0.018% for 3 days treatment<br>Randomized, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Active Comparator: Part 2: Ingenol mebutate gel 0.018% for 2 days treatment<br>Randomized 2 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Active Comparator: Part 2: Ingenol mebutate gel 0.027% for 3 days treatment<br>Randomized 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Active Comparator: Part 2: Ingenol mebutate gel 0.027% for 2 days treatment<br>Randomized 2 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Placebo Comparator: Part 2: Placebo for 3 days treatment<br>Randomized 3 days treatment | Drug: placebo<br> <br> |
| Placebo Comparator: Part 2: Placebo for 2 days treatment<br>Randomized 2 days treatment | Drug: placebo<br> <br> |
| Experimental: Part 1A: Ingenol mebutate gel 0.008%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1A: Ingenol mebutate gel 0.012%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1A: Ingenol mebutate gel 0.027%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1A: Ingenol mebutate gel 0.04%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1B: Ingenol mebutate gel 0.06%<br>Open-label, dose escalation, 2 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1A: Ingenol mebutate gel 0.018%<br>Open-label, dose escalation, 3 days treatment | Drug: Ingenol mebutate gel<br> <br> |
| Experimental: Part 1B: Ingenol mebutate gel 0.04%<br>Open-label, dose escalation, 2 days treatment | Drug: Ingenol mebutate gel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days | Dose tolerability was measures looking at the composite score of Local Skin Responses (LSR). The MTD was defined as the highest dose level with less than 4 subjects out of 12 experiencing dose limiting toxicity (DLT). DLT was defined as one or more of the following three local skin LSRs: Crusting Grade 4 Erosion/Ulceration Grade 4 Vesiculation/Pustulation Grade 4 or two or more of the following five LSRs: Erythema Grade 4 Crusting Grade 3 Swelling Grade 4 Erosion/Ulceration Grade 3 Vesiculation/Pustulation Grade 3 The grading is a scale of 1 to 4 (highest grade). | 8 days after initial treatment | 
| Part 2: Number of Subjects With Complete Clearance of AKs | Number of subjects with complete clearance of Actinic Keratosis lesions (AKs) at week 8 after 2 or 3 consecutive days of treatment with ingenol mebutate gel on the full face, full balding scalp or approximately 250 cm² on the chest | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Reduction in AK Count | Reduction in actinic keratosis lesion count from baseline to week 8 (percentage, adjusted for anatomical location and pooled site) | From baseline to Week 8 | 
| Part 2: Number of Subjects With Partial Clearance of AKs | Partial clearance of AKs at Week 8, defined as at least 75% reduction from baseline in the number of clinically visible AKs | Week 8 |