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

Phase 1

Completed

Conditions: Actinic Keratosis

Interventions: Drug: placebo
Drug: Ingenol mebutate gel

Registration Number: NCT01820260

Lead Sponsor: LEO Pharma

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 395

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:
1. Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or,
2. 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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Part 2: Placebo for 3 days treatment	placebo	Randomized 3 days treatment
Part 2: Placebo for 2 days treatment	placebo	Randomized 2 days treatment
Part 1A: Ingenol mebutate gel 0.008%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 1A: Ingenol mebutate gel 0.012%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 1A: Ingenol mebutate gel 0.018%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 1B: Ingenol mebutate gel 0.04%	Ingenol mebutate gel	Open-label, dose escalation, 2 days treatment
Part 1A: Ingenol mebutate gel 0.005%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 2: Ingenol mebutate gel 0.018% for 3 days treatment	Ingenol mebutate gel	Randomized, 3 days treatment
Part 2: Ingenol mebutate gel 0.018% for 2 days treatment	Ingenol mebutate gel	Randomized 2 days treatment
Part 2: Ingenol mebutate gel 0.027% for 3 days treatment	Ingenol mebutate gel	Randomized 3 days treatment
Part 2: Ingenol mebutate gel 0.027% for 2 days treatment	Ingenol mebutate gel	Randomized 2 days treatment
Part 1A: Ingenol mebutate gel 0.027%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 1A: Ingenol mebutate gel 0.04%	Ingenol mebutate gel	Open-label, dose escalation, 3 days treatment
Part 1B: Ingenol mebutate gel 0.06%	Ingenol mebutate gel	Open-label, dose escalation, 2 days treatment

Primary Outcome Measures

Name	Time	Method
Part 1: To Identify the Maximum Tolerated Dose (MTD) Levels After Once Daily Treatment for 2 or 3 Days	8 days after initial treatment	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).
Part 2: Number of Subjects With Complete Clearance of AKs	8 weeks	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

Secondary Outcome Measures

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