Safety and Tolerability Study of Ingenol Mebutate Compared to 5-FU to Treat Facial Actinic Keratosis

Study Overview
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Brief Summary
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Background: 5% 5-fluorouracil cream (5-FU) is a well-established treatment for actinic keratosis (AK) and ingenol mebutate gel (IMB) is a new topical field therapy. Objective: To compare tolerability and safety of IMB with 5-FU for the treatment of facial AKs. Methods: Open-label, prospective, randomized, controlled clinical trial with 100 patients with AKs within 25-cm2 contiguous field on the face. IMB was applied daily for three consecutive days. 5-FU was applied twice a day for four weeks. Treatment effect was evaluated at baseline and on days 2, 3, 4, 8, 15, 22, 29, 36 and 43, considering ITT populations.

Official Title
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Evaluation of the Tolerability and Safety of 0.015% Ingenol Mebutate Gel Compared to 5% 5-fluorouracil Cream for the Treatment of Facial Actinic Keratosis: a Prospective Randomized Trial

Conditions
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Actinic Keratosis

Intervention / Treatment
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* Drug: ingenol mebutate
* Drug: 5% 5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age of at least 18 years the presence of four to eight clinically typical, visible, and discrete AKs within 25-cm2 contiguous field on the face (cheek or forehead region) Women with childbearing potential had to be using effective birth control and have a confirmed negative urine pregnancy test prior to trial treatment. Exclusion Criteria: target treatment area was within 5 cm of an incompletely healed wound or within 10 cm of a suspected basal-cell or squamous-cell carcinoma if they have received previous treatment with ingenol mebutate gel on the face or scalp (previous treatment on trunk or extremities was acceptable) the selected treatment area had hyperkeratotic lesions or cutaneous horns and recalcitrant disease (lesions that had not responded to cryotherapy on two previous occasions) history or evidence of skin conditions that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum) anticipated need for hospitalization or outpatient surgery during the first 15 days after the first trial medication application known sensitivity or allergy to any of the ingredients of ingenol mebutate gel or 5-FU presence of sunburn within of the target treatment area; current enrolment or participation in any other interventional clinical trial within 30 days of entry into this trial women breastfeeding recent use of medications or other treatments that could interfere with evaluation of the target area, such as topical medications (e.g. steroids, keratolytics, immunomodulators), artificial tanners, immunomodulators, cytotoxic drugs or interferon /interferon inducers, phototherapy, systemic retinoids, biologic/monoclonal antibody drugs, or other therapies for AKs within eight weeks prior to the first visit of the trial.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: ingenol mebutate<br>Patients assigned to ingenol mebutate gel received an application a day for three consecutive days in a pre-determined area | Drug: ingenol mebutate<br>* an application a day for three consecutive days in a pre-determined area<br>* Other names: Picato;|
| Other: 5% 5-FU<br>Patients assigned to 5% 5-FU received two applications a day for four weeks in a pre-determined area | Drug: 5% 5-FU<br>* two applications a day for four weeks in a pre-determined area<br>* Other names: efudex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the LSR (local skin reactions)-Time Curve (AUC 0-43 days) | Primary endpoint was to compare the total local skin reaction grading scale (LSR) and the area under the curve (AUC) with respect to duration of effects, using a generalized linear model, assuming a logarithmic link function. Age, Fitzpatrick skin type and site of the treatment were considered as covariates. The scale ranged from 0 to 4 (with higher numbers indicating greater severity) for the following six local skin effects: erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ulceration (maximum score of 24). | Baseline and on day 43 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the each component of the total LSR-Time Curve (AUC 0-43 days) | A secondary endpoint was to evaluate and compare the AUC for each component of the total LSR using generalized linear models. The effect of treatment on the proportion of patients that completed the assigned treatment regimens was compared using generalized estimating equation model and logarithmic link function. | Baseline and on day 43 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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actinic keratosis, field cancerization, ingenol mebutate, 5-fluorouracil, tolerability, safety