Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Hypertrophic Actinic Keratoses

Study Overview
=================
Brief Summary
-----------------
Sequential therapy with cryosurgery and ingenol mebutate may optimize the treatment of hypertrophic AKs and also treat non-hypertrophic AKs in this anatomic location. Furthermore, use of ingenol mebutate will also be evaluated for potential treatment of subclinical lesions.

Detailed Description
-----------------
The investigators plan to treat 30 subjects. Each qualifying subject will have at least 3 hypertrophic AKs, defined as more than 3mm in thickness, on each dorsal hand. Cryotherapy will be standardized in all patients and for all treated lesions: 1-2 sprays, 5 seconds each, with a 5 second interval. All subjects will be treated with the same cryo-spray. Following cryotherapy, subjects will be randomized to treat either their right or left dorsal hand with ingenol mebutate gel. The decision to treat the right vs. the left hand will be chosen by chance, like flipping a coin. Neither the subject nor the study doctor will choose what arm receives the ingenol mebutate gel. The study doctor will not know which arm is treated with ingenol mebutate, so the subject should not reveal that information to him or her at any time during the study. Subjects will treat the randomized dorsal hand with ingenol mebutate 0.05% gel starting on the same day as the cryotherapy (Day 0). Subjects will utilize the once daily for two days regimen. Subjects will be followed on day 4 after their initial visit, day 8, day 15, day 29, and day 57, with a two day window period.

Official Title
-----------------
An Investigator-Initiated Study to Assess the Safety and Efficacy of Ingenol Mebutate 0.05% Gel When Used After Cryotherapy in the Treatment of Hypertrophic Actinic Keratoses (AK) on Dorsal Hands

Conditions
-----------------
Actinic Keratoses

Intervention / Treatment
-----------------
* Drug: Ingenol Mebutate
* Procedure: Cryotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adults at least 18 years old. Subjects must be in good general health as confirmed by the medical history. Subjects must be able to read, sign, and understand the informed consent Prior to cryosurgery, subjects have at least 3 hypertrophic actinic keratoses on each dorsal hand. Subject must be willing to forego any other treatments on the dorsum of the hands, including tanning bed use and excessive sun exposure while in the study. Subject is willing and able to participate in the study as an outpatient, making frequent visits to the study center during the treatment and follow-up periods and to comply with all study requirements including concomitant medication and other treatment restrictions. If subject is a female of childbearing potential she must have a negative urine pregnancy test result prior to study treatment initiation and must agree to use an approved method of birth control while enrolled in the study. Exclusion Criteria: Subjects with a history of melanoma anywhere on the body. Subjects with an unstable medical condition as deemed by the clinical investigator. Subjects with non-melanoma skin cancer on the dorsum of the hands. Subjects with any dermatologic disease in the treatment area that may be exacerbated by the treatment proposed or that might impair the evaluation of AKs. Subjects who have previously been treated with ingenol mebutate: on the dorsum of the hands in the past 6 months; or outside of the study area within the past 30 days. Women who are pregnant, lactating, or planning to become pregnant during the study period. Subjects who have experienced a clinically important medical event within 90 days of the visit (e.g., stroke, myocardial infarction, etc). Subjects who have active chemical dependency or alcoholism as assessed by the investigator. Subjects who have known allergies to any excipient in the study gel. Subjects who are currently participating in another clinical study or have completed another clinical study with an investigational drug or device on the study area within 30 days prior to study treatment initiation. Subjects who have received any of the following within 90 days prior to study treatment initiation: interferon or interferon inducers cytotoxic drugs immunomodulators or immunosuppressive therapies (inhaled/ intranasal steroids are permitted) oral or parenteral corticosteroids topical corticosteroids if greater than 2 gm/day any dermatologic procedures or surgeries on the study area (including any AK treatments) Subjects who have used any topical prescription medications on the study area within 30 days prior to study treatment initiation.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combination Therapy<br>Cryotherapy followed by Ingenol Mebutate Gel | Drug: Ingenol Mebutate<br>* Ingenol mebutate 0.05% gel<br>* Other names: PEP005 Gel;Procedure: Cryotherapy<br>* 1-2 sprays, 5 seconds each, with a 5 second interval<br>|
| Active Comparator: Cryotherapy Alone<br>Cryotherapy only | Procedure: Cryotherapy<br>* 1-2 sprays, 5 seconds each, with a 5 second interval<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Combination Therapy vs Cryotherapy Alone | To evaluate the safety of cryotherapy plus ingenol mebutate on dorsal hands and compare it to the safety of cryotherapy alone looking at Adverse Events. | Day 57 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Number of All Actinic Keratoses | To evaluate and compare the mean reduction in number of all AKs (hypertrophic and non-hypertrophic) on the dorsal hands of the combination cryotherapy- ingenol mebutate treated side vs. the cryotherapy alone side on Day 57 as compared to baseline | Baseline and Day 57 | 
| Change in Actinic Keratoses by Anatomic Site | To evaluate the number of AKs (both hypertrophic and non-hypertrophic) before therapy by anatomic site (dorsal hand) at Day 57 as compared to baseline | Baseline and Day 57 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Actinic