Efficacy of Ingenol Mebutate on Actinic Keratoses and Field Cancerization vs Cryotherapy

A Randomized Study to Evaluate the Efficacy of Ingenol Mebutate on Actinic Keratoses and Field Cancerization Compared to Cryotherapy

The main objective of this study is to compare the effectiveness of ingenol mebutate gel (150 mcg / g per day, to be applied on a predetermined area of 25 cm2 of skin of the face or scalp, for 3 days consecutive) cryotherapy (application with 5 seconds of freezing time of each lesion located in a predetermined skin area of 25 cm2 of the face or scalp) in the treatment of actinic keratosis and their field cancerization.

Study details:

This study is randomized. 50 subjects with at least two actinic keratoses of grade I and II, located in two different districts of 25 cm2 skin of the face or scalp, and who meet all the inclusion criteria will be enrolled in the study by the investigators in the three different centers mentioned above.

The investigators will assess the effect of treatment by confocal microscopy and digital dermoscopy. The investigator will acquire images of selected areas of the face and scalp before and after treatment. Data will be collected and analyzed by the coordinating centre.

Procedure for the study:

Recruitment of subjects; random assignment of treatment (ingenol mebutate gel 150 micrograms/g and cryotherapy) to the two skin areas of 25 cm2 of the subject recruited; evaluation of the two areas with reflectance confocal microscopy and digital dermoscope. The measurements will be carried out at time 0, after 1 month and 6 months. The investigator must fill out a form for each subject at the beginning (day 0), after 1 month and at the end of the study (after 6 months). The subject must complete a questionnaire at the beginning (day 0), after 1 month and at the last follow-up visit (after 6 months).

Measurement parameters: Dermoscopy and confocal microscopy will be used to assess the percentage reduction in actinic keratoses and the damage of the cancerous area in the two selected areas treated with ingenol mebutate gel or cryotherapy, respectively.

Adverse / side events will be collected at each visit by the investigator and will be contained in another form.

Study Overview

• Status: Completed
• Conditions: Actinic Keratosis
• Intervention / Treatment: Drug: Ingenol mebutate; Procedure: cryotherapy

Detailed Description

This study is designed to compare the efficacy of topical ingenol mebutate (150 mcg/g once daily on a selected facial or scalp target area of 25 cm2, for 3 consecutive days) with cryosurgery (applied for a freeze time of 5 seconds, on each lesion included in an area of 25 cm2 on face or scalp)

This is a national, post-marketing (phase 4), on label, interventional, randomized trial.

Subjects will attend a screening visit where they will be assessed for eligibility.

Two areas of treatment in the same patient have to be identified (e.g. scalp and cheek or two different part of the balding scalp), than these two areas will be randomized in a 2:1 ratio: one will be treated with cryosurgery and the other one with Picato Gel.

The cryosurgery will be performed in the same day during the visit (1 application for a freeze time of 5 seconds, on each lesion included in an area of 25 cm2 on face or scalp) Picato gel 150 mcg will be applied at home by the patient, according to current indication (RCP: 3 consecutive days for a total of three application in an area of 25 cm2) Subjects will be followed for 24 weeks (about 6 months) after the cryosurgery application (Visit 1).

Adverse events and patient compliance will be recorded 7 days after cryosurgery application and 5 days after first Picato gel application (Visit 2). The number of AKs present within the treatment areas will be counted at Visit 1 (Baseline AK count) and at Visits 3 - 4 (AKcount). The data obtained will provide information on the effect of Picato gel versus Cryosurgery on recurrence rate of AKs.

Furthermore, the trial will also provide data on the effect of Picato gel versus Cryosurgery on the appearance rate of new AKs.

The final results for all subjects will be included in a Final Clinical Study Report in the original submission. This includes final results for all primary and secondary endpoints as well as 6-month recurrence and Adverse Event data.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80131
    • Second University of Naples

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

A patient will be enrolled if he/she meets all of the following inclusion criteria:

• Current diagnosis of AK, with ≥2 lesions of grade I and/or II located in two different anatomical districts (within a contiguous 25 cm2 area on the face, scalp or forehead);
• Male ≥ 18 years of age or Female > 60 years of age;
• Skin type I or II according to Fitzpatrick;
• Patient has confirmed his/her willingness to participate in this study after being informed of all aspects of the study that are relevant to his/her decision to participate, by signing and dating the approved informed consent form, according to ICH and local laws.

The 25 cm2 contiguous treatment areas could be of any shape, e.g. 5 cm x 5 cm, 2 cm x 12.5 cm, 3 cm x 8.3 cm.

Exclusion Criteria:

A patient will be excluded if he/she meets any of the following exclusion criteria:

• Has received any therapy for AK within the past 3 months
• Has AK of grade III
• Has currently a skin cancer or shows an early stage of skin cancer;
• Has another skin disease that requires treatment with other medications in the AK area or in distance of 3 cm;
• Use of cosmetic or therapeutic products and procedures which could interfere with assessments of the treatment area;
• Immunosuppressive therapies or current treatment for cancer;
• Clinically unstable medical condition;
• High risk group for HIV infection or presentation of other infectious diseases (hepatitis A virus , hepatitis B virus , hepatitis C virus , Tuberculosis, etc);
• Allergies to the tested gel (ingenol mebutate and eccipients);
• Pregnancy and breastfeeding (see inclusion criteria);
• Psychiatric disease that may interfere with follow-up of study procedures;
• Participation in other clinical trials up to 30 days prior to day 1 of the study;
• Patient is, for any reason, considered by the investigator to be an unsuitable candidate for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ingenol mebutate; application of ingenol mebutate for 3 consecutive days on an area of face/scalp of 25 cm2	Drug: Ingenol mebutate; 150 mcg / g per day, to be applied on a predetermined area of 25 cm2 of skin of the face or scalp, for 3 days consecutive; Other Names: Picato
Active Comparator: cryotherapy; application of criotherapy on actinic keratosis present in an area of face/scalp of 25 cm2 different from the ingenol mebutate area	Procedure: cryotherapy; application with 5 seconds of freezing time of each lesion located in a predetermined skin area of 25 cm2 of the face or scalp; Other Names: cryosurgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
At least 75% reduction in the total AK count relative to baseline	The primary efficacy endpoint is the percentage change, at the end of the treatment period, in the number of AK lesions that were originally defined in the selected AK target area at baseline. The percentage change in the number of AK lesions is calculated as the number of lesions present at the end of the treatment period in the target area minus the number of AK lesions present in the target area at baseline visit divided by the number of lesions present in the target area at baseline. This variable will be analysed using a non-parametric analysis (Wilcoxon Rank-sum test).	6-month follow-up
Reduction of subclinical AK lesions according to a Reflectance Confocal Microscopy score	Change from baseline in RCM score of target area and RCM score of cancerization field at the end of the treatment period. Each of the 13 RCM criteria will be scored 0 (absent), 1 (<25%), 2 (25%-50%), 3 (50-75%), or 4(>75%). An overall score will be obtained by averaging the RCM scores at the epidermal, DEJ and dermal level. The same approach will be used for the RCM examination of the cancerization field. The above variables will be compared between the groups using a t-test, 95% confidence interval for the between-group difference will be provided.	6-month follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absence of new lesions after a follow-up period of 6 months	The count of AK lesions will be performed by exploration and palpation (numeric count) and the presence will be also confirmed by dermoscopic assessment (numeric count)	6-month follow-up
cosmetic outcome	cosmetic outcome will be evaluated by Patient's assessment of satisfaction to product at the end of the treatment period (specific questionnaire)	6-month follow-up

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Investigators: Principal Investigator: Giuseppe Argenziano, Prof, University of Campania "Luigi Vanvitelli"

Publications and helpful links

General Publications

• Andrews MD. Cryosurgery for common skin conditions. Am Fam Physician. 2004 May 15;69(10):2365-72.
• Frost CA, Green AC. Epidemiology of solar keratoses. Br J Dermatol. 1994 Oct;131(4):455-64. doi: 10.1111/j.1365-2133.1994.tb08544.x.
• Fu W, Cockerell CJ. The actinic (solar) keratosis: a 21st-century perspective. Arch Dermatol. 2003 Jan;139(1):66-70. doi: 10.1001/archderm.139.1.66. No abstract available.
• Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol. 2002 Apr;146 Suppl 61:20-3. doi: 10.1046/j.1365-2133.146.s61.6.x.
• Cohen JL. Actinic keratosis treatment as a key component of preventive strategies for nonmelanoma skin cancer. J Clin Aesthet Dermatol. 2010 Jun;3(6):39-44.
• Padilla RS, Sebastian S, Jiang Z, Nindl I, Larson R. Gene expression patterns of normal human skin, actinic keratosis, and squamous cell carcinoma: a spectrum of disease progression. Arch Dermatol. 2010 Mar;146(3):288-93. doi: 10.1001/archdermatol.2009.378.
• Vatve M, Ortonne JP, Birch-Machin MA, Gupta G. Management of field change in actinic keratosis. Br J Dermatol. 2007 Dec;157 Suppl 2:21-4. doi: 10.1111/j.1365-2133.2007.08268.x.
• Fidler B, Goldberg T. Ingenol mebutate gel (picato): a novel agent for the treatment of actinic keratoses. P T. 2014 Jan;39(1):40-6.

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2017
• Primary Completion (Actual): April 30, 2018
• Study Completion (Actual): July 30, 2018

Study Registration Dates

• First Submitted: December 2, 2016
• First Submitted That Met QC Criteria: December 8, 2016
• First Posted (Estimate): December 13, 2016

Study Record Updates

• Last Update Posted (Actual): September 24, 2019
• Last Update Submitted That Met QC Criteria: September 23, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Field Cancerization
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Precancerous Conditions; Keratosis, Actinic; Keratosis
• Other Study ID Numbers: IIS-PICATO 1264

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No