Relationship between severity of the local skin reactions and the rate of local skin reaction resolution in patients treated with ingenol mebutate gel

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Abstract

Background

Ingenol mebutate gel is a topical field treatment for actinic keratosis (AK). The treatment elicits application-site reactions in most patients. This analysis evaluated the relationship between the severity of reactions and the speed of their resolution.

Methods

Patients in Phase III studies were treated for AKs on the face (n=218), scalp (n=56), and trunk and extremities (n=209). All of the patients were treated with either ingenol mebutate gel 0.015% once daily for three consecutive days (face/scalp) or ingenol mebutate gel 0.05% once daily for two consecutive days (trunk/extremities). Local skin reactions (LSRs) were assessed on a 5-point scale from 0 to 4 in six categories, yielding composite scores in the range of 0 to 24.

Results

The composite LSR score on the day after the last application of ingenol mebutate gel was an important predictor of the speed of resolution of LSRs. The rate of resolution was greatest for AKs treated on the face, followed by the scalp, and then the trunk and extremities. All patients were expected to have minimal LSR scores for the face and scalp at 2 weeks, and for the trunk and extremities at 4 weeks.

Conclusion

The absolute reduction in LSR scores was proportional to the composite LSR score on the day after the last application of ingenol mebutate gel treatment. The rate of resolution for LSRs was dependent on the anatomic site treated as well as the day 4 composite score.

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Most cited references 11

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Ingenol mebutate gel for actinic keratosis.

Neil Swanson, Anita Melgaard, Brian Berman … (2012)

Actinic keratosis is a common precursor to sun-related squamous-cell carcinoma. Treating actinic keratoses and the surrounding skin area (i.e., field therapy) can eradicate clinical and subclinical actinic keratoses. Topical field therapy currently requires weeks or months of treatment. We investigated the efficacy and safety of a new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities). In four multicenter, randomized, double-blind studies, we randomly assigned patients with actinic keratoses on the face or scalp or on the trunk or extremities to receive ingenol mebutate or placebo (vehicle), self-applied to a 25-cm(2) contiguous field once daily for 3 consecutive days for lesions on the face or scalp or for 2 consecutive days for the trunk or extremities. Complete clearance (primary outcome) was assessed at 57 days, and local reactions were quantitatively measured. In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P<0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P<0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae. Ingenol mebutate gel applied topically for 2 to 3 days is effective for field treatment of actinic keratoses. (Funded by LEO Pharma; ClinicalTrials.gov numbers, NCT00742391, NCT00916006, NCT00915551, and NCT00942604.).

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Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials.

Norman Lee, S Dinehart, Mark G. Lebwohl … (2004)

The immune system plays a critical role in the development and pathogenesis of actinic keratosis (AK). Imiquimod has been shown to stimulate the cutaneous immune response and be effective for the treatment of nonmelanoma skin cancers. Two phase III, randomized, double-blind, vehicle-controlled studies evaluated the efficacy of imiquimod 5% cream compared with vehicle in the treatment of AK lesions on the face and balding scalp. A total of 436 participants at 24 centers in the United States and Canada were randomized to either imiquimod 5% or vehicle cream. Study cream was applied one time per day, 2 days per week for 16 weeks. Clearance of AK lesions was clinically assessed at an 8-week posttreatment visit. The complete clearance rate was 45.1% for the imiquimod group and 3.2% for the vehicle group. The difference in complete clearance rates (imiquimod minus vehicle) was 41.9% with a 95% confidence interval of 34.9% to 49%. The partial (> or =75%) clearance rate was 59.1% for the imiquimod group and 11.8% for the vehicle group. The difference in partial clearance rates (imiquimod minus vehicle) was 47.3% with a 95% confidence interval of 39.5% to 55.1%. The median percent reduction in AK lesions was 83.3% for the imiquimod group and 0% for the vehicle group. Local skin reactions were common. Severe erythema was reported by 17.7% of participants who received imiquimod and 2.3% of participants who received vehicle. Overall, imiquimod was very well tolerated. Imiquimod 5% cream used 2 times per week for 16 weeks is an effective and well-tolerated treatment for AK.

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Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response.

Robert H Rosen, Aditya K. Gupta, Stephen Tyring (2012)

Current topical agents for field therapy of actinic keratoses have single mechanisms of action and must be applied for weeks. Ingenol mebutate gel, a novel drug for field therapy of actinic keratoses, appears to have a dual mechanism of action: (1) rapid lesion necrosis and (2) specific neutrophil-mediated, antibody-dependent cellular cytotoxicity. Because of the rapid destruction of actinic keratosis lesions after application of ingenol mebutate gel, treatment is necessary for only 2 or 3 days. The subsequent immune-mediated response targets any residual dysplastic epidermal cells. This dual mechanism of action should provide efficacy equivalent to that of current topical agents with a substantially shorter treatment period. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Cosmet Investig Dermatol

Journal ID (iso-abbrev): Clin Cosmet Investig Dermatol

Journal ID (publisher-id): Clinical, Cosmetic and Investigational Dermatology

Title: Clinical, Cosmetic and Investigational Dermatology

Publisher: Dove Medical Press

ISSN (Electronic): 1178-7015

Publication date Collection: 2016

Publication date (Electronic): 24 August 2016

Volume: 9

Pages: 211-216

Affiliations

[1 ]Department of Dermatology, Mount Sinai School of Medicine, New York, NY, USA

[2 ]LEO Pharma A/S, Biostatistics, Ballerup, Denmark

Author notes

Correspondence: Shelbi C Jim On, Department of Dermatology, Mount Sinai School of Medicine, 5 E. 98th St, 5th Floor, Box 1,048, New York, NY 10029, USA, Tel +1 212 241 3288, Fax +1 212 876 8961, Email shelbi.jimon@ 123456mountsinai.org

Article

Publisher ID: ccid-9-211

DOI: 10.2147/CCID.S113044

PMC ID: 5003522

PubMed ID: 27601928

SO-VID: 36e62ef3-1549-44ee-b017-5beaed308d27

License:

The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

Relationship between severity of the local skin reactions and the rate of local skin reaction resolution in patients treated with ingenol mebutate gel

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Abstract

Background

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Karger: Dermatology

Most cited references 11

Ingenol mebutate gel for actinic keratosis.

Imiquimod 5% cream for the treatment of actinic keratosis: results from two phase III, randomized, double-blind, parallel group, vehicle-controlled trials.

Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response.

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