Regression Analysis of Local Skin Reactions to Predict Clearance of Actinic Keratosis on the Face in Patients Treated With Ingenol Mebutate Gel: Experience from Randomized Controlled Trials

February 2017 | Volume 16 | Issue 2 | Original Article | 112 | Copyright © February 2017

Shelbi Jim On MD,a Kim Mark Knudsen PhD,b Torsten Skov MD PhD,b and Mark Lebwohl MDa

aMount Sinai School of Medicine, New York, NY bLEO Pharma A/S, Ballerup, Denmark


Ingenol mebutate gel, a topical field treatment for actinic keratosis (AK), elicits inflammatory application-site reactions in most patients. This analysis explored the relationship between the intensity of local skin reactions (LSRs) and AK clearance, measured by the reduction in AK count from baseline in 218 patients who were treated for AK on the face in the pivotal Phase 3 studies. The analysis modeled the AK count at week 8, adjusted for baseline count, with the composite LSR score at 1 day after the last treatment application for each patient as a predictor to estimate the mean and 90% prediction interval for the percent reduction in AK count. The predicted mean percent reduction in AK count was higher in patients with higher composite LSR scores. Lower composite scores demonstrated a variable, less predictive percentage reduction in efficacy. Therefore, a large inflammatory reaction from ingenol mebutate gives a more reliable prognosis for improved AK clearance.

J Drugs Dermatol. 2017;16(2):112-114.


Actinic keratoses (AKs) are common epidermal lesions that occur on skin surfaces subjected to long-term sun exposure.1 AKs have a variable, but well-documented risk of progression to squamous cell carcinoma, providing the rationale for treatment.2,3 Although AKs are commonly treated with lesion-directed therapy, most often cryosurgery, field treatment has the advantage of treating multiple visible lesions and entire areas of sun-damaged skin, where latent, subclinical lesions are likely to exist.3 Effective field therapies include topical creams and gels containing pharmacologic agents such as uorouracil, imiquimod, and diclofenac. These can be easily applied by the patient at home. However, they can be associated with uncomfortable application site reactions and undesirable cosmetic effects. These occurrences may challenge patients’ adherence to a treatment regimen that may extend over several weeks.3 Ingenol mebutate gel, 0.015%, is a topical field therapy that involves a short-duration regimen, ie, once-daily application for 3 consecutive days.4 Short-term efficacy5 and sustained clearance to 1 year5,6 have been demonstrated in double-blind, randomized, Phase 3 studies5 and over long-term observational follow-up.5,6 The main side effects of ingenol mebutate treatment were the transient, in ammatory local skin reactions (LSRs). These generally occurred within 1 day of treatment, peaked in severity by approximately 1 week after treatment, and were largely resolved within 2 weeks (for the face and scalp) or 4 weeks (for the trunk and extremities).5,7 Patients who were treated with ingenol mebutate gel provided significantly higher scores for satisfaction with treatment effectiveness, and for global satisfaction, than patients receiving vehicle treatment, as assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) instrument.8 Notably, the scores for the side effects and convenience domains of the TSQM were similar between ingenol mebutate and vehicle groups.8 Prior to our study, it was not known whether the extent of AK clearance was related to the intensity of the in ammatory LSRs after treatment with ingenol mebutate. To investigate this question, we analyzed data from double-blind studies on facial AK, analyzing the reduction in AK count from baseline in relationship to LSR score.


Data were collected from 2 double-blind, randomized, Phase 3 studies (NCT00916006 and NCT00915551). Both studies evaluated ingenol mebutate gel, 0.015%, compared with vehicle gel, for treating 4 to 8 visible AKs in a contiguous, 25-cm2 area of the face or scalp.5 A total of 220 patients with AKs on the face were randomized to ingenol mebutate7 and applied ingenol mebutate once daily for 3 consecutive days to the treatment area. LSRs were evaluated for 6 parameters (erythema, ak- ing/scaling, crusting, swelling, vesiculation/pustulation, and