Journal of Clinical and Aesthetic Dermatology

DEC 2017

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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20 JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY December 2017 • Volume 10 • Number 12 O R I G I N A L R E S E A R C H and safety profiles of ingenol mebutate. The biological activity of the mebutate ester is provided by hydroxyl groups in the four-, five-, and 20-positions; however, these groups also reduce chemical thermostability and increase the risk of pH-dependent degradation through acyl migration. The physicochemical characteristics of the disoxate ester, including a reduced migration ability of the ester moieties on the aforementioned hydroxyl groups, improved stability in comparison with ingenol mebutate. 11 Furthermore, the disoxate ester has been shown to have increased cytotoxic potency to that of the mebutate derivative. 11 Preclinical data suggest that the mode of action of ingenol disoxate involves direct cellular cytotoxicity and the ability to induce proinflammatory mediators. 11 As compared with ingenol mebutate 0.05% gel, ingenol disoxate has previously demonstrated a similar safety profile and a dose response relationship for LSRs. In addition, ingenol disoxate 0.075% gel significantly reduced the AK lesion count as compared with ingenol mebutate (p<0.04). 12 Previous Phase I/II dose-finding trials of ingenol disoxate on the face, chest, and scalp (25–250cm 2 ) have demonstrated a greater efficacy when compared with vehicle and a well-defined LSR profile, which was associated with high treatment satisfaction. 13,14 The aims of this trial were to evaluate the safety, tolerability, and efficacy of ingenol disoxate gel in a once-daily regimen for three consecutive days, following application to the face or chest, scalp, or trunk or extremities. Cosmetic and patient satisfaction outcomes from this trial are presented in the accompanying paper. 15 METHODS Trial design. This was a Phase II, multicenter, open-label, eight-week trial evaluating the safety and efficacy of ingenol disoxate (LEO 43204) applied once daily for three consecutive days on either the face/ chest, scalp, or on the trunk/extremities (NCT02305888). The trial consisted of three periods: a 35-day screening period, a three-day treatment period, and an eight-week follow-up period (Figure 1). The protocol was approved by the appropriate independent ethics committees and institutional review boards and conformed to the ethical principles of the Declaration of Helsinki, the International Conference on Harmonisation and Good Clinical Practice, and all applicable regulatory requirements. All patients provided informed written consent. Inclusion and exclusion criteria. Patients aged 18 years or older with 5 to 20 clinically typical, visible, discrete AKs within a selected treatment area of sun-damaged skin either on the full face or a contiguous area of approximately 250cm 2 on their chest, exposed scalp (25–250cm 2 ), or a contiguous area of approximately 250cm 2 on their trunk or extremities were included. Patients could also have visible and discrete hyperkeratotic or hypertrophic lesions in this area; these lesions were marked on a transparency and each lesion was followed separately. Patients were excluded from the trial if the selected treatment area was within 5cm of an incompletely healed wound, a suspected basal cell carcinoma, or a suspected SCC. In addition, patients were excluded if they had received prior treatment of the selected area with ingenol mebutate gel within the last 12 months, had atypical nonresponsive lesions (i.e., did not respond to cryotherapy on two occasions), or had a history of skin conditions other than AK (e.g., eczema, unstable psoriasis, or xeroderma pigmentosum). Treatment. Patients received ingenol disoxate gel at the following concentrations dependent upon the region to be treated: face/ chest group at 0.018%; scalp group at 0.037%; and trunk/extremities group at 0.1%. On Day 1, the gel was applied under the supervision of trained research staff and, on Days 2 and 3, the patients self-applied the treatment at home. Patients were assigned to treatment groups via an interactive web response system. If a patient fulfilled the requirement for more than one treatment area, the following order of assignment was used: 1) trunk/extremities; 2) scalp; and 3) face/chest. Objectives and endpoints. The primary and secondary objectives of the trial were to evaluate the safety and efficacy of ingenol disoxate after a once-daily field treatment for three consecutive days, respectively. Safety endpoints (i.e., LSRs and AEs) were assessed on Days 1, 4, and 8, and Weeks 2, 4, and 8. The individual LSR components consisted of erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, and erosion/ ulceration. Each was graded on a scale of 0 FIGURE 1. Trial design—Times shown are representative of the window within which each visit occurred: screening took place within 35 days of Visit 2; Visits 2 and 3 occurred on Days 1 and 4, respectively; Visits 4 and 5 were conducted at Day 8 and Week 2, respectively ±2 days; Visit 6 occurred at Week 4 ±4 days; Visit 7 was at Week 8 ±7 days. *Represents actual sample size—one patient in the trunk and extremities group was excluded from the full analysis set because of incorrect dose assignment. AK: actinic keratosis; LSR: local skin response

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