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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21 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 to 4 (with higher numbers indicating greater severity), giving a maximum possible composite score of 24. 16 The primary endpoint of the trial was the number of patients who had dose-limiting events (DLEs) based on LSRs up to and including Day 8. DLEs were recorded according to predefined definitions (Table 1). The secondary endpoints of the trial were reduction in AK lesion count, analyzed separately for nonhyperkeratotic/hypertrophic lesions and for hyperkeratotic/hypertrophic lesions, and complete clearance of AK lesions (AKCLEAR 100), excluding hyperkeratotic/ hypertrophic lesions. An additional endpoint was partial clearance of AKs (AKCLEAR 75), defined as 75-percent reduction or more in baseline AK lesion count, excluding hyperkeratotic/hypertrophic lesions. AKCLEAR 100 and AKCLEAR 75 have been introduced as more descriptive terminology for the frequently used clinical endpoints of complete and partial clearance of AKs in a field. 13,14 AKCLEAR 100 was also analyzed in hyperkeratotic/hypertrophic lesions. Efficacy endpoints were assessed by AK lesion count at Week 4 and Week 8. Cosmetic and patient-reported outcomes including the Treatment Satisfaction Questionnaire for Medication (TSQM), 17 a cosmetic outcome questionnaire, and a global photo damage outcome assessment were also assessed at Week 8 (detailed analysis reported separately in Berman et al 15 ). Statistical methods. A formal sample size calculation was not performed for the initial part of the trial (for the initial 18 patients); however, a sample size was selected to determine an adequate precision rate of the DLEs. The numbers of subjects experiencing DLEs up to and including Day 8 were tabulated for the first 18 patients recruited in each treatment group and the results were presented for the Early Data Review Committee (Interim analysis). The sample size (n=62, including the initial 18 patients) for the latter part of the trial was selected to obtain a precision rate with respect to the secondary endpoints (i.e., reduction in AK lesion count and AKCLEAR 100) and as per previous trials. 13 The ratio of number of AK lesions at Week 8 relative to baseline was analyzed separately for each treatment group, using a negative binomial regression on the AK lesion count at Week 8 with the log baseline value as an offset variable. The estimated percent reduction in AK lesion count and a corresponding 95-percent confidence interval (CI) are presented. For the analysis of AK lesion count at Week 8 and Week 4, missing values were imputed using last observation carried forward. RESULTS Trial population. A total of 253 patients from 20 trial sites in the United States were enrolled in the trial. Of those, 189 were assigned to treatment groups. In total, 188 patients were included in the full analysis set and safety analysis set; one patient was excluded due to an incorrect dose assignment (face/chest, n=63, scalp; n=63; and trunk/extremities, n=62; Table TABLE 2. Baseline patient characteristics (full analysis set) CHARACTERISTIC INGENOL DISOXATE GEL FACE/CHEST 0.018% (n=63) SCALP 0.037% (n=63) TRUNK/EXTREMITIES 0.1% (n=62) Sex, n (%) Male 40 (63.5%) 62 (98.4%) 39 (62.9%) Female 23 (36.5%) 1 (1.6%) 23 (37.1%) Age, mean (SD) 64.0 years (8.8 years) 67.7 years (9.6 years) 66.7 years (9.6 years) Race, n (%) White 62 (98.4%) 62 (98.4%) 62 (100.0%) American Indian/Alaska native 1 (1.6%) 0 0 Other 0 1 (1.6) 0 Fitzpatrick skin type, n (%) I (burns easily, never tans) 8 (12.7%) 5 (7.9%) 12 (19.4%) II (burns easily, tans minimally) 30 (47.6%) 25 (39.7%) 36 (58.1%) III (burns moderately, tans gradually) 22 (34.9%) 30 (47.6%) 12 (19.4%) IV (burns minimally, always tans well) 3 (4.8%) 3 (4.8%) 2 (3.2%) Median duration of AK (range) 7 years (0–40 years) 10 years (0–36 years) 7 years (0–32 years) AK lesion count,* median (range) 10 years (5–20 years) 11 years (6–20 years) 11 years (5–20 years) Hyperkeratotic/hypertrophic lesions, n (%) 0 lesions 54 (85.7%) 53 (84.1%) 46 (74.2%) 1–2 lesions 7 (11.1%) 7 (11.1%) 7 (11.3%) ≥3 lesions 2 (3.2%) 3 (4.8%) 9 (14.5%) Previously treated for AK, n (%) 48 (76.2%) 52 (82.5%) 56 (90.3%) Non-melanoma skin cancer history, n (%) 24 (38.1%) 22 (34.9%) 20 (32.3%) *excluding hyperkeratotic or hypertrophic lesions AK: actinic keratosis; SD: standard deviation TABLE 1. Definition of dose-limiting events based on local skin responses TREATMENT AREA LOCAL SKIN RESPONSES Face/chest At least one of the following LSRs: crusting Grade 4, erosion/ ulceration Grade 4, vesiculation/ postulation Grade 4; or at least two of the following LSRs: erythema Grade 4, crusting Grade 3, swelling Grade 4, erosion/ ulceration Grade 3, vesiculation/ postulation Grade 3 Scalp Erosion/ulceration Grade 4 Trunk/extremities At least one of the following LSRs: crusting Grade 4, erosion/ ulceration Grade 4, vesiculation/ postulation Grade 4; or at least two of the following LSRs: crusting Grade 3, swelling Grade 4, erosion/ulceration Grade 3, vesiculation/postulation Grade 3 LSR: local skin response

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