TOPICAL FORMULATION TO IMPROVE HYPERPIGMENTATION 265 O ur study will evaluate a new topical formulation, SKNB19, consisting of synthetic re- combinant human EGF and TA as the key ingredients in a topical formulation. Both EGF and TA are implicated in improving hyperpigmentation (11,13,17–20). The cream also contains other synthetic recombinant human growth factors along with vitamin C, arbu- tin 3%, and niacinamide 5%, all of which have been individually shown to improve hy- perpigmentation (21–25). In this prospective, randomized split study, the effi cacy and safety of this topical cream is evaluated and compared with that those of hydroquinone 4% (HQ4%). M ETHODS S TUDY DESIGN AND POPULATION T his single-center, prospective, randomized controlled study investigates the safety and effi cacy of the proprietary product SKNB19 compared with HQ4% in treating hyperpig- mentation. B oth SKNB19 and HQ4% used in the study are manufactured by MD Med- ical Designs, Inc. (Beverly Hills, CA). HQ4% is mixed in a premanufactured anhydrous topical gel consisting of the following inactive ingredients: dimethicone, caprylyl methi- cone, PEG-12 dimethicone/PPG-20 crosspolymer, butyrospermum parkii (shea) butter, polysilicone-11, tocopheryl acetate, and butylated hydroxytoluene (BHT) (PCCA WO6 Anhydrous Topical Gel, Houston, TX). Tocopheryl acetate and BHT are not active ingre- dients and are serving as preservatives in this formula. S KNB19 comprises synthetic recombinant human EGF (0.001%) and TA (3%) as the key ingredients in a topical formulation. Other active ingredients include water-soluble vitamin C (5%), arbutin (3%), and niacinamide (5%). The active ingredients are mixed in a moisturizing cream base consisting of the following inactive ingredients: water, ca- prylic/capric triglyceride, isononyl isononanoate, C12-15 alkyl benzoate, silica, cetearyl alcohol, glyceryl stearate, PEG-100 stearate, ceteareth-20, polysorbate 60, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, xylitylglucoside, anhydroxylitol, xylitol, phenoxyethanol, ethylhexylglycerin, titanium dioxide, citric acid, citrus auran- tium bergamia (bergamot) fruit oil, citrus grandis (grapefruit) peel oil, citrus aurantium dulcis (orange) peel oil, and citrus tangerina (tangerine) peel oil. S ubjects older than 18 years with pigmentation on the face, as determined by clinical examination, were included in this study. Subtypes of hyperpigmentation that met inclu- sion criteria were melasma, PIH, and/or solar lentigines. Each patient was required to be free of using any whitening creams, retinol-based products, or treatments to correct their hyperpigmentation (i.e., lasers and peels) for the past 6 mo. In addition, patients were required to be out of direct sun during the duration of the treatment. Female patients who were pregnant, planning to be pregnant, or breast feeding were also excluded from the study. Written informed consent was obtained from all study subjects before enroll- ment. The protocol for the study was conducted according to the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. I n this split study, participants were assigned based on a computer-generated randomiza- tion protocol such that one side of the face with hyperpigmentation was treated with SKNB19 twice a day (morning and night application) and the other side was treated with HQ4% applied nightly only. Our early experience using SKNB19 before the onset of this

JOURNAL OF COSMETIC SCIENCE 266 study showed that it was well tolerated for use twice daily, whereas HQ4% was better tolerated nightly. All patients were instructed to apply a zinc oxide–based sunscreen to both sides of the face with sun protection factor 30 that was provided to them. A SSESSMENTS W e assessed hyperpigmentation at baseline (before treatment) and at 1 mo after treat- ment initiation using both patient self-assessment and independent reviewer assessments. Patients used a 5-point scale to self-assess their overall appearance, in each case a higher score denoted a better outcome. Patients also used a 4-point scale to assess redness, irrita- tion, and tolerability to the skin-brightening creams (Table I). For the patient self-assess- ment, a Wilcoxon signed-rank test was used to test whether there was a statistical difference between the two treatments in overall appearance, irritation, redness, and tol- erability. T hree-dimensional imaging was performed before treatment and again 1 mo follow- ing treatment initiation using a standardized Canfi eld Vectra 3D imaging system (Canfi eld Scientifi c Inc., Parsippany, NJ). The study used fi ve independent reviewers comprising two dermatologists, two facial plastic surgeons, and one oculoplastic surgeon. Each reviewer was blinded to the study treatment, assessed the images pre- and posttreatment, and graded the appearance of each side on overall appearance (see Supplementary Figures 1–8 for independent reviewer grading scale). The grading scale was as follows: -1 indicating worsened appearance, 0 indicating no change, 1 indicating mild improvement, 2 indicating moderate improvement, and 3 indicating signifi cant improvement (Table II). In addition, the independent reviewers also performed a qualitative comparative assess- ment of the sides treated with each cream and noted the “better overall” side. A Wilcoxon signed-rank test was used to test whether there was a statistical difference in overall ap- pearance between SKNB19- and HQ4%-treated sides. RES ULTS Eig hteen patients (16 females and two males) met the inclusion criteria and were en- rolled in the study. The mean age of the patients was 38.8 (±9.7) years (range: 23–61 years). Table I Patient Self-Assessment Survey Scale Score -1 0 1 2 3 Overall appearance Worsened No change Mild improvement Moderate improvement Signifi cant improvement Irritation — None Mild irritation Moderate irritation Signifi cant irritation Redness — None Mild redness Moderate redness Signifi cant redness Tolerability — No issues Mild issues Moderate issues Severe intolerability