James H. Herndon Jr., MD, FAAD; Elizabeth T. Makino, BS, CCRA, MBA;
Thomas J. Stephens, PhD; Rahul C. Mehta, PhD
Thomas J. Stephens & Associates, Carrollton, Texas; SkinMedica Inc., an Allergan Company, Carlsbad, California
Abstract
Objective: To evaluate the efficacy and tolerability of a multimodal skin-brightening regimen in subjects with facial hyperpigmentation. Design: Open-label, single-center clinical study with clinical assessments at baseline, Week 4, Week 8, and Week 12. Treatment: Subjects were instructed to apply the skin-brightening complex onto their facial skin, twice daily, for 12 weeks. Subjects also applied a nonprescription retinol product, moisturizer, and sunscreen. Participants: Twenty-one subjects, aged 41 to 65 years, with Fitzpatrick skin types II to IV and moderate-to-severe facial hyperpigmentation completed the study. Measurements: Overall hyperpigmentation and tolerability (objective and subjective) assessments were conducted at all visits. In addition, global improvement in hyperpigmentation was assessed at all follow-up visits. A self-assessment questionnaire was completed by subjects at Week 12. Results: At baseline and Weeks 4, 8, and 12, subjects were assessed for overall hyperpigmentation and global improvement. Standardized digital photographs were also taken of the subjects’ facial skin at all visits. Subjects completed a self-assessment questionnaire at Week 12. Statistically significant reductions in mean Overall Hyperpigmentation scores and significant improvements in mean Global Improvement scores compared to baseline were observed at all follow-up visits (all p<0.001). These clinical observations were supported by standardized digital photography. In addition, the skin-brightening regimen was highly rated by subjects on all of the questionnaire parameters. Conclusion: The results from this study suggest that the multimodality skin-brightening regimen may provide a comprehensive and optimal treatment option to help reduce facial hyperpigmentation. (J Clin Aesthet Dermatol. 2014;7(5):27–31.)
The most visible component in the human phenotype is the skin. It is characterized by a wide range of genetically determined colors. Changes in the natural color of human skin occur frequently. Disorders of hyperpigmentation (including melasma, postinflammatory hyperpigmentation, lentigo, etc.) are commonly seen in office-based dermatology practices worldwide. Topical hydroquinone has a long history of use in pigmentary disorders. While some controversy exists regarding the safety of hydroquinone,[1–5] its efficacy in various disorders of hyperpigmentation is, nonetheless, well established.[6–9] Due to this safety controversy, research has increased on hydroquinone-free skin lighteners. This has resulted in numerous cosmetic skin-brightening products entering the marketplace.
An improved understanding of melanogenesis has also led to new pathways as targets for topical therapy. Recently, in a randomized, double-blind study, a multimodal, hydroquinone-free, topical skin-brightening product was shown to have similar efficacy and tolerability as 4% hydroquinone in females with facial hyperpigmentation.[10] The key ingredients in the skin brightener were selected to address the various pathways involved in melanin production and control, including the reduction of melanocyte activation through free-radical scavenging and inflammatory cytokine suppression [tetrahexyldecyl ascorbate and 4-ethoxybenzaldehyde, respectively][11,12]; limiting the availability of tyrosinase, a key enzyme involved in melanin synthesis [retinol, linoleic acid, glabridin, and hexylresorcinol][13–16]; reducing the transfer of melanin to keratinocytes [niacinimide and 4-ethoxybenzaldehyde][12,17]; and lastly, to exfoliate existing melanin present in the epidermis [retinol].[18]
Additionally, a hyperpigmentation system containing this multimodality skin brightener (with a tri-retinol 1.1% product) was shown to have comparable efficacy and tolerability as a hydroquinone-based regimen.[19] The goal of this clinical study was to assess the efficacy and tolerability of a new multimodality hydroquinone-free skin brightener system utilizing a lower strength (0.5%) retinol for treatment of moderate-to-severe facial hyperpigmentation.
Materials and Methods
Twenty five subjects with Fitzpatrick skin types I to IV in good general health between the ages of 30 and 65 years with moderate-to-severe facial hyperpigmentation were enrolled in the study. Subjects were required to have a baseline score of 4 to 9 from the Investigator’s Overall Hyperpigmentation scale.
Subjects applied the skin brightener twice daily, morning and evening, onto their facial skin after cleansing. In the evenings, subjects also applied topical retinol 0.5%. During the first week, subjects were instructed to apply the retinol product every other evening. During subsequent weeks, subjects were to use retinol every night as tolerated. All subjects were provided with a standard skincare regimen (facial cleanser and SPF30+ sunscreen) to use during the course of the study.
Institutional Review Board approval was obtained prior to commencement. This study was conducted according to ethical and regulatory principles from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Prior to treatment, subjects provided informed consent. The study was conducted in Dallas, Texas, from September to December 2012.
Subjects were treated over a 12-week period with visits at baseline, Week 4, Week 8, and Week 12. Subjects arrived at the clinic having removed all makeup prior to the visit and had the following assessments at each visit:
Clinical efficacy. An investigator evaluated the face of each subject for the following parameters using a grading scale:
• Overall Hyperpigmentation (0=none, 1–3=mild, 4–6=moderate, 7–9=severe). These assessments were made at baseline and Weeks 4, 8, and 12.
• Investigator’s Global Improvement Assessment: (1= worse, 2=no improvement, 3=mild improvement, 4=moderate improvement, 5=marked improvement). These assessments were made at Weeks 4, 8, and 12.
Tolerability. Each subject was assessed by the investigator for erythema and peeling using a 4-point scale (0=none, 3=severe). Subjects assessed burning/stinging and itching on a 4-point scale (0=none, 3=severe).
Digital photography. Digital color photography was performed using both standard lighting and brown channel lighting to document changes in facial pigmentation.
Self-assessment questionnaires. Subjects completed a self-assessment questionnaire regarding their experience with the regimen at Week 12.
Statistical analysis. The per-protocol (PP) population was the population for efficacy and tolerance testing. The PP population included all subjects who were eligible to participate and completed the study according to the protocol. Clinical grading scores at each evaluation visit were compared to baseline scores using a paired t-test for Overall Hyperpigmentation and a Wilcoxon signed-rank test was used for Investigator’s Global Assessment and tolerance parameters. The average percentage change from baseline was calculated at each post-baseline evaluation visit. All differences were considered to be statistically significant at the p<0.05 level.
Results
The demographic data on the 21 subjects who completed the 12-week trial are presented in Table 1. Four subjects discontinued (2–investigator decision, 1–did not meet protocol criteria and 1–lost to follow-up). Investigator Overall Hyperpigmentation scores and Investigator Global Improvement Assessment scores showed statistically significant improvements over baseline at all visits (p<0.001) ( “href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure1_may2014.jpg”>Figure 1
and “href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure2_may2014.jpg”>Figure 2). A plateau effect for these efficacy parameters was not seen after 12 weeks of treatment. Mean scores for erythema, burning/stinging, or itching were rated as “mild” or less at all visits. In the subject questionnaire, 86 percent or more “Agreed” or “Strongly Agreed” with the statements regarding the skin-brightening system ( “href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure3_may2014.jpg”>Figure 3). “href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure4a4b_may2014.jpg”>Figure 4,
“href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure5a5b_may2014.jpg”>Figure 5, and
“href=”https://bwcbuildout.com/jcad/wp-content/uploads/Makinofigure6a6b_may2014.jpg”>Figure 6
illustrate the effects of treatment for 12 weeks.
Discussion
The human skin is very critical in the makeup of an individual’s physical appearance. Humans often seek to make improvements to their imperfections with a goal of increasing self-perception and overall quality of life.[20,21] Pigmentary changes in the skin are very common20,22 and result from many diverse factors (including genetics, hormonal changes, aging, environmental).[23] As the process of melanogenesis is becoming better understood, there are now multiple targets for pigmentation control. Topical skin-lightening agents that act on several stages of the melanogenesis pathway provide strong rationale for a combination of ingredients to produce a greater overall therapeutic effect. Similar to the clinical results from previous studies with this new skin brightener,10,19,24,25 no therapeutic plateau was reached after 12 weeks of treatment. This suggests that longer term treatment may achieve even greater efficacy.
Retinoids have been shown effective in the treatment of various disorders of hyperpigmentation.[26–29] The clinical results from this hyperpigmentation system study showed that substitution of a new lower strength retinol 0.5% product produced efficacy results very comparable to that achieved with the hyperpigmentation system utilizing a higher strength (1.1%) tri-retinol product.[19] In addition, this new system with the lower strength retinol had improved tolerability, particularly related to peeling.
Conclusion
Treatment with this new hydroquinone-free, multimodality skin brightener system (with a lower strength [0.5%] retinol product) was well tolerated and demonstrated consistent improvements in two distinct investigator efficacy assessments over the 12-week evaluation in the treatment of moderate-to-severe facial hyperpigmentation.
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