A pilot study examining a double‐conjugated, retinoid‐based skincare regimen for darker, blemish‐prone skin

Retinoids and alpha‐ and beta hydroxy acids are common components utilized in regimens for blemish‐prone skin. However, balancing efficacy and tolerability is often challenging.

of the US population will comprise this diverse and heterogenous group by the year 2030, 5,6 clinical trials in dermatology have historically focused on testing new products in individuals with lighter skin tones (FST I to FST III).[9] Acne and hyperpigmentation are among the most common dermatologic conditions in individuals with skin of color. 2,10Acne lesions in skin of color have marked inflammation and hyperpigmented epidermal macules with melanin granules. 2Compared to individuals with lighter skin, individuals with darker skin tones are less likely to develop nodulocystic acne but are more likely to develop inflammatory lesions, potentially leading to post-inflammatory hyperpigmentation (PIH), scarring, and keloids. 11,12Additionally, PIH is often more distressing to individuals with darker skin tones and often persists long after acne has cleared. 2,4,12[14] The AAD recognizes topical retinoids as first-line treatment for acne and hyperpigmentation and recommends early and aggressive treatment to minimize the risk of PIH and/or scarring. 1,2Retinoids reduce keratinocyte proliferation, increase epidermal turnover, normalize follicular differentiation, and have anti-inflammatory effects. 4tinoids help restore normal desquamation, unclog pores, reduce inflammation, and have been shown to reduce hyperpigmentation in individuals with skin of color. 4While topical retinoids, AHAs, and BHAs each afford unique benefits including the normalization of cellular differentiation and exfoliation in hydrophilic and lipophilic areas, 13 the potential for increased skin irritation is compounded when used in combination with one another. 4,15timal treatment for blemish-prone skin must balance reducing sebum, while minimizing irritation and disruption of the skin barrier.
A unique, double-conjugated molecule combines a retinoid with an AHA (lactic acid) to help minimize irritation typically associated with the use of retinoids.The double-conjugated structure allows for the gradual release of these key ingredients, optimizing delivery of both the retinoid and the AHA. 16Leveraging this technology, a novel formulation was developed specifically for blemish-prone skin (AHARet-SA).The proprietary, double-conjugated molecule is used in combination with salicylic acid and additional lactic acid, along with other targeted ingredients to balance skin surface sebum levels and support skin hydration, as shown in Table 1.Ingredients such as zinc PCA and niacinamide are incorporated to support reductions in sebum and transepidermal water loss (TEWL).Additionally, botanical extracts like green tea are included to help calm skin and reduce the appearance of redness. 15previous study evaluated the efficacy and tolerability of AHARet-SA when used nightly over 12 weeks in 20 participants with mild-to-moderate blemish-prone skin.15 In this study, significant mean percent improvement from baseline in the appearance of skin clarity and pore size was demonstrated at all timepoints (p ≤ 0.05).15 Participant satisfaction was high with the vast majority of participants reporting satisfaction in the overall appearance of their skin, as well as improvement in skin texture and smoothness after 12 weeks.Participants reported more even-looking skin with less redness and pore visibility at week 12.Few mild, transient adverse events (AEs) were reported with no participant discontinuing study participation due to an AE.This study began enrolling participants in February 2020, just prior to the COVID-19 pandemic being declared a national emergency (March 13, 2020).As a result of restrictions and mandates due to COVID-19, the population represented in this study was limited with the majority of participants representing FST II.
The aim of the study described herein was to evaluate the efficacy and tolerability of AHARet-SA in conjunction with a complementary skincare regimen in FST IV and V, and participants with mild-to-moderate blemish-prone skin.The regimen consisted of four products in addition to a gentle gel cleanser.The retinoid/AHAbased products included the application of exfoliating peel pads comprised of the double-conjugated retinoid/AHA molecule and a triple-acid blend (glycolic, lactic, and salicylic acids) up to 3 days/ week, followed by nightly application of AHARet-SA.A lightweight, noncomedogenic moisturizer was used by participants as needed, and a sheer, mineral-based sunscreen stick (SPF 56) was applied at least once daily.Participants who used products containing prescription retinoids or hydroquinone were eligible following a 4-week washout period.

| MATERIAL S AND ME THODS
Participants who had taken an oral retinoid (isotretinoin) within the prior 6 months or had undergone chemical peels, microdermabrasion, microneedling, or a like procedure within the prior 3 months were excluded from study participation.
Participants were provided with detailed instructions regarding product application.Following cleansing (AM/PM), participants applied a sheer, mineral-based sunscreen stick (SPF 56) every morning.
In the evening, participants used individually packaged exfoliating peel pads three times a week (Monday, Wednesday, and Friday) followed by application of AHARet-SA.Use of the exfoliating peel pads was then reduced to twice weekly (Monday and Friday) followed by application of AHARet-SA for the final 4 weeks of the study.A lightweight, noncomedogenic moisturizer was used as needed (AM/PM).
Products were weighed at each study visit to assess compliance.
Statistical analysis was performed by an independent statistician using the Delta percentage formula to determine mean percent improvement by calculating percent change for every participant, mean percent change, and standard deviation across all participants.
Mean and variability of percent change across participants was calculated using all timepoint measurements obtained from the same participant.
Institutional Review Board (Advarra, Columbia, MD) approval was obtained prior to study initiation, and all participants provided written, informed consent prior to study participation.The clinical research site followed all applicable guidelines in accordance with accepted standards for Good Clinical Practice (GCP).

| RE SULTS
Enrolled participants (N = 11) were female with a mean age of 38 years.Fifty-five percent (55%) of participants were FST IV, and 27% were FST V. Eighty-two (82%) of participants were African American.
As seen in Figures 2 and 3, there were significant improvements in the appearance of both skin tone (15%; p = 0.01) and pore size (22%; p = 0.01) by week 8, with continued improvements through week 12 (34%; p = 0.003, and 23%; p = 0.01, respectively).More than 36% of participants had achieved at least a 1-grade improvement in skin clarity at week 4 with 63% of participants demonstrating a ≥2-grade improvement from baseline by week 12. AEs were mild and transient, similar to those observed in the initial study conducted in lighter skin tones. 15ter 4 weeks, 80% of participants reported their skin felt less oily or greasy and healthier-looking with less visible pores.All participants reported their skin was less red-looking, felt smoother, and was not flaky or peeling at 8 weeks.After 12 weeks, 88% of participants reported that the overall appearance and texture of their skin had improved, noting their skin appeared less blotchy and more even-looking with fewer blemishes or breakouts and visibly fewer blackheads and small bumps.After 12 weeks of use, 100% of participants reported their pores were less visible, skin felt less oily or greasy, and that they would continue to use the regimen at the conclusion of the study.
There were moderate reductions in erythema at weeks 4 and 8, with a minimal increase from baseline at week 12.There was a minimal increase in dryness/flaking at all timepoints.Notably, participants reported their skin felt hydrated and was not flaking or peeling at the conclusion of the study.Mild, transient AEs possibly related to the study products were reported and included breakouts and irritation (dryness, stinging/burning upon initial application, and/or itching).AEs subsided over the course of the study.
No participant discontinued study products or participation in the study due to an AE.

| DISCUSS ION
Blemishes affect individuals of all ages and skin types and can have a substantial negative effect on self-esteem and quality of life at any age. 17 Importantly, every skincare regimen must include the use of a sunscreen.Because of increased risk of skin sensitivity to the sun when using products that include a retinoid and AHA/BHAcontaining ingredients, daily application of a sunscreen is critical.
While broad-spectrum, mineral-based sunscreens comprised of zinc and/or titanium oxide are preferred, they are often undesirable in individuals with darker skin tones due to the white, chalky film they often leave behind. 9The sunscreen used in this regimen was a transparent, matte, mineral-based, broad-spectrum sunscreen stick (SPF 56) designed for convenient use in a variety of skin tones.
Due to recruitment extending into the summer months and the potential for increased sun exposure and skin sensitivity, enrollment was limited to a small number of participants.Additional larger studies are recommended.

| CON CLUS IONS
A skincare regimen comprised of a double-conjugated retinoid/AHA/ BHA serum and exfoliating peel pads, a lightweight moisturizer, and a mineral-based sunscreen demonstrated substantial improvements from baseline in skin clarity, pore size, and skin tone over 12 weeks.
Enrolled participants in this pilot study were predominantly African American with FST IV and V with mild-to-moderate blemish-prone skin.Participants reported high levels of satisfaction, with few reports of mild, transient dryness and irritation, none of which led to discontinuation of the study products.

ACK N OWLED G M ENTS
We would like to thank Lynne Kolton Schneider, PhD, for her editorial assistance on this manuscript.Nelson is an employee of skinbetter science.
photographs for research, publication, and/or marketing purposes.Exclusion criteria included participants with dermatological disorders (e.g., severe acne vulgaris and/or cystic acne, acne conglobata, acne fulminans, severe rosacea, atopic dermatitis, psoriasis, seborrheic dermatitis), autoimmune diseases, acute illness, and open wounds/ lesions or irritated skin in the area to be treated.Participants who were pregnant, lactating, or planning a pregnancy during the study period were excluded.Participants were deemed eligible for inclusion following a 2-week washout period of any cosmetic product containing AHAs, BHAs, peptides, growth factors, skin lightening/ brightening agents, nonprescription vitamin A derivatives (retinoid/ retinol/retinal or like product), plant stem cell extracts, vitamin Cbased topical antioxidants, other antioxidants, or like products.

F I G U R E 2
-21  Management of blemishes during adulthood must be balanced with age-related skin changes.As such, efficacious, nonirritating products that support the skin barrier and provide additional benefits to aging skin are often desired.It is not uncommon for a skincare regimen to consist of multiple products in an effort to address aging and blemish-prone skin concerns in adult females.The double-conjugated retinoid/AHA-based molecule contained in the products used in this regimen was specifically designed to address mild-to-moderate blemish-prone skin and support the skin's barrier, mitigating irritation that often accompanies use of these individual ingredients.The double-conjugated retinoid/AHA serum used in this pilot study thoughtfully incorporates additional ingredients, including niacinamide, zinc, salicylic, and lactic acids, into one, stable formulation to help reduce sebum production, calm and support inflamed skin, and support hydration of the stratum corneum.This allows for a streamlined and highly tolerable product that can be used every night, supporting consistent use and facilitating positive outcomes for patients.Clinical benefits of this regimen in study participants included early significant mean improvements in skin clarity, skin tone, and pore size appearance.Mean improvement from baseline in fine lines/wrinkles was minimal, likely attributable to the younger demographic enrolled in this study.Although PIH was not a specific parameter assessed in this study, visible improvements were observed F I G U R E 1 Improvement in the appearance of skin clarity, pores, and skin tone from baseline over 12 weeks.Improvement in appearance from baseline to week 4. over time.Participants reported high levels of satisfaction throughout the study period.While use of the moisturizer was optional, all participants chose to apply the moisturizer twice daily at study onset, with the majority of participants tapering off to once per day towards the end of the study, which may have contributed to the low reported incidence of erythema, irritation, and flaking/dryness.

FU
N D I N G I N FO R M ATI O N Dr. Hartman and Dr. Dyck were investigators for this study; Diane