Evaluation of an advanced antioxidant and double‐conjugated retinoid/AHA cream in participants with FST IV–V

Topical antioxidants and retinoids are foundational components of an effective skincare regimen. Pyrroloquinoline quinone (PQQ) is a potent free radical scavenger that supports efficient mitochondrial energy creation. An advanced antioxidant combines topical allyl PQQ with existing WEL antioxidant technology (TAP) to comprehensively address extrinsic and intrinsic skin aging. In conjunction with TAP, a double‐conjugated retinoid/alpha hydroxy acid (AHA‐Ret) designed to minimize irritation and optimize delivery was used over 12 weeks to improve the appearance of photodamaged skin.


| INTRODUC TI ON
2][3] These distinctions can influence the safety and efficacy of dermatologic products, highlighting the need for clinical testing across a diverse group of skin types, races, and ethnicities.Foundational ingredients recommended for optimal skin health often include the use of retinoids (prescription or non-prescription), topical antioxidants, and sunscreens. 4However, many dermatologic products containing these agents have not been studied, either alone or in combinations, in a diverse range of races or ethnicities.
Oxidative stress mediates skin aging with both intrinsic and extrinsic factors, including the natural aging process and exposure to ultraviolet light, ozone, and pollution, contributing to the generation of reactive oxygen species (ROS).6][7][8] In addition to reducing the formation of free radicals, antioxidants can help prevent DNA damage caused by free radicals and contribute to reparative benefits. 4Evolving evidence highlights the important role certain antioxidants play in scavenging intrinsically generated free radicals.Intrinsically, mitochondria are the primary cellular source for the generation of ROS enabling epidermal differentiation. 9,10tochondria are critical for cell signaling, pigmentation, and vasculature homeostasis. 11As we age, mitochondria become less efficient, resulting in decreased energy production and increased generation of ROS, leading to oxidative stress and accelerated skin aging.
Optimal skin protection counteracts ROS generated by both intrinsic and extrinsic factors.
An advanced antioxidant combines WEL technology (comprised of 19 water-soluble, enzymatic, and lipid-soluble antioxidants) with topical allyl pyrroloquinoline quinone (PQQ) to address both extrinsic and intrinsic skin aging.3][14] PQQ is a redox cofactor found in a variety of edible plants that has been shown to have protective effects against free radical damage in mitochondria. 15PQQ supports the efficient creation of mitochondrial energy, which is necessary for the renewal and repair processes of the skin.However, owing to its inherent irritation and instability, formulating with PQQ as a topical agent has been problematic.The addition of an allyl (ester) group to the parent molecule addresses these barriers, enabling topical delivery to the skin in a stable, non-irritating format. 16unique, double-conjugated retinoid/alpha hydroxy acid molecule (AHA-Ret) employs multiple bonds, combining a retinoid with lactic acid to help minimize irritation that is typically associated with the use of a retinoid.The double-conjugated structure allows for the gradual release of these key ingredients, optimizing delivery of both the retinoid and the AHA.AHA-Ret represents a streamlined approach to skincare, combining the benefits of both a retinoid and an AHA, along with additional ingredients that benefit skin such as glycolic acid, niacinamide, ceramides, and a blend of peptides.17 In a previous 12-week clinical trial, nightly application of AHA-Ret led to reductions in the appearance of dyschromia, uneven skin tone, fine lines/wrinkles, erythema, and pore size from baseline at 12 weeks.17 Adverse Events (AEs) were local, mild, and transient in nature.
The objective of the study detailed herein was to evaluate the effectiveness and tolerability of a skincare regimen comprised of an advanced antioxidant containing topical allyl PQQ in combination with a AHA-Ret cream and a broad spectrum, mineral-based sunscreen in participants with FST IV-V.Institutional Review Board (Advarra, Columbia, MD) approval was obtained prior to study initiation and all participants provided written, informed consent prior to participation.The clinical research site followed all applicable guidelines in accordance with accepted standards for good clinical practice (GCP).

| RE SULTS
Twenty-two female participants were enrolled, and 21 participants completed the study.Participants had a mean age of 56 years and comprised a diverse population.Thirty-six percent of participants were African American, 32% were Caucasian, 14% were Asian/Pacific Islanders, and 18% identified as Other (Multi-race/Caucasian, Multi-race/African American, and Middle Eastern).Forty-one percent of participants were Hispanic.Fiftypercent of participants were FST IV and 50% were FST V. Enrolled participants were evenly split with half of study participants presenting with mild photodamage and half presenting with moderate photodamage at baseline.As early as Week 4, significant mean percent improvements from baseline in the appearance of erythema (47%, p = 0.004), skin dullness (30%, p < 0.0001), skin texture (27%, p < 0.0001), and skin tone (11%, p = 0.01) occurred (Figure 1).Continued improvements were demonstrated through Week 12 in skin dullness (64%, p < 0.0001), skin texture (54%, p < 0.0001), and skin tone (27%, p < 0.0001) (Figures 2A-D).At Week 12, >2-grade visible improvements from baseline were achieved by 81% of participants in the appearance of skin dullness (brightness), 67% in the appearance of skin texture, and 10% in the appearance of lines and wrinkles, erythema, and skin tone (discoloration).
Significant mean reductions from baseline occurred as early as 4 weeks in Mexameter measurements for both erythema and melanin, with significant reductions demonstrated through Week 12 (Figure 3).
After only 4 weeks of use, 91% of participants reported brighterlooking skin, 86% reported improvements in overall appearance of facial skin and sun damage, and 82% of participants reported that their skin looked healthier.At the conclusion of the study, 100% of participants reported improvements in the appearance of fine lines and wrinkles and that their skin was smoother, firmer, and softerlooking.In addition, 95% of participants reported improvements in overall appearance in facial skin and sun damage, noting brighter, F I G U R E 1 Mean percent improvements in appearance from baseline over 12 weeks.more radiant, and healthier-looking skin at Week 12 (Figure 4).F I G U R E 3 Significant mean reductions from baseline occurred as early as 4 weeks in Mexameter measurements for both erythema and melanin and over the 12-week study period (p < 0.05).
Unique structural and physiological differences between fair skin and darker skin tones influence overt manifestations of skin aging as well as response to treatment.A recent survey reported that many people with darker skin commented at the lack of available products for their skin types. 18Towards that end, this real-world clinical trial specifically examined the tolerability and efficacy of a skincare regimen that integrates foundational products and ingredients that together address both intrinsic and extrinsic aging in women with darker skin.
Clinical benefits of twice-daily application of TAP with evening application of AHA-Ret in participants with skin of color and photodamaged skin demonstrated early, significant improvements in the appearance of erythema, skin dullness (brightness), skin texture, and skin tone, with continued, progressive improvements in erythema over 12 weeks.Lower rates of improvement in lines/wrinkles, as assessed by the investigator may reflect milder severity in participants enrolled in this study, and generally reduced manifestation of lines and wrinkles in females with darker skin tones. 19Objective measurements of melanin and erythema demonstrated quantitative, significant reductions from baseline over the 12-week study duration.
Participants reported high levels of satisfaction throughout the study period, with 100% of participants reporting improvements in sun damage and blotchy-looking skin as early as 8 weeks, and 100% of participants reporting improvements in fine lines and wrinkles, smoother, firmer, and softer-looking skin at 12 weeks.
Combining foundational ingredients and novel technologies into a streamlined skincare regimen demonstrated real-world benefits in adult females with skin of color.Together, these products address both intrinsic and extrinsic photoaging, and skin rejuvenation in highly tolerable formulations in women with FSTs IV and V.
Clinical trials were previously performed on each of the two primary products examined in this current study, however, these products had not been studied together.These formulas, comprised of foundational ingredients including antioxidants and retinoid/AHAs, represent different mechanisms of action that are complementary to one another, and studying these products together represents more "real-world" application.Additionally, the initial studies conducted on AHA-Ret and TAP included adults with predominantly FST I-III.This current study allowed for evaluation in individuals with FST IV-V.Both individual products demonstrated high tolerability and benefits in their respective initial studies, as well as in the current study when utilized as part of a skincare regimen.
The inclusion of a sheer, broad spectrum sunscreen stick (SPF 56) provided effective skin protection without leaving an ashy or white film on skin and may have contributed to the overall performance of the skincare regimen.Nevertheless, it is essential to include a sunscreen when conducting skincare studies.This is even more important when studying products that contain vitamin A derivatives and AHAs, such as in AHA-Ret, as these ingredients may increase skin's sensitivity to the sun leading to the possibility of sunburn.Additionally, although in this study the use of a moisturizer was provided to participants as needed, moisturizers are frequently recommended by physicians for use in conjunction with retinoids or retinol-based products.
The goal of this study was to evaluate the tolerability and benefits of a skincare regimen in individuals with darker skin tones presenting with mild-to-moderate photoaged skin.Because photoaging occurs at a slower pace in individuals with FST VI than in individuals with lighter skin tones, this current study specifically included participants representing FST IV-V in an effort to evaluate changes over a short period of time.As the small sample size in this study presents limitations regarding the stratification of data, future studies are recommended for a larger number of participants representing FST IV-VI over an extended period of time.
In conclusion, application of an advanced antioxidant comprised of topical allyl PQQ, AHA-Ret cream and a broad spectrum, mineralbased sunscreen led to early, significant improvements from baseline in the appearance of photodamaged skin in females with FST IV and V. Participants reported high levels of satisfaction and the skincare regimen was highly tolerable over the 12-week study period.

AUTH O R CO NTR I B UTI O N S
Dr. Pearl E. Grimes was an investigator on this study; Diane B.
Nelson is an employee of skinbetter science.

ACK N OWLED G M ENTS
We would like to thank Lynne Kolton Schneider, PhD, for her editorial assistance on this manuscript.

FU N D I N G I N FO R M ATI O N
This study was supported by skinbetter science, LLC.
This single-center, open-label clinical trial evaluated the efficacy and tolerability of twice-daily (AM/PM) application of TAP in conjunction with nightly use of AHA-Ret over 12 weeks.Eligible female participants were 40-65 years of age with FST IV-V and mild (3) to moderate (6) facial photodamage based on a 10-point grading scale (0 = None, 1-3 = Mild, 4-6 = Moderate, 7-9 = Severe).Changes from baseline in lines/wrinkles, skin texture, skin tone (discoloration), erythema, and skin dullness (brightness) were assessed at Weeks 4, 8, and 12 using a six-point grading scale (0 = None to 5 = Severe), and global improvement was assessed using a five-point grading scale (0 = No improvement to 4 = Marked improvement).Quantitative assessment of melanin and erythema were obtained using non-invasive bioinstrumentation (Mexameter® MX 18, Courage+Khazaka electronic GmbH, Germany) from the same designated location on the face at Weeks 4, 8, and 12.The Mexameter objectively measures the two key components responsible for skin color-melanin and erythema (hemoglobin) based on absorption and reflection.Self-assessment questionnaires were completed at Weeks 4, 8, and 12, and tolerability was monitored throughout the study period.In addition to twice-daily use of TAP and nightly application of AHA-Ret, all participants were provided with a sheer, broad spectrum, mineral-based sunscreen (SPF 56), and a gentle cleanser for daily use.In addition, per the protocol and at the discretion of the investigator, a bland moisturizer was approved for use should a participant experience dryness or irritation.Digital images were obtained at baseline and Weeks 4, 8, and 12 using Canfield VISIA-CR Imaging System (Canfield Scientific Inc., Parsippany, NJ).Participants agreed to minimize sun exposure and apply sunscreen daily (15 min prior to being outdoors with reapplication every 2 h if engaging in outdoor activities), and to use only supplied skin care products.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, and seborrheic dermatitis), autoimmune diseases, acute illness, and open wounds/lesions or irritated skin.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, beta hydroxy acids (BHAs), peptides, growth factors, skin lightening/brightening agents, non-prescription vitamin A derivatives (retinoid/ retinol/retinal or like product), plant stem cell extracts, vitamin C-based topical antioxidants, other antioxidants, or like products.A 4-week washout period was required for products containing a prescription retinoid or hydroquinone.Participants who had taken an oral vitamin A derivative (e.g., 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.
Reduced redness and improved skin tone was reported by 90% of participants and nearly all stated they would continue to use the study products after conclusion of the study.Overall, 12 participants reported 15 events that were possibly related to the study products; all events were mild, localized, and transient in nature.Possibly related AEs included breakouts (n = 2), irritation (n = 1), temporary burning/stinging sensation with application (n = 4), redness (n = 1), peeling/flaking (n = 1), and dryness (n = 6).Of the 22 participants enrolled in the study, only 6 participants utilized a moisturizer based on reports of dryness at Week 4. By the following clinic visit (Week 8), all reports of dryness had resolved with the use of a bland moisturizer.No participant discontinued study products or the study due to an AE.

F I G U R E 2
Unretouched clinical photography shown on clean, product-free skin using standardized digital imaging.Image descriptions are based on average global improvement scores as assessed by the investigator.Visible improvements demonstrated from baseline following use of the skincare regimen after (A) 4 weeks, average result; (B) 8 weeks, average result; (C) 12 weeks, average result; and (D) 12 weeks, average result.

F I G U R E 4
Participant self-assessment questionnaire at Week 12.