Downie, Jeanine B. M.D.; Grimes, Pearl E. M.D.; Callender, Valerie D. M.D.
As in all organ systems, the skin and its appendages undergo characteristic changes with advanced aging. Indeed, the skin can be a major indicator of a person’s age, health, and vitality.1 Facial wrinkles can originate from chronologic skin aging, environmental factors, smoking, photoaging, hyperdynamic facial expressions, and skin folding that is secondary to the loss of underlying skeletal and soft-tissue support.2 These facial changes, although inevitable, are not altogether irremediable. Dermal fillers can be used to restore fullness that is naturally lost as fat diminishes from the face over time.
Within the past decade or so, soft-tissue fillers have increasingly come to offer patients a minimally invasive therapy for reducing the signs of aging. Soft-tissue fillers are used to fill facial lines and wrinkles and augment nasolabial folds. Treatment of dermal contour deformities, including fine lines, wrinkles, and folds, has been widely accepted to improve aesthetic appearance.1 A number of filling agents have been used, with varying levels of success, in attempts to correct dermal volume depletion and soft-tissue contour defects. These cosmetic fillers range from temporary (lasting a few weeks or months), to semipermanent (6 to 12 months), to permanent. They are derived from donated human sources, animal sources, or are completely synthetic. Hyaluronic acid–based products available for the treatment of facial wrinkles include Restylane (Medicis Aesthetics, Inc., Scottsdale, Ariz.) and Juvéderm (Allergan, Inc., Irvine, Calif.).
A recent addition to the treatment options is Belotero Balance (Merz Aesthetics, Greensboro, N.C.) (called Belotero Basic outside of the United States). Belotero is a fermented, non–animal-derived hyaluronic acid–based dermal contour filler with several unique properties in comparison with existing hyaluronic acid products. For example, Belotero contains a monophasic gel with variable density (viscosity) zones for better adaptation in the dermis.3 It is designed with a cohesive polydensified matrix, created during manufacturing of the hyaluronic acid product. After extraction and purification, hyaluronic acid derived from streptococcal cultures is cross-linked with a binding agent in two consecutively executed reactions. This two-step process results in a monophasic gel with zones of greater and lesser density. In this study, Belotero Balance is referred to as a cohesive polydensified matrix hyaluronic acid, following a precedent established in a report of the pivotal trial of the dermal filler compared with bovine collagen.4
Although studies of hyaluronic acids as dermal fillers appear with increasing frequency in the clinical literature, the presence of subjects with skin of color in patient study populations has been, to date at least, at odds with the percentage of patients with skin of color in the population at large.4 For example, in the pivotal trial comparing Belotero Balance with collagen, 96.6 percent of the subjects were Caucasian. In the extended study of the same trial, out to 96 weeks, 97.9 percent of subjects were Caucasian.5 Studies in Germany involved populations of Caucasians in similar percentages.6,7
Nevertheless, some studies and observations directed toward persons with skin of color can be found in the literature.8–15 The study described here adds to the growing body of literature of patients with skin of color who are treated with dermal fillers. The study is intended to clarify the safety and effectiveness of cohesive polydensified matrix hyaluronic acid in a sizable population of persons with skin of color.
The primary purpose of this study was to assess safety, specifically, the incidence of hyperpigmentation, hypopigmentation, and scarring following the use of cohesive polydensified matrix hyaluronic acid in the correction of nasolabial folds in subjects with Fitzpatrick skin types IV, V, and VI. Effectiveness was also assessed.
PATIENTS AND METHODS
This level I study was an open-label, multicenter trial. Institutional review board approval was obtained before commencement of the study. Safety was measured by means of live physician assessments and use of subject diaries. Effectiveness measurement tools included the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale administered by an evaluator investigator and a treating investigator. In addition, Global Aesthetic Improvement Scale assessment was conducted by study subjects at each site.
Treatment consisted of injection of hyaluronic acid with cohesive polydensified matrix into both nasolabial folds of subjects who were either a IV, V, or VI on the Fitzpatrick skin type scale and whose nasolabial folds were rated a 2 or 3 on the Wrinkle Severity Rating Scale. (A Fitzpatrick skin type of IV is described as skin that burns minimally and tans moderately; Fitzpatrick skin type V is described as skin that rarely burns and tans profusely; and Fitzpatrick skin type VI is described as skin that never burns and tans profusely.) On the Wrinkle Severity Rating Scale, a score of 0 represents the absence of nasolabial folds, a score of 1 represents mild nasolabial folds, 2 represents moderate nasolabial folds, 3 represents severe nasolabial folds, and 4 represents extreme nasolabial folds. The initial treatment was performed followed by an optional touch-up treatment at 2 weeks as needed to achieve optimal correction. The follow-up phase consisted of visits at 2, 4, 8, 12, 16, and 24 weeks after the last treatment.
A total of 93 subjects participated in the study (n = 80 women), with 88 subjects remaining in the study through 24 weeks. In Fitzpatrick skin type IV (n = 4), the mean age was 57.3 years. In Fitzpatrick skin type V (n = 37), the mean age was 50.9 years. In Fitzpatrick skin type VI (n = 52), the mean age was 51.5 years. Ninety (96.8 percent) of the subjects were African American. One subject was Caucasian, one subject was American Indian/Alaska Native, and one subject was Native Hawaiian/Pacific Islander.
Subjects had to be 18 to 75 years of age, of any race or sex. Subjects had to have bilateral nasolabial fold ratings of 2 (moderate) or 3 (severe) on the Wrinkle Severity Rating Scale and have Fitzpatrick skin type IV, V, or VI. Female subjects had to have a negative urine pregnancy test and, if of childbearing potential, had to agree to use an approved method of birth control throughout the study period.
Subjects with any of the following conditions were not allowed to enroll in the study: severe physical, neurologic or mental disease; excessive facial hair; any systemic or dermatologic disorder that in the opinion of the investigator would interfere with the study results or increase the risk of adverse events; personal history of allergic/anaphylactic reactions including hypersensitivity to local anesthetics (e.g., lidocaine), hyaluronic acid preparations, and/or Gram-positive bacterial protein; known history of keloids or bleeding disorders; leukoderma (vitiligo) or with a family history of leukoderma or other pigmentary disorders; active inflammatory process in the nasolabial fold area; severe scarring; and pregnancy or nursing. In addition, subjects planning major facial plastic surgery, recent participation in a trial (30 days), and/or subjects with a clinically important disease as judged by the treating investigator within 3 months of the study were excluded.
During the study period, subjects were not allowed any use of botulinum toxin products, nonpermanent cosmetic dermal fillers in the nasolabial fold area 1 year before the first visit and then throughout the study, permanent cosmetic dermal fillers, any skin resurfacing procedures, any prescription facial wrinkle therapies, any immunosuppressive or systemic steroids within 8 weeks of the start of treatment and throughout the study, and any anticoagulant therapies other than aspirin for cardiac prophylaxis (<325 mg/day). After meeting all protocol inclusion/exclusion criteria, subjects reviewed and signed a statement of informed consent and Health Insurance Portability and Accountability Act of 1996 authorization, thereby enrolling them in the study.
The hyaluronic acid with cohesive polydensified matrix (Belotero, a highly cross-linked, viscous hyaluronic acid gel derived from nonanimal sources), was allowed to be injected through a 27- or 30-gauge needle placed in the plane(s) of the apparent deformity; the defect was not to be overcorrected. Treatment consisted of either one treatment session or two treatment sessions separated by a 2-week interval. Each treatment session consisted of multiple mid to deep dermal injections of hyaluronic acid with cohesive polydensified matrix (up to a maximum of 3 ml per nasolabial fold over the two treatment sessions) into both nasolabial folds.
Gentle massage of the treated area was recommended following implantation. For pain-sensitive subjects, application of a topical anesthetic or infraorbital nerve block was allowed at the discretion of the treating investigator.
All subjects were assessed live for hypopigmentation, hyperpigmentation, and scarring at all follow-up visits. In addition, at each treatment phase, subjects were given a diary on which to record injection-site reactions, including severity and duration of procedure-related events such as redness, pain, swelling, bruising, and itching.
Effectiveness assessments included the use of the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale. Evaluator investigators and treating investigators at each site independently made live assessments of the severity of each nasolabial fold at each specified time point using the validated, five-point, Wrinkle Severity Rating Scale below. The grade represented the “best fit” based on the overall depth and length of the nasolabial fold based on a “snapshot” at a certain time point and were not based on a comparison to pretreatment photographs: 0, absent (no visible fold; continuous skin line); 1, mild (shallow but visible fold with a slight indentation; minor facial feature); 2, moderate (moderately deep folds; clear facial feature visible at normal appearance but not when stretched); 3, severe (very long and deep folds; prominent facial feature; <2 mm visible fold when stretched); and 4, extreme (extremely deep and long folds, detrimental to facial appearance; 2- to 4-mm V-shaped fold when stretched).
In addition, the evaluating investigators, treating investigators, and subject rated each nasolabial fold (left and right) compared with a baseline photograph for global aesthetic improvement using the following Global Aesthetic Improvement scale: 4, very much improved (optimal cosmetic result in this patient); 3, much improved (marked improvement in appearance from the initial condition, but not completely optimal for this patient; a touch-up might slightly improve the patient); 2, improved (obvious improvement in appearance from the initial condition, but a touch-up or retreatment is indicated); 1, no change (the appearance is equivalent to the baseline pretreatment appearance); and 0, worse (the appearance is worse than baseline pretreatment appearance).
All statistical analyses were descriptive in nature and noninferential. Continuous variables were summarized using the actual number of observations, mean, standard deviation, median, minimum, and maximum. Categorical variables were summarized using counts and percentages. All data were summarized by nasolabial fold side (left versus right) after further stratification by Fitzpatrick skin type (IV, V, VI; and IV, V, and VI combined) as appropriate. Background and demographic characteristics were summarized by using appropriate descriptive statistics; ethnicity, race, and sex were summarized using counts and percentages, by Fitzpatrick skin type. Adverse events were tabulated by Fitzpatrick skin type and nasolabial fold side, including type, rate, severity and duration. The initial injection volume, the touch-up injection volume, and the cumulative volume of cohesive polydensified matrix hyaluronic acid used during the study were summarized by Fitzpatrick skin type and nasolabial fold side, using continuous descriptive statistics.
Investigators were limited to a maximum volume of 3 ml per nasolabial fold over two treatment sessions. The mean volumes of cohesive polydensified matrix hyaluronic acid injected at the initial treatment session were 1.46 ml in the left nasolabial fold and 1.47 ml in the right nasolabial fold. Of the 93 subjects who received initial treatment, 67 (72 percent) also received 2-week touch-up injections. Of these, 66 subjects received touch-up injections in both nasolabial folds and one subject received a touch-up injection in only one nasolabial fold. The mean volumes of cohesive polydensified matrix hyaluronic acid injected at the touch-up session were 0.93 ml in the left nasolabial fold and 0.90 ml in the right nasolabial fold.
No scarring events (0 percent), one mild hypopigmentation event (1.1 percent), and two mild hyperpigmentation events (2.2 percent) were observed during live physician assessments (Table 1). Adverse events were considered to be possibly, probably, or definitely related to study product in 77.4 percent of the subjects. Almost all of these were classified as general disorders and injection-site conditions. The most frequently reported of these (>50 percent) were injection-site swelling, injection-site induration, and injection-site pain.
Adverse events considered to be possibly, probably, or definitely related to the injection procedure were reported in 32.3 percent of the subjects. All of these were classified as general disorders and injection-site conditions. The most frequently reported of these (>10 percent) were injection-site bruising and injection-site discoloration. The majority of the injection-site reactions were less than or equal to 7 days in duration. These events were typical of dermal filler injections with respect to type, rate, severity, and duration.
The incidence of systemic adverse events was low (11.8 percent) and considered to be unrelated to treatment. These were generally conditions that could be expected in a healthy adult population (e.g., influenza, gingival abscess).
Effectiveness assessments included use of the Wrinkle Severity Rating Scale and the Global Aesthetic Improvement Scale. At all time points through 24 weeks, the evaluating investigators’ and treating investigators’ Wrinkle Severity Rating Scale ratings for Fitzpatrick skin types IV, V, and VI combined showed improvement in both the left and right nasolabial folds. The same was true regarding Global Aesthetic Improvement Scale ratings by subjects. Before-and-after images of patients with Fitzpatrick skin types IV, V, and VI, treated with hyaluronic acid with cohesive polydensified matrix are shown in Figures 1 through 3.
Although studies of persons with skin of color who have been treated with dermal fillers appear relatively infrequently, several recent studies have assessed the use of dermal fillers in Fitzpatrick skin types IV through VI.8–14 These studies have shown efficacy similar to outcomes observed in skin types I through III. Despite concerns for the development of keloids and hypertrophic scars, keloids and scarring have not been observed in clinical trials. In addition, the incidence of pigmentary changes (hyperpigmentation and hypopigmentation) has been none to mild. In a study of variable-particle-size treatments in persons with skin of color, for example, mild or moderate pigmentation changes were noted in 17 patients (of 150), most of which were not present 12 weeks after injection.15 Only three patients retained postinflammatory hyperpigmentation. These findings are similar to the ones described in our study. Although Belotero Balance was recently approved for treatment of nasolabial folds in the United States, there were minimal clinical data in the pivotal trials regarding its efficacy and safety profile in people of color. Investigators sought to address any issues of safety and efficacy as an extension of the safety and effectiveness profile of the cohesive polydensified matrix hyaluronic acid at large.
This study examined the safety of cohesive polydensified matrix hyaluronic acid injection for the treatment of nasolabial folds in 93 subjects with Fitzpatrick skin types IV, V, and VI. Although not previously demonstrated with the use of dermal fillers, subjects with Fitzpatrick skin types IV, V, and VI are considered to be particularly sensitive to hypopigmentation, hyperpigmentation, and scarring.6 However, in this study, the frequency of hyperpigmentation and hypopigmentation after implantation of cohesive polydensified matrix hyaluronic acid was low, and no scarring was observed. The most common events were injection-site reactions typical of dermal filler injections. No serious adverse events or deaths were reported. Cohesive polydensified matrix hyaluronic acid was also demonstrated to be effective in the treatment of nasolabial folds as judged by study physicians and study subjects. Our results corroborate previously published data assessing positive treatment outcomes in patients with skin of color.
In this study, injection of cohesive polydensified matrix hyaluronic acid for the treatment of nasolabial folds showed no evidence of association with hypopigmentation, hyperpigmentation, and scarring up to 24 weeks after injection. Therefore, in this study, cohesive polydensified matrix hyaluronic acid was safe and well tolerated in subjects with Fitzpatrick skin types IV, V, and VI.
The authors express their appreciation to David J. Howell, Ph.D. (San Francisco, Calif.), and Kali Ghazali (Los Angeles, Calif.) for their editorial contributions on behalf of this article.
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