Restoring long‐lasting midface volume in the Asian face with a hyaluronic acid filler: A randomized controlled multicenter study

Hyaluronic acid (HA) filler treatment is a minimally‐invasive alternative to surgery to volumize the cheeks. HAVOL (Restylane® Volyme) is a flexible HA filler suited to contouring and volumizing the midface.

2][3][4][5][6] A gel from the Restylane ® range of fillers, Restylane Volyme (HA VOL ), previously known as Emervel Volume Lidocaine, recently received marketing approval in China for midface volume deficit and/or midface contour deficiency treatment.This is an HA filler produced using OBT™ technology, which creates soft (low G') and flexible (measured by xStrain) characteristics that are optimized to volumize dynamic areas of the face such as the midface.This filler has also been approved in the United States, 7 under the brand name Restylane Contour, for cheek augmentation and correction of midface contour deficiencies after demonstrating effectiveness in a predominantly Caucasian population. 8Other Restylane products approved for midface in China include Restylane Lyft Lidocaine, since 2021. 9nce HA fillers may have different risks or clinical performance across populations, it is important to study these in an Asian population. 10Facial architecture has been shown to differ between women of different ethnicities 11 and the anatomy and aesthetic goals of an Asian patient may differ from a Caucasian patient when it comes to midface volumization. 12Furthermore, in Asian individuals, gravitational soft-tissue descent of the midface can be greater with aging compared to other ethnicities due to their delicate facial skeletal framework. 13To support registration of the product (HA VOL ) in China, a study was performed to evaluate its effectiveness and safety in an Asian population for midface volume deficit and midface contour deficiency, and the results are presented herein.

| Study design
This was a randomized, evaluator-blinded, no-treatment controlled clinical investigation (NCT03289052) to evaluate the effectiveness and safety of treatment with HA VOL for correction of midface volume deficit and midface contour deficiency.The study was conducted at five centers in China between December 2017 and July 2019.The study was designed with a no-treatment control since no dermal filler products were approved for midface treatment in China at the time.
The study was approved by independent ethics committees, conformed to the Declaration of Helsinki, and was conducted in compliance with Good Clinical Practice.Subjects provided signed informed consent for participation.

| Study population
Chinese men and women aged 18 years or older seeking augmentation therapy for the midface with a Medicis Midface Volume Scale (MMVS, a four-point midface scale) score of 2, 3 or 4 (mild-tosubstantial volume loss) on each side of the face as assessed by the blinded evaluator were eligible.MMVS scores needed to be similar on both side of the face or differ by no more than 1 grade.
Subjects were excluded if they had active skin disease, scars or deformities, inflammation or related conditions near or in the area to be treated; had undergone previous permanent/semipermanent implant or filler treatments below the lower orbital rim; tissue revitalization treatment in the midface in the past 6 months; or had undergone neurotoxin treatment during the prior 9 months or HAor collagen-based therapy for facial tissue augmentation below the lower orbital rim within the prior 12 months.

| Treatment
Eligible subjects were randomized 3:1 to treatment with HA VOL or to no treatment (control) (stratified by center).The treating investigator did not disclose treatment information to the blinded evaluator.Subjects randomized to HA VOL were injected with the product at baseline and could receive optional touch-up injections 4 weeks later; the control group received no treatment at baseline but was offered treatment at 6 months as well as optional touch-up 4 weeks later.
Both sides of the midface were injected with HA VOL (containing 20 mg/mL HA and 3 mg/mL lidocaine hydrochloride) inferior to the maxillary prominence and superior to the nasal alae, including the area from the lateral canthus to the medial canthus and lateral to the nose.Injections were made at subcutaneous to supraperiosteal depth with a volume necessary for optimal aesthetic results.A maximum volume of 2 mL per side of the face was recommended.
The follow-up period after initial treatment including touch-up was 12 months after the last treatment.

| Outcome assessments
The objectives of the study were to evaluate effectiveness and safety of HA VOL in the treatment of midface volume deficit and/or midface contour deficiency.The primary effectiveness endpoint was percent responders, defined as at least 1-point improvement from baseline (on both sides of the face concurrently) on the blinded evaluator-assessed MMVS at 6 months after last injection for the treatment group, and after randomization for the control group.Volume change over time combining both sides of the midface was measured by digital 3D photography using the Vectra H1 imaging system and a validated method by Canfield Scientific Inc.The volume change was calculated by skin surface change before and after treatment in a defined area of interest at 1, 3, and 6 months for both groups, and additionally at 9 and 12 months after last treatment in the HA VOL group.Also, aesthetic improvement of midface fullness for both sides combined was evaluated.Aesthetic improvement (i.e., "improved," "much improved," or "very much improved") was based on the 5-graded Global Aesthetic Improvement Scale (GAIS), as assessed by the subject and treating investigator, respectively, at all follow-up visits.
Lastly, subject satisfaction was assessed at 3, 6, 9, and 12 months after last treatment in the HA VOL group, and 3 and 6 months after randomization in the control group.
Safety was evaluated by standard collection of adverse events (AEs) during the entire study and subject-reporting of predefined expected post-treatment events (swelling, bruising, erythema, itching, pain, and tenderness) for 4 weeks after each treatment.

| Statistical methods
Three analysis populations were defined for the study.The safety population was all subjects who were treated with HA VOL or randomized to the untreated group (analyzed according to the as-treated principle); the full analysis set (FAS) represented all subjects who were treated with HA VOL or randomized to the untreated group and analyzed as randomized was the primary population for all effectiveness analyses; and the per protocol (PP) analysis set was all subjects included in the FAS with no deviations from the protocol that could affect the primary variable.Statistical analyses were done using the SAS ® system version 9.4.
For comparison of the primary effectiveness endpoint (treatment group vs. control group), Fisher's exact test was used.
Missing values at Month 6 were imputed using the baseline observation carried forward method.Treatment was deemed successful if the p-value was <0.05, if the estimate of the percentage of responders among the HA VOL -treated subjects at 6 months was ≥0.60, and if it had a 95% CI lower limit of >0.50.In order to assess the robustness of the primary endpoint analysis, a logistic regression model was utilized including baseline MMVS and treatment group as factors.In addition, a sensitivity analysis was performed by rerunning the primary analyses based on the PP analysis set.
Response rates for secondary endpoints at different timepoints were compared using Fisher's exact test.Descriptive statistics were used for volume change, GAIS response rates, and safety variables.

| Subject population and treatment
In total, 148 subjects who met the selection criteria were randomized as follows: 111 to HA VOL and 37 to the no-treatment control.
The two groups were comparable in terms of demographics, with an overall mean age of 41 years and a majority of females (92%) in the study population.Baseline MMVS scores indicated mild or moderate loss of fullness on both sides of the face for most subjects at study entry (Table 1).Details of the volumes of HA VOL injected are presented in Table 2.For subjects randomized to HA VOL , the mean total volume injected was 3.4 mL, divided into an average of 3.0 mL administered to 111 subjects at Day 1 (initial treatment) and 2.1 mL to 26 subjects at the 4-week touch-up.

| Effectiveness
At 6 months, there were statistically significantly more responders in the HA VOL group than the untreated control group in the treatment of midface volume deficit and midface contour deficiency as measured by MMVS by the blinded evaluator (approximately 76% vs. 8%, respectively; a difference of 68% [CI: 55.7%-79.4%],p < 0.0001) (Figure 1).Therefore, the primary objective of this study was met, which was to demonstrate superiority of HA VOL to no treatment.The results were similar when repeating the analysis in the PP population and after correction for baseline values.
Results of the secondary effectiveness objectives also favored the HA VOL group.Based on the blinded evaluator assessments, HA VOL was statistically significantly more efficacious (87%) in terms of MMVS responder rate versus no treatment (6%) at 3 months after the last injection (p < 0.0001).This was followed by responder rates of 63% and 51% at months 9 and 12, respectively, for the HA VOL group.Figure 1 illustrates the MMVS responder rates over time for the blinded evaluator.Results were similar for the treating investigator: statistically significant MMVS responder rate differences were in favor of HA VOL at 1 (99% vs. 0% for control), 3, and 6 months after last treatment (both 87% vs. 3%) (all p < 0.0001).Improved MMVS for HA VOL continued past the controlled period of the study at 9 and 12 months after last treatment (77% and 59%, respectively, according to the treating investigator).
Regarding volume change over time by digital 3D photography (both sides of midface combined), HA VOL treatment resulted in an increase in midface volume by 3.6 mL at 1 month.After 3 months, it remained overall stable through the end of the study (Figure 2).
There was sustained volume change at 6 and 12 months after last treatment, as a high proportion of volume increase remained (83% and 78%, respectively) when compared to that achieved at 1 month.
Consistent with MMVS results, the GAIS scores showed aesthetic improvement in at least 96% of subjects at 1 month after last treatment with HA VOL , both when assessed by the subjects and by the treating investigators.Moreover, at least 89% and 80% of subjects were still improved at 6 and 12 months, respectively (Figure 3).Clinical photographs of improvement are shown in Figure 4.
The majority of subjects treated with HA VOL were satisfied with the treatment result overall (>97%), reported a natural look (>94%) and looking younger (>66%), and that the treatment had met or surpassed their expectations (>82%) and allowed them to feel more TA B L E 1 Baseline characteristics.attractive (>76%) through 12 months.At least 89% of treated subjects reported feeling better about themselves, and a high proportion would recommend the treatment to friends (>95%) and would receive the same treatment again (>91%).

| Safety
Overall, HA VOL was well tolerated with few related AEs; two subjects (1.4%) experienced four related AEs (implant site swelling, three mild and one moderate event) which resolved by the end of the study.No unexpected AEs related to HA VOL occurred and there were no treatment-related serious AEs.Based on subject diary collection of predefined, expected post-treatment events after each treatment, events were transient and mostly mild or moderate in intensity, and the most commonly reported were swelling and tenderness.F I G U R E 3 GAIS responder rate (both sides combined) for subjects randomized to HA VOL as assessed by treating investigators and subjects (FAS).
Responder is defined as a subject with a GAIS rating of at least "improved".
volume still remained (83% and 78%, respectively) when compared to the volume achieved at 1 month.Additionally, HA VOL was well tolerated, and there were no unanticipated product-related AEs.Flexible fillers are adapted to dynamic areas of the face, as supported by a pilot study evaluating facial expressions. 14Our current findings of increased midfacial volume align with these previous results, and suggest that HA VOL as a flexible gel is effective and optimal for treating large dynamic areas such as the cheek and midface.
The current results among Chinese subjects are consistent with previous studies of HA VOL supporting safety and long-lasting performance in the cheeks or midface among mainly Caucasians.A randomized, evaluator-blinded, parallel-group, multicenter study compared HA VOL to Juvéderm Voluma XC as the control in cheek augmentation. 8at study demonstrated noninferiority of HA VOL based on MMVS change from baseline at 3 months and showed maintained improvement and high subject satisfaction through 12 months.Another trial reported that 97% of subjects treated with HA VOL were improved on the MMVS (≥1-point improvement) as assessed by investigators through 6 months. 6The responder rate was confirmed as high (90%) when assessed by blinded evaluation at 2 months, which is similar to the MMVS responder rate found in the current study at 3 months (87%).
6][17] When assessing the long-term performance of HA VOL for full-facial volume restoration (i.e., not limited to cheeks), over 60% of volume was sustained at 18 months compared with optimal correction in 60 subjects using 3D imaging. 17HA VOL was used almost exclusively for cheek enhancement in a 6-month study conducted at French and German centers among 77 participants. 15gh subject satisfaction was reached, with the majority (80%) satisfied with the durability of the results.Another study using HA VOL in 56 subjects indicated that approximately 68% of cheek volume was preserved at 6 months compared to optimal correction. 16An open label study over 2 months showed high improvement in cheek augmentation and natural results after treatment with HA VOL . 18The common use of HA VOL in cheek augmentation is also highlighted in a prospective multicenter observational survey of 58 physicians using a range of OBT fillers to treat 1822 subjects. 19Our study combines the rigor of a multicenter RCT with the multiple perspectives of subject-reported outcomes, blinded and unblinded clinicians' evaluations, and objective measures, to confirm the safe and effective use of HA VOL in treatment of cheeks and midface in an Asian population.
To conclude, the results demonstrated that HA VOL was well tolerated and effective for midfacial treatment in a Chinese population, with MMVS results as measured by the blinded evaluator lasting through 6 months and sustained in 51% of subjects at 12 months, and high subject satisfaction throughout the study.In addition, results of this study are comparable to those on effectiveness and safety of HA VOL in previous studies conducted in non-Asian populations.

AUTH O R CO NTR I B UTI O N S
RR, HZ, HX, ZG, HW, XX, and YQ were investigators in the clinical study, and reviewed and approved the content of the manuscript.
TB and BA contributed to data interpretation, and reviewed and approved the content of the manuscript.BA contributed to study design.All authors agree to be accountable for the work.

ACK N OWLED G M ENTS
The authors would like to thank Galadriel Bonnel, PhD, RN, FNP, for editorial assistance.

FU N D I N G I N FO R M ATI O N
Galderma funded the study and provided the study products.

CO N FLI C T O F I NTE R E S T S TATE M E NT
RR, HZ, HX, ZG, HW, XX, and YQ were investigators in the clinical study.HW and HZ have received honoraria for lectures from Galderma China.TB and BA are employees of Galderma.

| 1987 REN
et al.Secondary effectiveness endpoints included percent responders on the MMVS as measured by the blinded evaluator at 3, 9, and 12 months after last treatment (3 months after randomization for the controls), and by the treating investigator at each visit.

TA B L E 2
Volume of HA VOL injected.F I G U R E 1 MMVS responder rate (both sides combined) by blinded evaluator (FAS);*p < 0.0001; Responder is defined as a subject with at least one grade improvement on the MMVS from baseline on both sides of the face; Missing values at Month 6 are imputed using baseline observation carried forward.Observed cases are used at Months 3, 9, and 12.

4
| DISCUSS ION HA VOL in Chinese subjects led to improved midface results as appreciated both by clinicians (including blinded evaluators) and subjects throughout this study with a 12-month follow-up.The primary effectiveness objective was met: HA VOL was shown to be superior to no treatment at 6 months (p < 0.0001) for midface volume deficit and midface contour deficiency as measured by MMVS.Likewise, improved aesthetic appearance of midface fullness (as measured by the GAIS) was noted up to 12 months by subjects and treating investigators, as well as high subject satisfaction.Volume change captured by 3D photography increased after 1 month to 3.6 mL, which was close to the total injected volume of 3.4 mL.Midfacial volume subsequently decreased with product degradation as can be expected.Nevertheless, improvement was sustained compared to baseline; at 6 and 12 months after last treatment, a high proportion of F I G U R E 2 Volume change over time based on 3D photography (FAS).

F I G U R E 4
Clinical photographs of a female subject, 44 years old, before and at different timepoints following treatment with HA VOL .The subject was injected at supraperiosteal depth with 1.5 mL HA VOL on each side of the face at baseline (no touch-up treatment).Blinded evaluator MMVS assessments.(A) baseline, MMVS: 2; (B) Month 3, MMVS:1; (C) Month 6, MMVS: 1; (D) Month 12, MMVS: 1.