Efficacy of a New Hyaluronic Acid Dermal Filler on Nasolabial Folds Correction: A Prospective, Comparative, Double-Blinded Clinical Trial

Abstract

BACKGROUND

Hyaluronic acid–based dermal fillers are the cornerstones of wrinkle correction and facial contour redefinition.

OBJECTIVE

To assess the efficacy and safety of EST_LF compared with RES_L for the treatment of nasolabial folds (NLFs).

MATERIALS AND METHODS

In this prospective, split-face, randomized, investigator and subject-blinded trial, 45 subjects with moderate-to-severe symmetrical NLFs were randomized to EST_LF on one side of the face and RES_L on the other side and were followed up for 9 months. The primary end point was change in WSRS score from the baseline to Month 1 (M1). Secondary end points included changes in WSRS score at other time points, aesthetic improvement, wrinkle volume quantification, adverse events, and local tolerance.

RESULTS

The efficacy difference between EST_LF and RES_L at M1 was in favor of EST_LF (−0.16, CI, −0.28 to −0.03]), demonstrating its noninferiority. Considering other time points, significant differences were observed at 3 and 6 months for EST_LF, assessed with WSRS, GAIS, or NLF volume quantification. Both treatments were well tolerated.

CONCLUSION

EST_LF is effective and well tolerated for the treatment of NLFs.

Dermal fillers have become the cornerstones of nonsurgical procedures to improve facial appearance, with hyaluronic acid (HA)-based preparations being the most frequently used for the correction of wrinkles and folds.

HA is a naturally occurring linear polysaccharide and an essential component of the extracellular matrix of all animal tissues.¹ In humans, the amount of HA in the skin decreases with age, which plays an important role in the appearance of wrinkles and aging features, resulting in decreased tissue volume, elasticity, and hydration. HA can bind 1,000 times its weight in water, which makes it an excellent substance for adding volume to the skin.²

Unmodified, natural HA has a half-life of approximately 24 hours before it is enzymatically broken down and metabolized.³ Chemical crosslinking of HA results in the formation of a viscoelastic polymer with improved resistance to enzymatic degradation, thereby prolonging tissue retention compared with natural HA. In addition, HA fillers may stimulate collagen synthesis and inhibit collagen degradation, which may further contribute to their long-duration effect.⁴

Several features differentiate the various HA fillers, including the type of crosslinking agent used, the degree of crosslinking, the percentage of crosslinked HA/amount of free (unmodified) HA present, and the viscoelastic properties.⁵ All these physicochemical attributes impact the clinical characteristics of each filler, such as clinical indication, ease of injection, projection capacity, longevity, clinical appearance, and side effects.⁶

ESTYME Fillers (Symatese, Chaponost, France) are new-generation HA dermal fillers, based on an innovative cold crosslinking process (C-HA PURE TECHNOLOGY by Symatese). This new technology, which is the subject of a patent application, induces less modification of HA, thus potentially enhancing the product's safety and providing more natural and long-lasting results to respond to patient satisfaction and physician needs. The aim of this study was to investigate the clinical efficacy and safety of ESTYME LIFT (EST_LF) in the correction of nasolabial folds (NLFs) up to 9 months after injection compared with a well-recognized HA-based dermal filler, Restylane Lidocaine (RES_L).

Materials and Methods

Ethical Approval

This investigation was conducted in accordance with the ethical principles initially outlined in the Declaration of Helsinki (1964) and the EN ISO standard 14155:2011. The study complies with local regulatory requirements, was registered at ANSM (n°2018-A00636–49), and received a favorable opinion from the CPP Sud Mediterranée (opinion 18.027). Informed consent was obtained from all subjects before the study procedures were conducted.

Study Design

This was a prospective, single-center, double-blind, randomized, split-face study conducted in France (Eurofins Dermscan-Pharmascan, Lyon, France) comparing the efficacy of a new HA-based dermal filler, hereinafter named EST_LF, versus RES_L, on the severity of NLFs.

On Day 0 (D0), a maximum of 2 mL of each product was randomly injected into the NLFs on each side of the subject's face to achieve an optimal aesthetic result. Safety and efficacy were assessed by the investigators and the subjects on D0, Day 14 (D14), Month 1 (M1), Month 3 (M3), Month 6 (M6), and Month 9 (M9) after injection.

To maintain a double-blind design, the study involved investigator injectors who performed all injections and a blinded evaluator–investigator who conducted the assessments.

Interventions

The investigational product, EST_LF, is composed of 22 mg/mL of HA gel and 0.3% lidocaine supplied in a 1.0-mL prefilled syringe.

The comparator, RES_L (Q-Med, Uppsala, Sweden), is composed of 20 mg/mL non–animal-derived stabilized HA (NASHA) and was also supplied in a 1.0-mL prefilled syringe.

The route and mode of injection as well as the injected volume were chosen at the injector's discretion based on the characteristics of the defect under correction. The same injection technique was used for the 2 products on the same subject.

Participants

Study participants were healthy adults aged between 30 and 70 years with approximately symmetrical NLFs on each side of the face, each fold scoring 3 (moderate) or 4 (severe) on the validated Wrinkle Severity Rating Scale (WSRS).⁷

Pregnant, parturient, or nursing women or those planning a pregnancy during the study, subjects with a known history of allergic reactions, including to one of the product components, and those suffering from any pathology that may interfere with the evaluation of the study results were excluded from the study. Subjects who underwent NLF correction with nonpermanent fillers or neurotoxins within 18 months before or those who received a permanent filler on the mid-face at any time were also excluded. Other main exclusion criteria included subjects who received anticoagulant, antiplatelet, or thrombolytic medication during the week before the injection session; chemotherapy agents; immunosuppressive medications or systemic corticosteroids within 3 months of enrollment; or high-dose amide-type anesthetics during the week before the injection session.

Assessments

Efficacy assessments were performed by a blinded evaluator–investigator using the WSRS on D0 before injection and on D14, M1, M3, M6, and M9 after injection.

NLF improvement was also evaluated by the subjects and the blinded evaluator–investigator using the Global Aesthetic Improvement Scale (GAIS) on D14, M1, M3, M6, and M9 after injection, on a 5-point scale from very much improved (1), much improved (2), improved (3), no change (4), to worse (5).

Wrinkle volume was measured for each NLF using the fringe projection system DermaTOP (Eotech, France) on D0 before treatment and at each time point.

Safety was evaluated on D0 before and immediately after injection and at each visit by the investigator, who examined each injected zone and side of the face for side effects and rated local tolerance using the Injection Site Reactions (ISR) scale (0: none, 1: mild, 2: moderate, 3: severe). General tolerance was assessed by reporting adverse events (AEs) and adverse device effects (ADEs) at each time point. ISRs that are unexpected (because they appeared a long time after injection or because they last more time than usual e.g.) will be reported as adverse events. The subjects completed a daily diary using the same scoring from D0 before injection to D14 visit.

Measures and End Points

The primary efficacy end point was the change in the WSRS score from the baseline to M1, assessed live by the blinded evaluator–investigator. Secondary efficacy end points included the following: (1) change in WSRS score from the baseline at the other time points, (2) change in GAIS score on each side of the face assessed by the blinded evaluator-investigator and the subjects, and (3) change in volume of NLFs from the baseline at each follow-up visit.

Safety end points were (1) the proportion of subjects presenting ISRs (redness, pain/tenderness, induration/firmness, swelling, lumps/bumps, bruising, itching, and discoloration) at each time point, as assessed by the investigator on the ISR scale; (2) the maximum duration and the maximum intensity of ISRs between D0 after injection and D14, as assessed by the subjects on the ISR scale; and (3) the percentage of subjects experiencing at least 1 AE or ADE at each time point.

Statistical Analysis

Analysis of the primary end point was performed on the per-protocol (PP) population, corresponding to any subject who had used the tested product at least one time and had not presented any major protocol deviation. Analyses of the secondary end points were performed both on the intention-to-treat (ITT, corresponding to all randomized subjects) and the PP populations. Analyses of the safety end points were performed on the safety population, which included any subject who had used the tested product at least one time.

Descriptive statistics (mean, median, SD, and minimum and maximum values) were used for analyses of quantitative data by visit point for each product.

The primary end point (change in WSRS score at M1) was analyzed with a covariance (ANCOVA) model with treatment and side as fixed factors, subject as a random factor, and value at the baseline as covariate. The mean between-treatment difference (EST_LF vs RES_L) was calculated with a two-sided 95% confidence interval (CI); the treatment was considered to be noninferior if the upper bound of the CI was <0.5 in both the ITT and the PP populations.

A paired Student test was used to compare the change in the WSRS score and wrinkle volume between the 2 products from the baseline at the other time points (secondary end points 1 and 3). In case of strong deviation, a Wilcoxon signed-rank test was used.

Change in GAIS score (secondary end point 2) was analyzed with a Wilcoxon signed-rank test to compare the 2 products. In addition, for each time point, the proportion of subjects with an improvement was computed and presented by product.

All statistical tests were evaluated at a 5% level of significance in a bilateral approach using Microsoft Excel and SAS GUIDE version 9.4.

Results

Subject Disposition

A total of 45 subjects were screened and randomized to receive the investigational products. All subjects completed the whole study period and thus formed the full analysis set (FAS). The ITT, PP, and safety populations all comprised the 45 subjects enrolled in the study. One subject missed evaluation on D14 because of a serious adverse event (SAE) not related to the investigational products. The subjects were predominantly women (84%) with ages ranging from 37 to 70 years (mean: 58 years). On average, each subject received 0.9 mL of product on each side of the face, with no significant difference in the injected volume between the 2 sides.

Primary Efficacy Outcome: Change in WSRS Score at Month 1

Mean WSRS scores were similar between the 2 product groups at the baseline (3.6 ± 0.5). After 1 month, mean WSRS scores significantly improved by 1.0 ± 0.6 for EST_LF and by 0.9 ± 0.6 for RES_L. The difference of changes between EST_LF and RES_L adjusted on the baseline was in favor of EST_LF with a result of −0.16 (CI: −0.28 to −0.03), demonstrating the noninferiority of EST_LF compared with RES_L (p < .001).

Secondary Efficacy Outcomes

Change in WSRS Score at the Other Time Points

Mean WSRS scores significantly improved for both products at all time points as compared with the baseline (Figure 1). When comparing the 2 products, mean WSRS scores were similar throughout the study period, except at 3- and 6-month follow-ups, where EST_LF exhibited greater clinical improvement in NLF severity than RES_L. The results were statistically significant (p = .018 and p = .037, respectively).

Figure 1.

Mean blinded evaluator–investigator-assessed wrinkle severity scores. WSRS improvement was defined as the NLF severity reduction compared with the baseline according to WSRS assessment. *p < .05 for the comparison between EST_LF and RES_L. WSRS, Wrinkle Severity Rating Scale.

Change in GAIS Score

Both treatments resulted in similar improvements in NLFs throughout the study (Figure 2). However, for the blinded evaluator–investigator, the comparison of the mean of GAIS assessment between the 2 products was significantly in favor of EST_LF at M3 and M6 (data not shown).

Figure 2.

Blinded evaluator–investigator and subject-assessed aesthetic improvement (GAIS). The responder rate was defined as the percentage of subjects who were assessed as either “very well improved,” “well improved,” or “improved” on the GAIS. GAIS, Global Aesthetic Improvement Scale.

When rated by the subjects themselves, both treatments led to a similar improvement in NLFs throughout the study period without any statistically significant difference between the products, regardless of the time point (Figure 2). Improvement was maintained up to 9 months after injection with 82% of subjects reporting an improvement of their aesthetic appearance with EST_LF and 78% with RES_L, which was slightly lower than the ratings of the blinded evaluator-investigator.

Wrinkle Volume Quantification

On D0 before injection, the mean volume of NFLs was similar between the 2 face sides (p = .6857). After injection from D14 to M9, the mean wrinkle volume improved significantly, meaning a decrease in NLF appearance compared with the baseline for both products (Figure 3). It should be noted that with the same injected volume, a statistically significant difference in NLF volume was observed between the 2 products at M6 in favor of EST_LF (p = .038).

Figure 3.

Wrinkle volume quantification of nasolabial folds. Wrinkle volume improvement was defined as the volume loss in NLFs compared with the baseline measured with DermaTOP. *p < .05 for the comparison between EST_LF and RES_L. ELF_LF, ESTYME LIFT; NLF, nasolabial fold; RES_L, Restylane.

Safety

Injection Site Reactions

Both products induced expected predefined ISRs on D0 after injection, the most encountered signs on both sides being redness (69% with EST_LF vs 76% with RES_L, p = .083), lumps/bumps (56% with EST_LF vs 44% with RES_L, p = .132), and induration/firmness (38% with EST_LF vs 33% with RES_L, p = .317). A few subjects also presented pain/tenderness, swelling, and itching. Only a few signs (induration/firmness, lumps/bumps) persisted up to D14, with no significant difference between the products. Most reactions resolved within 2 days and were low in intensity, except induration/firmness that lasted longer (6.11 ± 5.33 days with EST_LF vs 3.76 ± 3.94 days with RES_L, p = .044) and was assessed by the subjects as of mild-to-moderate intensity, regardless of the product.

Adverse Events and Adverse Device Effects

Overall, 69% of subjects reported 94 AEs during the study, of which 42 AEs were related or possibly related to the studied devices (ADE). Two SAEs not related to the study products were reported in 2 subjects.

Overall, 49% of subjects experienced at least 1 ADE during the study. ADEs were mild (84%) or moderate (16%) in intensity and resolved at the end of the study. Except for 1 application site folliculitis reported with RES_L, all ADEs were expected general disorders and concerned administration site conditions (induration, nodule, pain, inflammation, edema, hematoma, or pruritus).

Discussion

A large number of HA fillers are commercially available and differ in their technology, sources of material, formulations, and manufacturing processes. This study is the first to investigate the efficacy and safety of a new HA-based dermal filler, made from an innovative technology that improves the crosslinking efficiency of the HA chains, in comparison with RES_L for the correction of moderate-to-severe NLFs. The efficacy of EST_LF was confirmed with statistical noninferiority to RES_L treatment demonstrated at 4 weeks after injection. The difference in changes between EST_LF and RES_L was in favor of EST_LF (−0.16, CI: −0.28 to −0.03). Interestingly, the confidence intervals suggest the superiority of EST_LF. Improvement of NLF severity was sustained throughout the study period with EST_LF displaying a significantly higher efficacy over RES_L at M3 and M6. Wrinkle volume quantification of NLFs confirmed the filling effect of both products from injection to the end of the study (M9). This more objective approach also supported a significantly higher performance at M6 in favor of EST_LF. Notably, with similar injected volumes, subjective and quantitative methods revealed a better performance of EST_LF.

This efficacy was also supported by a high degree of aesthetic improvement according to the blinded evaluator-investigator and the subjects. Improvement in aesthetic appearance, as assessed by the blinded evaluator-investigator, was significantly higher at M3 and M6 for EST_LF subjects than for RES_L subjects.

EST_LF and RES_L presented similar safety profiles in this study. Only usual and expected local side effects were observed, and all ISRs were transient, mild, and low in intensity.

These results are consistent with those of previous studies evaluating HA-based dermal fillers that were shown to provide excellent aesthetic outcomes with high patient satisfaction and a low incidence and severity of complications.^8–12 The safety of EST_LF has been assessed up to 9 months after injection. Long-term safety of HA-based dermal fillers has been extensively studied, and those were proven to be safe with no treatment-related AEs occurring 12 to 24 months after injection. The complications resulting from dermal filler injections have been suggested to be directly related to the injection site technique rather than the type of HA filler.^13,14

In this study, EST_LF was compared with RES_L, which is a well-established option for antiwrinkle treatment and has been used in various trials as a reference treatment to investigate the clinical efficacy of other HA–based fillers.^15–19 RES_L and EST_LF present several similarities in terms of composition, biocompatibility, and indication. Despite these similarities, EST_LF displayed a distinct efficacy profile with significantly higher durable improvement in NLFs after 3 or 6 months that could be attributed to a heightened level of cohesiveness and controlled hydrophilicity.² The physicochemical properties of EST_LF will be reported and discussed in a separate publication to provide a further understanding of the product's performance.

EST_LF is not approved in the United States. This study demonstrated the excellent performance and safety profile of EST_LF allowing it to be authorized in Europe for NLF correction. These positive outcomes are encouraging for the development of other products based on the same innovative technology and designed for dedicated indications.

Conclusions

In this study, EST_LF was shown to be well tolerated and effective for the treatment of moderate-to-severe NLF. The primary end point of non-inferiority was met against a well-known HA control, with the results favoring EST_LF.