Comparative Clinical Study For The Efficacy And Safety Of Two Different Hyaluronic Acid-based Fillers With Tri-Hyal Versus Vycross Technology: A Long-term Prospective Randomized Clinical Trial Part 1
Jun 27, 2023
Abstract
Background: Hyaluronic acid-based fillers have an immediate volumizing effect for the treatment of dermal contour deformities and to smooth dermal depressions formed by the loss of volume. A previous study in 2016–2018 has shown the efficacy and safety of the HA-based filler ART FILLER® Volume on the midface only, but not in a comparative manner.
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Methods: In this context, an 18 months prospective randomized single-blind study of the non-inferiority of ART FILLER® Volume versus the reference product Juvéderm Voluma® was performed on the midface, temple, and jawline, and a non-comparative study on the chin. The efficacy and longevity were evaluated for the selected face areas via dedicated clinical scoring systems after a single filler injection without any re-touch or re-injection. The short- and long-term adverse effects were also recorded.
Results: The observations confirmed the non-inferiority of ART FILLER® Volume versus the reference product on the different injected areas. For both fillers, the beneficial effects on volume restoration were maintained 18 months post-injection; however, these effects were diminished over time. Furthermore, injections of Art Filler® Volume were well tolerated by the subjects and showed less acute side effects compared with the reference product which may be explained by a lower induction of inflammation.
KEYWORDS
anti-aging, facial injections, fillers, hyaluronic acid, skin rejuvenation
1 | INTRODUCTION
In the face region, aging is characterized by a loss of skin volume, particularly due to a decrease and a redistribution of fat, as well as dermal atrophy due to a reduction in collagen production by fibroblasts. Thus, preventing the loss of subcutaneous fat or the decrease in dermal thickness represent interesting strategies to counter the apparent aging of the face. The use of skin fillers is one of the most frequently used techniques to seek face rejuvenation. It allows the augmentation of soft tissues, the filling of wrinkles, and the treatment of superficial defects.1
Hyaluronic acid (hyaluronan or HA) is present in the extracellular matrix of the skin dermis and is a commonly used injectable dermal filler showing excellent efficiency to maintain tissue augmentation for about 6–9 months.2 Once injected into the skin, HA forms a viscous matrix thanks to its chemical properties based on its coiled structure in an aqueous solution. These characteristics allow HA to trap about 1000-fold of its weight in water, making HA an important player in tissue structure and volume.3 In addition to improving skin moisturizing and its antioxidant potential, Chunlin Ke et al. proved in 2011 that HA promotes skin cell regeneration and stimulates the production of collagen by dermis fibroblasts.4
Due to its short half-life in natural form (about 24–48 h),5,6 HA is chemically stabilized by a crosslinking process; the most used crosslinking agent is BDDE (1,4-butanediol diglycidyl ether). Depending on the molecular weight of the HA, the process, and the degree of crosslinking, the modified HA molecules convert into a highly viscous and insoluble gel that can be used for skin filling. These rheological characteristics of the HA gel determine its clinical effects and its longevity within the skin.
Hyaluronic acid is a natural linear polysaccharide presenting the advantage of not inducing immune responses. Therefore, adverse effects due to HA-based dermal fillers are in most cases minor and occur principally in a few hours or days post-injection. Apart from these immediate reactions at the injection sites that rapidly resolve, the tolerance to HA-based fillers is very good, and more serious events are exceptional.7
The ART FILLER® Volume (Laboratoires FILLMED) is an injectable HA-based filler indicated for the restoration of the volumes of the face, by subcutaneous injection, supra-periosteal, or in the deep dermis. This filler is characterized by the Tri-Hyal Technology combining 3 different structures of HA (free HA, long, and very long chains). It contains also 0.3% of lidocaine hydrochloride for its anesthetic properties. This concentration is used by many fillers on the market for several years and has no impact on tolerance and effectiveness with a significant benefit in terms of reducing the pain sensation during injections.8,9 However, based on the European Medical Devices Regulation, such a product needs a longitudinal performance, safety, and clinical benefits evaluation. Thus, to evaluate these parameters for ART FILLER® Volume, a randomized prospective and comparative study was conducted to evaluate the aesthetic performance of this product on the most frequently treated areas on the face, as well as their immediate and long-term tolerance. This study aims to document the filling capacity of ART FILLER® Volume, in comparison with a product presenting similar characteristics and considered as a reference, Juvéderm® Voluma (Allergan).10,11 The main objective of this study was to measure the restoration of the midface, temple, and jawline from baseline to 21 days post-injection and compared it with the reference product. The restoration of chin volume was also evaluated without comparison to the reference. The secondary objectives were to evaluate the long-term efficacy of the volume correction on the different face zones over 540 days (18 months), as well as to compare the safety and tolerance of ART FILLER® Volume and Juvéderm Voluma®.
2 | MATERIALS AND METHODS
2.1 | Test items and injection procedure
ART FILLER® Volume is a crosslinked HA of non-animal origin containing 0.3% of lidocaine hydrochloride for anesthetic properties and phosphate buffer at pH = 7.2. The gel is pre-filled in a 1.2 ml graduated disposable syringe. The reference product Juvéderm® Voluma presented the same characteristics as the HA gel and was used in a pre-filled 1 ml graduated syringe.
The same amount for each product was injected into the subjects via one single supra-periosteal bolus injection with a 27G1/2 (13 mm) TSK® needle or a 25G/55 mm cannula (SoftFil®). Each side of the face received either one or the other product according to the randomization, except for the chin where only ART FILLER® Volume was injected. The injection sites were determined randomly. The amount of product injected varied according to the deficit to be corrected, but a maximum of 1.2 ml was authorized to be injected for the midface, 1.2 ml for the temples, 1.2 ml for the jawline, and 1.0 ml for the chin (Figure 1B).
2.2 | Population
The pre-selection of the subjects (D-120 to D-7) was carried out by the SYRES company or the investigators according to the inclusion/non-inclusion criteria. Briefly, they were male or female aged 19 years or more, a Fitzpatrick Phototype I to IV, having a score of ≥2 on the Global Aesthetic Scale scoring on at least one area of interest. The eligible subjects received general information on the study scheme (Figure 1A). The subjects who were interested were then invited to proceed to the inclusion/randomization visit (D-7 to D0). During this visit, the baseline evaluation was performed by the investigators in the 5 selected centers. For some subjects, high-frequency ultrasound imaging was performed at GREDECO for this baseline visit. In total, 98 subjects were enrolled in this study. For each follow-up visit (D21, D90, D180, D270, D360, D450, and D540), the per-protocol population (PP) was defined by all the subjects seen at this visit and having an evaluation from the global aesthetical score. The study design is shown in Figure 1. The safety population includes all subjects enrolled and for whom at least one injection of one of the studied products has been performed.
2.3 | Evaluation criteria
The Global Aesthetic Clinical Score (GACS)12 was used for the main criteria of the study and was assessed at each visit for each injected area by the clinician in front of the subjects. This scoring system contains 7 grades scale, from 0 to 3 points with 0.5 point interval (1 grade). The score 0 represented no sagging or no volume loss and score 3 represented extreme sagging or extreme volume loss. In addition, the Medicis Midface Volume Scale (MMVS), Allergan Chin Retrusion scale, Allergan Temple hollowing scale, and Narins Jawline Scale were used to double the check for the evaluation of the secondary criteria. These different scales have been previously validated and published.13–16
2.4 | Ex vivo procedure
The skin explants were from donors (women between 32 and 49 years old) undergoing abdominoplasty surgery. A sterile microprobe (CMA/20) with a semi-permeable membrane (threshold 20 kDa) was inserted in the dermis of the skin explants to analyze the dermic interstitial fluid. The probe was continuously perfused (3 μl/min) with a sterile physiological buffer allowing a concentration gradient between the extracellular fluid and the inner part of the probe. After 1 h of stabilization (basal levels), the fillers were injected, and the perfusion liquid was collected each hour for 24 h. The concentrations of IL-8, TNF-α, and histamine in the harvested perfusates were evaluated by standard ELISA technics using specific commercial kits.
2.5 | Safety evaluation
Emerging local and general incidents during and after injections were reported by the subjects in a diary completed over the study and by the physicians who performed the injections during the entire follow-up period of the subjects. Evaluation of the appearance and the adverse events of the treated areas were collected at each visit through interrogation and clinical examination. The adverse events were classified as mild, moderate, and severe according to the intensity reported by the subjects. The causality of an AE about the Investigational Product(s) as a whole was categorized by the clinicians as certain, likely, possible, and excluded.
2.6 | Ethics statement
FILMED Laboratories submitted this protocol to the Ile de France V CPP (Ethics Committee) (St Antoine Hospital, 284 rue du Faubourg Saint Antoine, 75 012 Paris). This study was set up in the investigation centers only after obtaining the favorable opinion of this committee.
2.7 | Data analysis
The basal values and the values of the follow-up were calculated for each of the 4 treated zones and each treatment. A satisfactory correction was defined by a decrease of at least one grade (0.5 points) on the GACS scale. The success percentage was calculated by the ratio of satisfactory responses in each treated area to all PP populations. The non-inferiority comparisons were performed on paired data: a Wald confidence interval (CI) was constructed to compare the responder rate between treatments. The non-inferiority of ART FILLER® Volume for one area was concluded if the lower confidence limit was > −15% the lower confidence limit of Juvéderm® Voluma. The mean and the standard deviation changes in scores between D0 and the following days were calculated. The statistical significance of the evolution of the scores was calculated by a Wilcoxon test.
3 | RESULTS
3.1 | Population and subject disposition
In total, 98 subjects were enrolled in this study, 6 males and 92 females were included with an average age of 54.7 years old. Within this intention-to-treat population, 69% had no history of aesthetic treatment, and 20% had been previously submitted to an HA injection. The subject's weight was recorded before injection and during the study to follow their body mass index (BMI). They were injected in the different face areas by aesthetic surgeons at five different centers (Figure 1B). Among them, 56 subjects were injected on the midface, 72 for the jawline, 33 for the temple, and 25 for the chin. There was the possibility to inject a maximum of two zones per subject according to her/his need. During the study, seven subjects stopped voluntarily the study before the last evaluation visit.
3.2 | Evolution of the Global Aesthetic Clinical Score (GACS) and the success rate
The main objective of the study was to quantitatively measure the restoration of the chin, midface, jawline, and temple volumes after a single injection of ART FILLER® Volume versus the reference product Juvéderm® Voluma (except for the chin where only ART FILLER® Volume was injected). For each area, the volume restoration was assessed according to a Global Aesthetic Clinical Score (GACS), which determines the severity of the volume loss. As shown in Figure 2, the ART FILLER® Volume injection induced a significant reduction of the score for all areas after 21 days. Each injected area started from grade 2 at the baseline and was averagely reduced to 1.2 for the midface, 1.3 for the jawline, 0.9 for the temple, and 1.4 for the chin. These significant reductions were maintained throughout the investigation period until Day 540 (Figure 2). Except for the chin, the contralateral areas that received an injection with Juvéderm showed a similar evolution (Figure 2A–C), confirming the non-inferiority of ART FILLER® Volume for each specific area. The mean injection volume for all studied zones was 1.1 ml for both study products (min 0.8 and max 2 ml for the temple for both products, min 0.4, and max 1.2 ml for jawline for both products, and min 0.6 for ART FILLER® Volume and 0.5 ml for Juvéderm® Voluma and max 1.2 ml for both products). Considering the total syringe volume for each filler (1,2 ml for ART FILLER® Volume and 1,0 ml for Juvéderm® Voluma), this procedure required only 1 syringe for ART FILLER® Volume while 2 syringes were needed for the reference product.
The percentage of success 18 months after injection, represented by the subjects for whom the initial GACS score was reduced from 1 grade (0.5 points) on the GACS scale was 55% for the midface, 53% for the jawline, and 62% for the temple with both treatments (Figure 3A–C). The best success was observed on the chin with 73% of subjects for whom a decrease of one grade was still present at Day 540 (Figure 3D).
3.3 | Evaluation of the remanence of the fillers with the area's specific scales
To further quantify the restoration longevity of the face volumes by the fillers, each injected area was evaluated according to its specific scale. The Medicis Midface Volume score (MMVS) was significantly reduced by 18% on Day 21, and this reduction was kept significant until Day 360 (−7%) (Figure 4A). The Narins and Carruthers Jawline score was significantly reduced after the injection, from −36% on day 21 to −9% on Day 540 (Figure 4B). Similarly, the Allergan Temple Hollowing score was reduced by −46% on Day 21 and was kept significantly reduced until Day 540 by at least −18% (Figure 4C). Of note, all these scores evolved similarly for the contralateral side that was injected by the reference product Juvéderm® Voluma (Figure 4A–C). Finally, the Allergan Chin Retrusion score was also significantly reduced after the ART FILLER® Volume injection (from – 36% on Day 21 to −27% on Day 540) except for the one-time point at Day 270 (Figure 4D). The longevity of filler efficacy is illustrated by the follow-up pictures in Figure 5, showing a visible reduction of the volume loss that was maintained until 18 months.
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