A Multicenter, Double-Blinded, Randomized, Split-Face Study of the Safety and Efficacy of a Novel Hyaluronic Acid Gel for the Correction of Nasolabial Folds

Michael H. Gold, MD, Medical Director
Tennessee Clinical Research Center
2000 Richard Jones Road, Suite 223
Nashville, TN 37215, USA
Phone: 615-383-9660
Email drgold@goldskincare.com

Leslie Stafford Baumann, MD, CPI
Baumann Cosmetic & Research Institute
4500 Biscayne Blvd., Suites 105 & 101
Miami, FL 33137
305-531-5788

Clifford P. Clark III, MD
Orlando Aesthetic Institute
120 E. Par Street, Suite 1000
Orlando, FL 32804
407-629-5555

Joel Schlessinger, MD
Skin Specialists, PC
2802 Oak View Drive
Omaha, NE 68144
402-697-6599

Corresponding Author:
Michael H. Gold, MD, Medical Director;
Tennessee Clinical Research Center,
2000 Richard Jones Road, Suite 223
Nashville, TN 37215, USA
Phone: 615-383-9660
Fax: 615-383-6995
Email drgold@goldskincare.com

Disclosures: Dr. Gold is an advisor and consultant for Prollenium Medical Technologies, Inc., and has received research funding. Dr. Schlessinger is a paid speaker for Galderma Laboratories, LP. Dr. Baumann has no information to disclose.

Key Words: crosslinking agent, dermal filler, facial volume loss, soft-tissue augmentation

Abstract

Background. Injectable hyaluronic acid is frequently used to correct volume loss in nasolabial folds.
Objective. To compare the safety and efficacy of a novel hyaluronic acid gel to a non-animal stabilized hyaluronic acid (Comparator) gel for the correction of nasolabial folds (NLF).
Methods. Qualified subjects had NLF with a Wrinkle Severity Rating Scale (WSRS) score of 3 or 4 (moderate or severe). NLFs were treated with Test Product on one side of the face and Comparator on the other side of the face (facial side randomly assigned). Improvement from baseline was evaluated at weeks 1, 2, 4, 12, and 24 weeks. The primary study endpoint was the mean change in WSRS score from baseline to Week 24.
Results. The mean changes in WSRS score from baseline were 1.02 ±0.689 for Test Product and 0.91±0.762 for Comparator. The mean difference in change from baseline in WSRS scoring (Comparator minus Test Product) at Week 24 was -0.11 (-0.225-0.001, 95% confidence interval [CI]). The upper boundary
(0.001) of the 95% CI was less than the prespecified non-inferiority limit of 0.50, indicating that the Test Product was non-inferior to the Comparator. No subject discontinued the study due to adverse events.
Conclusion. The Test Product is safe and non-inferior to the Comparator for the correction of nasolabial folds.

Introduction

Hyaluronic acid (HA) is a glycosaminoglycan disaccharide found in the extracellular matrix of the skin, eye, and cartilage. Approximately half of human HA occurs in the skin. As a polyanionic polymer, HA is soluble and binds well with water.1

HA provides structure and moisture in human skin. As skin ages, dermal HA decreases and results in reduced water-binding capacity, reduced elasticity, volume loss, and the development of rhytids and other aging features.2,3

HA has several characteristics that make it suitable for use as a dermal filler. Because the chemical structure of HA is the same in all species, immunologic reactions and implant rejection are unlikely to occur.3-5  Other favorable characteristics are its presence in the skin and its ability to bind to substantial amounts of water.5

HA readily dissolves in water and forms a viscous gel.3 Unmodified HA, however, has a half-life of only a few weeks after injection into the dermis6 because it is quickly degraded by hyaluronidase and free radicals in the skin.5 To increase stability and longevity when injected into skin, manufacturers use crosslinking agents to bind HA polymer chains to each other. The result is a gel that resists enzymatic and free radical breakdown.5,7 The crosslinking agent used to stabilize most HA-based dermal fillers is 1,4-butanediol diglycidyl ether (BDDE).8

A variety of HA-based crosslinked fillers have been developed to correct facial wrinkles and folds, such as the nasolabial folds (NLF). Examples of FDA-approved crosslinked HA-based fillers are shown in Table 1. Table 1.

Hyaluronic-acid based, FDA-cleared fillers currently available in the United States9

Filler FDA Indication
Restylane* Injection into the mid to deep dermis for correction of moderate to severe facial wrinkles/folds (such as nasolabial folds) and for lip augmentation in those over the age of 21 years.
Restylane Lyft* (formerly Perlane) Correction of moderate to severe facial folds and wrinkles or in patients over the age of 21 who have age-related volume loss.
Restylane Silk* lip augmentation and dermal implantation for correction of perioral rhytids (wrinkles around the lips) in patients over the age of 21.
Restylane ReFyne* injection into the mid-to-deep dermis for the correction of moderate to severe facial wrinkles and folds (such as nasolabial fold) in patients over the age of 21.
Restylane DeFyne* injection into the mid-to-deep dermis for the correction of moderate to severe deep facial wrinkles and folds (such as nasolabial fold) in patients over the age of 21.
Juvederm Ultra† Injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds).
Juvederm Ultra Plus† Injection into the mid to deep dermis for correction of moderate to severe facial wrinkles and folds (such as nasolabial folds).
Juvederm Voluma XC† Deep (subcutaneous and/or supraperiosteal) injection for cheek augmentation to correct age-related volume deficit in the mid-face in adults over the age of 21.
Juvederm Volbella XC† Injection into the lips for lip augmentation and for correction of perioral rhytids in adults over the age of 21.
Juvederm Volift (Vollure ) XC† correction of moderate to severe facial wrinkles and folds, such as nasolabial folds, in adults over the age of 21.
Belotero Balance‡ Injection into facial tissue to smooth wrinkles and folds, especially around the nose and mouth (nasolabial folds).

*Galderma Laboratories, LP, Fort Worth, TX.
†Allergan PLc, Parsippany-Troy Hills, NJ.
‡Merz Aesthetics, Raleigh, NC.

The purpose of the present study was to compare the safety and efficacy of a novel HA gel to an established HA gel for the correction of NLF. Both products are non-animal stabilized HA gels.

Methods

Subjects (n=163, 156 females, aged 30 to 77 years, mean 55.4±10.1) enrolled in this Quorum IRB-approved study performed in accordance with Good Clinical Practice guidelines. Informed consent was obtained for all subjects.

Subjects. Qualified subjects had NLFs with a Wrinkle Severity Rating Scale (WSRS)10,11 score of 3 or 4 (moderate or severe) on the scale of Narins and colleagues10 in which 1 = absent (no visible fold, continuous skin line), 2 = mild (shallow but visible fold with slight indentation, minor facial feature, implant is expected to produce slight improvement in appearance), 3 = moderate (moderately deep folds, clear facial feature visible at normal apperance but not when stretched, excellent correction expected from injectable implant), 4 = severe (very long and deep folds, priminent facial feature, less than 2 mm visible when stretched, signifcant improvement expected from injectable implant), and 5 = extreme (extremely deep and long folds, detrimental to facial appearance, 2 to 4 mm visible V-shaped fold when stretched, unlikely to achieve satisfactory correction with injectable implant alone).

Subjects were excluded if they had facial tattoos; dermabrasion, facelift, or injectable neurotoxin below the orbital rim within the previous 6 months; tissue augmentation (bulking agents) for facial wrinkles and scars at the proposed injection sites within the past 6 months; previous augmentation with permanent implants; scarring at intended treatment sites; evidence of scar-related disease or delayed healing activity within 1 year prior to the study; history of keloid formation or hypertrophic scars; facial wounds or infection; history of allergy to natural rubber latex or lidocaine; compromised or suppressed immune system; and history of bleeding or connective tissue disorders. Subjects who used systemic corticosteroids or immunosuppressive medication within 30 prior to study treatment; topical steroids on the face within 14 days prior to treatment and throughout the study period; concomitant anticoagulant or antiplatelet therapy; aspirin or NSAIDs within 1 week prior to study treatment; OTC wrinkle products or prescription wrinkle treatments within 4 weeks prior to treatment and during the study period; and any investigational product within 30 days of providing informed consent were also excluded. Pregnancy or lactation were grounds for exclusion. Women of childbearing potential provided a negative urine pregnancy test and agreed to use medically accepted contraception methods during the study period.

Procedure. NLFs were treated with Test Product (Revanesse Versa, Prollenium Medical Technologies, Inc., Aurora, ON, Canada) on one side of the face and Comparator (Restylane
[original], Galderma Laboratories, L.P., Fort Worth, TX.) on the other side of the face. The side of the face for each product was randomly assigned. The evaluating investigator and subject were blinded and injections were performed by an experienced unblinded physician. Topical anesthetic was not used and ice was applied before treatment at the investigator’s discretion. Injections were intradermal, targeting the mid-dermis for best results. Test Product and Comparator were each provided in 1.0 mL pre-filled syringes and a maximum of 2.0 mL was used per treatment on each NLF. Needles were thin-walled and 27-gauge in size. Test Product and Comparator were comparable in ease of injection and extrusion force. Product was injected with the dominant hand while the nondominant hand immobilized the NLF by applying gentle downward traction to its most inferior part. The injector used a linear threading technique beneath the fold and a fanning technique for the peri-alar sulcus followed by gentle massage for wide portions of the fold. Injection technique and volume of injected product were as similar as possible on both sides of the face. The treatment protocol is shown in Table 2.

Table 2. Treatment protocol

Study Element Per Protocol Subjects Retreated Subjects
Week
0 1 2 4 12 24 28 40 52
Scheduling Window (days) None ± 2 ± 2 ± 4 ± 4 ± 7 ± 7 ± 7 ± 7
Treatment x x†
WSRS, iGAI, pGAI x x x x x x x x
Adverse events x x x x x x x x x
Interim visit x x x x
Touch-up* x
Investigator ease of use x
Patient comfort rating x x‡
End of study x
Retreatment (TP) visit† x
FU visit x
FU telephone x
End of study x

*If iGAI score = 3 or 4.
† Optional open-label retreatment with TP for subjects whose WSRS score returned to baseline or as needed for optimal correction if WSRS scores had not returned to baseline.
‡ Only for subjects who received a touch-up.
WSRS = wrinkle Severity Rating Scale; iGAI = Investigator Global Aesthetic Improvement, pGAI – subject Global Aesthetic Improvement; TP = Test Product; FU = follow-up.

All initial treatments were administered at baseline (Week 0). In addition to WSRS, evaluations included the Global Aesthetic Improvement Scale (GAI)7,10 of the investigator (iGAI) and the patient (pGAI) as well as adverse events recorded in a diary of each subject. For the GAI evaluations, the patients were asked, “How would you rate improvement in your appearance compared to your iitial condition using the scale below?” The GAI scale was 1 = worse (the appearance is worse than the original condition), 2 = no change (the appearance is the same as the original condition), 3 = improved (obvious improvement in appearance from the initial condition, a touch-up might further improve the result), 4 = much improved (marked improvement in appearance from the initial condition, but not completely optimal, a touch-up might slightly improve the result), and 5 = very much improved
(optimal cosmetic result). Evaluations were performed at baseline and at all interim and follow-up visits. Based on the use of photographs, the WSRS is designed to quantify facial folds by visual assessment of the length and apparent depth of the fold without referring to baseline. In contrast, the GAI scale is used to grade overall improvement in each fold by comparing its appearance at follow-up against a high-magnification photograph taken before treatment.10

Additional Test Product injections were performed at the interim follow-up visit (Week 1±2 days) if the iGAI score was 3 or 4. For subjects not requiring retreatment, the study period ended at Week 24.

Patient Comfort was assessed using a numerical scale (0 = most uncomfortable, 10 = most comfortable). Investigator Ease of Use was similarly rated (0= not easy, 10 = most easy.

Subject Populations. Data were analyzed in three segments: the intent-to-treat population (ITT, n=163), including all randomized subjects who received study product; modified intent-to-treat population (mITT, n=153), including all randomized subjects who met the inclusion/exclusion criteria, were randomized, received both products, and returned for at least 1 bilateral post-injection assessment of WSRS; and the per-protocol population (PP, n=125) which included all randomized subjects who met inclusion/exclusion criteria, received both products, completed Week 24 follow-up within the specified time window, had bilateral WSRS data, and had no significant protocol violations which, in the investigators’ opinion, would have affected the evaluations.

Data Analysis. Efficacy was evaluated with the PP and mITT populations. Results from the PP population were considered definitive and those from the mITT population were supportive. The primary study endpoint for each treatment was the change in WSRS score from baseline to Week 24. To compare the efficacies of the two treatments, the mean change from baseline of the Test Product was compared to the mean change from baseline of the Comparator, assuming normal distribution of data. If the upper boundary of the 95% confidence interval (CI) for the Test Product data was less than a pre-specified non-inferiority limit of 0.50, the Test Product was considered non-inferior to the Comparator.

Treatment success was evaluated by secondary efficacy endpoints at Week 24 which included the percentage of subjects with at least a 1-point improvement in WSRS from baseline, the iGAI score, and pGAI score. Frequencies and percentages for the Test Product and Comparator were compared using the Wilcoxon matched-pairs signed rank test using p<0.05 as the cutoff level for significance. No adjustments in p value were made for multiple comparisons.

For the PP population results were evaluated using only the available data. For the mITT population missing efficacy data were imputed using the last observation carried forward method.

Safety and other evaluations were performed on the ITT population. Frequency and percentage of participants experiencing adverse events, including treatment-emergent adverse events (TEAEs), were tabulated by treatment group.

Results
Efficacy

Primary Endpoint. For PP subjects, the mean changes in WSRS score from baseline were 1.02 ±0.689 for the Test Product and 0.91±0.762 for the Comparator (Figure 1). The mean difference in change from baseline in WSRS scoring
(Comparator minus Test Product) at Week 24 was -0.11 (-0.225 to 0.001, 95% CI). The upper boundary of the 95% CI (0.001) was less than the prespecified non-inferiority limit of 0.50, indicating that Test Product was non-inferior to Comparator. Results for the mITT population were similar. The mean change in WSRS score from baseline was 1.09±0.692 for Test Product and 0.95±0.746 for Comparator. The mean difference in change from baseline in WSRS scoring at Week 24 was -0.14 with a 95% CI of -0.234 to 0.040.

Secondary Endpoint. Treatment success at Week 24 in the PP population was 78.4% (98/125) with the Test Product and 72.8% (91/125) with the Comparator (Figure 2). For the mITT population the values were 81.7% (125/153) with Test Product and 75.8% (116/153) with Comparator. Differences between treatments were not significant for the PP population (p = 0.130) and of borderline significance for the mITT population (p = 0.059).

iGAI Scores. The percentage of PP subjects reported as much improved or very much improved was 59.2% (74/124) with the Test Product and 47.2% (59/124) with Comparator (Figure 2). The corresponding values for mITT subjects were 60.8% (93/153) with the Test Product and 49.7% (76/153) with the Comparator. Differences were statistically significant (p = 0.005 and p<0.001 for PP and mITT populations, respectively) in favor of the Test Product.

pGAI Scores. The percentage of PP subjects reported as much improved or very much improved was 44.4% (55/124) with Test Product and 30.6% (38/124) with Comparator (Figure 2). Corresponding values for mITT subjects were 44.4% (68/153) with the Test Product and 30.7% (47/153) with the Comparator. Differences were statistically significant (p = 0.002) for both the PP and mITT populations.

Patient Comfort and Ease of Use. The mean Patient Comfort score was 5.23±2.132 (range 0 to 10) for Test Product and 5.18±2.058 (range 0 to 10) for Comparator. The mean Investigator Ease-of-Use score was 8.93±1.425 (range 4 to 10) for Test Product and 9.12±1.104 (range 6 to 10) for Comparator.

Safety

No subject discontinued the study due to adverse events. Among ITT subjects (n=163) one or more injection site TEAEs were reported for 114 (69.9%) with Test Product and 137 (84.0%) with Comparator. The most common injection site TEAEs were hematoma (50.3% Test Product, 47.2% Comparator), swelling (47.2% Test Product, 71.2% Comparator), and pain (38.0% Test Product, 66.3% Comparator). Severe TEAEs were reported in 12 participants (0.6% for Test Product, 7.4% for Comparator). Only 2 subjects reported non-injection site TEAEs (headache 3.1%, arthralgia 1.8%). TEAEs were experienced by 5 participants, one of which was considered related to treatment (possible vascular event, left lip and ala of the nose with Comparator), leading to treatment interruption.

Discussion

The efficacy of the Test Product has been demonstrated by results of both the PP and mPP populations. In the PP population, the Test Product was shown to be non-inferior to Comparator as shown by the small difference (-0.11, Comparator minus Test Product) in change from baseline in WSRS scores at Week 24. This was supported by (1) the upper limit value (0.0001) of the 95% CI (-0.225 to 0.0001) which was less than the prespecified non-inferiority limit of 0.50, (2) the treatment success rate at week 24 (1-grade improvement in WSRS score from baseline, 78.4% for Test Product and 72.8% for Comparator), and (3) the respective response rates for Test Product vs. Comparator (pGAI = 44.4% vs 30.6% [significant] and iGAI = 59.2% vs. 47.2% [significant]). The mPP population results were similar.

The safety of the Test Product was shown by the data of the mITT group. Injection-site TEAEs were severe in only 0.6% of Test Product subjects and in 7.4% of Comparator subjects. Specifically, swelling was noted in only 47.2% of Test Product- injected sites compared to 71.2% for Comparator-injected sites, and pain was noted in 38.0% and 66.3% of sites, respectively. The latter finding is important because control of pain in HA filler treatment is crucial in motivating patients to return for treatment.12 True complications such as injection into vascular supply, persistent nodule formation, tissue necrosis, allergic reaction, infection, granuloma formation, and a visible blue hue (Tyndall effect)12M were not observed.
The gel of the Test Product is balanced with the water content of skin tissue, so that once implanted, it neither releases or absorbs water. The injecting physician can visually judge correction without having to account for uptake or release of fluid by the filler. Although the HA does degrade over time, the crosslinked network of polymer chains expands slowly in response, which partially offsets this effect and increases longevity of correction.13

Crosslinked HA gel has many advantages as an injectable filler. In contrast to collagen fillers, HA does not require skin allergy testing prior to injection. HA adds volume to skin because it can bind 1,000 times its own volume in water2 due to its polyanionic and hydrogen-bonding nature.5 Since injections are typically repeated while some correction remains (6-9 months), the change in the appearance of the target area is less dramatic after the repeat injection and only a fraction of the initial injection volume is used. The result is a more natural appearance and less noticeable treatment effects.7,14 Finally, since cutaneous HA is naturally broken down by hyaluronidase and free radicals in the skin, hyaluronidase can be used to resolve overcorrection and injections that are too superficial.15,16

Rao and colleagues17 have reported that breakdown of HA by hyaluronidase may vary among HA fillers. The Test Product has been shown to break down in the presence of hyaluronidase in vitro and physician users have reported that hyaluronidase (150 units/mL) has successfully corrected injections of Test Product into patients.13

A variety of crosslinked HA fillers are commercially available. Although the chemical structure of unmodified HA is identical across different species, not all crosslinked HA gels are identical. Crosslinking changes the rheological properties of HA gels and manufacturers use different techniques for crosslinking. Physicians must then decide which product is appropriate for each application and, if necessary, modify their injection technique18 which is discussed in detail.6

To optimize outcomes with crosslinked HA gels, researchers1,3,5,6,18-26 have studied the rheological (flow) properties of the major HA products available. Rheological properties play a role in injection and positioning of the gel into the target tissue and in optimizing their clinical use. Rheological terms are defined in Table 3 and the measured or calculated values for crosslinked HA fillers are in Table 4. Values of the latter were obtained in vitro with a Rheometer by oscillatory deformation.21 The oscillation frequency (0.7 Hz) falls within a range of applied shearing force in which changes in elasticity and viscosity are linear, reproducible, and physiologically relevant.21

Table 3. Rheological terms in the context of dermal fillers6,23,24

Term Symbol Definition Application
Shearing Force Forces that push one part of a body in a given direction and another part in the opposite direction Shear forces are applied during injection of a filler.
Viscosity ή Resistance to flow; measure of how well a gel in the fluid phase resists shearing forces A highly viscous filler is difficult to inject
Complex Viscosity ή* How well a gel in the solid phase resists deformation by external forces How well a gel flows from a needle during injection.
Elastic modulus G’ How well a gel in the fluid phase resists deformation by external forces measure of gel stiffness, such as when the filler is pushed through a fine-bore needle
Viscous modulus G” Measure of the viscosity of a gel A viscous gel has a high G”
Tan δ Tan δ G”/G’; measure of elasticity If tan δ <1, filler is more elastic than viscous; if tan δ>1, filler is more viscous than elastic
Complex modulus G* The square root of G’2 + G” 2 measures the total resistance to deformation
Extrusion Force required to inject a filler at a fixed rate through a needle Force required to inject a filler at a fixed rate through a needle

Rheological properties can be used as a guide to selecting fillers to achieve a desirable end point. For example, fillers with a low viscosity and elasticity (such as the Test Product and Juvederm) spread more easily in tissue and have a softer feel than those with higher elasticity and viscosity. These fillers would therefore be appropriate for the periocular region and fine rhytides because of the lower risk of contour irregularities after injection.21 Fillers of low elasticity are suited to areas where volume and softness are more important than volume, such as the lips.1 Although lips may be augmented with either low elasticity-low viscosity or high elasticity-high viscosity fillers,21 low and moderate elasticity HA fillers are most frequently used.25 Low-viscosity fillers are also easier to inject because the force needed to inject the filler at a fixed rate through a needle/cannula (extrusion force) is less with low-viscosity fillers.24

Table 4. Properties of cross-linked hyaluronic acid (HA) soft-tissue fillers at 0.7 Hz (most at 30° C.1,2,6,21,26,27

HA Filler HA Conc (mg/ml) XL agent % CL Rheological Values (0.7 Hz) Injection layer Sizing?
G’
(Pa)
G”
(Pa)
G* ή*
(Cp)
Tan δ
Revanesse Versa 25 BDDE 7% 112 32 116.5 26,477* 0.286 Intradermal Yes
Restylane 20 BDDE 1.2 565 106 574.9 131,310 0.187 Subdermal Yes
Restylane Lyft (formerly Perlane) 20 BDDE 1.4 541 86 547.8 124,950 0.158 Subdermal Yes
Restylane Silk 20 BDDE
Restylane ReFyne 20 (Na hyaluronate) BDDE
Restylane DeFyne 20 (Na hyaluronate) BDDE
Restylane SubQ 20 BDDE 863 101 868.9 198,370 0.117
Juvederm Ultra 24 BDDE 9 94 35 100.3 25,627 0.376 Subdermal No
Juvederm Ultra Plus 24 BDDE 11 135 38 140.2 36,384 0.279 Subdermal No
Juvederm Voluma XC 20 BDDE 270 28 271.4 66,947 0.103 No
Juvederm Volbella XC 15 BDDE
Juvederm Volift (Volurre XC) No
Belotero 22.5 BDDE 39 24 45.8 10,453 0.603 No

BDDE = 1,4-butanediol diglycidyl ether; XL = crosslinking; CL = crosslinking; G’ = elastic modulus; G” = viscous modulus; G*= complex modulus = ; √G’2 + G”2; ή* = complex viscosity; tan δ = G”/G’; Pa = Pascal; Cp = Centipoise.

*Calculated from the relation |ή*| = √(ή’)2+(ή”)2 in which ή’ = G’/ω and ή”= G”/ω and
ω = 4.4 radians/second, the oscillation velocity (0.7 Hz) expressed in radians/second.

After evaluating rheological properties of major crosslinked HA gels, researchers have reported the following: (1) persistence of crosslinked HA fillers in the skin is proportional to both concentration and elasticity (stiffness) of the gel,20 (2) dermal fillers of low viscosity under high shear can be injected through a small-gauge needle,19 (3) fillers with greater viscosity and elasticity will tend to spread less after implantation, (4) fillers with high G’ and ή values (very firm and viscous) may be better suited for treating deep folds and creating volume and lift, such as in the mid- and lower face, and (5) fillers with low G’ and ή* values may be more appropriate for shallow folds and lines.21,25

As shown in Table 4, rheological values of the Test Product are similar to those of Juvederm Ultra. Since G’ and ή* values are low, Test Product and Juvederm Ultra are optimally suited to correcting shallow folds and lines, can be injected through a small-gauge needle, and will spread well after implantation. The HA concentrations are nearly identical and the percent crosslinking is similar.

The present study compared the Test Product with Restylane, which has much higher rheological values. The objective of this study, however, was to show that the Test Product is not inferior to Restylane, which is clearly demonstrated by the WSRS, treatment success, iGAI, pGAI, patient comfort, and ease-of-use data.

The advanced crosslinking process used in the manufacture of the Test Product is designed to promote links between different HA polymer chains and to minimize less effective links on parts of the same chain. An optimal degree of crosslinking inhibits the natural degradation of the filler, thus prolonging longevity in the treated area. The milling process of the Test Product results in small, spherical, and uniform particles to promote optimal integration in the treated area; slow, predictable breakdown; and ease of injection.13

Conclusion

The Test Product, Revanesse Versa, is safe and non-inferior to the Comparator, Restylane, for the correction of nasolabial folds.

Figure Captions

Figure 1. Comparison of Test Product with Comparator for primary efficacy variable, change in score of Wrinkle Severity Rating Scale (WSRS) from baseline. Note the similarity between the two, suggesting non-inferiority.

Figure 2. Comparison of Test Product with Comparator for secondary efficacy variables of treatment success, as well as change from baseline for Investigator Global Aesthetic Improvement (iGAI) and Patient Global Aesthetic Improvement (pGAI). Note the similarity between the two, suggesting non-inferiority.

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