Treatment of the lips with hyaluronic acid (HA)-based dermal fillers aims to add volume to naturally thin lips or to restore lip volume and contour because of age-related thinning, and treatment of the perioral region aims to restore structural support of oral commissures and correct age-related perioral lines.1–4 VYC-15L (Juvéderm Volbella XC; Allergan plc, Dublin, Ireland) is a malleable, lidocaine-containing, HA-based filler suited for lip and perioral enhancement. It is produced using a novel crosslinking process based on Vycross technology (Allergan plc, Dublin, Ireland), which combines low– and high–molecular weight HA to create a tightly crosslinked network with improved moldability, improved ease of product flow during injection, decreased tendency to absorb water (enabling patients and physicians to gauge results at the time of treatment), and increased duration of effect.1
This report presents data on the safety and effectiveness of VYC-15L compared with nonanimal stabilized HA (NASHA) with lidocaine (Restylane-L; Medicis Aesthetics; Scottsdale, AZ) at 3 months (primary end point) and other end points for VYC-15L through 1 year after treatment.
This prospective, multicenter, randomized, controlled study was conducted at 13 investigational sites in the US, each with an unblinded treating investigator (TI) and a blinded evaluating investigator (EI) who performed all safety and effectiveness assessments.
Eligible subjects were randomized 3:1 to treatment with VYC-15L or NASHA, with randomization stratified by Fitzpatrick skin type. Subjects were blinded to treatment assignment, which was based on a central block randomization schedule and an automated interactive voice/web response system. The TI injected product into the lips and mid-to-deep dermis of the perioral area (including the vermilion body, oral commissures, vermilion border, Cupid bow, and philtral column) as needed using a 30-gauge half-inch needle. If judged necessary by the TI, an optional touch-up treatment was given 30 days later. Injection volume was determined based on the TI's clinical experience, and was not to exceed 1.5 mL for each lip (upper and lower) at each of the initial and touch-up treatments. Additional treatment could be injected into the perioral area provided that the total volume did not exceed 6.0 mL for the initial and touch-up treatments combined. Subjects completed a safety diary for 30 days after each treatment and attended safety follow-up visits at 3 and 14 days after treatments. Subsequent visits to assess safety and treatment effectiveness were at 1, 3, 6, and 9 months and 1 year after last treatment.
The study was conducted in compliance with Good Clinical Practice principles and was registered at Clinicaltrials.gov (identifier NCT01998581). Institutional review board approval was obtained for each site before any subjects were enrolled, and all subjects provided written informed consent.
Subjects aged 22 years or older were eligible if they had a TI- and EI-assessed overall lip fullness score of 0 (minimal), 1 (mild), or 2 (moderate) on the validated 5-point Allergan Lip Fullness Scale (LFS)5 and desired a ≥1-point improvement or if they had Fitzpatrick skin Type V or VI with an overall lip fullness score of 3 (marked) or 4 (very marked) and desired treatment of the vermilion body of 1 or both lips. For treatment of perioral lines, subjects were required to have an Allergan Perioral Lines Severity Scale (POLSS) score of severe or moderate as agreed on by the TI and EI.
Subjects were excluded if they had lip tattoos, piercings, facial hair, or scars; undergone oral surgery within 6 weeks before enrolment; received permanent facial implants; received semipermanent dermal filler treatment within 24 months or temporary dermal filler treatment within 12 months in a facial region below the orbital rim; undergone facial augmentation with fat or botulinum toxin injections below the orbital rim within 6 months; or undergone a cosmetic procedure of the face or neck within 6 months.
The blinded EI evaluated overall lip fullness using the 5-point LFS, severity of perioral lines at rest using the 4-point POLSS, severity of perioral lines at maximal contraction using the 4-point Allergan Perioral Lines at Maximal Contraction (POLM) scale, oral commissures severity using the 4-point Allergan Oral Commissures Severity Scale (OCSS) (each 4-point scale scored as 0 = none; 1 = mild; 2 = moderate; and 3 = severe),6 and global aesthetic improvement using the 5-point Global Aesthetic Improvement Scale (GAIS; 2 = much improved to −2 = much worse). The TI used 11-point scales to rate ease of injection (0 = difficult; 10 = easy) and product moldability (0 = stiff; 10 = moldable). Subjects completed the 22-item Satisfaction With Lips and 12-item Lip Lines modules of the validated FACE-Q questionnaire7 and used 11-point scales to rate hydration of the lips (0 = dry/chapped; 10 = soft/smooth) and natural look and natural feel of the lips (0 = unnatural looking/feeling; 10 = natural looking/feeling).
Subjects were monitored for adverse events (AEs), EI-assessed features of the lips and mouth area using an 8-item form (each item scored from 0 to 10), the presence/absence of Tyndall effect, and lip sensation using 2-point discrimination and light touch. Subjects recorded the occurrence and severity of injection site responses (ISRs) in a diary for 30 days after each treatment and rated pain during treatment on an 11-point scale (0 = no pain; 10 = worst pain imaginable). The subject-assessed 23-item Recovery Early Life Impact module of FACE-Q was completed on Day 3 after each treatment.8 A speech and language professional evaluated pronunciation requiring normal lip function from video recordings of subjects.
The primary effectiveness end point was the mean change in overall lip fullness on the LFS from baseline to Month 3. The secondary effectiveness end points were the percentage of POLSS responders at Month 3, defined as subjects with a ≥1-point improvement from baseline in perioral line severity, and the mean change from baseline to Month 3 in the FACE-Q Satisfaction With Lips module score.
The primary effectiveness analysis determined whether VYC-15L was noninferior to NASHA in improving lip fullness. An independent, 2-sample t-test with a 1-sided 95% confidence interval (CI) for the treatment difference (VYC-15L minus NASHA) in mean LFS score change from baseline to Month 3 was constructed. Noninferiority was concluded if the lower limit of this CI was greater than −0.5.
For determination of POLSS responders, only subjects with baseline POLSS scores of moderate or severe who received perioral lines treatment were included in the analysis. All FACE-Q module scores were transformed using the conversion tables created by the FACE-Q developers, in which the lowest and highest scores were 0 and 100, respectively. Paired t-tests were used to test the statistical significance of mean changes from baseline in POLSS scores and FACE-Q scores.
Subjects were treated between November 2013 and April 2014. Of the 268 subjects enrolled, 34 subjects were screen failures, 8 subjects enrolled before study treatments were available at the investigational site, and 1 subject withdrew consent before randomization, resulting in 225 subjects randomized to VYC-15L (n = 169) or NASHA (n = 56). One subject assigned to VYC-15L discontinued before receiving treatment. Touch-up treatment was administered to 61.9% (104/168) and 67.9% (38/56) of subjects in the VYC-15L and NASHA groups, respectively.
The treatment groups had similar demographic and baseline characteristics (Table 1). All Fitzpatrick skin types were represented in this study; the majority (61.2%) was Fitzpatrick skin Types II or III. A majority had never smoked (53.6%) or were former smokers (34.4%). Median exposure to sunlight was 2 hours per day.
The median volume for initial plus touch-up treatment was 2.6 mL with each product for the lips and perioral area. Injection sites and the median injection volumes at each site were similar for VYC-15L and NASHA (Table 2). Anesthesia was administered to 74.6% of subjects before initial treatment, most commonly a topical agent (50.4%).
Tunneling and serial puncture were the most common injection techniques; fanning was used infrequently and only for perioral lines and oral commissures. Nearly all injections were subdermal to the vermilion body of the upper lip (99.5%) and lower lip (99.1%), and nearly all injections were intradermal to the vermilion borders of the upper (97.4%) and lower lips (98.6%) and perioral lines (99.2%). All injections to the oral commissures, Cupid bow, and philtral columns were intradermal.
For TI-rated ease of injection, scores of 7 to 10 were given to 97.6% (164/168) and 80.4% (45/56) of VYC-15L and NASHA subjects, respectively, after initial treatment, and to 99.0% (103/104) and 97.4% (37/38) of VYC-15L and NASHA subjects, respectively, after touch-up treatment. The proportions of VYC-15L and NASHA subjects receiving ease of injection scores of 10 for initial treatment were 82.7% (139/168) and 30.4% (17/56), and for touch-up treatment were 85.6% (89/104) and 42.1% (16/38), respectively. For moldability, the proportion receiving scores of 7 to 10 was higher with VYC-15L than with NASHA after initial treatment (97.6% [164/168] vs 60.7% [34/56]) and after touch-up treatment (99.0% [103/104] vs 65.8% [25/38]). The proportions of subjects receiving scores of 10 for moldability were higher with VYC-15L than with NASHA on initial treatment (69.6% [117/168] and 30.4% [17/56]) and touch-up treatment (76.9% [80/104] and 36.8% [14/38]).
The primary effectiveness end point was met. The mean change from baseline to Month 3 in LFS score was 1.1 with VYC-15L and 1.0 with NASHA; the difference in mean change from baseline to Month 3 between VYC-15L and NASHA was 0.07. The corresponding lower limit of the 95% CI for this treatment difference was −0.15, which is greater than the prespecified margin of −0.5. At Month 3, the percentage of LFS responders was 80.3% (122/152) with VYC-15L compared with 70.8% (34/48) with NASHA. The LFS responder rate with VYC-15L was 61.8% at 1 year (Figure 1). Representative photographs of a subject's lips and perioral area at baseline and Month 3 after treatment with VYC-15L are illustrated in Figure 2.
For subjects who received VYC-15L treatment of the perioral lines, 65.4% and 66.2% were POLSS responders at Month 3 and Year 1, respectively (Table 3). Mean POLSS scores were significantly improved from 2.5 at baseline to 1.6 at Month 3 (mean change from baseline: −0.9; p < .001) and 1.8 at Year 1 (mean change from baseline: −0.7; p < .001). POLM responder rates were 50.6% at Month 3 and 30.9% at Year 1 (Table 3). For subjects who received treatment of the oral commissures with VYC-15L, 59.2% and 53.3% were OCSS responders at Month 3 and Year 1, respectively (Table 3).
Mean FACE-Q Satisfaction With Lips scores were significantly improved from baseline at each time point through Year 1 (p ≤ .001 for subjects treated with VYC-15L; Figure 3A). Similar results were obtained on the FACE-Q Satisfaction With Lip Lines module (Figure 3B). The percentages of subjects with improvement in FACE-Q Satisfaction With Lips scores and Satisfaction With Lip Lines scores at Month 3 were 96.1% (147/153) and 88.2% (135/153), respectively, and remained high at Year 1 (79.7% [98/123] and 74.8% [92/123], respectively).
On the GAIS, EIs rated 92.9% of subjects in the VYC-15L group as “improved” or “much improved” in appearance at Month 3; at Year 1, 58.5% of subjects in the VYC-15L group were GAIS responders (Figure 4).
Scores of 7 to 10 (“very satisfied”) were given for natural look of the lips by 84.4% of VYC-15L subjects at Month 3 and by 93.5% at Year 1. Similarly, scores of 7 to 10 for natural feel of the lips were given by 87.7% of subjects at Month 3 and by 92.7% at Year 1. Overall, 54.5% of subjects in the VYC-15L group showed improvement from baseline in lip hydration at Month 3.
Subgroup analysis of the primary effectiveness end point was performed by Fitzpatrick skin type groupings. At Month 3, the mean (SD) change from baseline in overall LFS score with VYC-15L was 1.1 (0.9), 1.1 (0.7), and 0.8 (0.4) for subjects with Fitzpatrick skin Types I/II, III/IV, and V/VI, respectively.
The mean scores for subject-rated procedural pain on initial treatment were 3.1 and 3.2 for VYC-15L and NASHA, respectively, and 3.1 and 3.8, respectively, on touch-up treatment, demonstrating minimal subject injection pain.
Nearly all subjects reported ISRs after the combined initial and touch-up treatments with VYC-15L and NASHA (98.1% and 98.0%, respectively); the most common ISRs were swelling (94.8% and 98.0%), firmness (91.6% and 94.1%), and lumps/bumps (91.6% and 90.2%). Rates were ≥5 percentage points lower with VYC-15L than with NASHA for redness, pain after injection, itching, and discoloration. Severe ISRs were reported less frequently in the VYC-15L group compared with the NASHA group (46.1% and 56.0%, respectively). Overall, 52.0% of subjects in the VYC-15L group and 54.0% in the NASHA group had resolution of their ISRs within 2 weeks of treatment. The most common ISRs lasting for 15 to 30 days in these respective groups were lumps and bumps (39.4% and 41.3%) and firmness (21.1% and 25.0%).
Injection site responses that were ongoing after 30 days were classified as AEs. During the initial and touch-up treatment periods, 50.0% (84/168) of subjects in the VYC-15L group and 51.8% (29/56) in the NASHA group had treatment-related AEs. The most common treatment-related AEs in the VYC-15L and NASHA groups were typical reactions to dermal fillers including injection site mass (diary term lumps/bumps, 32.1% and 26.8%, respectively), injection site bruising (17.9% and 19.6%), and injection site pain (11.9% and 21.4%). For both products, most treatment-related AEs were mild or moderate in severity; severe AEs were reported in 1.2% of subjects in the VYC-15L group and 7.1% of subjects in the NASHA group.
The time to onset of treatment-related AEs was most commonly within 1 day of treatment. Treatment-related AEs with onset after 30 days in the VYC-15L group were experienced by 4 subjects (2.4%) with lumps/bumps, 2 subjects (1.2%) with swelling, and 1 subject (0.6%) with swelling and lumps. All these AEs were of mild or moderate severity and resolved without sequelae in a mean of 96 days (range, 5–279). All but 2 of these AEs resolved without intervention: 1 case of mild lower lip swelling due to subject biting her lip was treated with acetaminophen, and 1 case of moderate lip swelling (without redness or infection) during a beach vacation was treated with doxycycline. All the lumps/bumps were reported by investigators as an accumulation of product and were not inflammatory, hot, or red. The final case was a subject with moderate upper lip swelling and a few small bumps (but no itching or redness) that improved substantially within 1 day and was completely resolved within 5 days despite the subject declining any treatment. There were no treatment-related serious AEs or deaths.
At Day 3 after initial treatment, the mean scores on the FACE-Q Recovery Early Life Impact module differed significantly between treatment groups based on nonoverlapping CIs, favoring VYC-15L (mean score: 81.1; 95% CI: 78.3–83.9) over NASHA (mean score: 73.1; 95% CI: 68.7–77.4) as less disruptive to daily activities.
Neither treatment reduced lip sensation on the 2-point discrimination and light touch assessments or affected pronunciation. A Tyndall effect was noted on Day 14 after initial treatment in 2 subjects (1.2%) who received VYC-15L and 1 subject (1.8%) who received NASHA. On the EI assessment of the features of the lips and mouth, most subjects in both treatment groups were given scores of 0 to 3 at all time points, indicating favorable EI assessments of the lips and mouth. Specific assessments included lip surface appearance (i.e., flaky, chapped, and peeling); hyperpigmentation or hypopigmentation; visible lumps and bumps; palpable lumps, bumps, or mucoceles; and firmness or nodularity. Finally, there were no differences between treatment groups for incidence of ISRs and device-related AEs when analyzed by Fitzpatrick skin type categories I/II, III/IV, and V/VI.
This study met its primary end point, with improvement in overall lip fullness similar for VYC-15L compared with NASHA at 3 months. In addition, VYC-15L treatment resulted in improvements in perioral lines at rest and subject-rated satisfaction with lips and lip lines. Further support for the effectiveness of VYC-15L was demonstrated by improvements in the appearance of perioral lines at maximal contraction, severity of the oral commissures, and in overall aesthetic appearance. The subgroup analyses showed that VYC-15L is effective for all Fitzpatrick skin types. Taken together, these findings illustrate the effectiveness of VYC-15L for lip and perioral enhancement.
Responder rates with VYC-15L treatment differed across the scales used. Specifically, responder rates for perioral line severity and oral commissures severity were generally lower than responder rates for lip fullness. Several factors may contribute to this difference. First, although responder rates were defined by ≥1-point improvements for all scales, differences in the number of reportable severity scores (i.e., 5-point LFS vs 4-point POLM and OCSS) may have affected investigator assessments. Second, the lower rates on the POLM may be related to the fact that dermal fillers are intended for treatment of static lines more so than dynamic lines. Therefore, effects of dermal fillers as measured by the POLM scale may be less pronounced. Finally, this study enrolled subjects based on lip fullness criteria, and therefore the LFS was the scale most likely to show response to treatment.
Most subjects reported improvements over baseline on the FACE-Q Satisfaction With Lips and Lip Lines modules with VYC-15L, coinciding with similar improvements on investigator-assessed global aesthetic improvement. In a study conducted in Europe, the percentage of investigators who reported they were satisfied with subject's lips and mouth was 90.2% at Month 3 and 62.1% at 1 year in subjects treated with VYC-15L.3,9 The TIs in this study and the European study favored VYC-15L over NASHA in terms of ease of injection and moldability.3,9 This observation is consistent with the product characteristics of VYC-15L, which were designed to require a low extrusion force during injection and enable ease of molding.1
Safety outcomes, including ISRs and treatment-related AEs, were consistent with previous studies with VYC-15L and other products in the Juvéderm family.1,3,4,9,10 Most treatment-related AEs occurred within 1 day of treatment. Subjects in this study were less likely to report severe ISRs after VYC-15L versus NASHA, which was also observed in subjects in the European study.3,9 Notably, mean scores on the FACE-Q Recovery Early Life Impact module on Day 3 were significantly higher in the VYC-15L group compared with the NASHA group, demonstrating that treatment with VYC-15L produces less disruption to normal daily activities compared with NASHA treatment. This confirms previous findings from the European study.3,9
In conclusion, this study shows that VYC-15L is safe and effective for lip and perioral enhancement, with treatment effects persisting through 1 year. Subjects expressed high levels of satisfaction with the treatment results, and EIs provided consistent assessments of the aesthetic improvements across multiple rating scales.
The authors thank Susan C. Taylor, MD, for her review and feedback of the manuscript outline. Treating and evaluating investigators, respectively, at each study site were D. E. Bank, MD and William Nolan, MD, Mt Kisco, NY; Ashish Bhatia, MD and Te Shao Hsu, MD, Naperville, IL; Brian Biesman, MD and Jennifer Martin, MD, Nashville, TN; Lisa Donofrio, MD and Ronald Savin, MD, New Haven, CT; R. G. Geronemus, MD and Jeremy Brauer, MD, New York, NY; Dee Anna Glaser, MD, Natalie Semchyshyn, MD and Ian Maher, MD, St. Louis, MO; Richard Glogau, MD, Patricia Engasser, MD, and Kristin Hudacek, MD, San Francisco, CA; Mary Lupo, MD and Katherine Holcomb, MD, New Orleans, LA; Alexander Rivkin, MD and Robert Cohen, MD, Los Angeles, CA; A. Shamban, MD and Soheil Simzar, MD, Santa Monica, CA; Susan C. Taylor, MD, Philadelphia, PA and Allison Britt-Kimmins, MD, Chadds Ford, PA; Susan Weinkle, MD and John Demetree, MD, Bradenton, FL; and Robert Weiss, MD and Margaret Weiss, MD, Hunt Valley, MD.
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