Lorenc, Z. Paul M.D.; Fagien, Steven M.D.; Flynn, Timothy C. M.D.; Waldorf, Heidi A. M.D.
Signs of aging of the face, including facial wrinkles and exaggerated nasolabial folds, are associated with photoaging; facial expression; environmental factors; volume loss; and exposure to ultraviolet radiation, nicotine, and alcohol. Several aesthetic strategies may be used to correct the aging face, depending on the nature and cause of facial wrinkles and folds. Dermal fillers are a common strategy for correction, as they involve minimally invasive treatment to reduce the signs of aging.1
The most commonly used dermal filler is hyaluronic acid; several hyaluronic acid gels are now available in the United States, and those hyaluronic acids are discussed in detail elsewhere in this Supplement. All hyaluronic acids share certain common properties and also maintain key differences. The chemical structure of pure hyaluronic acid is always the same regardless of source (hyaluronic acids are either animal- or bacteria-based). Pure hyaluronic acid is non–cross-linked, has a linear polymer, and is a chain molecule. Hyaluronic acids differ in their molecular weight distributions, and nuances in the manufacturing process define the physiochemical characteristics of each hyaluronic acid filler. Because the pure non–cross-linked hyaluronic acid degrades rapidly when injected because of tissue enzymes, hyaluronic acid products are cross-linked to resist enzymatic degradation and to increase the stiffness of the gel.2
These cross-linked hyaluronic acids result in longer lasting correction, although the extent to which hyaluronic acids can be cross-linked is limited by the need for soft gel properties for extrusion through the syringe and needle. (Increased cross-linking corresponds with increased gel stiffness.) Belotero Balance (Merz Aesthetics, Greensboro, N.C.) is a hyaluronic acid of high cross-link density. It also uses a cohesive polydensified matrix technology that results in a cohesive gel with zones of greater and lesser density3 for better adaptation by the dermis and allows for a soft, smooth fill. Belotero Balance’s cohesive polydensified matrix technology produces a product that is not uniform in structure. The result is that it is softer in some places and harder in others. This variable density and lower G′ than other hyaluronic acids makes it useful for injection into fine lines. Belotero Balance also has low viscosity, which allows it to be injected easily and spread into surrounding tissues. In this article, we review four studies: two pivotal studies that demonstrated the noninferiority, then superiority, of Belotero Balance to bovine collagen; a third study that compared the safety and 12-month longevity of Belotero Balance to Juvéderm XC (Allergan, Inc., Irvine, Calif.) and Restylane (Medicis Pharmaceutical Corp., Scottsdale, Arizona); and, finally, a 5-year retrospective chart analysis of patients who received Belotero Balance (called Basic in Europe). A fifth study on the use of Belotero Balance in persons of color is included in this Supplement as a standalone article.4 (Editor’s note: In Europe and some other parts of the world, Belotero Balance is known as Belotero Basic. To reduce confusion and avoid cumbersome language, the authors have used Belotero Balance throughout this article to report both North American and European studies.)
SIX-MONTH PRIMARY ENDPOINT STUDY
In this study by Narins and colleagues, investigators set out to compare the safety and efficacy of Belotero Balance with bovine collagen (Allergan) in the correction of moderate to severe nasolabial folds in a split-face study.5 Bovine collagen was chosen as the comparator because all previously marketed hyaluronic acids in the United States have been evaluated against bovine collagen in their pivotal clinical trials for U.S. Food and Drug Administration approval.6–9
The prospective, randomized, double-blind, active-controlled study was conducted in the United States at six sites from November of 2006 to July of 2007. Subjects were seeking correction of moderate to severe bilateral nasolabial folds, were aged 18 to 75 years, and included men and women. Nasolabial fold severity was measured using the Wrinkle Severity Rating Scale (Table 1). Subjects were required to have bilateral nasolabial folds with Wrinkle Severity Rating Scale scores of 2 or 3, as determined by a blinded evaluator.
After eligibility was confirmed, one nasolabial fold was injected with Belotero Balance and the contralateral nasolabial fold was injected with bovine collagen at the baseline visit. For each subject, the treatment was determined using a random allocation schedule. The initial treatment was evaluated after 2 weeks, with a touch-up injection permitted to achieve optimal correction. The follow-up phase consisted of visits at weeks 2, 4, 8, 12, 16, and 24 after the last injection.
For the hyaluronic acid injections, prefilled, 1-ml, single-use syringes were used. The amount of filler injected was at the discretion of the investigator and dependent on Wrinkle Severity Rating Scale score, and achieving an optimal cosmetic result was the endpoint.
Collagen injections were implanted based on product instructions. The amount used was also at the discretion of the investigator and was based on the Wrinkle Severity Rating Scale score.
In both treatment arms, topical anesthetic was allowed before injection for pain-sensitive subjects. Alternatively, infraorbital nerve block was permitted (e.g., 1% lidocaine). However, local anesthetic infiltration of the study injection site was not permitted.
The subject, treating investigator, and blinded evaluator performed independent effectiveness assessments at 2, 4, 8, 12, 16, and 24 weeks using the Wrinkle Severity Rating Scale, the Global Aesthetic Improvement Scale, and the visual analogue scale. The study’s primary endpoint for effectiveness was the mean change in the Wrinkle Severity Rating Scale score of each nasolabial fold at week 12 as determined by the blinded evaluator, and safety was determined based on the frequency of adverse events.
Results of the primary effectiveness endpoint demonstrated superiority (and noninferiority) of Belotero Balance over bovine collagen (p < 0.001). The mean change, as determined by the blinded evaluator, using the Wrinkle Severity Rating Scale from baseline at week 12 was 1.25 ± 0.63 for Belotero Balance and 0.98 ± 0.72 for bovine collagen, for a difference of 0.27 ± 0.77. Comprehensive Wrinkle Severity Rating Scale results from this study are listed in Table 2.5
In addition, Belotero Balance was favored over bovine collagen by the treating investigator and the blinded evaluator using the Global Aesthetic Improvement Scale at weeks 12, 16, and 24. The mean Global Aesthetic Improvement Scale evaluation for subjects was similar to those of the treating investigators and blinded evaluators, although the results were not statistically significant at week 12 (p = 0.38). By week 16, though, the results were statistically significant (p = 0.003). Finally, the visual analogue scale fill state was in favor of Belotero Balance, based on evaluations from the blinded evaluators and the treating investigators by week 12 and from subjects by week 16.
According to the treating investigators, overall, more than twice the percentage of subjects maintained correction on the Belotero Balance side compared with the bovine collagen–treated side from weeks 2 to 24. Figure 1 shows representative results of patients treated with Belotero Balance and collagen.5
Severe procedure-related adverse events associated with Belotero Balance included injection-site swelling in eight subjects (6.8 percent) and injection-site bruising in 10 subjects (8.6 percent). For bovine collagen, severe procedure-related adverse events were injection-site erythema and injection-site swelling, each occurring in 10 patients (8.5 percent). Most injection-site responses were mild to moderate in severity and were less than 7 days’ duration. There were no significant differences between the two groups in the proportion of adverse events considered to be related to the injection-site procedure.
This study demonstrated Belotero Balance to be superior (and noninferior) for the correction of moderate to severe nasolabial folds over the course of a 24-week postinjection period. Patients who received Belotero Balance experienced better clinical correction and a smoother, more natural appearance compared with bovine collagen, and these results were maintained for the duration of the study. In fact, more than twice the percentage of subjects maintained correction on the Belotero Balance side (54.4 percent) than on the bovine collagen side (22.3 percent).
OPEN-LABEL EXTENSION STUDY
In this study, 95 of 118 subjects from the primary endpoint study continued into an open-label extension study consisting of treatment with Belotero Balance in both nasolabial folds at the completion of the office visit at week 24.10 Touch-up treatments were allowed to maintain optimal correction, and subjects were assessed at weeks 32, 48, 72, and 96.
At each of the four follow-up evaluations, subjects experienced decreases in the severity of nasolabial folds from baseline on the Wrinkle Severity Rating Scale as evaluated by treating physicians (Fig. 2). The effects persisted in the majority (approximately 80 percent) of subjects, who went without repeated treatment for at least one interval of 48 weeks. The filler was well tolerated, with only one of 34 total adverse events (injection-site bruising) considered to be related to the study device. The bruising was reported on both sides of the face and was described as moderate by the investigator and resolved in 3 days. The study also tested in 79 subjects, for whom pretreatment and posttreatment samples were available, the potential for Belotero Balance to produce an antibody response. Immunoglobulin G titer increased from before to after treatment in only one subject, and all tests for immunoglobulin E antibody were negative.
Investigators also assessed mean Global Aesthetic Improvement Scale scores in the open-label extension study. Findings were similar to Wrinkle Severity Rating Scale scores in that treating investigators judged appearance of nasolabial folds in subjects treated with hyaluronic acid with cohesive polydensified matrix as indicating “greater improvement” than patients treated with bovine collagen at 32, 48, 72, and 96 weeks, as noted in Figure 3.
The effects of Belotero Balance in this long-term, open-label study persisted in the majority of subjects without repeated treatment for at least one interval of 48 weeks.
BELOTERO BALANCE COMPARED WITH OTHER HYALURONIC ACIDS
Until an article published by Prager et al. last year,11 data comparing the safety and longevity of hyaluronic acids to each other have not been available. In this prospective, split-face, randomized, two-arm study, a total of 40 subjects were divided into two treatment arms: comparison A and comparison B. In comparison A, 20 subjects received Belotero Balance (called Basic in Europe) in one nasolabial fold and Restylane in the other. In comparison B, 20 subjects received Belotero Balance in one nasolabial fold and Juvéderm in the other. Fold severity was measured using the Merz Aesthetics nasolabial severity scale to measure changes from baseline at 4 weeks, 6 months, 9 months, and 12 months (Fig. 4).12
All three fillers are manufactured using a cross-linking process with 1,4-butanediol diglycidyl ether, although each is produced in different ways. Restylane is a particulated, sieved gel,2 and Belotero Balance and Juvéderm are both nonsieved, “cohesive” gels. The mean volume used of each hyaluronic acid was slightly less than 1.5 ml per nasolabial fold; filler was injected according to instructions for use in the mid to deep dermis to full correction as assessed by the treating physician. Overcorrection was not allowed.
Originally, the trial was designed for 4 weeks, but the trial was extended to 12 months to assess cosmetic effectiveness and participant satisfaction of the hyaluronic acids under investigation. During these 12 months, patients in both arms were evaluated at three initial visits: one screening visit, the baseline visit (during which the injections took place), and a 1-month visit. Subsequent visits were at 6, 9, and 12 months after injection. The study was performed at a single site in Germany and was a phase IV clinical comparison pursuant to Good Clinical Practice. An innovative standardized tool called Phase-shift Rapid In-Vivo Measurement of Skin (GF Messtechnik GmbH, Teltow/Berlin, Germany) was used to measure differences in depth of nasolabial folds treated with Belotero Balance versus Restylane. (Investigators did not have access to Phase-shift Rapid In-Vivo Measurement of Skin during the arm comparison of Belotero Balance with Juvéderm.)
The safety profiles of all three hyaluronic acids were generally favorable. No serious adverse events occurred during the study, and no adverse event led to the premature withdrawal of any participant. Treatment-emergent adverse events were injection-site related and included hematoma, erythema, and swelling. These site-specific adverse events were mild to moderate in severity and comparable across each of the hyaluronic acids. However, swelling was observed in 25 percent of the Juvéderm subjects and in none of the Belotero Balance subjects. This swelling may be attributed, to some extent, to the vasodilatory properties of lidocaine (which is premixed with Juvéderm).
Aesthetic results were similar across all three hyaluronic acids, as measured by mean change in the five-point Merz Nasolabial Folds–At Rest Severity Scale (Fig. 3) at 4 weeks and at 6, 9, and 12 months. As expected, results at 4 weeks yielded better scores than at later time points. The study used the standardized Phase-shift Rapid In-Vivo Measurement of Skin tool, which measured intraindividual differences in depth and evenness of nasolabial folds treated with Belotero versus Restylane. As measured by Phase-shift Rapid In-Vivo Measurement of Skin, the Belotero-treated nasolabial fold demonstrated greater evenness than the Restylane-treated nasolabial fold at 4 weeks, resulting in a more even, smooth outcome. The intraindividual depth differences between Belotero and Restylane as determined from the Phase-shift Rapid In-Vivo Measurement of Skin system were a mean change of −109.5 µm for Belotero and a mean change of −71.8 µm for Restylane (p < 0.0001).
In addition to the depth measurements, a blinded subinvestigator rated nasolabial fold improvement as an improvement of at least one point from baseline to the 1-month follow-up visit on the Merz Scale. Finally, although 16 of the 40 subjects expressed no preference for one hyaluronic acid over another, when preference was stated, participants in both study arms preferred Belotero Balance.
Five-Year Retrospective Review
A retrospective, noncontrolled, nonrandomized, single-site, multipatient study was conducted at a clinic in Bad Soden, Germany, to determine the safety and efficacy of Belotero Balance based on a chart review of 317 patients who were treated over a period of 5 years. Patients were aged 24 to 87 years (mean, 55 years) and presented for a total of 668 treatments.13 Areas treated included the forehead, tear trough, crow’s feet, zygomatic arch, cheek, nasolabial folds, perioral lines, marionette lines, lip volume, lip contour, oral commissure, chin, prejowl sulcus, hands, and acne scars. In this study, longevity persisted up to 14 months (Fig. 5).
The chart review revealed no severe adverse events in any patient, including any persistent nodules or granulomas. There were no observations of the Tyndall effect, despite treatment of superficial lines in the periorbital, perioral, and cheek areas using microdroplets or linear threading techniques. The adverse events that were reported included those commonly associated with dermal fillers—erythema, edema, and ecchymosis—all of which were of short duration.
Information about patient satisfaction was anecdotal. No formal measures of patient satisfaction or efficacy were used, but the patient charts show no evidence of abiding patient dissatisfaction. Some patients mentioned that they were surprised by the mild, short-term adverse events described above.
Hyaluronic acids are the most commonly used dermal fillers for the correction of nasolabial fold and other signs of the aging face. Properties of hyaluronic acids are similar, but each product is manufactured differently, and characteristics of each vary from one to the other.
Two pivotal studies demonstrate the superiority of Belotero Balance over bovine collagen in patients evaluated at 6 months in the first study and at 18 months in the second. In the first study, more than half of the patients maintained optimal correction at 6 months on the Belotero-treated side of the face. In the second trial, most patients went through at least one cycle of 48 weeks without touch-up treatment.
In a trial comparing three hyaluronic acid products, Belotero Balance was compared with Restylane in one treatment arm and with Juvéderm in another. All three hyaluronic acids had a generally favorable safety profile, and treatment-emergent adverse events were injection-site related. Aesthetic results were similar across the three products, but Belotero Balance demonstrated greater evenness compared with Restylane at 4 weeks. Finally, a 5-year retrospective study of patients at a single treatment site in Germany demonstrated long-term safety and patient satisfaction, with evidence of effectiveness persisting up to 14 months.
Editorial and writing assistance for this article was funded by Medical Education Advocates. The authors acknowledge the editorial and writing assistance of Mark R. Vogel, M.A., a medical communications specialist in San Francisco.
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