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Functional Safety Assessments Used in a Randomized Controlled Study of Small Gel Particle Hyaluronic Acid for Lip Augmentation

Smith, Stacy R. MD*; Vander Ploeg, Heather M. BS, MBA; Sanstead, Mary BSN, RN; Albright, Craig D. PhD; Theisen, Michael J. PhD; Lin, Xiaoming MS, RN§

doi: 10.1097/DSS.0000000000000164
Original Article
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BACKGROUND Dermal fillers are commonly injected in the lips for aesthetic treatment. Small gel particle hyaluronic acid (SGP-HA) is the only filler approved by the US Food and Drug Administration for this indication, based on a pivotal trial of effectiveness and safety.

OBJECTIVE To assess multiple measures of tolerability and lip function in a randomized controlled trial of SGP-HA (without lidocaine) for lip augmentation.

MATERIALS AND METHODS Patients were randomized to SGP-HA (n = 135) or no treatment (n = 45) at baseline; all could receive SGP-HA after 6 months. Assessments for tolerability and lip function at clinic visits throughout the study included lip texture, firmness, symmetry, movement, function, and sensation; device palpability; mass formation; and ease of repeat injection.

RESULTS Many assessments were normal (lip function, sensation) or unremarkable (movement, mass formation, ease of reinjection) in most patients. Nearly all abnormalities with other assessments (texture, firmness, symmetry, device palpability) were mild and transient (<4 weeks).

CONCLUSION Lip augmentation with SGP-HA showed excellent safety with the assessments used in this study. Further study should be conducted to validate these assessments with the goal of developing a comprehensive scale for measuring potential functional complications and risks.

*Private Practice, Encinitas, California;

Valeant Dermatology, Division of Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey;

Complete Healthcare Communications, Inc., Chadds Ford, Pennsylvania;

§Ancor Pharmaceuticals Inc., Palo Alto, California

Address correspondence and reprint requests to: Stacy R. Smith, MD, 561 Saxony Place, Suite 102, Encinitas, CA 92024, or e-mail: ssmith@stacyrsmithmd.com

Supported by Valeant Pharmaceuticals. Editorial Support for this publication was provided by Complete Healthcare Communications. Other study investigators included David Bank, MD, Fredric Brandt, MD, Sue Ellen Cox, MD, Lisa Donofrio, MD, Jeffrey Dover, MD, Richard Glogau, MD, Steven Grekin, DO, Mark Nestor, MD, Ava Shamban, MD, Daniel Stewart, DO, Robert Weiss, MD, and their staffs.

Small gel particle hyaluronic acid without lidocaine (SGP-HA; Restylane, Valeant Dermatology, a Division of Valeant Pharmaceuticals North America LLC, Bridgewater, NJ), a nonanimal-source dermal filler, was originally approved for the correction of facial wrinkles such as nasolabial folds. The US Food and Drug Administration approved SGP-HA for submucosal lip augmentation in patients older than 21 years.1

The objective of this article is to report the safety findings from a large, randomized controlled clinical study that includes detailed assessments of multiple aspects of tolerability and lip function.2

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Materials and Methods

Patients

Patients with Fitzpatrick skin types I, II, or III and a baseline score of 1 or 2 (very thin or thin) on both the upper and lower lips as assessed by the treating investigator were eligible for enrolment.3 Patients with Fitzpatrick skin Types IV, V, or VI were eligible for enrolment if they had a Medicis Lip Fullness Scale score of 1 or 2 for one or both lips at baseline. Patients with mild lip asymmetry at screening were permitted to enroll, but patients were excluded if they had abnormal lip findings.2

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Study Design

This prospective, randomized evaluator-blinded study was conducted at 12 US study centers in accordance with the US Code of Federal Regulations on Good Clinical Practice, consistent with the Declaration of Helsinki and International Conference on Harmonisation. The study protocol and informed consent forms were approved before use by an Institutional Review Board (Quorum Institutional Review Board, Seattle, WA). Each patient provided written informed consent before enrolment and initiation of study procedures.

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Study Treatment

Eligible patients (N = 180) were randomized 3:1 to receive SGP-HA (n = 135) or no treatment (n = 45). Small gel particle hyaluronic acid was provided at a concentration of 20 mg/mL in sterile 1.0-mL syringes with a sterilized 30-gauge × 0.5-in needle. Small gel particle hyaluronic acid was administered (recommended total volume, ≤1.5 mL in upper and ≤1.5 mL in lower lip at each treatment session) by submucosal injection (linear retrograde threading, linear antegrade threading, and serial puncture) and included the vermilion border or other appropriate depth at the discretion of the investigator. Patients in the SGP-HA group could be treated at baseline and at 6 months; patients in the no-treatment group could receive their first treatment at the 24-week visit. Patients could receive touch-up injections 2 weeks after each treatment to ensure optimal correction.

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Lip Assessments

Lip assessments (Table 1) were performed separately for each lip by a trained, experienced nonblinded staff member at screening/baseline immediately before treatment, at follow-up visits (72 hours; touch-up [if performed]; Weeks 2, 4, 8, 12, 16, and 20), at the Week 24 follow-up/treatment, and at follow-up visits after Week 24. Assessment of lip symmetry compared the left and right sides of the upper and lower lips separately (Figure 1). Assessment of lip texture compared the visual and tactile surface of the lips after treatment with findings at screening/baseline, lip firmness compared the responsiveness of the lips with stress or pressure applied by the assessor, and palpability referred to expected and unexpected changes in the lips that the assessor could precisely identify by feel. Mass formation could have presented as a palpable or visible lump in or on the lips but was considered separately from palpability.

TABLE 1

TABLE 1

Figure 1

Figure 1

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Statistics

Lip assessment scores were summarized by treatment and visit.

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Results

Patients

Patient disposition and demographic characteristics were previously described.2

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Lip Texture

For patients initially treated with SGP-HA, 97.7% (2351 of 2406) of lip texture assessments throughout the study were normal, 1.6% (38 of 2406) mildly abnormal, and 0.7% (16 of 2406) moderately abnormal. The moderately abnormal lip texture findings returned to normal within 4 weeks. One patient had severely abnormal lower lip texture at Week 4 that returned to normal by Week 8. This patient assessed the lip appearance as improved from baseline at Week 4 and expressed satisfaction with the treatment result despite the abnormal lip texture. In patients who received their first or second injection at 24 weeks, 93.6% (925 of 988) of assessments of lip texture for the upper and lower lips were normal at 72 hours posttreatment and subsequent visits, whereas 6.3% (62 of 988) were mildly abnormal. One patient with moderately abnormal upper lip texture 72 hours after the second injection returned to normal within 2 weeks. The great majority (99.7%; 313 of 314) of assessments of lip texture were normal at 4 weeks after the 6-month treatment.

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Lip Firmness

For patients initially treated with SGP-HA, 91.3% (2196 of 2406) of lip firmness assessments throughout the study were normal, and 8.7% (209 of 2406) were mildly abnormal. Moderately, abnormal lip firmness was reported in 1 patient treated with SGP-HA at 72 hours after initial treatment and returned to normal by Week 4. No patient treated with SGP-HA had severely abnormal lip firmness at any time. For patients who received their first or second injection of dermal filler at 24 weeks, 89.1% (882 of 990) of lip firmness assessments were normal at 72 hours posttreatment and at subsequent visits, whereas 10.9% (108 of 990) were mildly abnormal. The majority (95.6%; 302 of 316) of assessments of lip firmness was normal at 4 weeks after the 6-month treatment; remaining abnormalities were mild.

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Lip Symmetry

At baseline, 6.7% (9 of 135) of patients in the group to be initially treated with SGP-HA had mild upper-lip asymmetry, and 0.7% (1 of 135) had mild lower-lip asymmetry. After the first injection of SGP-HA, 91.8% (2208 of 2406) of symmetry assessments were normal, 7.4% (177 of 2406) were mildly abnormal, and 0.5% (11 of 2406) was moderately abnormal. Severely abnormal lip symmetry was observed infrequently (0.4%; 10 of 2406); these events typically resolved within 4 weeks. Ten patients in the SGP-HA treatment group had mild lip asymmetry at baseline, and most were corrected after their injections. For patients who received their first or second injection of dermal filler at 24 weeks, 86.4% (855 of 990) of symmetry assessments for the upper and lower lips were normal at 72 hours posttreatment and at subsequent visits, whereas 11.6% (115 of 990) were mildly abnormal, 1.4% (14 of 990) were moderately abnormal, and 0.6% (6 of 990) was severely abnormal. The majority (94.6%; 299 of 316) of assessments of lip symmetry was normal at 4 weeks after the 6-month treatment; remaining abnormalities were mild (5.1%; 16 of 316) or moderate (0.3%; 1 of 316).

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Device Palpability

For patients initially treated with SGP-HA, most device palpability assessments throughout the study yielded normal findings of not palpable (13.5%; 289 of 2136) or palpable with expected feel (85.9%; 1834 of 2136), whereas few abnormal findings of palpable with unexpected feel were recorded (0.6%; 13 of 2136). Device palpability decreased over time. Small gel particle hyaluronic acid was palpable with expected feel for 90.2% (220 of 244) of assessments at Week 8 but 61.6% (143 of 232) at Week 24. This palpability with expected feel was directly associated with the degree of augmentation seen, and the gradual decrease was thought to be consistent with the expected resorption of the implant. Patients in the no-treatment group were eligible to receive their first treatment with SGP-HA at Week 24, after which the device was either not palpable (10.2%; 101 of 990) or palpable with expected feel (89.4%; 885 of 990) at most assessments. Unexpected feel of the product occurred in 0.4% (4 of 990) of assessments between 72 hours posttreatment and Week 4 (i.e., after initial treatment and retreatment at 6 months) and was managed by massaging the lips to create more uniform density of the product.

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Lip Movement

All patients successfully pronounced the list of 10 specified words, except that the assessment of some words was inadvertently omitted for 1 patient at Week 16 (SGP-HA group), 2 patients at Week 24 (1 in each group), and 1 patient at Week 4 after a second treatment with SGP-HA at 6 months.

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Lip Function

All patients at all assessments were able to drink water through a straw and therefore were rated as having normal lip function.

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Lip Sensation

All patients exhibited normal lip sensation at all visits using the cotton wisp test. Lip sensation according to the monofilament test was decreased in 1 patient in the SGP-HA group at Week 12 and in 1 patient in the SGP-HA group at Week 16. Lip sensation using the monofilament test was normal at all subsequent assessments.

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Mass Formation

One patient developed a mass on the upper lip 2 weeks after a second SGP-HA treatment at 6 months. The mass (a mucocele; not treatment-related) was successfully managed by drainage, and the lip returned to normal by the next follow-up visit at 4 weeks. All other assessments revealed no mass formation on the lips.

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Ease of Repeat Injection

Injection was no more difficult at the second treatment compared with the first in 91 of 93 cases (97.8%). In 2 patients, the second injection was more difficult presumably because of the presence of dermal filler; however, both patients expressed treatment satisfaction at the next follow-up visit.

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Discussion

The present results further demonstrate the safety and tolerability of SGP-HA in adult patients undergoing aesthetic lip augmentation. Lip safety assessments were extensive, covering a number of visual, tactile, and functional components important for appearance, normal daily activities, and patient satisfaction. This study represents the first use of an extensive battery of lip assessments to evaluate the safety of a dermal filler for aesthetic lip augmentation.

The lip safety assessments reported here are based on a set of stringently defined outcomes using scientifically grounded principles. All assessments were performed by research site staff who had received training to understand the meaning of the assessment scales and to describe functional lip abnormalities using these assessment scales. Most abnormal findings reported in this study were mild in severity and transient, consistent with previous observations.4–6 At least some of the abnormalities of lip texture, firmness, and symmetry in this study were likely to be due to swelling after injection, which is a common procedure-related event. Posttreatment lip asymmetry may result from a lack of injector expertise or by posttreatment product displacement; however, patients may present with anatomic asymmetry or with pseudoasymmetry caused by the action of facial muscles. The palpability of SGP-HA with expected feel tracks well with the previously reported efficacy of SGP-HA for lip augmentation.2 However, the presence of dermal filler may rarely affect the ease of injection and should be assessed by injectors before retreatment.

Risk-benefit considerations are important to patients seeking aesthetic augmentation procedures. Among patients with any abnormal lip assessments in this study, nearly all (99%) had ratings of improved or better on the Global Aesthetic Improvement Scale and the majority of patients (77%) chose to receive retreatment. These findings indicate that SGP-HA has an acceptable risk–benefit profile.

Although this study demonstrates the utility of this battery of lip safety assessments, the results should be viewed in light of certain limitations. For example, the comparator was no treatment. Also, these assessments inevitably contain some subjective components that depend on the training and experience of the evaluators to accurately distinguish normal from abnormal results and to grade degrees of functional impairment from mild to severe. Also, because some patients may have some limitations of lip function or asymmetry before treatment, the same evaluator should evaluate the patient at baseline and follow-up whenever possible.

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Conclusion

The functional lip safety assessment results used in the pivotal study for SGP-HA reported in this article allow physicians to fully communicate potential risks and complications before injection.

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References

1. Restylane (hyaluronic acid). Instructions for use. Medicis Aesthetics Inc.: Scottsdale, 2011.
2. Glogau RG, Bank D, Brandt F, Cox SE, et al.. A randomized, evaluator-blinded, controlled study of the effectiveness and safety of small-gel-particle hyaluronic acid for lip augmentation. Dermatol Surg 2012;38(7 Pt 2):1180–92.
3. Kane MAC, Lorenc ZP, Lin X, Smith SR. Validation of a lip fullness scale for assessment of lip augmentation. Plast Reconstruct Surg 2012;129:822e–8e.
4. Buck DW II, Alam M, Kim JY. Injectable fillers for facial rejuvenation: a review. J Plast Reconstr Aesthet Surg 2009;62:11–8.
5. Smith KC. Reversible vs. nonreversible fillers in facial aesthetics: concerns and considerations. Dermatol Online J 2008;14:3.
6. Olenius M. The first clinical study using a new biodegradable implant for the treatment of lips, wrinkles, and folds. Aesthetic Plast Surg 1998;22:97–101.
© 2015 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.