Effectiveness and Safety of Small Gel Particle Hyaluronic

A Randomized, Evaluator-Blinded, Controlled Study of theEffectiveness and Safety of Small Gel Particle HyaluronicAcid for Lip Augmentation

RICHARD G. GLOGAU, MD,* DAVID BANK, MD, FREDRIC BRANDT, MD, SUE ELLEN COX, MD,

LISA DONOFRIO, MD, JEFFREY DOVER, MD,** STEVEN GREKIN, DO, IRA LAWRENCE, MD,

XIAOMING LIN, MS, RN, MARK NESTOR, MD, PHD, AVA SHAMBAN, MD,***

DANIEL STEWART, DO, ROBERT WEISS, MD, ROBERT A. AXFORD-GATLEY, MD,

MICHAEL J. THEISEN, PHD, AND STACY SMITH, MD

OBJECTIVES To assess the effectiveness and safety of small gel particle hyaluronic acid (SGP-HA) for lipaugmentation.

METHODS Adults (n = 180; aged 1865) scoring 1 (very thin) to 2 (thin) on the 5-point validated Medicis LipFullness Scale (MLFS) for the upper or lower lip were randomized (3:1) to SGP-HA ( 1.5 mL/lip) or notreatment. Co-primary effectiveness end points were blinded-evaluator MLFS score for upper or lower lip atweek 8. Secondary end points (MLFS score, independent photographic review, Global Aesthetic ImprovementScale [GAIS], safety assessments) were measured throughout the study.

RESULTS Statistically significantly more MLFS responders ( 1 grades of MLFS improvement at week 8)received SGP-HA (93% combined upper and lower lip responders [95% upper lip; 94% lower lip]) than notreatment (29% combined; p < .001). SGP-HA improved self-assessed combined lip GAIS (97% week 8; 74%week 24) significantly more than no treatment (0% throughout; p < .001). The SGP-HA group reportedanticipated swelling (58%) and bruising (44%), 88% mild or 11% moderate severity, without unanticipateddevice adverse events.

CONCLUSIONS SGP-HA is highly effective and well tolerated for lip augmentation. Statistically significantimprovement was evident based on the MLFS at 8 weeks, with visible results reported in the majority ofparticipants 6 months after treatment.

Medicis Aesthetics Inc. (Scottsdale, AZ) provided funding and materials for this study. Canfield loanedphotographic equipment. Complete Healthcare Communications, Inc. (Chadds Ford, PA) provided editorialsupport. Dr. Glogau is a consultant to Medicis and Allergan. Dr. Nestor is a consultant to Medicis.Dr. Shamban serves on the advisory board to Medicis.

Durable, nonpermanent dermal fillers, such ashyaluronic acid (HA) products and formerlycollagen, are used in procedures for augmenting the

lips and perioral areas, including increasing the

overall volume of the lip or enhancing the vermilion

border, and sculpting and accentuating lip

*Richard G. Glogau, MD, Inc., San Francisco, California; Center for Dermatology, Cosmetic and Laser Surgery,Mount Kisco, New York; Dermatology Research Institute LLC, Coral Gables, Florida; Aesthetic Solutions, ChapelHill, North Carolina; The Savin Center, New Haven, Connecticut; **SkinCare Physicians, Chestnut Hill,Massachusetts; Grekin Skin Institute, Warren, Michigan; Medicis Aesthetics, Scottsdale, Arizona; Center forClinical and Cosmetic Research, Aventura, Florida; Department of Dermatology, University of Miami Miller School ofMedicine, Miami, Florida; ***Ava T Shamban, MD, Inc., Santa Monica, California; Michigan Center for Skin CareResearch, Clinton Township, Michigan; Maryland Laser Skin and Vein Institute, Hunt Valley, Maryland; CompleteHealthcare Communications, Inc., Chadds Ford, Pennsylvania; Dermatology and Consulting, Cardiff, California

2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: 1076-0512 Dermatol Surg 2012;38:11801192 DOI: 10.1111/j.1524-4725.2012.02473.x

1180

contours.13 The clinical effectiveness of filler agents

is judged on aesthetic outcomes, including lip

fullness, smoothness, softness and flexibility, and

absence of nodules.47

Restylane (Medicis Aesthetics Inc., Scottsdale, AZ)

is a nonanimal-source small gel particle hyaluronic

acid (SGP-HA) that the U.S. Food and Drug

Administration (FDA) has approved for mid to deep

dermal implantation for the correction of moderate

to severe facial wrinkles and folds.8 It is supplied as

a clear gel formulation of small particles of HA in a

single-use syringe. The physical characteristics and

structure of an HA soft tissue filler and its rheolog-

ical properties are established during the manufac-

turing process. SGP-HA is formed by passing

stabilized gel through screens with a specific pore

size, producing well-defined gel particles that are

uniform in shape and diameter. This manufacturing

method coupled with other variables such as HA

concentration and percentage of cross-linking results

in a gel particle that is stiff but elastic, capable of

resisting deformation and maintaining its original

shape when subjected to external and skin tension

forces.911 Such characteristics may play an impor-

tant role in predicting how an HA filler may behave

in the skin and its ability to provide structural

support, definition, volume, and lift.

The effectiveness and safety of SGP-HA in the

treatment of facial wrinkles and folds was evaluated

in three prospective, randomized comparator trials

involving 430 treated patients.8 The injection of

SGP-HA was found to be as effective as the

correction of moderate to severe facial folds and

wrinkles as a bovine collagen product (previously in

common use, but no longer available in the United

States) and another HA dermal filler.

A retrospective review of 685 patients treated with

SGP-HA for lip augmentation in clinical practice

found that 61% were satisfied with their results after

9 months.12 Adverse effects, other than transient

injection site erythema and occasional bruising, were

rare and easily managed; induration and sterile

suppuration at the injection site required drainage in

one patient and were self-limiting with warm com-

presses and topical corticosteroid cream in a second

patient. Many reports, including an open-label

study, in the literature describe the effectiveness of

HA in lip augmentation.6,12,13 In a small, open-label

pilot study, 89% (16/18) of patients treated with

SGP-HA had greater lip fullness, as measured by an

improvement of one grade or more on the validated

Medicis Lip Fullness Scale (MLFS) in both lips after

8 weeks.13 This prespecified improvement criterion

was met in 18 (100%) patients for the upper lip and

in 16 (89%) for the lower lip. The clinical relevance

of this MLFS improvement was consistent with

improved scores on the subjective Global Aesthetic

Improvement Scale (GAIS). No treatment-related

adverse events (AEs) were reported.

This article presents the results of a randomized, no

treatmentcontrolled, evaluator-blinded study that

assessed the safety and effectiveness of SGP-HA for

soft tissue lip augmentation.

Methods

Patients

Eligible patients were adult men and women no

older than 65 seeking lip augmentation at 12

investigational centers and scoring 1 or 2 on the 5-

point MLFS (1 = very thin, 5 = very full) for the

upper and lower lips in patients with Fitzpatrick skin

type I, II, or III or for one or both lips in patients

with skin type IV, V, or VI, as assessed at baseline by

the treating investigator. Participants were required

to abstain from any other facial plastic surgery or

cosmetic procedures during the 9-month study

period. Exclusion criteria included a history of

severe or multiple allergies, including allergy or

hypersensitivity to injectable HA gel or local anes-

thetics; history of any disease resulting in edema of

the face or changes in facial contour during the study

period; history of any tissue augmentation therapy

or aesthetic facial surgical therapy below the level of

the lower orbital rim; any contraindication to the

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1181

implant procedures, including use of anticoagulants;

and significant abnormalities of the lips. A central

institutional review board (Quorum Review IRB,

Seattle, WA) approved the study protocol and

documents. Patients provided written informed

consent before being admitted to the study. The

study was conducted in accordance with the Decla-

ration of Helsinki and Good Clinical Practice.

Treatments

Patients were randomly assigned 3:1 to receive SGP-

HA or no treatment. A centralized randomization

system was used to ensure enrollment of a minimum

of 30 patients with darker skin types based on

classification of Fitzpatrick skin types IV, V, or VI.

Patients randomized to the no-treatment group were

untreated after screening and baseline assessments

(described below). Patients randomized to SGP-HA

were treated initially with SGP-HA for optimal lip

augmentation, which was defined as the best possi-

ble aesthetic result that could be obtained for an

individual patient, as agreed upon by the treating

investigator and patient. Patients could optionally

receive an additional touch-up treatment at 2 weeks.

All patients (treated and untreated groups) could

receive SGP-HA treatment after 6 months. SGP-HA

supplies were commercial Restylane, 1.0-mL syringe

of SGP-HA gel supplied with a 30-G, 0.5-inch

needle. The recommended dose of SGP-HA was up

to 1.5 mL per lip in any given injection session.

Recommended techniques were linear antegrade or

retrograde threading (most often used for enhance-

ment of the vermilion border) and serial puncture,

although injection techniques and anesthetic type

and use were at the discretion of the treating

investigator.

Assessments

The screening visit and initial treatment could be

performed on the same day for patient convenience.

Baseline assessments were obtained before treat-

ment, including pretreatment photographs, MLFS

score by the treating investigator, and safety

parameters (lip texture, firmness, symmetry, move-

ment, function, sensation, and mass formation).

Diaries were dispensed to all patients with instruc-

tions to record daily the extent (none, tolerable,

affects activities, disabling) of bruising, redness,

swelling, pain, tenderness, itching, and other events

around or on the lips for the first 14 days after

treatment. Seventy-two hours after treatment, a

safety visit assessed safety parameters and inter-

viewed the patient regarding AEs. At weeks 2 and 4

after treatment, MLFS (treating investigator), GAIS

(treating investigator and patient), safety parame-

ters, and AEs were assessed; photographs obtained;

and diaries returned (week 2). At weeks 8, 12, 16,

20, and 24 after treatment, MLFS (live evaluations

of patients by treating and blinded investigators),

GAIS (treating investigator and patient), safety

parameters, and AEs were assessed, and photo-

graphs were obtained.

The MLFS is a validated, 5-point scale of lip fullness

(1 = very thin; 2 = thin; 3 = medium; 4 = full;

5 = very full), used in this study to assess effective-

ness in the upper and lower lips separately. The

MLFS has been validated in a separate study.14 Each

lip (upper and lower) receives a separate score at

each visit. The GAIS is a well-accepted categorical

scale used to evaluate aesthetic improvement

(Table 1). The treating investigator and patient

scored each lip separately on the GAIS at each time

point after treatment. As a final assessment, three

TABLE 1. Global Aesthetic Improvement Scale

Score Rating Definition

3 Very much

improved

Optimal cosmetic result

2 Much

improved

Marked improvement,

but not completely optimal

1 Improved Obvious improvement

0 No change Appearance essentially

same as baseline

1 Worse Worse than originalappearance

2 Muchworse

Marked worsening in

appearance

3 Very muchworse

Obvious worsening in

appearance

LIP AUGMENTATION WITH SMALL GEL PARTICLE HYALURONIC ACID

DERMATOLOGIC SURGERY1182

reviewers blinded to treatment randomization per-

formed an independent photographic review (IPR) at

the end of the study using the MLFS.

Statistical Methods

Effectiveness and safety were analyzed based on the

intention-to-treat (ITT) population, including all

treated patients and those randomized to no treat-

ment. The co-primary effectiveness end points were

the blinded evaluator MLFS scores for upper and

lower lips at week 8. A responder was defined as a

patient with an at least 1-grade improvement on the

MLFS for upper and lower lips assessed by the

blinded evaluator at week 8 over the treating

investigators baseline MLFS assessment. This pro-

cedure ensured that the blinded evaluator had no

knowledge of the patients lip fullness at baseline.

The proportion of responders was calculated for

each group at week 8 and the statistical difference

analyzed using the Fisher exact test; p < .05 for the

treatment difference on both lips was considered

effective. Enrollment of at least 160 patients (120

with SGP-HA treatment and 40 with no treatment)

was targeted to have an estimated 99% power to

detect a difference in response at week 8 for the

primary effectiveness end point of 70% in the

treated patients compared with 25% in the patients

who received no treatment. Separate from analysis

of the overall study population, a prespecified

analysis was performed to compare treatment

response to SGP-HA with no treatment at week 8 only

in patients with Fitzpatrick skin types IV, V, and VI.

The secondary effectiveness analyses included the

treating investigator and blinded evaluator MLFS

assessments at other study visits, IPR evaluation (the

median score of the three reviewers MLFS assess-

ments was used), and the proportion of responders

on the GAIS calculated for each treatment group as

rated by the treating investigator and the patient.

Differences in the proportion of responders (based

on the MLFS or the GAIS) between the SGP-HA and

no treatment groups was evaluated using the Fisher

exact test. Correlations between GAIS ratings by the

treating investigator and patient were assessed sep-

arately at each time point for the upper and lower

lips using Spearman rank correlation coefficients;

agreement between the MLFS ratings by the treating

investigator and blinded evaluator and from IPR

assessments was assessed based on weighted kappa

statistics. Safety was assessed based on the occur-

rence of all reported and observed treatment-emer-

gent AEs (TEAEs) in patients throughout the

6-month study period.

Results

Of 180 patients randomized, 135 received SGP-HA,

and 45 received no treatment and were included in

the ITT population. Eighty patients in the SGP-HA

group received a touch-up 2 weeks after the first

treatment session. One hundred sixteen (86%) in the

SGP-HA group and 39 (87%) in the no-treatment

group completed the study. The majority of enrolled

patients were women (99%) and white (94%), with

a mean age of 47.6; 139 (77%) patients had

Fitzpatrick skin type I, II, or III, and 41 (23%) had

Fitzpatrick skin type IV, V, or VI. The demographic

characteristics of the SGP-HA and no treatment

groups were similar (Table 2).

Effectiveness

At week 8, 134 patients who received SGP-HA were

evaluated in person for upper lip treatment response,

and 127 (95%) were responders, having at least a

1-grade improvement on the MLFS; lower lip

treatment response was evaluated in 122 patients, of

whom 115 (94%) were MLFS responders. In com-

parison, the prevalence of MLFS responders at week

8 in the untreated group was 36% for the upper lip

(16/44) and 38% for the lower lip (15/39). The

prevalence of combined upper and lower lip MLFS

responders at week 8 differed significantly

(p < .001) between the SGP-HA treated group

(93%, 125/135) and the untreated group (29%,

13/45). A prespecified analysis of patients with

Fitzpatrick skin types IV, V, and VI found a similar

pattern of response (Table 3). Significant differences

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1183

between the SGP-HA and no-treatment groups were

observed at all time points after week 8, up to and

including week 24, at which point, 70% of the

SGP-HA group were MLFS responders, compared

with 37% of the control patients (p < .001;

Figure 1). Representative baseline and posttreat-

ment results are shown in Figure 2.

The percentages of responders as assessed by the

treating investigator also showed statistically signif-

icant between-treatment differences and were in

close agreement with the findings of the blinded

evaluators at all time points. Furthermore, the

blinded IPR analysis demonstrated statistically sig-

nificant differences in proportions of MLFS

responders at each time point through 24 weeks

(p < .05). Although the proportion of responders

according to IPR was notably lower in each group

than according to live evaluation, this finding is

expected based on prior studies and because photo-

graphs rarely provide the same level of information

or detail as seen with live grading.15

The findings for GAIS scoring according to patients

and unblinded treating investigators are shown in

Figure 3. Significant differences between the SGP-

HA and no-treatment groups were seen at all visits

(p < .001). No untreated patients rated themselves

TABLE 2. Patient Characteristics

Characteristic

No Treatment

(n = 45)

Small Gel Particle

Hyaluronic Acid

(n = 135) Total (n = 180)

Age, mean standard deviation,median (range)

47.2 10.9,47.0 (25.065.0)

47.8 10.5,51.0 (18.065.0)

47.6 10.6,50.0 (18.065.0)

Female, n (%) 45 (100) 134 (99) 179 (99)

Race, n (%)

White 41 (91) 128 (95) 169 (94)

American Indian or Alaskan native 1 (2) 1 (

as improved at any time point; treating investigators

rated 0% to 8.8% of patients in this group as

improved at any time point.

The volume of SGP-HA injected was left to the

discretion of the treating investigators to achieve the

optimal aesthetic result for individual patients, with

TABLE 3. Proportion of Responders to Small Gel Particle Hyaluronic Acid (SGP-HA) Compared With No

Treatment at Week 8*

No Treatment SGP-HA

Overall ITT population

Upper lip

n/N 16/44 127/134

Proportion of responders (95% CI) 0.364 (0.2240.522) 0.948 (0.8950.979)

Lower lip

n/N 15/39 115/122


Upper and lower lips combined

n/N 13/45 125/135


Fitzpatrick IV, V, VI subpopulation

Upper lip

n/N 5/9 28/30


Lower lip

n/N 0/4 17/18


Upper and lower lips combined

n/N 3/10 29/31


CI, confidence interval.

*Response is defined as an improvement of 1 points in Medicis Lip Fullness Scale score in the intention-to-treat (ITT) population fromthat assessed by the treating investigator at baseline to that assessed by the blinded evaluator at week 8.Includes the entire ITT population (patients with both lips eligible for efficacy evaluation plus those with Fitzpatrick IV, V, VI with only one

lip eligible for efficacy evaluation).p < .02 for SGP-HA versus no treatment based on Fisher exact test.

Figure 1. Percentage of responders (1 grade improvement from baseline based on the Medicis Lip Fullness Scale) aftertreatment with small gel particle hyaluronic acid (SGP-HA) or no treatment, according to live assessments by blindedevaluators. The first assessment occurred at 8 weeks. Statistical significance of difference was p < .001 for SGP-HA versusno treatment at all time points.

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1185

(A) (D)

(B) (E)

(C) (F)

Figure 2. Representative photographs of patients lips (A,D) before treatment, (B,E) 8 weeks after treatment, and (C,F)24 weeks after treatment. The patient on the left received 1.2 mL in her lower lip followed by 0.2 mL touch-up and 1.5 mL inher upper lip followed by 0.5 mL touch-up. The patient on the right received 0.9 mL in her lower lip followed by 0.3 mLtouch-up and 0.9 mL in her upper lip followed by 0.5 mL touch-up.

0

20

40

60

80

100

0 4 8 12 16 20 24

GA

IS R

espo

nder

s, %

Weeks

Paent InvesgatorRangs Rangs

SGP-HAUpper LipLower LipBoth Lips

No treatmentUpper LipLower LipBoth Lips

Figure 3. Percentage of responders (1 grade improvement from baseline based on the Global Aesthetic ImprovementScale) after treatment with small gel particle hyaluronic acid (SGP-HA) or no treatment according to patients (triangularsymbols; percentage of responders in the no-treatment group was zero at all time points) and according to live assessmentsby unblinded treating investigators (circular symbols; there is complete overlap between the values for both lips and upperlip). Statistical significance of difference was p < .001 for SGP-HA versus no treatment at all time points, for patientassessments and treating investigator assessments.



a recommended maximum volume of 1.5 mL per lip

at each treatment session. The mean volume injected

at the initial visit was 1.3 mL (range 0.32.5 mL)

for upper lips and 1.1 mL (range 0.12.0 mL) for

lower lips. For patients who required touch-up

injections 2 weeks after the initial treatment, the

mean volumes were 0.5 mL (range 0.081.8 mL) for

upper lips and 0.4 mL (range 0.051.0 mL) for

lower lips. The mean total volume injected at the

initial session plus 2-week touch-up was 1.6 mL

(range 0.43.6 mL) for upper lips and 1.3 mL

(range 0.12.6 mL) for lower lips. Patients ran-

domized to receive SGP-HA who subsequently

underwent repeat treatment at month 6 required

mean volumes of 1.0 and 0.9 mL for upper and

lower-lip correction, respectively, including any

touch-ups. Post hoc subgroup analyses found no

predictive correlation between volume, age, race,

injection technique, or need for touch-up and

effectiveness according to MLFS scores at week 8.

Safety

Safety assessments included review of safety

parameters (lip texture, firmness, symmetry, move-

ment, function, sensation, mass formation, and

device palpability) and patient-reported AEs at each

visit.

The specific lip safety assessments showed no

significant effect on lip sensation or function. Rare

findings of changes in texture or asymmetry were

short lived and well tolerated. No persistent lumps

or nodules were noted.

There were 1,062 TEAEs reported in patients who

received SGP-HA (Table 4); the majority of these

were classified as mild (88%; 936/1,062) or mod-

erate (11%; 116/1,062) in intensity, whereas only 10

(1%; 10/1,062) were classified as severe. Only three

patients had severe treatment-related AEs (pain,

swelling), all of which resolved within 5 days

without the need for prescription medications or

medical intervention.16 The most commonly

reported TEAEs were pain, swelling, tenderness,

contusion (bruising or ecchymosis), and erythema,

which were most often considered mild or moderate

in severity and generally lasted 5 to 10 days after the

procedure. The occurrence of any TEAEs was lower

in patients who received injections of SGP-HA by

serial puncture than in those treated with a linear

injection technique (Table 4). This difference corre-

sponded primarily to a lower occurrence of pain,

swelling, and contusion in patients receiving serial

puncture injections. TEAEs were generally less

frequent and less severe with repeat treatment. The

volume of SGP-HA injected had little effect on the

frequency of TEAEs. The respective incidences of the

five most common TEAEs (swelling, contusion,

tenderness, pain, and erythema) according to injec-

tion volume were, for the upper lip and more than

1.5 mL (n = 83), 51%, 42%, 17%, 16%, and 12%;

for the upper lip and 1.5 mL or less (n = 89); 57%,

27%, 27%, 25%, and 21%; for the lower lip and

more than 1.5 mL, 57%, 43%, 20%, 20%, and

13%; and for the lower lip and 1.5 mL or less, 51%,

28%, 18%, 19%, and 16%. Using more than 3 mL

of SGP-HA per treatment session compared with

3 mL or less may increase the incidence of moderate

to severe AEs in the lip area (43%, 33/76 vs 21%,

20/96; p = .001).

The most common AEs reported in patients diaries

were redness, bruising, tenderness, pain, and swell-

ing; a majority of patients (5695%) considered

them tolerable. The percentage of patients reporting

symptoms and the severity of the symptoms gener-

ally fell with subsequent treatments.

Five serious AEs (SAEs) were reported; four were

judged to be unrelated to treatment, and one (transient

ischemic attack)was consideredprobably not related to

the device and not related to the procedure. The SAE of

transient ischemic attack resolved 1 day after onset,

three of the other SAEs resolvedwithin 3 to 7 days after

onset, and resolution of the fifth SAE was unknown

(patient was found to be pregnant, did not receive SGP-

HA, andwaswithdrawn from the study and then lost to

follow-up). No deaths were reported during the study,

and no patients discontinued because of an AE.

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1187

TABLE4.Summary

ofTreatm

ent-EmergentAdverseEvents

(TEAEs)

LinearRetrograde

LinearAntegradeandRetrograde

LinearRetrogradeandSerial

Puncture

LinearAntegrade,Retrograde,

andSerialPuncture

SGP-HA

SGP-HA

SGP-HA

SGP-HA

No

Treatm

ent

(n=12)

First

Treatm

ent

(n=43)

Second

Treatm

ent

(n=21)

No

Treatm

ent

(n=8)

First

Treatm

ent

(n=68)

Second

Treatm

ent

(n=47)

No

Treatm

ent

(n=6)

First

Treatm

ent

(n=25)

Second

Treatm

ent

(n=11)

No

Treatm

ent

(n=8)

First

Treatm

ent

(n=31)

Second

Treatm

ent

(n=14)

TEAE

n(%

)

AnyTEAE

4(33)

42(98)

21(100)

3(38)

59(87)

35(74)

3(50)

23(92)

2(18)

4(50)

20(65)

2(14)

TEAEsin

5%

ofpatients

Swelling*

042(98)

21(100)

037(54)

30(64)

015(60)

00

1(3)

0

Contusion

015(35)

5(24)

041(60)

20(43)

012(48)

00

4(13)

0

Pain

015(35)

8(38)

1(13)

17(25)

11(23)

02(8)

00

00

Tenderness

04(9)

00

19(28)

15(32)

011(44)

1(9)

00

0

Erythema

03(7)

00

18(26)

10(21)

02(8)

00

2(6)

0

Headach

e0

2(5)

00

7(10)

3(6)

01(4)

02(25)

1(3)

0

Skinexfoliation

01(2)

00

10(15)

2(4)

00

00

3(10)

0

Naso

pharyngitis

03(7)

00

5(7)

2(4)

01(4)

01(13)

00

Oralherpes

1(8)

1(2)

00

2(3)

2(4)

02(8)

00

1(3)

0

Sinusitis

1(8)

1(2)

00

3(4)

1(2)

1(17)

00

02(6)

0

Mass

05(12)

2(10)

00

00

00

00

1(7)

Upperresp

iratory

tract

infection

01(2)

01(13)

1(1)

01(17)

2(8)

00

2(6)

0

Edema

01(2)

00

00

05(20)

1(9)

00

0

Lip

swelling

00

00

5(7)

00

2(8)

00

00

Ecchymosis

00

00

2(3)

00

4(16)

00

00

Acn

e0

00

02(3)

1(2)

02(8)

00

00

Herpessimplex

2(17)

2(5)

00

00

00

00

00

Influenza

01(2)

00

1(1)

00

00

02(6)

0

Urinary

tract

infection

02(5)

00

1(1)

00

1(4)

00

00

Lip

exfoliation

00

00

00

00

00

3(10)

0

Arthropodbite

02(5)

00

00

00

00

00

Influenza-like

illness

00

00

1(1)

00

00

1(13)

00

Inso

mnia

02(5)

00

00

00

00

00

Rhinitis

00

00

00

00

01(13)

1(3)

0



TABLE4.Continued LinearRetrograde

LinearAntegradeandRetrograde

LinearRetrogradeandSerial

Puncture

LinearAntegrade,Retrograde,

andSerialPuncture

SGP-HA

SGP-HA

SGP-HA

SGP-HA

No

Treatm

ent

(n=12)

First

Treatm

ent

(n=43)

Second

Treatm

ent

(n=21)

No

Treatm

ent

(n=8)

First

Treatm

ent

(n=68)

Second

Treatm

ent

(n=47)

No

Treatm

ent

(n=6)

First

Treatm

ent

(n=25)

Second

Treatm

ent

(n=11)

No

Treatm

ent

(n=8)

First

Treatm

ent

(n=31)

Second

Treatm

ent

(n=14)

TEAE

n(%

)

Rhinorrhea

00

00

00

00

00

2(6)

0

Bronch

itis

00

01(13)

00

00

00

00

Contact

derm

atitis

1(8)

00

00

00

00

00

0

Depression

00

00

00

00

1(9)

00

0

Dysp

lastic

nevus

syndrome

00

1(5)

00

00

00

00

0

Jointsp

rain

00

00

00

1(17)

00

00

0

Lip

disco

loration

00

1(5)

00

00

00

00

0

Muscle

spasm

s1(8)

00

00

00

00

00

0

Oraldysesthesia

00

00

00

00

00

01(7)

Oralhypoesthesia

00

00

00

00

00

01(7)

Sinusheadach

e0

00

00

01(17)

00

00

0

TEAEsoccurringin5%

ofthesafety

populationsoftheSGP-HAorno-treatm

entgroupsare

listedforeach

injectiontype.

*Swellingoffacialareasfrom

anycause,includinglocalanestheticorbruising.

Includessloughingoftheskin,peeling,desq

uamation,andsu

perficialdesq

uamation.

Tyndalleffect

22orotherdisco

lorationnotcausedbybruising.

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1189

Discussion

Multiple assessment methods were used to confirm

the benefit of SGP-HA for lip augmentation.

Whether live grading by blinded evaluators, live

grading by unblinded treating investigators, or

independent review by blinded evaluators of

photographs taken during the study, all assessment

methods showed significant differences in lip fullness

between patients treated with SGP-HA and the no-

treatment group. The results from the unblinded

physicians demonstrated the best response, but

results from the live evaluations by blinded physi-

cians closely matched those results. That the

response measured from the IPR was the lowest is

not surprising because in-person examination of

patients allows three-dimensional assessment, inter-

active repositioning of the lips, and assessment with

movementviews that are not possible with

photographs.

The results of the current study clearly demonstrated

the durability of the augmentation provided by

SGP-HA. All of the pivotal assessments (live blinded

evaluations, unblinded evaluator scoring, and IPR)

showed statistically significant differences in MLFS

response between the treatment group and the

control group through 6 months (week 24). The

data from the GAIS scoring, on which patients and

physicians noted significant differences at all time

points, further corroborated the persistence of effect.

This durability compares favorably with collagen

products (animal and human, no longer available in

the United States), which produce results that last an

average of approximately 3 months.6

SGP-HA treatment for lip augmentation was well

tolerated. The majority of reported AEs were mild to

moderate in severity, anticipated in their nature

(swelling, contusion, pain), and generally resolved

promptly. No persistent nodules, masses, or signif-

icant asymmetry were noted during the study.

A number of injection techniques are used for SGP-

HA treatment, and the choice of injection techniques

used in this study was left to the discretion of the

treating investigators to reflect clinical practice.

Different injection techniques may influence the final

treatment outcome.8,17 The recommended tech-

niques in this study were serial puncture or linear

antegrade threading for the body of the lips and

linear retrograde threading for enhancement of the

vermilion border. Instructions included taking care

to avoid intramuscular injection or excess deposition

of material into individual areas, gentle palpation

for uniform deposition, and topical cooling if

excessive swelling occurred after the injection. A

somewhat surprising finding was fewer AEs with the

serial puncture technique. It is generally thought that

reducing the number of needle punctures and

threading the needle along a plane of tissue before or

during implantation will lead to less bleeding or

bruising when performing facial wrinkle correction.

These unexpected findings from this study may

warrant further investigation to confirm whether

injectors should adjust their technique when per-

forming lip augmentation.

A number of dermal fillers (carboxymethylcellulose

gel with calcium hydroxyapatite microspheres,

collagen with polymethylmethacrylate microspheres,

silicone polymethylsiloxane, and HA formulations

other than SGP-HA) have been studied for lip

augmentation but do not have FDA approval for this

indication, and large randomized controlled trials are

lacking.7 Soft tissue fillers differ in effectiveness,

safety, and tolerability.6,18 Fillers derived from non-

animal sources pose less risk of allergic reactions;

animal-source collagen fillers, although no longer

available in the United States, are associated with

allergic reactions and short persistence, whereas

nonanimal-source HA has little antigenic specificity,

conferring a low risk for an allergic response.4,19 In

contrast to collagen, superficial injection of HA fillers

may produce nodules and the Tyndall effect. No such

effects were observed in the present study with SGP-

HA. A clinical advantage with HA fillers is the

reversibility of the effect; HA can be hydrolyzed with

hyaluronidase, resulting in the dispersion of the filler

and reversal of lip augmentation within hours. The



FDA has recently approved SGP-HA for lip augmen-

tation, based largely on results of the pivotal study

presented in this report.8

The results of this study should be interpreted in the

context of its limitations. Blinded evaluators per-

formed the baseline primary efficacy end point

assessments, whereas unblinded treating investiga-

tors performed the week 8 assessments. This

approach ensured that knowledge of treatment

assignment did not bias the baseline MLFS scores.

It could be argued that scoring by the blinded

evaluators and treating investigators might have

been inconsistent, reducing the accuracy of assess-

ments of postbaseline changes in lip fullness, but the

MLFS has high interobserver reliability, with

weighted kappa values (range 0.600.83) that indi-

cate substantial to almost perfect agreement.14,20

Therefore, it is likely that any between-observer

effects on baseline scoring were minimal. The

protocol specified that investigators could use their

discretion regarding the injection techniques and

comfort measures used, which may have introduced

technique-related variability of results, but permit-

ting investigator discretion enabled this study to

more authentically reflect clinical practice than a

protocol that dictated details of technique. Evidence

that discretionary choice of technique influenced

outcomes was seen in a higher rate of AEs with

linear threading than with serial puncture.

Lip augmentation is associated with procedural dis-

comfort that is frequently managed using topical or

infiltrative anesthetics or regional blocks. Nearly all

(96%) patients enrolled in the present study received

an anesthetic during the first SGP-HA treatment,

including topical, regional, or a combination of both

types of anesthesia. Injecting local anesthetic for an

infraorbital or submental nerve block can distort

anatomic features and complicate the augmentation

procedure. A recently available FDA-approved for-

mulation of SGP-HA is premixed with lidocaine to

circumvent this effect.21 This formulation was not

included in the present study because it was not yet

approved when the study took place.

Conclusions

SGP-HA is highly effective and well tolerated for lip

augmentation. Statistically significant improvement

was evident based on the MLFS at 8 weeks, with

visible results reported in the majority of patients

6 months after treatment.

Acknowledgments The independent photographic

reviewers were Michael A.C. Kane, MD (New York,

NY), Z. Paul Lorenc, MD (New York, NY), and

Mark Rubin, MD (Beverly Hills, CA).

References

1. Beer KR. Rejuvenation of the lip with injectables. Skin Therapy

Lett 2007;12:57.

2. Glavas IP. Filling agents. Ophthalmol Clin North Am

2005;18:24957, vvi.

3. Buck DW II, Alam M, Kim JY. Injectable fillers for facial

rejuvenation: a review. J Plast Reconstr Aesthet Surg 2009;62:

118.

4. Ali MJ, Ende K, Maas CS. Perioral rejuvenation and lip

augmentation. Facial Plast Surg Clin North Am 2007;15:491500, vii.

5. Clymer MA. Evolution in techniques: lip augmentation. Facial

Plast Surg 2007;23:216.

6. Sarnoff DS, Saini R, Gotkin RH. Comparison of filling agents for

lip augmentation. Aesthet Surg J 2008;28:55663.

7. Smith KC. Reversible vs. nonreversible fillers in facial aesthetics:

concerns and considerations. Dermatol Online J 2008;14:3.

8. Medicis Aesthetics Inc. Restylane (hyaluronic acid). Instructionsfor use. Scottsdale, AZ: Medicis Aesthetics Inc; 2011.

9. Kablik J, Monheit GD, Yu L, Chang G, et al. Comparative

physical properties of hyaluronic acid dermal fillers. Dermatol

Surg 2009;35:30212.

10. Sundaram H, Voigts B, Beer K, Meland M. Comparison of the

rheological properties of viscosity and elasticity in two categories

of soft tissue fillers: calcium hydroxylapatite and hyaluronic acid.

Dermatol Surg 2010;36:185965.

11. Stocks D, Sundaram H, Michaels J, Durrani MJ, et al.

Rheological evaluation of the physical properties of hyaluronic

acid dermal fillers. J Drugs Dermatol 2011;10:4449.

12. Bosniak S, Cantisano-Zilkha M, Glavas IP. Nonanimal stabilized

hyaluronic acid for lip augmentation and facial rhytid ablation.

Arch Facial Plast Surg 2004;6:37983.

13. Solish N, Swift A. An open-label, pilot study to assess the

effectiveness and safety of hyaluronic acid gel in the restoration

of soft tissue fullness of the lips. J Drugs Dermatol 2011;10:

1459.

GLOGAU ET AL

38 :7 PART I I : JULY 2012 1191

14. Kane MAC, Lorenc ZP, Lin X, Smith SR. Validation of a lip

fullness scale for assessment of lip augmentation. Plast Reconstr

Surg 2012;129:822e8e.

15. Cohen SR, Holmes RE. Artecoll: a long-lasting injectable wrinkle

filler material: report of a controlled, randomized, multicenter

clinical trial of 251 subjects. Plast Reconstr Surg 2004;114:96476; discussion 9779.

16. Medicis Aesthetics Inc. Restylane injectable gel lip augmentation

indication: general and plastic surgery devices panel meeting

(Data on File). Scottsdale, AZ: Medicis Aesthetics; 2011.

17. Glogau RG, Kane MA. Effect of injection techniques on the rate

of local adverse events in patients implanted with nonanimal

hyaluronic acid gel dermal fillers. Dermatol Surg 2008;34:

S1059.

18. Niamtu J 3rd. Complications in fillers and Botox. Oral

Maxillofac Surg Clin North Am 2009;21:1321, v.

19. Andre P. Evaluation of the safety of a non-animal stabilized

hyaluronic acid (NASHA Q-Medical, Sweden) in European

countries: a retrospective study from 1997 to 2001. J Eur Acad

Dermatol Venereol 2004;18:4225.

20. Landis JR, Koch GG. The measurement of observer agreement for

categorical data. Biometrics 1977;33:15974.

21. Medicis Aesthetics Inc. Restylane-L. Instructions for use.

Scottsdale, AZ: Medicis Aesthetics Inc; 2010.

22. Hirsch RJ, Narurkar V, Carruthers J. Management of injected

hyaluronic acid induced Tyndall effects. Lasers Surg Med

2006;38:2024.

Address correspondence and reprint requests to:Richard G. Glogau, MD, San Francisco Dermatology, 350Parnassus Ave, Suite 400, San Francisco, CA 94117, ore-mail: [email protected]



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