Restylane

CLINICAL PHARMACOLOGY

Clinical Trials

The safety and effectiveness of Restylane in the treatment of facial folds and wrinkles (nasolabial folds and oral commissures) were evaluated in three prospective randomized controlled clinical studies involving 430 Restylane-treated subjects.

Restylane was shown to be effective when compared to crosslinked collagen and crosslinked hyaluronic acid dermal fillers with respect to the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds.

Table 1: Maximum Intensity of Symptoms after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study 31GE0003)1

  Restylane side Zyplast side Restylane side Zyplast side
Total patients reporting symptoms
n
(%)
Total patients reporting symptoms
n
(%)
None
n
(%)
Mild
n
(%)
Moderate
n
(%)
Severe
n
(%)
None
n
(%)
Mild
n
(%)
Moderate
n
(%)
Severe
n
(%)
Bruising 72
(52.2%)
67
(48.6%)
63
(45.6%)
32
(23.2%)
35
(25.4%)
5
(3.6%)
68
(49.3%)
43
(31.2%)
23
(16.7%)
1
(0.7%)
Redness 117
(84.8%)
117
(84.8%)
17
(12.3%)
56
(40.6%)
54
(39.1%)
7
(5.1%)
17
(12.3%)
72
(52.2%)
37
(26.8%)
8
(5.8%)
Swelling 120
(87.0%)
102
(73.9%)
14
(10.1%)
54
(39.1%)
61
(44.2%)
5
(3.6%)
32
(23.2%)
65
(47.1%)
35
(25.4%)
2
(1.4%)
Pain 79
(57.2%)
58
(42.0%)
55
(39.9%)
40
(29.0%)
34
(24.6%)
5
(3.6%)
76
(55.1%)
46
(33.3%)
10
(7.2%)
2
(1.4%)
Tenderness 107
(77.5%)
89
(64.5%)
27
(19.6%)
60
(43.5%)
43
(31.2%)
4
(2.9%)
45
(32.6%)
70
(50.7%)
17
(12.3%)
2
(1.4%)
Itching 42
(30.4%)
33
(23.9%)
91
(65.9%)
31
(22.5%)
11
(8.0%)
0
(0.0%)
101
(73.2%)
27
(19.6%)
6
(4.4%)
0
(0.0%)
Other 34
(24.6%)
33
(23.9%)
93
(67.4%)
14
(10.1%)
15
(10.9%)
5
(3.6%)
94
(68.1%)
20
(14.5%)
10
(7.2%)
3
(2.2%)
1 Events are reported as local events; because of the design (split-face) of the study, causality of the systemic adverse events cannot be assigned.

Table 2: Duration of Adverse Events after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study 31GE0003)

  Restylane side Zyplast side Restylane side Zyplast side
Total patients reporting symptoms n
(%)
Total patients reporting symptoms n
(%)
Number of days Number of days
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
Bruising 72
(52.2%)
67
(48.6%)
7
(5.1%)
56
(40.6%)
6
(4.4%)
3
(2.2%)
7
(5.1%)
53
(38.4%)
5
(3.6%)
2
(1.4%)
Redness 117
(84.8%)
117
(84.8%)
19
(13.8%)
68
(49.3%)
18
(13.0%)
12
(8.7%)
19
(13.8%)
71
(51.4%)
15
(10.9%)
12
(8.7%)
Swelling 120
(87.0%)
102
(73.9%)
16
(11.6%)
84
(60.9%)
16
(11.6%)
4
(2.9%)
14
(10.1%)
70
(50.7%)
16
(11.6%)
2
(1.4%)
Pain 79
(57.2%)
58
(42.0%)
29
(21.0%)
48
(34.8%)
2
(1.4%)
0
(0.0%)
31
(22.5%)
25
(18.1%)
1
(0.7%)
1
(0.7%)
Tenderness 107
(77.5%)
89
(64.5%)
21
(15.2%)
78
(56.5%)
6
(4.4%)
2
(1.4%)
27
(19.6%)
54
(39.1%)
6
(4.4%)
2
(1.4%)
Itching 42
(30.4%)
33
(23.9%)
11
(8.0%)
25
(18.1%)
6
(4.4%)
0
(0.0%)
8
(5.8%)
22
(15.9%)
3
(2.2%)
0
(0.0%)
Other 34
(24.6%)
33
(23.9%)
7
(5.1%)
23
(16.7%)
3
(2.2%)
1
(0.7%)
10
(7.2%)
15
(10.9%)
6
(4.4%)
2
(1.4%)

Table 3: Maximum Intensity of Symptoms after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study MA-1400-02)1

  Restylane Perlane Restylane Patients Perlane Patients
Total patients reporting symptoms n
(%)
Total patients reporting symptoms n
(%)
None
n
(%)
Tolerable2
n
(%)
Affected Daily Activity2
n
(%)
Disabling2
n
(%)
None
n
(%)
Tolerable2
n
(%)
Affected Daily Activity2
n
(%)
Disabling2
n
(%)
Bruising 111
(78.2%)
122
(86.5%)
28
(20.1%)
82
(59%)
28
(20.1%)
1
(0.7%)
17
(12.2%)
97
(69.8%)
24
(17.3%)
1
(0.7%)
Redness 114
(80.3%)
118
(83.7%)
25
(18%)
96
(69.1%)
17
(12.2%)
1
(0.7%)
21
(15.1%)
105
(75.5%)
12
(8.6%)
1
(0.7%)
Swelling 127
(89.4%)
128
(90.8%)
12
(8.6%)
102
(73.4%)
23
(16.5%)
2
(1.4%)
11
(7.9%)
107
(77%)
19
(13.7%)
2
(1.4%)
Pain 108
(76.1%)
114
(80.9%)
31
(22.3%)
93
(66.9%)
14
(10.1%)
1
(0.7%)
25
(18%)
96
(69.1%)
18
(12.9%)
0
(0%)
Tenderness 123
(86.6%)
130
(92.2%)
16
(11.5%)
109
(78.4%)
12
(8.6%)
2
(1.4%)
9
(6.5%)
112
(80.6%)
18
(12.9%)
0
(0%)
Itching 67
(47.2%)
45
(31.9%)
72
(51.8%)
66
(47.5%)
1
(0.7%)
0
(0%)
94
(67.6%)
40
(28.8%)
3
(2.2%)
2
(1.4%)
Other3 3
(2.1%)
1
(0.7%)
NA NA NA NA NA NA NA NA
1 Missing values are not reported.
2 Prospective definitions for: tolerable, affected daily activity and disabling were not provided in the diary or protocol.
3 Two patients reported pimples (one Perlane/one Restylane); one Restylane patient reported a sore throat; one Restylane patient reported a runny nose; degree of disability was not reported for any of the four events.

Table 4: Duration of Adverse Events after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study MA-1400-02)1

  Restylane Patients Perlane Patients Restylane Patients Perlane Patients
Total patients reporting symptoms
n
(%)
Total patients reporting symptoms
n
(%)
Number of days2 Number of days2
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
Bruising 111
(78.2%)
122
(86.5%)
9
(8.1%)
69
(62.2%)
30
(27%)
3
(2.7%)
6
(4.9%)
81
(66.4%)
28
(23%)
7
(5.7%)
Redness 114
(80.3%)
118
(83.7%)
31
(27.2%)
71
(62.3%)
9
(7.9%)
3
(2.6%)
19
(16.1%)
87
(73.7%)
8
(6.8%)
4
(3.4%)
Swelling 127
(89.4%)
128
(90.8%)
12
(9.4%)
93
(73.2%)
19
(15.0%)
3
(2.4%)
6
(4.7%)
100
(78.1%)
17
(13.3%)
5
(3.9%)
Pain 108
(76.1%)
114
(80.9%)
37
(34.3%)
69
(63.9%)
2
(1.9%)
0
(0%)
46
(40.4%)
66
(57.9%)
2
(1.8%)
0
(0%)
Tenderness 123
(86.6%)
130
(92.2%)
21
(17.1%)
92
(74.8%)
9
(7.3%)
1
(0.8%)
24
(18.5%)
89
(68.5%)
16
(12.3%)
1
(0.8%)
Itching 67
(47.2%)
45
(31.9%)
22
(32.8%)
38
(56.7%)
6
(9.0%)
1
(1.5%)
19
(42.2%)
23
(51.1%)
3
(6.7%)
0
(0%)
Other3 3
(2.1%)
1
(0.7%)
3
(100%)
0
(0%)
0
(0%)
0
(0%)
1
(100%)
0
(0%)
0
(0%)
0
(0%)
1 Missing values are not reported.
2 Data are cumulated from up to four injection sites per patient with earliest and latest time point for any reaction provided.
3 Two patients reported pimples (one Perlane/one Restylane); one Restylane patient reported a sore throat; one Restylane patient reported a runny nose; degree of disability was not reported for any of the four events.

Table 5: Maximum Intensity of Symptoms after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study MA-1400-01)1,2

  Restylane Perlane Restylane Patients Perlane Patients
Total patients reporting symptoms
n
(%)
Total patients reporting symptoms
n
(%)
None
n
(%)
Tolerable3
n
(%)
Affected Daily Activity3
n
(%)
Disabling3
n
(%)
None
n
(%)
Tolerable3
n
(%)
Affected Daily Activity3
n
(%)
Disabling3
n
(%)
Bruising 70
(46.7%)
74
(49.3%)
79
(53%)
66
(44.3%)
4
(2.7%)
0
(0%)
75
(50.3%)
67
(45%)
7
(4.7%)
0
(0%)
Redness 87
(58%)
92
(61.3%)
62
(41.6%)
81
(54.4%)
6
(4%)
0
(0%)
57
(38.3%)
85
(57%)
7
(4.7%)
0
(0%)
Swelling 125
(83.3%)
121
(80.7%)
24
(16.1%)
109
(73.2%)
14
(9.4%)
2
(1.3%)
28
(18.8%)
108
(72.5%)
11
(7.4%)
2
(1.3%)
Pain 96
(64%)
103
(68.7%)
53
(35.6%)
84
(56.4%)
11
(7.4%)
1
(0.7%)
46
(30.9%)
90
(60.4%)
12
(8.1%)
1
(0.7%)
Tenderness 122
(81.3%)
130
(86.7%)
27
(18.1%)
110
(73.8%)
11
(7.4%)
1
(0.7%)
19
(12.8%)
116
(77.9%)
13
(8.7%)
1
(0.7%)
Itching 53
(35.3%)
58
(38.7%)
96
(64.4%)
49
(32.9%)
4
(2.7%)
0
(0%)
91
(61.1%)
54
(36.2%)
4
(2.7%)
0
(0%)
Other4 3
(2%)
3
(2%)
NA 3
(100%)
0
(%)
0
(%)
NA 3
(100%)
0
(%)
0
(%)
1 Missing values are not reported.
2 Events are reported as local events; because of the design (split-face) of the study, causality of the systemic adverse events cannot be assigned.
3 Prospective definitions for: tolerable, affected daily activity and disabling were not provided in the diary or protocol.
4 Two patients reported mild transient headache and one patient reported mild “twitching”; neither could be associated with a particular product.

Table 6: Duration of Adverse Events after Initial Treatment for the Nasolabial Fold Indication, Patient Diary (Study MA-1400-01)1,2

  Restylane Patients Perlane Patients Restylane Patients Perlane Patients
Total patients reporting symptoms
n
(%)
Total patients reporting symptoms
n
(%)
Number of days3 Number of days3
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
n
(%)
2-7
n
(%)
8-13
n
(%)
14
n
(%)
Bruising 70
(46.7%)
74
(49.3%)
13
(18.6%)
51
(72.9%)
6
(8.6%)
0
(0%)
23
(31.1%)
44
(59.5%)
6
(8.1%)
1
(1.4%)
Redness 87
(58%)
92
(61.3%)
33
(37.9%)
52
(59.8%)
2
(2.3%)
0
(0%)
38
(41.3%)
52
(56.5%)
2
(2.2%)
0
(0%)
Swelling 125
(83.3%)
121
(80.7%)
23
(18.4%)
89
(71.2%)
12
(9.6%)
1
(0.8%)
22
(18.2%)
85
(70.2%)
11
(9.1%)
3
(2.5%)
Pain 96
(64%)
103
(68.7%)
27
(28.1%)
67
(69.8%)
2
(2.1%)
0
(0%)
32
(31.1%)
67
(65%)
2
(1.9%)
2
(1.9%)
Tenderness 122
(81.3%)
130
(86.7%)
28
(23%)
87
(71.3%)
7
(5.7%)
0
(0%)
26
(20%)
94
(72.3%)
6
(4.6%)
4
(3.1%)
Itching 53
(35.3%)
58
(38.7%)
22
(41.5%)
27
(50.9%)
4
(7.5%)
0
(0%)
29
(50%)
26
(44.8%)
2
(3.4%)
1
(1.7%)
Other4 3
(2%)
3
(2%)
3
(100%)
0
(0%)
0
(0%)
0
(0%)
3
(100%)
0
(0%)
0
(0%)
0
(0%)
1 Missing values are not reported.
2 Events are reported as local events; because of the design (split-face) of the study, causality of the systemic adverse events cannot be assigned.
3 Data are cumulated from up to two injection sites per patient with earliest and latest time point for any reaction provided.
4 Two patients reported mild transient headache and one patient reported mild “twitching”; neither could be associated with a particular product.

Table 7: All Investigator-Identified Adverse Experiences (72 Hours) Number of Events per Patient per Study for the Nasolabial Fold Indication

Study Term MA-1400-01 MA-1400-02
Number of Events Restylane
(N=150)
Number of Events Perlane
(N=150)
Number of Events Restylane
(N=142)
Number of Events Perlane
(N=141)
Ecchymosis 9 10 48 44
Edema 4 4 6 10
Erythema 13 13 3 5
Tenderness 4 4 7 5
Pain 2 2 2 2
Hyperoigmentation 2 3 0 1
Pruritus 2 1 1 0
Papule 1 0 2 2
Burning 1 0 0 0
Hypopigmentation 1 0 0 0
Injection site scab 3 0 0 0

Table 8: Investigator-Identified Adverse Experiences (2 Weeks or More After Implantation) (Number of Patients) (Restylane v. Specified Active Controls—All Studies for the Nasolabial Fold Indication)

Study Term MA-1400-01 Restylane
(n=150)
(%)
MA-1400-01 Perlane
(n=150)
(%)
MA-1400-02 Restylane
(n=142)
(%)
MA-1400-02 Perlane
(n=141)
(%)
31GE0003 Restylane
(n=138)
(%)
31GE0003 Zyplast
(n=138)
(%)
Ecchymosis 4 (2.7%) 7 (4.6%) 14 (9.9%) 15 (10.6%) 8 (5.8%) 6 (4.3%)
Edema 0 (0%) 0 (0%) 2 (1.4%) 3 (2.1%) 11 (8.0%) 14 (10.1%)
Erythema 2 (1.3%) 2 (1.3%) 1 (0.7%) 2 (1.4%) 30 (21.7%) 37 (26.8 %)
Tenderness 0 (0%) 1 (0.7%) 0 (0%) 1 (0.7%) 8 (5.8%) 10 (7.2%)
Pain 0 (0%) 0 (0%) 1 (0.7%) 0 (0%) 4 (2.9%) 3 (2.2%)
Papule 1 (0.7%) 0 (0%) 2 (1.4%) 1 (0.7%) 5 (3.6%) 13 (9.4%)
Pruritus 1 (0.7%) 0 (0%) 1 (0.7%) 0 (0%) 4 (2.9%) 8 (5.8%)
Rash 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (0.7%) 1 (0.7%)
Hyperpigmentation 8 (5.3%) 7 (4.7%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Injection site scab 1 (0.7%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Skin exfoliation 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)

Table 9: MA-004-03 Adverse Events Reported by Restylane Patients Treated in the Nasolabial Folds

Adverse Event Number of Subjects with Events(%)
N=75
Total Number of Events† Mild Severity Moderate Severe
Swelling 18 (24%) 46 37 9 0
Bruising 14 (19%) 33 19 12 2
Pain/Soreness 4 (5%) 14 12 2 0
Discoloration 3 (4%) 5 5 0 0
Infection 1 (1%) 1 0 0 1
Hardness/Nodule 2 (3%) 3 2 1 0
† Most subjects had bilateral events at either the initial injection or touch-up. Bilateral events are counted as two events.

Table 10: MA-1300-15 Intensity of Adverse Event, Subject Diary for the Lip Augmentation Indication Study

  No Treatment
(N=45)
1st Treatment
(N=172)
2nd treatment
(N=93)
No Treatment
(N=45)
1st Treatment with Restylane
(N=172)
2nd Treatment with Restylane
(N=93)
Subjects Reporting Symptoms Subjects Reporting Symptoms Subjects Reporting Symptoms None Tolerable Affects Daily Activity Disabling None Tolerable Affects Daily Activity Disabling None Tolerable Affects Daily Activity Disabling
Maximum Severity Reported for any Diary AE
  Upper and Lower Lips Combined 2 167 89 37 (95%) 2 (5%) 0 0 2 (1%) 88 (52%) 62 (37%) 17 (10%) 1 (1%) 60 (67%) 25 (28%) 4 (4%)
Bruising
  Upper and Lower Lips Combined 2 147 58 37 (95%) 2 (5%) 0 0 22 (13%) 109 (65%) 33 (20%) 5 (3%) 31 (35%) 48 (53%) 10 (11%) 1 (1%)
Redness
  Upper and Lower Lips Combined 1 130 60 38 (97%) 1 (3%) 0 0 39 (23%) 118(70%) 12 (7%) 0 30 (33%) 55 (62%) 2 (2%) 3 (3%)
Swelling
  Upper and Lower Lips Combined 0 166 89 39 (100%) 0 0 0 3 (2%) 90 (53%) 65 (38%) 11 (7%) 1 (1%) 64 (71%) 22 (25%) 3 (3%)
Pain (includes burning)
  Upper and Lower Lips Combined 1 146 72 38 (97%) 1 (3%) 0 0 23 (14%) 111 (66%) 27 (16%) 8 (5%) 18 (20%) 55 (61%) 14 (16%) 3 (3%)
Tenderness
  Upper and Lower Lips Combined 1 164 81 38 (97%) 1 (3%) 0 0 5 (3%) 120 (71%) 40 (24%) 4 (2%) 9 (10%) 63 (70%) 15 (17%) 3 (3%)
Itching
  Upper and Lower Lips Combined 0 56 23 39 (100%) 0 0 0 114 (67%) 51 (30%) 5 (3%) 0 67 (74%) 22 (25%) 1 (1%) 0

Table 11: MA-1300-15 Duration of Adverse Event, Subject Diary for the Lip Augmentation Indication Study

Location/Adverse Event No Treatment at Baseline (N=45)
Number of Days
Any
n (%)
n (%) 2-7
n (%)
8-13
n (%)
14
n (%)
Upper and Lower Lip Combined
Bruising 2 (4%) 2 (100%) 0 0 0
Redness 1 (2%) 1 (100%) 0 0 0
Swelling 0 0 0 0 0
Pain (includes Burning) 1 (2%) 1 (100%) 0 0 0
Tenderness 1 (2%) 1 (100%) 0 0 0
Itching 0 0 0 0 0
  First Treatment with Restylane (N=172)
Number of Days
Any1
n (%)
n (%) 2-7
n (%)
8-13
n (%)
14
n (%)
Upper and Lower Lip Combined
Bruising 147 (85%) 7 (5%) 93 (63%) 43 (29%) 4 (3%)
Redness 130 (76%) 20 (15%) 86 (66%) 23 (18%) 1 ( < 1%)
Swelling 166 (97%) 3 (2%) 88 (53%) 50 (30%) 25 (15%)
Pain (includes Burning) 146 (85%) 35 (24%) 95 (65%) 14 (10%) 2 (1%)
Tenderness 164 (95%) 11 (7%) 81 (49%) 49 (30%) 23 (14%)
Itching 55 (32%) 16 (29%) 32 (58%) 7 (13%) 0
  Second Treatment with Restylane (N=93)
Number of Days
Any1
n (%)
n (%) 2-7
n (%)
8-13
n (%)
14
n (%)
Upper and Lower Lip Combined
Bruising 59 (63%) 3 (5%) 40 (68%) 16 (28%) 0
Redness 60 (65%) 16 (27%) 38 (63%) 5 (8%) 1 (2%)
Swelling 89 (96%) 10 (11%) 54 (61%) 21 (24%) 4 (5%)
Pain (includes Burning) 72 (77%) 21 (30%) 43 (60%) 5 (7%) 3 (4%)
Tenderness 81 (87%) 5 (6%) 52 (65%) 16 (20%) 8 (10%)
Itching 23 (25%) 10 (43%) 13 (57%) 0 0
1 Duration of “other” diary symptoms could not be calculated.

Table 12:MA-1300-15 Summary of Treatment Emergent Adverse Events for the Lip Augmentation Indication Study

Adverse Event No Treatment at Baseline
(N=45)
First Treatment with Restylane
(N=172)
Second Treatment with Restylane
(N=93)
Events Subjects Events Subjects Events Subjects
Pain 1 1 (2%) 97 36 (21%) 51 19 (20%)
Swelling 0 0 224 100 (58%) 103 52 (56%)
Tenderness 0 0 69 38 (22%) 29 16 (17%)
Nasopharyngitis 3 2 (4%) 9 9 (5%) 2 2 (2%)
Contusion (bruising/ ecchymosis) 0 0 131 76 (44%) 41 26 (28%)
Headache 3 2 (4%) 17 12 (7%) 3 3 (3%)
Erythema 0 0 57 29 (17%) 19 10 (11%)
Skin Exfoliation** 0 0 21 14 (8%) 2 2 (2%)
**Includes sloughing of the skin, peeling, desquamation, and superficial desquamation.

Table 13: MA-1300-13K Maximum Intensity of Symptoms after Initial Treatment, Subject Diary for the Lip Augmentation Indication Pilot Study

Reaction (N=20) Total subjects reporting symptoms
n (%)
None
n (%)
Tolerable
n (%)
Affected Daily Activity
n (%)
Disabling
n(%)
Bruising 17 (85%) 3 (15%) 13 (65%) 4 (20%) 0 (0%)
Redness 14 (70%) 6 (30%) 12 (60%) 2 (10%) 0 (0%)
Swelling 19 (95%) 1 (5%) 12 (60%) 7 (35%) 0 (0%)
Pain 17 (85%) 3 (15%) 17 (85%) 0 (0%) 0 (0%)
Tenderness 19 (95%) 1 (5%) 18 (90%) 1 (5%) 0 (0%)
Itching 2 (10%) 18 (90%) 2 (10%) 0 (0%) 0 (0%)
Mass Formation1 18 (90%) 2 (10%) 17 (85%) 1 (5%) 0 (0%)
1 Documentation of mass formation was the result of a miscommunication with the subjects. Subjects were specifically instructed to record any product palpability as mass formation in their diary, whether or not the palpability was the intended feel of the product.

31GE0003: Prospective, Randomized, Blinded, Controlled, Clinical Study

Design

1:1 randomized, prospective study at 6 U.S. centers, which compared the safety and effectiveness of Restylane and Zyplast in a “within-patient” control model of augmentation correction of bilateral nasal folds, using Restylane on the randomized nasal labial fold and the control treatment on the opposite nasal labial fold. Patients were partially masked; evaluating physicians were independent and masked; treating physicians were unmasked.

Effectiveness was studied with 6-month follow-up. Safety was studied with 12-month follow-up.

Endpoints

Effectiveness
Primary

The difference in effect of Restylane and Zyplast on the visual severity of the nasolabial folds, as assessed by an Evaluating Investigator at 6 months after baseline.

Secondary

Wrinkle Severity Rating Scale (WSRS) score assessed at other follow-up points by the evaluating investigator and by the subject.

Global Aesthetic Improvement (GAI): Very much improved / much improved / improved / no change / worse, assessed at 2, 4, and 6 months by the evaluating investigator and by the subject.

Number of treatment sessions to achieve optimal cosmesis.

The primary evaluation parameter was the 5-point WSRS Score. A change in WSRS=1 was considered to be clinically significant during follow-up. Baseline was defined to begin at the follow-up demonstrating that optimal correction had been sustained for 2 weeks.

Optimal correction was defined to be the best cosmetic result obtainable, as determined by the evaluating physician. A specific, objective score or goal for correction was not defined; 2 injectable implant sessions were expected.

Outcomes

Demographics

The study enrolled a population of predominately healthy, female, Caucasian non-smokers with history of prior facial aesthetic procedures and minimal sun exposure. There were few men or other racial/ ethnic groups; few smokers or patients with extensive sun exposure.

Gender     Tobacco use    
Male: 9 (6.6%) Non-smokers 118 (86.1%)
Female: 128 (93.4%) Smokers: 19 (13.9%)
Ethnicity Sun Exposure
Caucasian: 122 (89.0%) None: 83 (60.6%)
Black: (1.5%) Natural Sun: 52 (38.0%)
Asian: (1.5%) Artificial: 2 (1.5%)
Hispanic: 11 (8.0%)      

Effectiveness
Primary

Based on the per patient evaluation, the WSRS scores at 6 months by the evaluating investigator demonstrated that WSRS for

Restylane was lower (better) than Control: in 78 patients

Restylane was equal to Control: in 46 patients

Restylane was higher (worse) than Control: in 13 patients

For the entire cohort, however, the Mean of the WSRS Score by evaluating investigator demonstrated that while there was essentially no difference between Restylane and Control-treated cohort sides at pre-treatment (0.02 units WSRS) and baseline (0.01 units WSRS), for the cohort of 134 atients, there was a difference of 0.58 units of WSRS at 6 months.

Table 14: Blinded Evaluator Mean Wrinkle Severity Scores

  N Restylane Control Absolute Difference
Pre-treatment 138 3.29 3.31 0.02
Baseline 138 1.80 1.79 0.01
6 months 134 2.36 2.94 0.58

MA-1400-02: Prospective, Randomized, Blinded, Controlled Clinical Study

Design

1:1 randomized, prospective study at 17 U.S. centers, which compared the safety and effectiveness of Restylane and Perlane following treatment to baseline condition. Patients were randomized to either Restylane or Perlane treatment. A touch-up was allowed 2 weeks after initial treatment. Patients were partially masked; evaluating physicians were independent and masked; treating physicians were unmasked.

Effectiveness was studied with 6 months follow-up. Safety was studied with 6 months follow-up.

Endpoints

Effectiveness
Primary

The difference in effect of Restylane at week 12 versus baseline condition on the visual severity of the nasolabial folds, as assessed by the Blinded Evaluator.

The primary study endpoint was wrinkle severity 12 weeks after optimal correction was achieved. Wrinkle severity was evaluated on a five-step validated Wrinkle Severity Rating Scale (WSRS) (i.e., none, mild, moderate, severe, extreme) by a live evaluator blinded to treatment. Patient success was defined as maintaining at least a one point improvement on the WSRS at 12 weeks after optimal correction was achieved. The percent of patient successes were calculated for each treatment group. Each group was compared to its own baseline, with no comparison of Restylane to Perlane.

Secondary

Wrinkle Severity Rating Scale (WSRS) assessed at other follow-up points (2, 6, and 24 weeks after optimal correction) by the Blinded Evaluator, the investigator and the patient and compared to baseline score by the same evaluator. Duration of effect was defined as 6 months or time point, if earlier, at which less than 50% of patients had at least a 1-grade response remaining in both nasolabial folds (NLFs).

Safety assessments included: collection of patient symptoms in a 14-day diary; investigator evaluation of adverse experiences at 72 hours, and at 2, 6, 12, and 24 weeks; development of humoral or cellmediated immunity; and the relationship of adverse experiences to injection technique.

Outcomes

Demographics

The study enrolled 283 (i.e., 142 Restylane and 141 Perlane ) patients with moderate to severe NLF wrinkles. The patients were predominantly healthy ethnically diverse females. Bilateral NLFs and oral commissures were corrected with 2.1 mL to 5.2 mL of Restylane. The greatest amount used in any patient was 8.8 mL.

Gender Female: 266 (94%); Male: 17 (6%)

Ethnicity White: 226 (80%); Hispanic or Latino: 31 (11%); African American: 23 (8%); Asian: 3 (1%)

Efficacy

The results of the blinded evaluator assessment of NLF wrinkle severity for Restylane and control (Perlane) are presented in Table 15. In the primary effectiveness assessment at 12 weeks, 77% of the Restylane and 87% of the control patients had maintained at least a 1-point improvement over baseline.

Table 15: Blinded Evaluator Wrinkle Severity Response Scores

Time point No. of Restylane Patients No. of Restylane Pts. maintaining ≥ 1 Unit Improvement of NLF on WSRS No. of Perlane Patients No. of Perlane Pts. maintaining ≥ 1 Unit Improvement of NLF on WSRS
6 weeks 136 113 (83%)1 136 121 (89%)1
12 weeks 140 108 (77%)1 141 122 (87%)1
24 weeks 140 103 (74%)1 138 87 (63%)1
1 All p-values < 0.0001 based on t-test compared to baseline condition

Antibody Testing

15/142 (10.6%) subjects displayed a pre-treatment antibody response against Restylane (which was believed to be related to co-purifying Streptococcus capsule antigens). One subject also developed measurable increase in antibody titer after Restylane injection. 7/21 (33.3%) patients with antibodies against Restylane had adverse experiences at the injection site, which was similar to the local adverse event rate observed in the entire Restylane population (i.e., 53/142 (37%)). No severe events were noted and the subject who developed an antibody response after Restylane injection did not experience any adverse event at the injection site. Immediate type skin testing demonstrated that no patient developed IgE to Restylane. Post-exposure histopathology of skin biopsies of an implant site on each patient demonstrated that no patient developed cell-mediated immunity to Restylane.

MA-1400-01: Prospective, Randomized, Blinded, Controlled Clinical Study

Design

1:1 randomized, prospective study at 10 U.S. centers, which compared the safety and effectiveness of Restylane and Perlane following treatment to baseline condition in 150 patients with pigmented skin and predominantly African-American ethnicity. Patients were randomized to Restylane or Perlane treatment in a “within-patient” model of augmentation correction of bilateral nasolabial folds (NLFs) and oral commissures with one treatment assigned to one side and the other treatment to the other side. A touch-up was allowed 2 weeks after initial treatment. Patients and treating physicians were partially masked. Evaluations were performed by live investigator assessment for the primary analysis.

Effectiveness was studied with 6 months follow-up. Safety was studied with 6 months follow-up.

Endpoints

Effectiveness
Primary

The difference in effect of Restylane at week 12 versus baseline condition on the visual severity of the NLFs.

The primary study endpoint was wrinkle severity 12 weeks after optimal correction was achieved. Wrinkle severity was evaluated with a five-step validated Wrinkle Severity Rating Scale (WSRS) (i.e., none, mild, moderate, severe, extreme) by an on-site blinded evaluator. Patient success was defined as maintaining at least a one point improvement on the WSRS at 12 weeks after optimal correction was achieved. The percent of patient successes was calculated for each group. Each treatment group was compared to its own baseline, with no comparison of Restylane to Perlane.

Secondary

Wrinkle Severity Rating Scale (WSRS) was assessed at other follow-up points (2, 6, and 24 weeks after optimal correction) by the investigator and the patient and compared to baseline score by the same evaluator. A photographic assessment of patient outcomes was also performed. Duration of effect was defined as 6 months or time point, if earlier, at which less than 50% of patients had at least a 1-grade response at both nasolabial folds.

Safety assessments included: collection of patient symptoms in a 14-day diary; investigator evaluation of adverse experiences at 72 hours, and at 2, 6, 12, and 24 weeks; development of humoral or cellmediated immunity; and the relationship of adverse experiences to injection technique.

Outcomes

Demographics

The study enrolled 150 patients with moderate to severe NLF wrinkles. The patients were predominantly healthy African-American females.

Gender Female: 140/150 (93%); Male 10/150 (7%)

Ethnicity White: 2 (1.3%); Hispanic or Latino: 9 (6%); African-American: 137 (91%); American Indian: 2 (1.3%)

Fitzpatrick Skin Type I to III: 0 (0%); IV: 44 (29%); V: 68 (45%); VI: 38 (25%)

Efficacy

The results of the live blinded evaluator assessment of wrinkle severity for Restylane and control (Perlane) are presented in Table 16 and are based on the Intent-to-Treat analysis. In the primary effectiveness assessment at 12 weeks, 93% of the Restylane-treated and 92% of the Perlane-treated NLF maintained at least a 1-point improvement over baseline.

Table 16: Live Evaluator Wrinkle Severity Response Scores

Time point No. of patients No. of Restylane Pts. maintaining 1 Unit Improvement on WSRS 95% Restylane Confidence Interval No. of Perlane Pts. maintaining1 1 Unit Improvement on WSRS 95% Perlane Confidence Interval
6 weeks 148 142 (96%)1 92-99% 140 (95%)1 90-99%
12 weeks 149 139 (93%)1 89-98% 137 (92%)1 87-97%
24 weeks 147 108 (73%)1 66-81% 104 (71%)1 63-77%
1 All p-values < 0.0001 based on t-test compared to baseline condition

Antibody Testing

9/150 (6%) subjects displayed a pre-treatment antibody response against Restylane (which was believed to be related to co-purifying Streptococcus capsule antigens). No subjects developed a measurable increase in antibody titer after Restylane injection. 1/6 (17%) patients with antibodies against Restylane had adverse experiences at the injection site as compared to the local adverse event rate observed in the entire Restylane population (i.e., 28/150 (18.7%)). All the adverse experiences in the patients with a humoral response against Restylane were mild in severity. Immediate type skin testing demonstrated that no patient developed IgE to Restylane. Post-exposure histopathology of skin biopsies of an implant site on each patient demonstrated that no patient developed cell-mediated immunity to Restylane.

MA-04-003

The duration of effectiveness of Restylane for correction of nasolabial folds (NLF) was evaluated in a randomized, evaluator-blinded, multi-center study. Restylane was shown to have an overall duration of effectiveness of 18 months from baseline following re-treatment at 4.5 or 9 months.

MA-04-003: Randomized Clinical Study

Design

Randomized, evaluator-blinded study at 3 U.S. centers, which compared the safety and effectiveness of Restylane using two re-treatment schedules. Initially Restylane was injected in both nasolabial folds (NLF). Subsequently, one NLF was re-treated at 4.5 months after the initial treatment. The contralateral NLF was treated with Restylane and re-treated at 9 months (±1 week). The Blinded Evaluators were blinded to the re-treatment schedule while patients and treating physicians were not.

Effectiveness was studied at 18 months after the initial injection (i.e., either 9 or 13.5 months after the second treatment).

Endpoints

Effectiveness
Primary

The difference in effect of Restylane injected 4.5 or 9 months after the initial treatment on the visual severity of the nasolabial folds was assessed by an Evaluating Investigator at 18 months after the baseline treatment. The primary study endpoint was the proportion of subjects with at least one grade improvement in the Wrinkle Severity Rating Scale (WSRS) from baseline as assessed by the Blinded Evaluator at the 18 month visit.

Secondary

The Wrinkle Severity Rating Scale (WSRS) score was assessed by the evaluating investigator at all follow-up visits prior to the 18 month visit and at all visits by subjects and independent photographic reviewers.

Global Aesthetic Improvement Scale (GAIS) comparing the pre-treatment appearance at all follow-up visits up to 18 months, was determined by the treating investigator and patient. The GAIS is a 5-point scale for assessing global aesthetic improvement: “very much improved / much improved / improved / no change / worse.”

Safety

Severity and duration of injection site reactions and adverse events were recorded.

Outcomes

Demographics

The study enrolled an adult population of predominately Caucasian, healthy, non-smoking females.

Number of Subjects Age Gender Race Prior Augmentation to NLF History of Tobacco Use History of Sun Exposure
75 Mean ± SD 53.8 ± 8.4 Male 5 (6.7%) White 50 (66.7%) Yes 6 (8.0%) No 55 (73.3%) No 63 (84.0%)
  Median 54 Female 70 (93.3%) Black 3 (4.0%) No 69 (92.0%) Yes 20 (26.7%) Yes 12 (16.0%)
  Minimum 26     Hispanic 22 (29.3%)            
  Maximum 73                    

Number of Subjects enrolled and observed at 4.5, 9, 12, 15 and 18 months

  SCR/TRT Touch-up Wk2 M 4.5 M9 M12 M15 M18
Enrolled 75 - 75 75 75 75 75 75
Withdrew Consent (total) 0 - 1 5 6 6 6 7
Lost to Follow-up 0 - 0 2 4 4 4 4
Missed Visit 0 - 2 1 0 1 1 1
Actual 75 44 72 67 65 64 64 64

Volume (mL) of Restylane Treatment Used by Visit

Visit Side Assigned to Re-treatment at 4.5 Months Side Assigned to Re-treatment at 9 Months
Baseline
  N 75 75
  Mean± SD 1.1 ± 0.61 1.1 ± 0.56
  Median 1.0 1.0
  Minimum 0.1 0.2
  Maximum 2.5 2.5
Touch-up Visit
  N 44 44
  Mean ± SD 0.5 ± 0.22 0.5 ± 0.21
  Median 0.5 0.5
  Minimum 0.2 0.2
  Maximum 1.0 1.0
Re-treatment Visit (4.5 Months/9 months)
  N 67 63
  Mean ± SD 0.7 ± 0.33 0.7 ± 0.36
  Median 0.8 0.6
  Minimum 0.2 0.1
  Maximum 1.8 2.0

Effectiveness

The results of the blinded evaluator assessment of NLF wrinkle severity for subjects treated at baseline, 4.5 or 9 months is presented in the Figure below for subject outcomes at 4.5, 9, 12, 15 and 18 months after initial treatment.

Blinded evaluator assessment of NLF wrinkle severity - Illustration

At 18 months after the initial treatment, the blinded evaluator determined that 97% of the NLFs re-treated at 4.5 months displayed at least 1 WSRS grade improvement over baseline, with a mean change in wrinkle severity score of 1.7 units. At 18 months after the initial treatment, the blinded evaluator determined that 95% of the NLFs re-treated at 9 months displayed at least 1 WSRS grade improvement over baseline, with a mean change in wrinkle severity score of 1.6 units.

Blinded evaluator assessment of NLF wrinkle severity - Illustration

MA-1300-15

The safety and effectiveness of Restylane for lip fullness augmentation was evaluated in a randomized, evaluator blinded, no treatment controlled study.

MA-1300-15: Randomized Clinical Study

Design

This was a randomized, evaluator blinded, no treatment as a control study of 180 subjects who were seeking lip fullness augmentation at 12 investigational centers. At entry of the study, subjects were randomized in a 3:1 ratio to (1) Restylane treatment or (2) no treatment. The study recruited a minimum of 30 subjects with darker skin types based on classification of Fitzpatrick skin types IV, V, or VI. Each lip qualified by MLFS score was analyzed for effectiveness and all lips were analyzed for safety. Subjects randomized to treatment at baseline were re-treated at 6 months and subjects randomized to no treatment at baseline received their first treatment at 6 months. The safety of all subjects was then monitored for one month after the 6 month treatment.

Endpoints

Effectiveness
Primary

The primary effectiveness objective was to identify whether Restylane was more effective in lip augmentation than no treatment. This was determined by the blinded evaluator assessment of lip fullness at 8 weeks after the first treatment as compared to the baseline assessment by the treating investigator, separately in the upper and lower lips (co-primary endpoints), using separate 5-grade Medicis Lip Fullness Scales (MLFS) with photoguides for each (one scale for upper lip and one scale for lower lip). Treatment success was defined as at least a one grade improvement in the MLFS for the blinded evaluator assessments at Week 8 (as compared to the treating investigator's baseline assessment of the MLFS) for both the upper and lower lips.

The primary safety objective was to define the incidence of all adverse events; including subject complaints reported during the first fourteen days after treatment as recorded in the subject diary; safety assessments at the 72 hour visits; treating investigator assessments at 2, 4, 8, 12, 16, 20, 24 weeks as well as 2 and 4 weeks after the 6 month treatment; and any reported or observed adverse events.

Secondary

Secondary effectiveness objectives included

Assessment of lip fullness augmentation after treatment with Restylane as compared to no treatment, as measured by the blinded evaluator, treating investigator, and IPR at post-baseline time points as compared to the baseline assessment. Response was determined by at least one grade improvement from baseline in the upper and lower lips using the MLFS.

Identification of lip improvement at each time point after treatment with Restylane as compared to no treatment using the GAIS by the treating investigator and the subject. Response is defined as a GAIS rating of “improved” or better in the upper or lower lips.

The secondary safety objectives included assessment of lip texture, firmness, symmetry, product palpability, mass formation, lip movement, function, and sensation.

Outcomes

Demographics

The study enrolled an adult population of predominately Caucasian healthy females.

Characteristics Total
(N=180)
Characteristics Total
(N=180)
Age (years) Race
  n 180   American Indian/Alaskan Native 2 (1%)
  Mean (S.D.) 47.6 (10.6)   Black/African American 2 (1%)
  Median 50.0   Native Hawaiian/Pacific Islander 1 ( < 1%)
  Minimum 18   Asian 0
  Maximum 65   White 169 (94%)
Gender   Other 6 (3%)
  Male 1 ( < 1%) Ethnicity
  Female 179 (99%)   Not Hispanic or Latino 161 (89%)
      Hispanic or Latino 19 (11%)
    Fitzpatrick Skin
      I, II, and III 139 (77%)
      IV and V 41 (23%)

Volume (mL) of Restylane used:

Assessment (upper and lower lips) Initial Treatment 6 Month Treatment
No Treatment
(N=45)
Restylane (1st Treatment)
(N=135)
No Treatment (1st Treatment)
(N=45)
Restylane (2nd Treatment)
(N=135)
Volume of Injection (mL) (includes treatment and touch up)
n - 135 37 93
Mean (S.D.) - 2.853 (0.984) 2.387 (1.380) 1.783 (0.921)
Median - 3.000 2.250 1.700
Minimum - 0.60 0.60 0.03
Maximum - 5.60 8.00 5.00

Effectiveness

The purpose of this study was to evaluate the safety and effectiveness of Restylane for soft tissue augmentation of the lips. The results confirm that Restylane is highly effective for adding fullness to both the upper and lower lips for at least 6 months.

The results of the blinded evaluator MLFS assessments of lip fullness are presented in the figure below for subject outcomes 8, 12, 16, 20, and 24 weeks.

Proportion (%) of MLFS Responders Measured by the Blinded Evaluator - Illustration

p-value < 0.001 for all time points

Subjects assessed lip improvement at each time point after treatment with a 7-point non-validated GAIS. When upper and lower lip outcomes were combined, the following percentage of Restylane subjects assessed themselves as improved or better from Baseline: 97.7% (Week 2), 99.2% (Week 4), 96.7% (Week 8), 91.7% (Week 12), 85.0% (Week 16), 76.1% (Week 20), and 74.1% (Week 24). No patients in the No Treatment group assessed themselves as improved from Baseline at any visit.

80% of the eligible subjects elected to receive re-treatment at Week 24 which suggests that subjects believed that the safety concerns associated with Restylane lip injections were less than the aesthetic value provided by the device.

MA-1300-13K

Design

A prospective, open label, single center, blinded evaluator study in 20 subjects

Endpoints

The effectiveness evaluation parameter was the Global Aesthetic Improvement Scale (GAIS)

To assess the incidence and severity of adverse experiences from Restylane when used in the lips

Outcomes

A total of 20 subjects (2 male, 18 female) were enrolled and 19 subjects completed the study. One 80 year old subject died during the study due to cardio-respiratory arrest. Mean age was 52.8 years old. Seventeen subjects were white.

At 12 weeks, 7/19 (37%) subjects were rated as improved on their GAIS assessment by the Blinded Evaluator. At 12 weeks, all (100%) subjects rated themselves as improved on their GAIS assessment.

Parameter N n Subjects with Lip Improvement Percent 90% Cl p-Value1
Lip Improvement Using the Blinded Evaluator's Assessment1 20 19 7 37% (0.19, 0.58) 0.820
Lip Improvement Using the Treating Investigator's Assessment 20 19 19 100% (0.85, 1.00) < 0.001
Lip Improvement Using the Subject's Assessment 20 17 17 100% (0.84, 1.00) < 0.001
1 Due to the protocol deviation, the live blinded evaluator's assessment was a photo assessment.

Mean Volume Used
Lip Statistic Volume of Injection (mL)
Upper N 20
Mean (S.D.) 0.82 (0.30)
Median 0.73
Min, Max 0.08, 1.40
Lower N 20
Mean (S.D.) 0.88 (0.37)
Median 0.80
Min, Max 0.05, 1.80
Total N 20
Mean (S.D.) 1.69 (0.62)
Median 1.60
Min, Max 0.13, 3.20

Last reviewed on RxList: 7/8/2013
This monograph has been modified to include the generic and brand name in many instances.

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