Perlane-L

CLINICAL PHARMACOLOGY

Clinical Trials

The safety and effectiveness of Perlane in the treatment of facial folds and wrinkles (nasolabial folds and oral commissures) were evaluated in four prospective randomized controlled clinical studies involving 509 Perlane-treated patients. Perlane was shown to be effective when compared to cross-linked collagen and cross-linked hyaluronic acid dermal fillers with respect to the correction of moderate to severe facial folds and wrinkles, such as nasolabial folds.

The safety and pain reduction effect of Perlane-L in the treatment of facial folds and wrinkles (nasolabial folds) was evaluated in a prospective randomized controlled clinical study involving 60 patients. The addition of lidocaine to Perlane resulted in a statistically significant reduction in the pain experienced by the patients. The study also showed that the safety profile of Perlane-L was consistent with Perlane.

Table 1: Maximum Intensity of Symptoms after Initial Treatment, Patient Diary
(Study MA-1400-02)1

  Perlane Restylane Perlane Patients Restylane 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 122
(86.5%)
111
(78.2%)
17
(12.2%)
97
(69.8%)
24
(17.3%)
1
(0.7%)
28
(20.1%)
82
(59%)
28
(20.1%)
1
(0.7%)
Redness 118
(83.7%)
114
(80.3%)
21
(15.1%)
105
(75.5%)
12
(8.6%)
1
(0.7%)
25
(18%)
96
(69.1%)
17
(12.2%)
1
(0.7%)
Swelling 128
(90.8%)
127
(89.4%)
11
(7.9%)
107
(77%)
19
(13.7%)
2
(1.4%)
12
(8.6%)
102
(73.4%)
23
(16.5%)
2
(1.4%)
Pain 114
(80.9%)
108
(76.1%)
25
(18%)
96
(69.1%)
18
(12.9%)
0
(0%)
31
(22.3%)
93
(66.9%)
14
(10.1%)
1
(0.7%)
Tenderness 130
(92.2%)
123
(86.6%)
9
(6.5%)
112
(80.6%)
18
(12.9%)
0
(0%)
16
(11.5%)
109
(78.4%)
12
(8.6%)
2
(1.4%)
Itching 45
(31.9%)
67
(47.2%)
94
(67.6%)
40
(28.8%)
3
(2.2%)
2
(1.4%)
72
(51.8%)
66
(47.5%)
1
(0.7%)
0
(0%)
Other3 1
(0.7%)
3
(2.1%)
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 2: Duration of Adverse Events after Initial Treatment, Patient Diary
(Study MA-1400-02)1

  Perlane Restylane Perlane Patients Restylane Patients
Total patients reporting symptoms
n (%)
Total patients reporting symptoms
n (%)
Number of days2 Number of days2
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
Bruising 122
(86.5%)
111
(78.2%)
6
(4.9%)
81
(66.4%)
28
(23%)
7
(5.7%)
9
(8.1%)
69
(62.2%)
30
(27%)
3
(2.7%)
Redness 118
(83.7%)
114
(80.3%)
19
(16.1%)
87
(73.7%)
8
(6.8%)
4
(3.4%)
31
(27.2%)
71
(62.3%)
9
(7.9%)
3
(2.6%)
Swelling 128
(90.8%)
127
(89.4%)
6
(4.7%)
100
(78.1%)
17
(13.3%)
5
(3.9%)
12
(9.4%)
93
(73.2%)
19
(15.0%)
3
(2.4%)
Pain 114
(80.9%)
108
(76.1%)
46
(40.4%)
66
(57.9%)
2
(1.8%)
0
(0%)
37
(34.3%)
69
(63.9%)
2
(1.9%)
0
(0%)
Tenderness 130
(92.2%)
123
(86.6%)
24
(18.5%)
89
(68.5%)
16
(12.3%)
1
(0.8%)
21
(17.1%)
92
(74.8%)
9
(7.3%)
1
(0.8%)
Itching 45
(31.9%)
67
(47.2%)
19
(42.2%)
23
(51.1%)
3
(6.7%)
0
(0%)
22
(32.8%)
38
(56.7%)
6
(9.0%)
1
(1.5%)
Other3 1
(0.7%)
3
(2.1%)
1
(100%)
0
(0%)
0
(0%)
0
(0%)
3
(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 3: Maximum Intensity of Symptoms after Initial Treatment, Patient Diary
(Study MA-1400-01)1,2

  Perlane Restylane Perlane Patients Restylane 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 74
(49.3%)
70
(46.7%)
75
(50.3%)
67
(45%)
7
(4.7%)
0
(0%)
79
(53%)
66
(44.3%)
4
(2.7%)
0
(0%)
Redness 92
(61.3%)
87
(58%)
57
(38.3%)
85
(57%)
7
(4.7%)
0
(0%)
62
(41.6%)
81
(54.4%)
6
(4%)
0
(0%)
Swelling 121
(80.7%)
125
(83.3%)
28
(18.8%)
108
(72.5%)
11
(7.4%)
2
(1.3%)
24
(16.1%)
109
(73.2%)
14
(9.4%)
2
(1.3%)
Pain 103
(68.7%)
96
(64%)
46
(30.9%)
90
(60.4%)
12
(8.1%)
1
(0.7%)
53
(35.6%)
84
(56.4%)
11
(7.4%)
1
(0.7%)
Tenderness 130
(86.7%)
122
(81.3%)
19
(12.8%)
116
(77.9%)
13
(8.7%)
1
(0.7%)
27
(18.1%)
110
(73.8%)
11
(7.4%)
1
(0.7%)
Itching 58
(38.7%)
53
(35.3%)
91
(61.1%)
54
(36.2%)
4
(2.7%)
0
(0%)
96
(64.4%)
49
(32.9%)
4
(2.7%)
0
(0%)
Other4 3
(2%)
3
(2%)
NA 3
(100%)
0
(0%)
0
(0%)
NA 3
(100%)
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 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 4: Duration of Adverse Events after Initial Treatment, Patient Diary
(Study MA-1400-01)1,2

  Perlane Restylane Perlane Patients Restylane Patients
Total patients reporting symptoms
n (%)
Total patients reporting symptoms
n (%)
Number of days3 Number of days3
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
Bruising 74
(49.3%)
70
(46.7%)
23
(31.1%)
44
(59.5%)
6
(8.1%)
1
(1.4%)
13
(18.6%)
51
(72.9%)
6
(8.6%)
0
(0%)
Redness 92
(61.3%)
87
(58%)
38
(41.3%)
52
(56.5%)
2
(2.2%)
0
(0%)
33
(37.9%)
52
(59.8%)
2
(2.3%)
0
(0%)
Swelling 121
(80.7%)
125
(83.3%)
22
(18.2%)
85
(70.2%)
11
(9.1%)
3
(2.5%)
23
(18.4%)
89
(71.2%)
12
(9.6%)
1
(0.8%)
Pain 103
(68.7%)
96
(64%)
32
(31.1%)
67
(65%)
2
(1.9%)
2
(1.9%)
27
(28.1%)
67
(69.8%)
2
(2.1%)
0
(0%)
Tenderness 130
(86.7%)
122
(81.3%)
26
(20%)
94
(72.3%)
6
(4.6%)
4
(3.1%)
28
(23%)
87
(71.3%)
7
(5.7%)
0
(0%)
Itching 58
(38.7%)
53
(35.3%)
29
(50%)
26
(44.8%)
2
(3.4%)
1
(1.7%)
22
(41.5%)
27
(50.9%)
4
(7.5%)
0
(0%)
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 5: Maximum Intensity of Symptoms after Initial Treatment, Patient Diary
(Study MA-1400-03)1

  Perlane-L Perlane Perlane-L 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 36
(60.0%)
33
(55.0%)
24
(40.0%)
32
(53.3%)
4
(6.7%)
0
(0.0%)
27
(45.0%)
29
(48.3%)
4
(6.7%)
0
(0.0%)
Redness 34
(56.7%)
31
(51.7%)
26
(43.3%)
31
(51.7%)
3
(5.0%)
0
(0.0%)
29
(48.3%)
29
(48.3%)
2
(3.3%)
0
(0.0%)
Swelling 42
(70.0%)
39
(65.0%)
18
(30.0%)
34
(56.7%)
8
(13.3%)
0
(0.0%)
21
(35.0%)
34
(56.7%)
5
(8.3%)
0
(0.0%)
Pain 28
(46.7%)
26
(43.3%)
32
(53.3%)
25
(41.7%)
3
(5.0%)
0
(0.0%)
34
(56.7%)
24
(40.0%)
2
(3.3%)
0
(0.0%)
Tenderness 50
(83.3%)
49
(81.7%)
10
(16.7%)
45
(75.0%)
5
(8.3%)
0
(0.0%)
11
(18.3%)
47
(78.3%)
2
(3.3%)
0
(0.0%)
Itching 16
(26.7%)
12
(20.0%)
44
(73.3%)
15
(25.0%)
1
(1.7%)
0
(0.0%)
48
(80.0%)
12
(20.0%)
0
(0.0%)
0
(0.0%)
Other3 3
(5.0%)
1
(1.7%)
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 Other included symptoms of acne, lumpiness, and red/purple mark. Diary entries of hurts to swallow, lack of energy, feeling of sickness, achy, headache, and broken capillaries could not be associated with a particular product.

Table 6: Duration of Adverse Events after Initial Treatment, Patient Diary
(Study MA-1400-03)1

  Perlane-L Perlane Perlane-L Patients Perlane Patients
Total patients reporting symptoms
n (%)
Total patients reporting symptoms
n (%)
Number of days3 Number of days3
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
1
n (%)
2-7
n (%)
8-13
n (%)
14
n (%)
Bruising 36
(60.0%)
33
(55.0%)
6
(16.7%)
27
(75.0%)
3
(8.3%)
0
(0.0%)
5
(15.2%)
23
(69.7%)
4
(12.1%)
1
(3.0%)
Redness 34
(56.7%)
31
(51.7%)
9
(26.5%)
24
(70.6%)
0
(0.0%)
1
(2.9%)
9
(29.0%)
18
(58.1%)
3
(9.7%)
1
(3.2%)
Swelling 42
(70.0%)
39
(65.0%)
4
(9.5%)
33
(78.6%)
4
(9.5%)
1
(2.4%)
6
(15.4%)
29
(74.4%)
3
(7.7%)
1
(2.6%)
Pain 28
(46.7%)
26
(43.3%)
17
(60.7%)
11
(39.3%)
0
(0.0%)
0
(0.0%)
15
(57.7%)
11
(42.3%)
0
(0.0%)
0
(0.0%)
Tenderness 50
(83.3%)
49
(81.7%)
6
(12.0%)
40
(80.0%)
4
(8.0%)
0
(0.0%)
8
(16.3%)
35
(71.4%)
6
(12.2%)
0
(0.0%)
Itching 16
(26.7%)
12
(20.0%)
5
(31.3%)
10
(62.5%)
1
(6.3%)
0
(0.0%)
5
(41.7%)
7
(58.3%)
0
(0.0%)
0
(0.0%)
Other2,4 3
(5.0%)
1
(1.7%)
0
(0.0%)
3
(100.0%)
0
(0.0%)
0
(0.0%)
0
(0.0%)
1
(100.0%)
0
(0.0%)
0
(0.0%)
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 Other included symptoms of acne, lumpiness, and red/purple mark. Diary entries of hurts to swallow, lack of energy, feeling of sickness, achy, headache, and broken capillaries could not be associated with a particular product.

Table 7: All Investigator-Identified Adverse Events (72 Hours) Number of Events per Patient per Study

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

Table 8: Investigator-Identified Adverse Events (2 Weeks or More After Implantation) (Number of Patients) (Perlane v. Specified Active Controls—All Studies)

Study Term MA-1400-01 Perlane
(n=150)
(%)
MA-1400-01 Restylane
(n=150)
(%)
MA-1400-02 Perlane
(n=141)
(%)
MA-1400-02 Restylane
(n=142)
(%)
31GE0101 Perlane
(n=150)
(%)
31GE0101 Hylaform
(n=150)
(%)
31GE0002 Perlane
(n=68)
(%)
31GE0002 Zyplast
(n=68)
(%)
Ecchymosis 7 (4.6%) 4 (2.7%) 15 (10.6%) 14 (9.9%) 6 (4.0%) 2 (1.3%) 0 (0%) 0 (0%)
Edema 0 (0%) 0 (0%) 3 (2.1%) 2 (1.4%) 14 (9.3%) 6 (4.0%) 4 (5.9%) 9 (13.2%)
Erythema 2 (1.3%) 2 (1.3%) 2 (1.4%) 1 (0.7%) 13 (8.7%) 8 (5.3%) 6 (8.8%) 8 (11.8%)
Tenderness 1 (0.7%) 0 (0%) 1 (0.7%) 0 (0%) 2 (1.3%) 0 (0%) 0 (0%) 0 (0%)
Pain 0 (0%) 0 (0%) 0 (0%) 1 (0.7%) 13 (8.7%) 3 (2.0%) 0 (0%) 2 (2.9%)
Papule 0 (0%) 1 (0.7%) 1 (0.7%) 2 (1.4%) 11 (7.3%) 1 (0.7%) 1 (1.5%) 6 (8.8%)
Pruritus 0 (0%) 1 (0.7%) 0 (0%) 1 (0.7%) 2 (1.3%) 3 (2.0%) 3 (4.4%) 5 (7.4%)
Rash 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (0.7%) 0 (0%) 0 (0%) 0 (0%)
Hyperpigmentation 7 (4.7%) 8 (5.3%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Injection site scab 0 (0%) 1 (0.7%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)
Skin exfoliation 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (0.7%) 0 (0%) 0 (0%)

Table 9: All Investigator-Identified Adverse Events (14 Days) Number of Events per Patient per Study

Study Term MA-1400-03
Number of Events Perlane-L
(n=142)
Number of Events Perlane
(n=141)
Ecchymosis 19 23
Edema 24 24
Erythema 25 25
Pain 14 14
Papule 1 1
Pruritus 9 5
Tenderness 30 30

Some patients had multiple adverse events or had the same adverse events at bilateral injection sites. No adverse events were of severe intensity. Patients were queried on adverse events on the day of injection and at the Day 14 visit.

Table 10: MA-1400-03—Related AE by prior procedure. By Subjects

Prior procedure Related AE p-value*
Yes No
Yes 9 (69.2%) 4 1.00
No 31 (66.0%) 16
* Fisher's exact test

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 Perlane and Restylane following treatment to baseline condition. Patients were randomized to either Perlane or Restylane 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 Perlane 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 was calculated for each treatment group. Each group was compared to its own baseline, with no comparison of Perlane to Restylane.

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 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 events at 72 hours, and at 2, 6, 12, and 24 weeks; development of humoral or cell-mediated immunity; and the relationship of adverse events to injection technique.

Outcomes

Demographics

The study enrolled 283 (i.e., 141 Perlane and 142 Restylane) patients with moderate to severe NLF wrinkles. The patients were predominantly healthy ethnically diverse females. Bilateral NLFs and oral commissures were corrected in most patients with 1.9 mL to 4.6 mL of Perlane. The greatest amount used in any patient was 9.0 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 Perlane and control (Restylane) are presented in Table 11. In the primary effectiveness assessment at 12 weeks, 87% of the Perlane and 77% of the control patients had maintained at least a 1 point improvement over baseline.

Table 11: Blinded Evaluator Wrinkle Severity Response Scores

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

Antibody Testing

15/141 (10.6%) patients displayed a pre-treatment antibody response against Perlane, (which was believed to be related to co-purifying Streptococcus capsule antigens). One patient also developed a measurable increase in antibody titer after Perlane injection. 4/16 (27%) patients with antibodies against Perlane had adverse events at the injection site, which was similar to the local adverse event rate observed in the entire Perlane population (i.e., 49/141 (35%)). With the exception of one moderate bruising event, all the adverse events in the patients with a humoral response against Perlane were mild in severity. No severe events were noted and the patient who developed an antibody response after Perlane injection did not experience any adverse event at the injection site. Immediate type skin testing demonstrated that no patient developed IgE to Perlane. Post-exposure histopathology of skin biopsies of an implant site on each patient demonstrated that no patient developed cell-mediated immunity to Perlane.

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 Perlane and Restylane following treatment to baseline condition in 150 patients with pigmented skin and predominantly African-American ethnicity. Patients were randomized to either Perlane or Restylane 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 Perlane 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 patients success was calculated for each group. Each treatment group was compared to its own baseline, with no comparison of Perlane to Restylane.

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 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 events at 72 hours, and at 2, 6, 12, and 24 weeks; the development of humoral or cellmediated immunity; and the relationship of adverse events 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 Perlane and control (Restylane) are presented in Table 12 and are based on the Intent-to-Treat analysis. In the primary effectiveness assessment at 12 weeks, 92% of the Perlane -treated and 93% of the Restylane-treated NLF maintained at least a 1 point improvement over baseline.

Table 12: Live Evaluator Wrinkle Severity Response Scores

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

Antibody Testing

6/150 (4%) patients displayed a pre-treatment antibody response against Perlane (which was believed to be related to co-purifying Streptococcus capsule antigens). No patients developed a measurable increase in antibody titer after Perlane injection. 0/6 (0%) patients with antibodies against Perlane had adverse events at the injection site as compared to the local adverse event rate observed in the entire Perlane population (i.e., 14/150 (9%)). All the adverse events in the patients with a humoral response against Perlane were mild in severity. Immediate type skin testing demonstrated that no patient developed IgE to Perlane. Post-exposure histopathology of skin biopsies of an implant site on each patient demonstrated that no patient developed cell-mediated immunity to Perlane.

MA-1400-03: Randomized, Blinded, Controlled Clinical Study

Design

1:1 randomized, prospective study at 3 U.S. centers, which compared the safety, tolerability, and pain reduction of Perlane-L to Perlane in 60 patients. Patients were randomized to Perlane-L or Perlane treatment in a “within-patient” model of bilateral nasolabial folds (NLFs) correction, with one treatment assigned to one side and the other treatment to the remaining side. Patients and treating physicians were blinded; evaluating physicians were independent and blinded. The study included 51.7% of patients with darker skin types based on classification of Fitzpatrick Skin Types IV, V, or VI (36.7% Skin Type IV and 15.0% Skin Type V or VI).

Pain was assessed by each patient for each treatment site independently on the Visual Analog Scale (VAS) at the end of injection and at 15-minute intervals for 60 minutes post-treatment. Patient assessment of appearance using the Global Aesthetic Improvement Scale (GAIS) (Very much improved / much improved / improved / no change / worse) was performed at the Day 14 visit. Safety was studied with 14-day follow-up.

Endpoints

Primary

The proportion of patients that had a within-patient difference in the VAS (Perlane – Perlane-L) of at least 10 mm at injection together with a 95% confidence interval. The objective was to show that the confidence interval lay above 50%.

Secondary

The proportion of patients that had a within-patient difference in VAS of at least 10 mm at postinjection time points (15, 30, 45 and 60 minutes after injection) together with a 95% confidence interval, the mean VAS by treatment and within-patient difference in VAS at each time point, the comparison of VAS between Perlane-L and Perlane, at each time point, and patient assessment on GAIS by treatment.

Safety assessments included: collection of patient symptoms in a 14-day diary and investigator evaluation of adverse events at 14 days.

Outcomes

Demographics

The study enrolled 60 patients with moderate to severe NLF wrinkles. The patients were predominantly healthy ethnically diverse females.

Gender Female: 56 (93.3%); Male: 4 (6.7%)

Ethnicity White: 39 (65.0%); Hispanic or Latino: 16 (26.7%); African American: 5 (8.3%)

Fitzpatrick Skin Type- Type I-III; 29 (48.3 %); Type IV: 22 (36.7%); Type V and VI: 9 (15.0%)

Volume

The mean volume of Perlane-L per wrinkle was 1.11 mL. The mean volume of Perlane per wrinkle was 1.10 mL.

Volume Injected per Wrinkle (mL) (Study MA-1400-03)

Treatment Volume (mL)
n Mean Std Min Median Max
Perlane-L per NLF 60 1.11 0.49 0.50 1.00 3.00
Perlane per NLF 60 1.10 0.49 0.50 1.00 3.00
Difference within patient* 60 -0.01 0.14 -0.50 0.00 0.50
* Perlane volume – Perlane-L volume
Abbreviations: n = number of patients; std = standard deviation; Min = minimum; Max = maximum

Primary: The primary efficacy analysis for pain reduction showed that 95.0% of patients had a within-patient difference in VAS (Perlane minus Perlane-L) of at least 10 mm at the time of injection. The primary objective was met, since statistically more than 50% of patients had at least 10 mm lower VAS score on the side treated with Perlane-L (confidence interval was 86.1 to 99.0). At 15 minutes post injection, 56.7% still had a within-patient difference in VAS of at least 10 mm.

Treatment Difference (Δ) in VAS (Perlane Side – Perlane-L Side) — ITT Population (Study MA-1400-03)

Time point No. of patients with assessments** Number of patients with Δ > 10 mm
n % 95% LCL 95% UCL
Treatment* 60 57 95.0 86.1 99.0
15 Minutes 60 34 56.7 43.2 69.4
30 Minutes 60 24 40.0 27.6 53.5
45 Minutes 60 11 18.3 9.5 30.4
60 Minutes 60 5 8.3 2.8 18.4
**Denominator (N), % = 100
*n/N; UCL=upper confidence limit; LCL=lower confidence limit

Secondary: Both pain scores decreased over time, but the mean within-patient difference on VAS (Perlane – Perlane-L) was statistically significantly larger than zero at all time points (at injection and at 15, 30, 45 and 60 minutes post-injection).

Patients' Mean VAS Assessments of Pain by Time Point (Study MA-1400-03)

Time point VAS pain by treatment (mm) VAS difference (mm)* p-value**
Perlane-L Perlane
Treatment 15.2 49.6 34.4 < 0.001
15 Minutes 4.7 21.3 16.5 < 0.001
30 Minutes 3.2 12.8 9.6 < 0.001
45 Minutes 2.4 7.4 5.0 < 0.001
60 Minutes 2.3 5.7 3.4 0.002
* Within-patient difference (Perlane side – Perlane-L side),
** One-sample T-test

At Day 14, patients showed improvement from baseline: 95% on the Perlane-L side of the face and 96.7% on the Perlane side of the face.

Global Aesthetic Improvement Scale (GAIS) Evaluation at the Day 14 Visit (Study MA-1400-03)

Category GAIS
Perlane-L Perlane
n % n %
Very Much Improved (4) 24 40.0 24 40.0
Much Improved (3) 18 30.0 19 31.7
Improved (2) 15 25.0 15 25.0
No Change (1) 3 5.0 2 3.3
Worse (0) 0 0.0 0 0.0

31GE0101: Prospective, Randomized, Blinded, Controlled Clinical Study

Design

1:1 randomized, prospective study at 6 Canadian centers, which compared the safety and effectiveness of Perlane and Hylaform. Patients were randomized to either Perlane or Hylaform in a “within-patient” model of augmentation correction of bilateral nasolabial folds (NLFs) 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 were partially masked; evaluating physicians were independent and masked; treating physicians were partially masked.

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

Endpoints

Effectiveness
Primary

The difference in effect of Perlane as compared to Hylaform on the visual severity of the NLFs, as assessed by a Blinded Evaluator at 6 months after baseline.

The primary evaluation parameter was a five-step validated Wrinkle Severity Rating Scale (WSRS) score (absent, mild, moderate, severe, extreme) by the Blinded Evaluator at 6 months. Success was defined as maintaining at least a one point improvement of the NLF on the WSRS at 6 months after optimal correction was achieved. The percent of successful NLFs after Perlane and control treatments were compared, as well as a within-patient matched analysis (McNemar's Test).

Secondary

Wrinkle Severity Rating Scale (WSRS) was assessed at other follow-up points (2 weeks and 3, 4.5, and 6 months after optimal correction) by the Blinded Evaluator and the patient. Global Aesthetic Improvement (GAI): very much improved /much improved / improved / no change / worse, assessed at same time points by patient.

Safety assessments included: investigator evaluation of adverse events at all time points.

Outcomes

Demographics

The study enrolled 150 patients with moderate to severe nasolabial fold wrinkles. The patients were predominantly healthy white females. The study was completed by 140 of 150 patients at six months and additional safety data were available in 122 of 150 patients at 9 months.

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

Ethnicity White: 142/150 (95%); Non-caucasian: 8/150 (5%)

Efficacy

The results of the blinded evaluator assessments are presented in Table 13 and are based on an Intentto- Treat (ITT) analysis. At 6 months, 113/150 (75%) of the Perlane-treated NLFs maintained at least a single point improvement on the WSRS compared to 57/150 (38%) of the control-treated NLFs.

Table 13: Blinded Evaluator Wrinkle Severity Response Rates

Time point Number of NLFs No. of Perlane NLFs maintaining ≥ 1 Unit Improvement on WSRS No. of Hylaform NLFs maintaining ≥ 1 Unit Improvement on WSRS
3 months 150 131 (87%) 94 (63%)
4.5 months 150 110 (73%) 69 (46%)
6 months 150 113 (75%) 57 (38%)

Table 14 shows the results for the within-patient investigator assessment of NLF on the WSRS.

Table 14: Evaluating Investigator's Assessment of NLF Severity; Score Change From Pre-Treatment Until 3, 4.5, and 6 Months After Last Treatment

Mos. after last treatment Perlane superior to Hylaform n (%) Perlane equal to Hylaform n (%) Hylaform superior to Perlane n (%) p-value*
3 95 (63.3%) 46 (30.7%) 9 (6.0%) p < 0.001
4.5 87 (58.0%) 54 (36.0%) 9 (6.0%) p < 0.001
6 96 (64.0%) 42 (28.0%) 12 (8.0%) p < 0.001
* McNemar's test with %=n/N, where N=Number of patients in the ITT population

31GE0002: Prospective, Randomized, Blinded, Controlled Clinical Study

Design

1:1 randomized, prospective study at 2 Scandinavian centers, which compared the safety and effectiveness of Perlane and Zyplast. Patients were randomized to either Perlane or Zyplast in a “withinpatient” model of augmentation correction of bilateral nasolabial folds (NLFs) with one treatment assigned to one side and the other treatment to the other side. Patients were partially masked; evaluating physicians were independent and masked; treating physicians were partially masked. A touch-up was allowed 2 weeks after the initial treatment. Re-treatment was allowed at 6 or 9 months.

Effectiveness was studied with 9 months follow-up. Safety was studied with 12 months follow-up.

Endpoints

Effectiveness
Primary

Superiority of correction of the NLF by Perlane as compared to Zyplast based on the visual severity of the NLF, as assessed by a Blinded Evaluator at 6 months after optimal correction was achieved.

The primary evaluation parameter was a five-step validated Wrinkle Severity Rating Scale (WSRS) score (absent, mild, moderate, severe, extreme) by the Blinded Evaluator at 6 months. NLF success was defined as maintaining at least a one point improvement on the WSRS at 6 months after optimal correction was achieved. The within patient comparison of Perlane and control treatments was evaluated in a matched analysis (McNemar's Test).

Secondary

Superiority of correction of the NLF by Perlane or Zyplast based on the visual severity of the NLFs, as assessed by a Blinded Evaluator at 9 months after baseline.

Safety assessments included: investigator evaluation of adverse events at all time points.

Outcomes

Demographics

The study enrolled 68 patients with correctable NLF wrinkles. The patients were predominantly healthy white females.

Gender Female: 65 (96%); Male: 3 (4%)

Ethnicity White: 68/68 (100%)

Efficacy

The results of the blinded evaluator assessments are presented in Table 15. At the primary effectiveness time point of 6 months, the Perlane-treated NLF experienced more improvement from baseline (judged by the WSRS) in 50% of the patients; the control-treated side experienced more improvement in 10.3% of the patients.

Table 15: Evaluating Investigator's Assessment; Difference in the Severity Rating Scale From Pre-Treatment Until 2, 4, 6, and 9 Months After Baseline

Time point Perlane NLF is superior to control NLF
n (%)
Perlane NLF is equal to control NLF
n (%)
Control NLF is superior to Perlane NLF
n (%)
p-value1
2 months2 32 (47.1%) 28 (41.2%) 8 (11.8%) 0.0001
4 months2 38 (55.9%) 25 (36.8%) 5 (7.4%) 0.0001
6 months2 34 (50.0%) 27 (39.7%) 7 (10.3%) 0.0003
9 months3 21 (48.8%) 16 (37.2%) 6 (14.9%) 0.0039
1 McNemar's test
2 Percent=n/Number of patients in the ITT population at Month 6
3 Percent=n/Number of patients in the ITT population at Month 9; includes only patients not re-treated (n=43)

Last reviewed on RxList: 7/5/2013
This monograph has been modified to include the generic and brand name in many instances.

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