Efficacy and Safety of OnabotulinumtoxinA for Treating Crow's Feet Lines Alone or in Combination With Glabellar Lines: A Multicenter, Randomized, Controlled Trial Marion Moers-Carpi, MD,* Jean Carruthers, MD,† Steven Fagien, MD,‡ Mary Lupo, MD,xk Henry Delmar, MD,¶ Derek Jones, MD,# Christine Somogyi, RN,** Elisabeth Lee, MPH,** Xiaofang Lei, PhD,** Suzanne MacKinnon, MRes,** Paula G. Davis, PhD,†† Ramana Yalamanchili, PhD, MBA,†† Antoinette Campo,†† and Frederick C. Beddingfield, III, MD, PhD#**
BACKGROUND This was the second study in a Phase 3 program treating crow’s feet lines (CFL) with onabotulinumtoxinA. OBJECTIVE To evaluate the efficacy and safety of onabotulinumtoxinA treatment of CFL alone or with glabellar lines (GL). METHODS This multicenter, double-blind, placebo-controlled, repeat treatment, 7-month study randomized subjects with moderate-to-severe CFL and GL (maximum contraction) to onabotulinumtoxinA 44 U (CFL: 24 U, GL: 20 U; n = 305), onabotulinumtoxinA 24 U (CFL: 24 U, GL: placebo; n = 306), or placebo (n = 306). Coprimary end points were investigator-assessed and subject-assessed proportion of subjects achieving a CFL Facial Wrinkle Scale Grade of 0 or 1 (maximum smile; Day 30, Cycle 1). Additional efficacy end points and safety/ adverse events (AEs) were evaluated. RESULTS All primary and secondary end points were achieved; statistically significant differences favored onabotulinumtoxinA (p < .001, all comparisons vs placebo). Investigator and subject responder rates were: CFL, 54.9% and 45.8%; CFL + GL, 59.0% and 48.5%; and placebo, 3.3% (both), respectively. Responder rates on other end points also significantly favored onabotulinumtoxinA treatments. Most AEs were mild or moderate. Two subjects discontinued: 1 serious AE unrelated to treatment (myocardial infarction) and 1 treatment-related AE (injection site pain). CONCLUSION OnabotulinumtoxinA was effective and well tolerated for treating moderate-to-severe CFL alone or in combination with GL. M. Moers-Carpi, J. Carruthers, S. Fagien, M. Lupo, H. Delmar, and D. Jones are consultants and/or investigators for Allergan, Inc. C. Somogyi, E. Lee, X. Lei, S. MacKinnon, and F. C. Beddingfield are employees of Allergan, Inc., and receive compensation in salary, as well as stock or stock options (or both), at the time the study was conducted. The remaining authors have indicated no significant interest with commercial supporters.
O
nabotulinumtoxinA is widely approved for the treatment of glabellar lines (GL). This study is the second in a large-scale Phase 3 program evaluating
the efficacy and safety of onabotulinumtoxinA for the treatment of crow's feet lines (CFL). The first study compared a single treatment of onabotulinumtoxinA
*Private Clinic, Hautok, Munich, Germany; †Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada; ‡Private Practice, Boca Raton, Florida; xDepartment of Dermatology, Tulane University School of Medicine, New Orleans, Louisiana; kPrivate Practice, New Orleans, Louisiana; ¶Centre de Chirurgie Esthétique du Cap d'Antibes, Cap d'Antibes, France; #Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; **Allergan, Inc., Irvine, California; ††SCI Scientific Communications and Information, Parsippany, New Jersey. Dr. Beddingfield and Ms. Somogyi are now at Kythera Biopharmaceuticals, Inc., Calabasas, California Supported by Allergan, Inc., Irvine, California. Writing and editorial assistance to the authors was provided by SCI Scientific Communications & Information, Parsippany, New Jersey and was funded by Allergan, Inc., Irvine, California.
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© 2014 by the American Society for Dermatologic Surgery, Inc. Published by Lippincott Williams & Wilkins ISSN: 1076-0512 Dermatol Surg 2015;41:102–112 DOI: 10.1097/DSS.0000000000000220
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24 U with placebo in subjects with moderate-to-severe CFL at maximum smile.1 Based on prespecified end points, onabotulinumtoxinA was shown to be effective in reducing the appearance of CFL, and treatment was safe and well tolerated. However, in clinical practice and as characterized in the literature, it is common to treat multiple facial rhytides simultaneously and repeatedly.2,3 This study investigated the efficacy and safety of repeated onabotulinumtoxinA treatment of CFL alone and simultaneous treatment of CFL and GL.
Methods Study Design and Subjects This was a multicenter (34 sites), 7-month, doubleblind, randomized, placebo-controlled, parallel-group
Phase 3 study with 2 treatment cycles of either onabotulinumtoxinA (Botox Cosmetic; Allergan, Inc., Irvine, CA) or placebo (www.clinicaltrials.gov identifier: NCT01189760). Subjects were at least 18 years of age who met severity criteria for both CFL and GL (moderate-to-severe bilaterally symmetrical CFL at maximum smile and moderate-to-severe GL at maximum frown). Baseline CFL severity determination was based on both investigator and subject ratings using the Facial Wrinkle Scale (FWS; 0 = none, 1 = mild, 2 = moderate, and 3 = severe); GL ratings were assessed by the investigator using the FWS. To participate, subjects had to provide written informed consent. Other key inclusion and exclusion criteria are listed in Table 1. The study was conducted in accordance with guidelines and regulations for Good Clinical Practice, all relevant local and country
TABLE 1. Key Inclusion and Exclusion Criteria Inclusion Criteria Male or female of at least 18 years of age Bilaterally symmetrical moderate-to-severe CFL at maximum smile on the FWS as rated by both investigator and subject on Day 1 (before study)
Exclusion Criteria Concurrent or previous botulinum toxin treatment of any serotype Specified facial treatments or procedures within particular time points before study that could interfere with treatments in this study or with interpretation of results
Sufficient visual acuity without the use of eyeglasses (contact lens use acceptable) to accurately assess their facial wrinkles
Prior upper facial or mid facial surgery or permanent aesthetic procedures/treatments
Female subjects of childbearing potential must have had a negative urine pregnancy test at Day 1 before study treatment; must be using a reliable means of contraception
Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick sebaceous skin, or the inability to substantially lessen lateral canthal rhytides even by physically spreading them apart, as determined by the investigator Presence of any clinically relevant abnormal finding as observed from the neurologic assessment Any eyebrow or eyelid ptosis at baseline, as determined by the investigator Infection or skin disorder at the injection sites History of facial nerve palsy Females who were pregnant, nursing, or planning a pregnancy Any uncontrolled systemic disease Current enrolment in an investigational drug or device study or participation in such a study within 30 days of entry into this study Permanent make-up that would interfere with the assessment of facial wrinkles Subject had a condition or was in a situation that in the investigator’s opinion may have put the subject at significant risk, confounded the study results, or interfered significantly with the subject’s participation in the study
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privacy guidelines, and in compliance with the Declaration of Helsinki. The planned enrolment was 900 subjects. Procedures Eligible subjects were randomized 1:1:1 to 1 of 3 groups on Day 1: onabotulinumtoxinA 44 U (24 U to CFL areas, 20 U to GL area), onabotulinumtoxinA 24 U (12 U per side to CFL areas, placebo to GL area), or placebo (to both CFL and GL areas).1 OnabotulinumtoxinA was reconstituted as previously described.1 To maintain the blind, all medications were reconstituted and prepared by individuals who had no interactions with subjects.1 Subjects received 11 injections: 3 in each CFL area and 5 in the GL area (Figure 1). The volume of each injection was 0.1 mL, and each onabotulinumtoxinA injection contained 4 U. After the first treatment, follow-up visits were at Weeks 1 and 2 and then on Days 30, 60, 90, and 120. Subjects received their second treatment on Day 120, which was Day 1 of the second treatment cycle. The second treatment was identical to the first with visits at Weeks 1 and 2. Subsequent follow-up visits were on Days 150 and 180 (Days 30 and 60 of Cycle 2, respectively). The exit visit was on Day 210 (Day 90 of Cycle 2).
Efficacy Outcome Measures Outcome measures used in this study have been described in detail previously.1 The primary time point for all efficacy assessments was Day 30 of treatment Cycle 1. Primary Primary efficacy outcomes were based on investigator and subject assessments of CFL severity at maximum smile using the FWS (CFL-FWS). Responder rates for the coprimary end points were the proportion of subjects achieving a Grade of 0 (none) or 1 (mild) on the FWS, as assessed independently by investigators and subjects. For the United States Food and Drug Administration (US FDA) only, the composite primary end point was the proportion of subjects achieving at least a 2-grade improvement from baseline on both the investigator's and subject's FWS assessments on a per-subject basis. Investigator and subject FWS assessments were also analyzed separately. Secondary Two secondary end points were the proportion of subjects achieving at least a 1-grade improvement in the CFL-FWS during maximum smile and at rest, as assessed by the investigator.
Figure 1. Injection sites and patterns. (A) Schematic of 11 injection sites. (B) Crow’s feet lines injection pattern. The first injection was in the orbicularis oculi at the level of the lateral canthus, at least 1.5 to 2.0 cm temporal to the lateral canthus and just temporal to the lateral orbital rim (A). The second injection was 1.0 to 1.5 cm above this first injection site and at an approximate 30° medially (B). The third injection was 1.0 to 1.5 cm below the first at an approximate 30° medially (C). (C) Modified CFL injection pattern. If the lines in the crow’s feet region were primarily below the lateral canthus, the injector had the option to inject below the lateral canthus. Injections were given in a line angling from anteroinferior to superoposterior. The most anterior injection was given lateral to a line drawn vertically from the lateral canthus and the most inferior injection superior to the maxillary prominence.
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Assessment of facial lines by patient-reported outcomes (PROs) included the Subject's Global Assessment of Change in CFL (SGA-CFL), 3 of 11 items comprising the Facial Line Outcomes (FLO-11) questionnaire (Item 2: “look older,” Item 5: “look less attractive,” and Item 8: “look tired”), the SelfPerception of Age (SPA), and the Subject Assessment of Satisfaction of Appearance. The FLO-11 and SPA are validated instruments.1 In addition to assessments of CFL, investigators assessed several other end points, including GL severity during maximum frown and at rest (GLFWS). Responder rates were the proportion of subjects with an improvement from baseline of at least 1 grade on the GL-FWS.
linked immunosorbent assay), and positive samples were then screened for neutralizing antibodies to BoNTA (mouse protection assay). Data Analyses Efficacy analyses were performed on the intent-totreat (ITT) population (all subjects randomized to the study). Missing values for efficacy variables were imputed using the last observation carried forward. For the US FDA only, subjects with missing data for the primary ITT FWS responder analysis at a given visit were considered nonresponders for that visit. Safety analyses were conducted on all subjects who received study drug. Results
Safety Measurements Subjects Adverse Events Adverse events were classified as mild, moderate, or severe, if applicable. Investigators determined relationship to study drug. Serious AEs were any events at any dose that were deemed life threatening or resulted in death, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Other events could be considered serious if they jeopardized the patient and required intervention to prevent any of these outcomes. Allergan also classifies all cancer AEs and abortions as serious events.
The study enrolled 917 subjects (Figure 2). At baseline, there were no among-group or betweengroup differences in demographic characteristics (Table 2). Groups did not differ significantly in CFL or GL severity, according to either investigator or subject assessments, or in baseline ratings on PRO measures. At baseline, 80.0% of subjects in the onabotulinumtoxinA 44-U group, 78.4% of subjects in the onabotulinumtoxinA 24-U group, and 72.9% of subjects in the placebo group were unsatisfied or very unsatisfied with their CFL appearance. Efficacy
Neurologic Assessments At the request of the US FDA, standardized neurologic assessments were conducted prospectively at each visit to identify events indicating possible local or distant spread of toxin. Neurologic symptoms were assessed by a focused symptom questionnaire and a focused neurologic examination. Immunogenicity Blood samples were collected from subjects on Days 1 (pretreatment), 120 (pretreatment, Cycle 2), 150 (Day 30, Cycle 2), and 210 (Day 90, Cycle 2) or at earlier discontinuation. Samples were assessed for botulinum toxin Type A (BoNTA)-binding antibodies (enzyme-
For all primary and secondary end points, responder rates were significantly higher in the onabotulinumtoxinA treatment groups than in the placebo group at the primary time point of Day 30 and through Day 90; several end points remained significant through Day 120, when treatment Cycle 2 was administered. Specific efficacy outcomes are described below. Coprimary End Point The proportion of CFL-FWS responders as rated by both investigators and subjects was significantly greater (p < .001) at the primary efficacy time point for each
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Figure 2. Subject disposition and exit status.
onabotulinumtoxinA-treated group than for the placebo-treated group (Figure 3). At the primary time point, investigator-rated responder rates were 59.0% in the onabotulinumtoxinA 44-U (CFL + GL) group, 54.9% in the onabotulinumtoxinA 24-U (CFL only) group, and 3.3% in the placebo group. Corresponding subject-rated responder rates were 48.5% (onabotulinumtoxinA 44 U; CFL + GL), 45.8% (onabotulinumtoxinA 24 U; CFL only), and 3.3% (placebo). Statistically significant betweengroup differences (p < .001) were maintained at all visits in treatment Cycle 1. The responder rate was numerically higher in the onabotulinumtoxinA 44-U
group than in the onabotulinumtoxinA 24-U group at most time points and was statistically significant for the investigators' ratings at Week 1, treatment Cycle 1 (p = .022). The results for treatment Cycle 2 were similar (Figure 3). Composite End Point For the US FDA-required composite end point, at Day 30, the responder rate was significantly greater for the onabotulinumtoxinA-treated subjects than for the placebo-treated subjects (21.3% onabotulinumtoxinA 44-U group, 20.6% onabotulinumtoxinA 24-U group, compared with 0.0% placebo group; p < .001).
TABLE 2. Baseline Demographics and Characteristics OnabotulinumtoxinA 44 U (CFL + GL)
OnabotulinumtoxinA 24 U (CFL)
50 (9.7)
Placebo
Total
p
49.6 (9.5)
49.0 (9.3)
49.5 (9.5)
.552
87.5
89.2
85.9
87.6
.472
88.2
88.2
86.6
87.7
.782
Moderate
35.7
37.6
36.9
36.8
.892
Severe
64.3
62.4
63.1
63.2
Moderate
36.1
36.9
36.6
36.5
Severe
63.9
63.1
63.4
63.5
Mean age (SD), years Sex, % Female Race, % White Investigator rating of CFL severity (maximum smile), %
Subject rating of CFL severity (maximum smile), %
106
.975
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Figure 3. Proportion of subjects with ratings of “none” or “mild” on the FWS (maximum smile). (A) Investigator’s ratings: the proportion of responders was significantly greater for each onabotulinumtoxinA-treated group than for the placebotreated group (p < .001, all comparisons, both treatment cycles); the proportion of responders was significantly higher in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group at Week 1 (p = .022) in treatment Cycle 1. (B) Subject’s ratings: the proportion of responders was significantly greater for each onabotulinumtoxinA-treated group than for the placebo-treated group (p < .001, all comparisons, both treatment cycles).
Investigator-Assessed Responder Rates on Crow's Feet Lines–Facial Wrinkle Scale At maximum smile, the proportion of subjects with an improvement of at least 1 grade on the FWS was significantly greater in the onabotulinumtoxinA 44-U and onabotulinumtoxinA 24-U groups than in the placebo group (p < .001) at all time points in both treatment cycles (Figure 4). Similarly, a significantly greater proportion of subjects achieved at least a 1-grade improvement in the investigator assessment of CFL severity at rest in the onabotulinumtoxinA groups than in the placebo group (p < .001) at all time points in both treatment cycles. Responder rates were significantly higher in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group at the majority of time points, both at maximum smile and at rest (Figure 4). Patient-Reported Outcomes Statistically significant improvements were observed on the SGA-CFL, FLO-11 items, and the SPA measure at the primary time point (Day 30, treatment Cycle 1)
in the onabotulinumtoxinA-treated groups compared with placebo. At the same time, the proportion of subjects with improvements on these measures was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group (data not shown). Subject's Global Assessment of Change in Crow's Feet Lines At Day 30 of treatment Cycle 1, 62.6% of subjects in the onabotulinumtoxinA 44-U group and 52.0% of subjects in the onabotulinumtoxinA 24-U group classified themselves as “very much improved” or “much improved,” compared with 3.9% of subjects in the placebo group (Figure 5). Differences between each onabotulinumtoxinA-treated group and the placebo group were statistically significant at all time points in each treatment cycle (p < .001). In addition, the proportion of responders among subjects treated with onabotulinumtoxinA 44 U was significantly greater than the proportion treated with onabotulinumtoxinA 24 U up to Day 30 in Cycle 1 (p # .013) and Day 60 in Cycle 2 (p # .024).
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Figure 4. Proportion of investigator-assessed subjects with an improvement from baseline of at least 1 grade on the FWS. (A) At maximum smile: the proportion of responders was significantly greater (p < .001, all visits, all comparisons) in each onabotulinumtoxinA group than in the placebo group. The responder rate was also significantly greater in the onabotulinumtoxinA 44-U group (CFL + GL) than in the onabotulinumtoxinA 24-U group (CFL) at all time points through Day 60 in both treatment cycles (p # .009). (B) At rest: the proportion of responders was significantly greater (p < .001, all visits, all comparisons) in each onabotulinumtoxinA group than in the placebo group. The responder rate was also significantly greater in the onabotulinumtoxinA 44-U group (CFL + GL) than in the onabotulinumtoxinA 24-U group (CFL) at all time points except Day 120 of treatment Cycle 1 (p # .030).
Facial Line Outcomes-11 Questionnaire: Psychological Impact Items 2, 5, and 8 For each of the 3 items on the FLO-11 questionnaire, the proportion of responders was significantly greater for onabotulinumtoxinA-treated subjects than for placebo-treated subjects at all time points for each treatment cycle (p < .001, data not shown). Furthermore, the responder rate was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group through Day 90 in both treatment cycles for Item 2 (p # .006, Cycle 1; p # .023,
Cycle 2); Day 60, Cycle 1 (p # .031) and Day 30, Cycle 2 (p # .020) on Item 5; and Day 30, Cycle 1 (p # .002) and Day 90, Cycle 2 (p # .047) on Item 8. Self-Perception of Age Self-Perception of Age analyses were based on subjects who rated themselves as looking their current age or older than their current age at baseline. At Day 30 of Cycle 1, 50.6% and 33.6% of onabotulinumtoxinA-treated subjects (44 U [n = 265] and 24 U [n = 265], respectively) rated themselves in a younger
Figure 5. Proportion of subjects rating themselves as “very much improved” or “much improved” on the Subject’s Global Assessment of Change in CFL.
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age category than at baseline, compared with 9.1% of the placebo group (n = 263; p < .001, all betweengroup comparisons). On Day 30 of Cycle 2, the corresponding rates were 51.2% (n = 256), 33.6% (n = 253), and 9.2% (n = 229; p < .001, all betweengroup comparisons). Subject Assessment of Satisfaction of Appearance Significantly greater percentages of subjects in both onabotulinumtoxinA treatment groups were very satisfied or satisfied at Day 30 of each treatment cycle than were subjects in the placebo group (p < .001). At Day 30 of treatment Cycle 1, responder rates were 58.2% (173/297), 48.5% (144/297), and 6.8% (20/ 296) in the onabotulinumtoxinA 44-U group, onabotulinumtoxinA 24-U group, and placebo group, respectively; also, the responder rate was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group (p = .012). Results were similar at Day 30 of treatment Cycle 2 (data not shown). Glabellar Lines–Facial Wrinkle Scale During maximum frown and at rest, the proportion of responders was significantly greater in the onabotulinumtoxinA 44-U group than in the placebo group at all time points in both treatment cycles (p < .001; data not shown).
placebo-treated subject discontinued because of injection site pain and 1 onabotulinumtoxinA 24 Utreated subject discontinued because of a myocardial infarction, deemed not treatment related. Treatment-related AEs were reported in 9.6% of all subjects: 33 (10.8%) in the onabotulinumtoxinA 44-U group, 37 (12.1%) in the onabotulinumtoxinA 24-U group, and 18 (5.9%) in the placebo group. The most common were injection site hematoma (onabotulinumtoxinA 44 U, 3.0%; onabotulinumtoxinA 24 U, 4.9%; placebo, 1.3%), injection site hemorrhage (onabotulinumtoxinA 44 U, 1.3%; onabotulinumtoxinA 24 U, 1.6%; placebo, 0.7%), and headache (onabotulinumtoxinA 44 U, 4.3%; onabotulinumtoxinA 24 U, 2.9%; placebo, 3.3%). The majority were described as mild. One onabotulinumtoxinA 24 U-treated subject reported a severe event during Cycle 2, a sensation of bilateral orbital eye pressure that resolved without treatment. Neurologic Assessments and Spread of Toxin Nine subjects (6 onabotulinumtoxinA 44 U, 2 onabotulinumtoxinA 24 U, 1 placebo) experienced events that were identified as having potential relationship to possible spread of toxin. After detailed medial assessment, ptosis was considered a local pharmacological effect. There were no events deemed related to distant spread of toxin.
Safety Measures Adverse Events A total of 41.9% (384/917) reported at least 1 AE, most of which were determined by investigators to be unrelated to treatment. The most common AEs (reported by $1% of subjects) are listed in Table 3. During the entire study, 45.6% of the onabotulinumtoxinA 44-U group, 41.5% of the onabotulinumtoxinA 24-U group, and 38.6% of the placebo group reported at least 1 AE. The overall incidence of AEs was 30.9% during treatment Cycle 1 (120 days) and was 20.3% during treatment Cycle 2 (90 days). Most AEs were mild to moderate in severity. No deaths occurred during the course of the study. Two discontinuations were attributed to AEs: 1
Immunogenicity Serum-neutralizing antibodies against onabotulinumtoxinA were not detected in any onabotulinumtoxinA-treated subjects. Discussion This study is the first large-scale, randomized, placebocontrolled, Phase 3 study to document the efficacy and safety of repeated doses of onabotulinumtoxinA to treat CFL alone or in combination with GL, which is typical of clinical practice. Compared with the first study in the Phase 3 program, the population in this study was older and had more severe lines at baseline. Subjects in this study also were required to have moderate-to-severe CFL and GL as assessed by the investigator. Nevertheless, when CFL and GL were
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TABLE 3. Most Common Adverse Events With an Incidence $1% Preferred Term (MedDRA)
Abbreviated System Organ Class Overall Eye disorders Gastrointestinal disorders
Overall
Injury, poisoning, and procedural complications
127 (41.5)
Total, n (%), N = 917
118 (38.6)
384 (41.9) 28 (3.1)
15 (4.9)
7 (2.3)
6 (2.0)
1 (0.3)
3 (1.0)
0 (0.0)
4 (0.4)
Overall
8 (2.6)
8 (2.6)
16 (5.2)
32 (3.5)
Nausea
2 (0.7)
1 (0.3)
4 (1.3)
7 (0.8)
Vomiting Diarrhea
0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0)
3 (1.0) 3 (1.0)
3 (0.3) 3 (0.3)
27 (8.9)
28 (9.2)
10 (3.3)
65 (7.1)
15 (4.9)
19 (6.2)
5 (1.6)
39 (4.3)
4 (1.3)
5 (1.6)
3 (1.0)
12 (1.3)
Injection site hemorrhage Overall
58 (19.0)
63 (20.6)
55 (18.0)
176 (19.2)
Nasopharyngitis
24 (7.9)
18 (5.9)
15 (4.9)
57 (6.2)
Upper respiratory tract infection
9 (3.0)
12 (3.9)
10 (3.3)
31 (3.4)
Sinusitis
5 (1.6)
5 (1.6)
6 (2.0)
16 (1.7)
Bronchitis
5 (1.6)
4 (1.3)
4 (1.3)
13 (1.4)
Influenza Urinary tract infection
3 (1.0) 3 (1.0)
4 (1.3) 4 (1.3)
4 (1.3) 3 (1.0)
11 (1.2) 10 (1.1)
Oral herpes
3 (1.0)
4 (1.3)
1 (0.3)
8 (0.9)
Pneumonia
2 (0.7)
2 (0.7)
3 (1.0)
7 (0.8)
Gastroenteritis
1 (0.3)
5 (1.6)
3 (1.0)
9 (1.0)
Acute sinusitis Pharyngitis streptococcal
0 (0.0) 0 (0.0)
3 (1.0) 1 (0.3)
2 (0.7) 4 (1.3)
5 (0.5) 5 (0.5)
Overall
16 (5.2)
14 (4.6)
25 (8.2)
55 (6.0)
Joint sprain
3 (1.0)
0 (0.0)
2 (0.7)
5 (0.5)
Fall
2 (0.7)
1 (0.3)
4 (1.3)
7 (0.8)
Laceration
2 (0.7)
0 (0.0)
4 (1.3)
6 (0.7)
Arthropod bite Procedural pain
1 (0.3) 1 (0.3)
4 (1.3) 3 (1.0)
0 (0.0) 3 (1.0)
5 (0.5) 7 (0.8)
15 (4.9)
11 (3.6)
12 (3.9)
38 (4.1)
4 (1.3)
2 (0.7)
4 (1.3)
10 (1.1)
Musculoskeletal and Overall connective tissue Back pain disorders Arthralgia
2 (0.7)
0 (0.0)
3 (1.0)
5 (0.5)
Intervertebral disc protrusion
1 (0.3)
3 (1.0)
2 (0.7)
6 (0.7)
Neoplasm benign, malignant, and unspecified
Overall Basal cell carcinoma
4 (1.3) 1 (0.3)
4 (1.3) 3 (1.0)
1 (0.3) 0 (0.0)
9 (1.0) 4 (0.4)
Nervous system disorders
Overall
24 (7.9)
20 (6.5)
21 (6.9)
65 (7.1)
Headache
19 (6.2)
14 (4.6)
18 (5.9)
51 (5.6)
Dizziness
1 (0.3)
3 (1.0)
1 (0.3)
5 (0.5)
1 (0.3) 1 (2.6)
2 (0.7) 0 (0.0)
2 (0.7) 0 (0.0)
5 (0.5) 1 (0.9)
Reproductive system Overall and breast Prostatitis* disorders
110
139 (45.6)
Placebo, n (%), n = 306
Eyelid edema
General disorders Overall and administration Injection site site conditions hematoma
Infections and infestations
OnabotulinumtoxinA OnabotulinumtoxinA 44 U, n (%), n = 305 24 U, n (%), n = 306
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TABLE 3. (Continued ) Preferred Term (MedDRA)
Abbreviated System Organ Class
OnabotulinumtoxinA OnabotulinumtoxinA 44 U, n (%), n = 305 24 U, n (%), n = 306
Respiratory, thoracic, Overall and mediastinal Cough disorders Oropharyngeal pain Skin and Overall subcutaneous Actinic keratosis tissue disorders Dermatitis Vascular disorders
Placebo, n (%), n = 306
Total, n (%), N = 917
8 (2.6)
6 (2.0)
8 (2.6)
22 (2.4)
3 (1.0)
3 (1.0)
0 (0.0)
6 (0.7)
0 (0.0)
0 (0.0)
4 (1.3)
4 (0.4)
13 (4.3)
8 (2.6)
11 (3.6)
32 (3.5)
4 (1.3)
0 (0.0)
1 (0.3)
5 (0.5)
1 (0.3)
1 (0.3)
3 (1.0)
5 (0.5)
Pruritus
1 (0.3)
0 (0.0)
3 (1.0)
4 (0.4)
Overall
2 (0.7)
3 (1.0)
4 (1.3)
9 (1.0)
Hypertension
1 (0.3)
3 (1.0)
3 (1.0)
7 (0.8)
*Based on male population. MedDRA, Medical Dictionary for Regulatory Activities.
treated simultaneously, responder rates on the CFLFWS tended to be higher than when CFL were treated alone. Responder rates for CFL in both onabotulinumtoxinA treatment groups were consistently and significantly higher than placebo responder rates, and as expected, responder rates for GL in the one onabotulinumtoxinA-treated group were consistently and significantly higher than placebo responder rates. Importantly, simultaneous treatment of CFL and GL with onabotulinumtoxinA consistently resulted in significantly greater response rates on PROs than when CFL were treated alone. Together, these findings suggest that the benefits of treating both CFL and GL exceed those of treating CFL alone, which may have important implications for clinical practice. As in the first study in this program,1 no serious treatment-related AEs occurred. In addition, no clinically meaningful between-group differences in the incidence of AEs occurred, demonstrating that repeated treatment with onabotulinumtoxinA is well tolerated, whether CFL are treated alone or in combination with GL. Some limitations of this study can be noted. Although this study allowed modification of the injection pattern for CFL based on clinical presentation, response rates were not assessed according to treatment pattern. In addition, the treatment interval was stipulated
a priori; therefore, treatment effect could not be followed to its end in some subjects. Future studies in which retreatment is based on response criteria will help provide additional real-world experience to inform response duration. Despite the large scale of the study, sample sizes for males, subjects of diverse ethnicities, and subject age (>65 years) were relatively small, and the study was not designed to evaluate differences in these various subgroups. Related to the additional inclusion criteria of moderate-to-severe GL at maximum frown, the baseline CFL severity was greater in this study than in the foregoing study (approximately 63% of subjects were rated as severe in this study as compared with approximately 50% in the preceding study). This may account for the higher responder rates in the preceding study, as subjects with more severe CFL at baseline may be less likely to achieve a grade of none or mild after treatment compared with subjects with less severe CFL. Therefore, an important area for future exploration will be the evaluation of response rates as a function of baseline severity.
Conclusion Repeated treatment with onabotulinumtoxinA was effective and well tolerated for the treatment of moderate-to-severe CFL alone or in combination with GL. Improvements in appearance were generally numerically
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greater when CFL and GL areas were treated simultaneously, as assessed by both investigators and subjects. Differences favoring treating both areas together versus the CFL alone were particularly apparent in PROs, representing what is most important to patients. The safety profile was consistent with previous aesthetic studies of onabotulinumtoxinA including the GL indication approved by various regulatory authorities, and no new safety signals were detected.4–6 The results of this largescale Phase 3 study support both the efficacy and tolerability of repeated onabotulinumtoxinA treatments of CFL alone or in combination with GL. Dosing and results reported in this study are specific to the formulation of BoNTA manufactured by Allergan, Inc. This formulation is not interchangeable with other botulinum toxin products and cannot be converted using a dose ratio. References 1. Carruthers A, Bruce S, de Coninck A, Connolly S, et al. Efficacy and safety of onabotulinumtoxinA for the treatment of crow's feet lines:
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a multicenter, randomized, controlled trial [submitted]. Dermatol Surg 2014;40:1181–90. 2. Carruthers A, Carruthers J. A single-center, dose-comparison, pilot study of botulinum neurotoxin type A in female patients with upper facial rhytids: safety and efficacy. J Am Acad Dermatol 2009;60: 972–79. 3. Carruthers A, Carruthers J. A single-center dose-comparison study of botulinum neurotoxin type A in females with upper facial rhytids: assessing patients' perception of treatment outcomes. J Drugs Dermatol 2009;8:924–29. 4. Lowe NJ, Ascher B, Heckmann M, Kumar C, et al; on behalf of the Botox Facial Aesthetics Study Team. Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet. Dermatol Surg 2005;31:257–62. 5. Carruthers A, Carruthers J, Lowe NJ, Menter MA, et al; for the BOTOXÒ Glabellar Lines I & II Study Groups. One-year, randomised, multicenter, two-period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. J Clin Res 2004;7:1–20. 6. Brin MF, Boodhoo TI, Pogoda JM, James LM, et al. Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol 2009;61:961–71.
Address correspondence and reprint requests to: Marion Moers-Carpi, MD, Private Clinic, Hautok, Residenzstr. 7, 80333, Munich, Germany, or e-mail: [email protected]
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BACKGROUND This was the second study in a Phase 3 program treating crow’s feet lines (CFL) with onabotulinumtoxinA. OBJECTIVE To evaluate the efficacy and safety of onabotulinumtoxinA treatment of CFL alone or with glabellar lines (GL). METHODS This multicenter, double-blind, placebo-controlled, repeat treatment, 7-month study randomized subjects with moderate-to-severe CFL and GL (maximum contraction) to onabotulinumtoxinA 44 U (CFL: 24 U, GL: 20 U; n = 305), onabotulinumtoxinA 24 U (CFL: 24 U, GL: placebo; n = 306), or placebo (n = 306). Coprimary end points were investigator-assessed and subject-assessed proportion of subjects achieving a CFL Facial Wrinkle Scale Grade of 0 or 1 (maximum smile; Day 30, Cycle 1). Additional efficacy end points and safety/ adverse events (AEs) were evaluated. RESULTS All primary and secondary end points were achieved; statistically significant differences favored onabotulinumtoxinA (p < .001, all comparisons vs placebo). Investigator and subject responder rates were: CFL, 54.9% and 45.8%; CFL + GL, 59.0% and 48.5%; and placebo, 3.3% (both), respectively. Responder rates on other end points also significantly favored onabotulinumtoxinA treatments. Most AEs were mild or moderate. Two subjects discontinued: 1 serious AE unrelated to treatment (myocardial infarction) and 1 treatment-related AE (injection site pain). CONCLUSION OnabotulinumtoxinA was effective and well tolerated for treating moderate-to-severe CFL alone or in combination with GL. M. Moers-Carpi, J. Carruthers, S. Fagien, M. Lupo, H. Delmar, and D. Jones are consultants and/or investigators for Allergan, Inc. C. Somogyi, E. Lee, X. Lei, S. MacKinnon, and F. C. Beddingfield are employees of Allergan, Inc., and receive compensation in salary, as well as stock or stock options (or both), at the time the study was conducted. The remaining authors have indicated no significant interest with commercial supporters.
O
nabotulinumtoxinA is widely approved for the treatment of glabellar lines (GL). This study is the second in a large-scale Phase 3 program evaluating
the efficacy and safety of onabotulinumtoxinA for the treatment of crow's feet lines (CFL). The first study compared a single treatment of onabotulinumtoxinA
*Private Clinic, Hautok, Munich, Germany; †Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada; ‡Private Practice, Boca Raton, Florida; xDepartment of Dermatology, Tulane University School of Medicine, New Orleans, Louisiana; kPrivate Practice, New Orleans, Louisiana; ¶Centre de Chirurgie Esthétique du Cap d'Antibes, Cap d'Antibes, France; #Division of Dermatology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; **Allergan, Inc., Irvine, California; ††SCI Scientific Communications and Information, Parsippany, New Jersey. Dr. Beddingfield and Ms. Somogyi are now at Kythera Biopharmaceuticals, Inc., Calabasas, California Supported by Allergan, Inc., Irvine, California. Writing and editorial assistance to the authors was provided by SCI Scientific Communications & Information, Parsippany, New Jersey and was funded by Allergan, Inc., Irvine, California.
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© 2014 by the American Society for Dermatologic Surgery, Inc. Published by Lippincott Williams & Wilkins ISSN: 1076-0512 Dermatol Surg 2015;41:102–112 DOI: 10.1097/DSS.0000000000000220
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24 U with placebo in subjects with moderate-to-severe CFL at maximum smile.1 Based on prespecified end points, onabotulinumtoxinA was shown to be effective in reducing the appearance of CFL, and treatment was safe and well tolerated. However, in clinical practice and as characterized in the literature, it is common to treat multiple facial rhytides simultaneously and repeatedly.2,3 This study investigated the efficacy and safety of repeated onabotulinumtoxinA treatment of CFL alone and simultaneous treatment of CFL and GL.
Methods Study Design and Subjects This was a multicenter (34 sites), 7-month, doubleblind, randomized, placebo-controlled, parallel-group
Phase 3 study with 2 treatment cycles of either onabotulinumtoxinA (Botox Cosmetic; Allergan, Inc., Irvine, CA) or placebo (www.clinicaltrials.gov identifier: NCT01189760). Subjects were at least 18 years of age who met severity criteria for both CFL and GL (moderate-to-severe bilaterally symmetrical CFL at maximum smile and moderate-to-severe GL at maximum frown). Baseline CFL severity determination was based on both investigator and subject ratings using the Facial Wrinkle Scale (FWS; 0 = none, 1 = mild, 2 = moderate, and 3 = severe); GL ratings were assessed by the investigator using the FWS. To participate, subjects had to provide written informed consent. Other key inclusion and exclusion criteria are listed in Table 1. The study was conducted in accordance with guidelines and regulations for Good Clinical Practice, all relevant local and country
TABLE 1. Key Inclusion and Exclusion Criteria Inclusion Criteria Male or female of at least 18 years of age Bilaterally symmetrical moderate-to-severe CFL at maximum smile on the FWS as rated by both investigator and subject on Day 1 (before study)
Exclusion Criteria Concurrent or previous botulinum toxin treatment of any serotype Specified facial treatments or procedures within particular time points before study that could interfere with treatments in this study or with interpretation of results
Sufficient visual acuity without the use of eyeglasses (contact lens use acceptable) to accurately assess their facial wrinkles
Prior upper facial or mid facial surgery or permanent aesthetic procedures/treatments
Female subjects of childbearing potential must have had a negative urine pregnancy test at Day 1 before study treatment; must be using a reliable means of contraception
Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick sebaceous skin, or the inability to substantially lessen lateral canthal rhytides even by physically spreading them apart, as determined by the investigator Presence of any clinically relevant abnormal finding as observed from the neurologic assessment Any eyebrow or eyelid ptosis at baseline, as determined by the investigator Infection or skin disorder at the injection sites History of facial nerve palsy Females who were pregnant, nursing, or planning a pregnancy Any uncontrolled systemic disease Current enrolment in an investigational drug or device study or participation in such a study within 30 days of entry into this study Permanent make-up that would interfere with the assessment of facial wrinkles Subject had a condition or was in a situation that in the investigator’s opinion may have put the subject at significant risk, confounded the study results, or interfered significantly with the subject’s participation in the study
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privacy guidelines, and in compliance with the Declaration of Helsinki. The planned enrolment was 900 subjects. Procedures Eligible subjects were randomized 1:1:1 to 1 of 3 groups on Day 1: onabotulinumtoxinA 44 U (24 U to CFL areas, 20 U to GL area), onabotulinumtoxinA 24 U (12 U per side to CFL areas, placebo to GL area), or placebo (to both CFL and GL areas).1 OnabotulinumtoxinA was reconstituted as previously described.1 To maintain the blind, all medications were reconstituted and prepared by individuals who had no interactions with subjects.1 Subjects received 11 injections: 3 in each CFL area and 5 in the GL area (Figure 1). The volume of each injection was 0.1 mL, and each onabotulinumtoxinA injection contained 4 U. After the first treatment, follow-up visits were at Weeks 1 and 2 and then on Days 30, 60, 90, and 120. Subjects received their second treatment on Day 120, which was Day 1 of the second treatment cycle. The second treatment was identical to the first with visits at Weeks 1 and 2. Subsequent follow-up visits were on Days 150 and 180 (Days 30 and 60 of Cycle 2, respectively). The exit visit was on Day 210 (Day 90 of Cycle 2).
Efficacy Outcome Measures Outcome measures used in this study have been described in detail previously.1 The primary time point for all efficacy assessments was Day 30 of treatment Cycle 1. Primary Primary efficacy outcomes were based on investigator and subject assessments of CFL severity at maximum smile using the FWS (CFL-FWS). Responder rates for the coprimary end points were the proportion of subjects achieving a Grade of 0 (none) or 1 (mild) on the FWS, as assessed independently by investigators and subjects. For the United States Food and Drug Administration (US FDA) only, the composite primary end point was the proportion of subjects achieving at least a 2-grade improvement from baseline on both the investigator's and subject's FWS assessments on a per-subject basis. Investigator and subject FWS assessments were also analyzed separately. Secondary Two secondary end points were the proportion of subjects achieving at least a 1-grade improvement in the CFL-FWS during maximum smile and at rest, as assessed by the investigator.
Figure 1. Injection sites and patterns. (A) Schematic of 11 injection sites. (B) Crow’s feet lines injection pattern. The first injection was in the orbicularis oculi at the level of the lateral canthus, at least 1.5 to 2.0 cm temporal to the lateral canthus and just temporal to the lateral orbital rim (A). The second injection was 1.0 to 1.5 cm above this first injection site and at an approximate 30° medially (B). The third injection was 1.0 to 1.5 cm below the first at an approximate 30° medially (C). (C) Modified CFL injection pattern. If the lines in the crow’s feet region were primarily below the lateral canthus, the injector had the option to inject below the lateral canthus. Injections were given in a line angling from anteroinferior to superoposterior. The most anterior injection was given lateral to a line drawn vertically from the lateral canthus and the most inferior injection superior to the maxillary prominence.
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Assessment of facial lines by patient-reported outcomes (PROs) included the Subject's Global Assessment of Change in CFL (SGA-CFL), 3 of 11 items comprising the Facial Line Outcomes (FLO-11) questionnaire (Item 2: “look older,” Item 5: “look less attractive,” and Item 8: “look tired”), the SelfPerception of Age (SPA), and the Subject Assessment of Satisfaction of Appearance. The FLO-11 and SPA are validated instruments.1 In addition to assessments of CFL, investigators assessed several other end points, including GL severity during maximum frown and at rest (GLFWS). Responder rates were the proportion of subjects with an improvement from baseline of at least 1 grade on the GL-FWS.
linked immunosorbent assay), and positive samples were then screened for neutralizing antibodies to BoNTA (mouse protection assay). Data Analyses Efficacy analyses were performed on the intent-totreat (ITT) population (all subjects randomized to the study). Missing values for efficacy variables were imputed using the last observation carried forward. For the US FDA only, subjects with missing data for the primary ITT FWS responder analysis at a given visit were considered nonresponders for that visit. Safety analyses were conducted on all subjects who received study drug. Results
Safety Measurements Subjects Adverse Events Adverse events were classified as mild, moderate, or severe, if applicable. Investigators determined relationship to study drug. Serious AEs were any events at any dose that were deemed life threatening or resulted in death, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect. Other events could be considered serious if they jeopardized the patient and required intervention to prevent any of these outcomes. Allergan also classifies all cancer AEs and abortions as serious events.
The study enrolled 917 subjects (Figure 2). At baseline, there were no among-group or betweengroup differences in demographic characteristics (Table 2). Groups did not differ significantly in CFL or GL severity, according to either investigator or subject assessments, or in baseline ratings on PRO measures. At baseline, 80.0% of subjects in the onabotulinumtoxinA 44-U group, 78.4% of subjects in the onabotulinumtoxinA 24-U group, and 72.9% of subjects in the placebo group were unsatisfied or very unsatisfied with their CFL appearance. Efficacy
Neurologic Assessments At the request of the US FDA, standardized neurologic assessments were conducted prospectively at each visit to identify events indicating possible local or distant spread of toxin. Neurologic symptoms were assessed by a focused symptom questionnaire and a focused neurologic examination. Immunogenicity Blood samples were collected from subjects on Days 1 (pretreatment), 120 (pretreatment, Cycle 2), 150 (Day 30, Cycle 2), and 210 (Day 90, Cycle 2) or at earlier discontinuation. Samples were assessed for botulinum toxin Type A (BoNTA)-binding antibodies (enzyme-
For all primary and secondary end points, responder rates were significantly higher in the onabotulinumtoxinA treatment groups than in the placebo group at the primary time point of Day 30 and through Day 90; several end points remained significant through Day 120, when treatment Cycle 2 was administered. Specific efficacy outcomes are described below. Coprimary End Point The proportion of CFL-FWS responders as rated by both investigators and subjects was significantly greater (p < .001) at the primary efficacy time point for each
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Figure 2. Subject disposition and exit status.
onabotulinumtoxinA-treated group than for the placebo-treated group (Figure 3). At the primary time point, investigator-rated responder rates were 59.0% in the onabotulinumtoxinA 44-U (CFL + GL) group, 54.9% in the onabotulinumtoxinA 24-U (CFL only) group, and 3.3% in the placebo group. Corresponding subject-rated responder rates were 48.5% (onabotulinumtoxinA 44 U; CFL + GL), 45.8% (onabotulinumtoxinA 24 U; CFL only), and 3.3% (placebo). Statistically significant betweengroup differences (p < .001) were maintained at all visits in treatment Cycle 1. The responder rate was numerically higher in the onabotulinumtoxinA 44-U
group than in the onabotulinumtoxinA 24-U group at most time points and was statistically significant for the investigators' ratings at Week 1, treatment Cycle 1 (p = .022). The results for treatment Cycle 2 were similar (Figure 3). Composite End Point For the US FDA-required composite end point, at Day 30, the responder rate was significantly greater for the onabotulinumtoxinA-treated subjects than for the placebo-treated subjects (21.3% onabotulinumtoxinA 44-U group, 20.6% onabotulinumtoxinA 24-U group, compared with 0.0% placebo group; p < .001).
TABLE 2. Baseline Demographics and Characteristics OnabotulinumtoxinA 44 U (CFL + GL)
OnabotulinumtoxinA 24 U (CFL)
50 (9.7)
Placebo
Total
p
49.6 (9.5)
49.0 (9.3)
49.5 (9.5)
.552
87.5
89.2
85.9
87.6
.472
88.2
88.2
86.6
87.7
.782
Moderate
35.7
37.6
36.9
36.8
.892
Severe
64.3
62.4
63.1
63.2
Moderate
36.1
36.9
36.6
36.5
Severe
63.9
63.1
63.4
63.5
Mean age (SD), years Sex, % Female Race, % White Investigator rating of CFL severity (maximum smile), %
Subject rating of CFL severity (maximum smile), %
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.975
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Figure 3. Proportion of subjects with ratings of “none” or “mild” on the FWS (maximum smile). (A) Investigator’s ratings: the proportion of responders was significantly greater for each onabotulinumtoxinA-treated group than for the placebotreated group (p < .001, all comparisons, both treatment cycles); the proportion of responders was significantly higher in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group at Week 1 (p = .022) in treatment Cycle 1. (B) Subject’s ratings: the proportion of responders was significantly greater for each onabotulinumtoxinA-treated group than for the placebo-treated group (p < .001, all comparisons, both treatment cycles).
Investigator-Assessed Responder Rates on Crow's Feet Lines–Facial Wrinkle Scale At maximum smile, the proportion of subjects with an improvement of at least 1 grade on the FWS was significantly greater in the onabotulinumtoxinA 44-U and onabotulinumtoxinA 24-U groups than in the placebo group (p < .001) at all time points in both treatment cycles (Figure 4). Similarly, a significantly greater proportion of subjects achieved at least a 1-grade improvement in the investigator assessment of CFL severity at rest in the onabotulinumtoxinA groups than in the placebo group (p < .001) at all time points in both treatment cycles. Responder rates were significantly higher in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group at the majority of time points, both at maximum smile and at rest (Figure 4). Patient-Reported Outcomes Statistically significant improvements were observed on the SGA-CFL, FLO-11 items, and the SPA measure at the primary time point (Day 30, treatment Cycle 1)
in the onabotulinumtoxinA-treated groups compared with placebo. At the same time, the proportion of subjects with improvements on these measures was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group (data not shown). Subject's Global Assessment of Change in Crow's Feet Lines At Day 30 of treatment Cycle 1, 62.6% of subjects in the onabotulinumtoxinA 44-U group and 52.0% of subjects in the onabotulinumtoxinA 24-U group classified themselves as “very much improved” or “much improved,” compared with 3.9% of subjects in the placebo group (Figure 5). Differences between each onabotulinumtoxinA-treated group and the placebo group were statistically significant at all time points in each treatment cycle (p < .001). In addition, the proportion of responders among subjects treated with onabotulinumtoxinA 44 U was significantly greater than the proportion treated with onabotulinumtoxinA 24 U up to Day 30 in Cycle 1 (p # .013) and Day 60 in Cycle 2 (p # .024).
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Figure 4. Proportion of investigator-assessed subjects with an improvement from baseline of at least 1 grade on the FWS. (A) At maximum smile: the proportion of responders was significantly greater (p < .001, all visits, all comparisons) in each onabotulinumtoxinA group than in the placebo group. The responder rate was also significantly greater in the onabotulinumtoxinA 44-U group (CFL + GL) than in the onabotulinumtoxinA 24-U group (CFL) at all time points through Day 60 in both treatment cycles (p # .009). (B) At rest: the proportion of responders was significantly greater (p < .001, all visits, all comparisons) in each onabotulinumtoxinA group than in the placebo group. The responder rate was also significantly greater in the onabotulinumtoxinA 44-U group (CFL + GL) than in the onabotulinumtoxinA 24-U group (CFL) at all time points except Day 120 of treatment Cycle 1 (p # .030).
Facial Line Outcomes-11 Questionnaire: Psychological Impact Items 2, 5, and 8 For each of the 3 items on the FLO-11 questionnaire, the proportion of responders was significantly greater for onabotulinumtoxinA-treated subjects than for placebo-treated subjects at all time points for each treatment cycle (p < .001, data not shown). Furthermore, the responder rate was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group through Day 90 in both treatment cycles for Item 2 (p # .006, Cycle 1; p # .023,
Cycle 2); Day 60, Cycle 1 (p # .031) and Day 30, Cycle 2 (p # .020) on Item 5; and Day 30, Cycle 1 (p # .002) and Day 90, Cycle 2 (p # .047) on Item 8. Self-Perception of Age Self-Perception of Age analyses were based on subjects who rated themselves as looking their current age or older than their current age at baseline. At Day 30 of Cycle 1, 50.6% and 33.6% of onabotulinumtoxinA-treated subjects (44 U [n = 265] and 24 U [n = 265], respectively) rated themselves in a younger
Figure 5. Proportion of subjects rating themselves as “very much improved” or “much improved” on the Subject’s Global Assessment of Change in CFL.
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age category than at baseline, compared with 9.1% of the placebo group (n = 263; p < .001, all betweengroup comparisons). On Day 30 of Cycle 2, the corresponding rates were 51.2% (n = 256), 33.6% (n = 253), and 9.2% (n = 229; p < .001, all betweengroup comparisons). Subject Assessment of Satisfaction of Appearance Significantly greater percentages of subjects in both onabotulinumtoxinA treatment groups were very satisfied or satisfied at Day 30 of each treatment cycle than were subjects in the placebo group (p < .001). At Day 30 of treatment Cycle 1, responder rates were 58.2% (173/297), 48.5% (144/297), and 6.8% (20/ 296) in the onabotulinumtoxinA 44-U group, onabotulinumtoxinA 24-U group, and placebo group, respectively; also, the responder rate was significantly greater in the onabotulinumtoxinA 44-U group than in the onabotulinumtoxinA 24-U group (p = .012). Results were similar at Day 30 of treatment Cycle 2 (data not shown). Glabellar Lines–Facial Wrinkle Scale During maximum frown and at rest, the proportion of responders was significantly greater in the onabotulinumtoxinA 44-U group than in the placebo group at all time points in both treatment cycles (p < .001; data not shown).
placebo-treated subject discontinued because of injection site pain and 1 onabotulinumtoxinA 24 Utreated subject discontinued because of a myocardial infarction, deemed not treatment related. Treatment-related AEs were reported in 9.6% of all subjects: 33 (10.8%) in the onabotulinumtoxinA 44-U group, 37 (12.1%) in the onabotulinumtoxinA 24-U group, and 18 (5.9%) in the placebo group. The most common were injection site hematoma (onabotulinumtoxinA 44 U, 3.0%; onabotulinumtoxinA 24 U, 4.9%; placebo, 1.3%), injection site hemorrhage (onabotulinumtoxinA 44 U, 1.3%; onabotulinumtoxinA 24 U, 1.6%; placebo, 0.7%), and headache (onabotulinumtoxinA 44 U, 4.3%; onabotulinumtoxinA 24 U, 2.9%; placebo, 3.3%). The majority were described as mild. One onabotulinumtoxinA 24 U-treated subject reported a severe event during Cycle 2, a sensation of bilateral orbital eye pressure that resolved without treatment. Neurologic Assessments and Spread of Toxin Nine subjects (6 onabotulinumtoxinA 44 U, 2 onabotulinumtoxinA 24 U, 1 placebo) experienced events that were identified as having potential relationship to possible spread of toxin. After detailed medial assessment, ptosis was considered a local pharmacological effect. There were no events deemed related to distant spread of toxin.
Safety Measures Adverse Events A total of 41.9% (384/917) reported at least 1 AE, most of which were determined by investigators to be unrelated to treatment. The most common AEs (reported by $1% of subjects) are listed in Table 3. During the entire study, 45.6% of the onabotulinumtoxinA 44-U group, 41.5% of the onabotulinumtoxinA 24-U group, and 38.6% of the placebo group reported at least 1 AE. The overall incidence of AEs was 30.9% during treatment Cycle 1 (120 days) and was 20.3% during treatment Cycle 2 (90 days). Most AEs were mild to moderate in severity. No deaths occurred during the course of the study. Two discontinuations were attributed to AEs: 1
Immunogenicity Serum-neutralizing antibodies against onabotulinumtoxinA were not detected in any onabotulinumtoxinA-treated subjects. Discussion This study is the first large-scale, randomized, placebocontrolled, Phase 3 study to document the efficacy and safety of repeated doses of onabotulinumtoxinA to treat CFL alone or in combination with GL, which is typical of clinical practice. Compared with the first study in the Phase 3 program, the population in this study was older and had more severe lines at baseline. Subjects in this study also were required to have moderate-to-severe CFL and GL as assessed by the investigator. Nevertheless, when CFL and GL were
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TABLE 3. Most Common Adverse Events With an Incidence $1% Preferred Term (MedDRA)
Abbreviated System Organ Class Overall Eye disorders Gastrointestinal disorders
Overall
Injury, poisoning, and procedural complications
127 (41.5)
Total, n (%), N = 917
118 (38.6)
384 (41.9) 28 (3.1)
15 (4.9)
7 (2.3)
6 (2.0)
1 (0.3)
3 (1.0)
0 (0.0)
4 (0.4)
Overall
8 (2.6)
8 (2.6)
16 (5.2)
32 (3.5)
Nausea
2 (0.7)
1 (0.3)
4 (1.3)
7 (0.8)
Vomiting Diarrhea
0 (0.0) 0 (0.0)
0 (0.0) 0 (0.0)
3 (1.0) 3 (1.0)
3 (0.3) 3 (0.3)
27 (8.9)
28 (9.2)
10 (3.3)
65 (7.1)
15 (4.9)
19 (6.2)
5 (1.6)
39 (4.3)
4 (1.3)
5 (1.6)
3 (1.0)
12 (1.3)
Injection site hemorrhage Overall
58 (19.0)
63 (20.6)
55 (18.0)
176 (19.2)
Nasopharyngitis
24 (7.9)
18 (5.9)
15 (4.9)
57 (6.2)
Upper respiratory tract infection
9 (3.0)
12 (3.9)
10 (3.3)
31 (3.4)
Sinusitis
5 (1.6)
5 (1.6)
6 (2.0)
16 (1.7)
Bronchitis
5 (1.6)
4 (1.3)
4 (1.3)
13 (1.4)
Influenza Urinary tract infection
3 (1.0) 3 (1.0)
4 (1.3) 4 (1.3)
4 (1.3) 3 (1.0)
11 (1.2) 10 (1.1)
Oral herpes
3 (1.0)
4 (1.3)
1 (0.3)
8 (0.9)
Pneumonia
2 (0.7)
2 (0.7)
3 (1.0)
7 (0.8)
Gastroenteritis
1 (0.3)
5 (1.6)
3 (1.0)
9 (1.0)
Acute sinusitis Pharyngitis streptococcal
0 (0.0) 0 (0.0)
3 (1.0) 1 (0.3)
2 (0.7) 4 (1.3)
5 (0.5) 5 (0.5)
Overall
16 (5.2)
14 (4.6)
25 (8.2)
55 (6.0)
Joint sprain
3 (1.0)
0 (0.0)
2 (0.7)
5 (0.5)
Fall
2 (0.7)
1 (0.3)
4 (1.3)
7 (0.8)
Laceration
2 (0.7)
0 (0.0)
4 (1.3)
6 (0.7)
Arthropod bite Procedural pain
1 (0.3) 1 (0.3)
4 (1.3) 3 (1.0)
0 (0.0) 3 (1.0)
5 (0.5) 7 (0.8)
15 (4.9)
11 (3.6)
12 (3.9)
38 (4.1)
4 (1.3)
2 (0.7)
4 (1.3)
10 (1.1)
Musculoskeletal and Overall connective tissue Back pain disorders Arthralgia
2 (0.7)
0 (0.0)
3 (1.0)
5 (0.5)
Intervertebral disc protrusion
1 (0.3)
3 (1.0)
2 (0.7)
6 (0.7)
Neoplasm benign, malignant, and unspecified
Overall Basal cell carcinoma
4 (1.3) 1 (0.3)
4 (1.3) 3 (1.0)
1 (0.3) 0 (0.0)
9 (1.0) 4 (0.4)
Nervous system disorders
Overall
24 (7.9)
20 (6.5)
21 (6.9)
65 (7.1)
Headache
19 (6.2)
14 (4.6)
18 (5.9)
51 (5.6)
Dizziness
1 (0.3)
3 (1.0)
1 (0.3)
5 (0.5)
1 (0.3) 1 (2.6)
2 (0.7) 0 (0.0)
2 (0.7) 0 (0.0)
5 (0.5) 1 (0.9)
Reproductive system Overall and breast Prostatitis* disorders
110
139 (45.6)
Placebo, n (%), n = 306
Eyelid edema
General disorders Overall and administration Injection site site conditions hematoma
Infections and infestations
OnabotulinumtoxinA OnabotulinumtoxinA 44 U, n (%), n = 305 24 U, n (%), n = 306
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MOERS-CARPI ET AL
TABLE 3. (Continued ) Preferred Term (MedDRA)
Abbreviated System Organ Class
OnabotulinumtoxinA OnabotulinumtoxinA 44 U, n (%), n = 305 24 U, n (%), n = 306
Respiratory, thoracic, Overall and mediastinal Cough disorders Oropharyngeal pain Skin and Overall subcutaneous Actinic keratosis tissue disorders Dermatitis Vascular disorders
Placebo, n (%), n = 306
Total, n (%), N = 917
8 (2.6)
6 (2.0)
8 (2.6)
22 (2.4)
3 (1.0)
3 (1.0)
0 (0.0)
6 (0.7)
0 (0.0)
0 (0.0)
4 (1.3)
4 (0.4)
13 (4.3)
8 (2.6)
11 (3.6)
32 (3.5)
4 (1.3)
0 (0.0)
1 (0.3)
5 (0.5)
1 (0.3)
1 (0.3)
3 (1.0)
5 (0.5)
Pruritus
1 (0.3)
0 (0.0)
3 (1.0)
4 (0.4)
Overall
2 (0.7)
3 (1.0)
4 (1.3)
9 (1.0)
Hypertension
1 (0.3)
3 (1.0)
3 (1.0)
7 (0.8)
*Based on male population. MedDRA, Medical Dictionary for Regulatory Activities.
treated simultaneously, responder rates on the CFLFWS tended to be higher than when CFL were treated alone. Responder rates for CFL in both onabotulinumtoxinA treatment groups were consistently and significantly higher than placebo responder rates, and as expected, responder rates for GL in the one onabotulinumtoxinA-treated group were consistently and significantly higher than placebo responder rates. Importantly, simultaneous treatment of CFL and GL with onabotulinumtoxinA consistently resulted in significantly greater response rates on PROs than when CFL were treated alone. Together, these findings suggest that the benefits of treating both CFL and GL exceed those of treating CFL alone, which may have important implications for clinical practice. As in the first study in this program,1 no serious treatment-related AEs occurred. In addition, no clinically meaningful between-group differences in the incidence of AEs occurred, demonstrating that repeated treatment with onabotulinumtoxinA is well tolerated, whether CFL are treated alone or in combination with GL. Some limitations of this study can be noted. Although this study allowed modification of the injection pattern for CFL based on clinical presentation, response rates were not assessed according to treatment pattern. In addition, the treatment interval was stipulated
a priori; therefore, treatment effect could not be followed to its end in some subjects. Future studies in which retreatment is based on response criteria will help provide additional real-world experience to inform response duration. Despite the large scale of the study, sample sizes for males, subjects of diverse ethnicities, and subject age (>65 years) were relatively small, and the study was not designed to evaluate differences in these various subgroups. Related to the additional inclusion criteria of moderate-to-severe GL at maximum frown, the baseline CFL severity was greater in this study than in the foregoing study (approximately 63% of subjects were rated as severe in this study as compared with approximately 50% in the preceding study). This may account for the higher responder rates in the preceding study, as subjects with more severe CFL at baseline may be less likely to achieve a grade of none or mild after treatment compared with subjects with less severe CFL. Therefore, an important area for future exploration will be the evaluation of response rates as a function of baseline severity.
Conclusion Repeated treatment with onabotulinumtoxinA was effective and well tolerated for the treatment of moderate-to-severe CFL alone or in combination with GL. Improvements in appearance were generally numerically
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ONABOTA FOR CROW' S FEET AND GLABELLAR LINES
greater when CFL and GL areas were treated simultaneously, as assessed by both investigators and subjects. Differences favoring treating both areas together versus the CFL alone were particularly apparent in PROs, representing what is most important to patients. The safety profile was consistent with previous aesthetic studies of onabotulinumtoxinA including the GL indication approved by various regulatory authorities, and no new safety signals were detected.4–6 The results of this largescale Phase 3 study support both the efficacy and tolerability of repeated onabotulinumtoxinA treatments of CFL alone or in combination with GL. Dosing and results reported in this study are specific to the formulation of BoNTA manufactured by Allergan, Inc. This formulation is not interchangeable with other botulinum toxin products and cannot be converted using a dose ratio. References 1. Carruthers A, Bruce S, de Coninck A, Connolly S, et al. Efficacy and safety of onabotulinumtoxinA for the treatment of crow's feet lines:
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a multicenter, randomized, controlled trial [submitted]. Dermatol Surg 2014;40:1181–90. 2. Carruthers A, Carruthers J. A single-center, dose-comparison, pilot study of botulinum neurotoxin type A in female patients with upper facial rhytids: safety and efficacy. J Am Acad Dermatol 2009;60: 972–79. 3. Carruthers A, Carruthers J. A single-center dose-comparison study of botulinum neurotoxin type A in females with upper facial rhytids: assessing patients' perception of treatment outcomes. J Drugs Dermatol 2009;8:924–29. 4. Lowe NJ, Ascher B, Heckmann M, Kumar C, et al; on behalf of the Botox Facial Aesthetics Study Team. Double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of botulinum toxin type A in subjects with crow's feet. Dermatol Surg 2005;31:257–62. 5. Carruthers A, Carruthers J, Lowe NJ, Menter MA, et al; for the BOTOXÒ Glabellar Lines I & II Study Groups. One-year, randomised, multicenter, two-period study of the safety and efficacy of repeated treatments with botulinum toxin type A in patients with glabellar lines. J Clin Res 2004;7:1–20. 6. Brin MF, Boodhoo TI, Pogoda JM, James LM, et al. Safety and tolerability of onabotulinumtoxinA in the treatment of facial lines: a meta-analysis of individual patient data from global clinical registration studies in 1678 participants. J Am Acad Dermatol 2009;61:961–71.
Address correspondence and reprint requests to: Marion Moers-Carpi, MD, Private Clinic, Hautok, Residenzstr. 7, 80333, Munich, Germany, or e-mail: [email protected]
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