COSMETIC A Prospective, Split-Face, Randomized, Double-Blind Study Comparing OnabotulinumtoxinA to IncobotulinumtoxinA for Upper Face Wrinkles Ruth Hill Yeilding, M.D. John P. Fezza, M.D. Winter Park and Sarasota, Fla.
Background: The authors sought to compare the newest U.S. Food and Drug Administration–approved botulinum toxin type A product, incobotulinumtoxinA, to onabotulinumtoxinA for upper face wrinkles. This is the first prospective, split-face, randomized, double-blind study addressing three types of facial wrinkles using a 1:1 dose ratio. Methods: The study was designed, institutional review board approval was obtained, and 45 patients were enrolled. A three-judge independent reviewer panel compared photographs of patients to the upper face validated assessment scales, selecting a grade ranging from 0 (no lines) to 4 (very severe) for the degree of glabellar lines, crow’s feet, and forehead lines for each side of the face for photographs taken before treatment and 3 days, 2 weeks, 3 months, and 4 months after treatment. For toxin comparison, the difference in the magnitude of the degree of wrinkle scale at each period compared to before treatment was calculated and statistical analysis performed. Individual wrinkle types and all three wrinkle types combined were analyzed. Results: Both products offered significant reduction in individual and combined wrinkles at comparable time points; however, onabotulinumtoxinA had significantly greater combined dynamic wrinkle reduction at 3 days (p < 0.010), 2 weeks (p < 0.008), 3 months (p < 0.013), and 4 months (p < 0.045). Conclusions: For identical dosage, both onabotulinumtoxinA and incobotulinumtoxinA are safe and effective in reducing dynamic wrinkles in the upper face; however, for the authors’ dosages, onabotulinumtoxinA had statistically greater efficacy at 3 days, 2 weeks, 3 months, and 4 months. (Plast. Reconstr. Surg. 135: 1328, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.
P
hysician experience with one botulinum toxin type A, onabotulinumtoxinA (Botox; Allergan, Irvine, Calif.), is far greater than with the newest U.S. Food and Drug Administration–approved alternative incobotulinumtoxinA (Xeomin; distributed by Merz Aesthetics, Inc., and Merz Pharmaceuticals, LLC, Greensboro, From YMD Eye & Face; and Center for Sight. Received for publication April 24, 2014; accepted September 25, 2014. This trial is registered under the name “Split-Face Prospective Study Comparing Botox to Xeomin for the Treatment of Facial Wrinkles,” Clinical Trials.gov identification number NCT02122536 (https://clinicaltrials.gov/ct2/show/ NCT02122536). Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001255
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N.C.). OnabotulinumtoxinA was first used in U.S. Food and Drug Administration studies in 1978, and was approved by the U.S. Food and Drug Administration in 1988 for treatment of strabismus and blepharospasm. The first cosmetic use was published by Carruthers in 1992, and cosmetic U.S. Food and Drug Administration approval for reduction of moderate to severe glabella lines occurred in 2002. According to Allergan, Inc., the manufacturer of onabotulinumtoxinA, Disclosure: Dr. Fezza is a speaker, consultant, and on the advisory board of Allergan and on the advisory board of Merz. He is also a speaker for Lumenis. The other author has no conflicts of interest to declare. No external funding was received for this study.
www.PRSJournal.com
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin onabotulinumtoxinA remains the dominant neurotoxin in use today, with an estimated 82 percent share of the aesthetic neurotoxin market.1 IncobotulinumtoxinA received U.S. Food and Drug Administration approval for cervical dystonia and blepharospasm in 2010. Cosmetic approval for glabella lines came in 2011. Although onabotulinumtoxinA has a 900-kDa complexing protein, incobotulinumtoxinA is the only U.S. Food and Drug Administration–approved botulinum toxin type A product without complexing proteins. It is postulated that a botulinum toxin type A product without complexing protein would provide less of an immunosuppressant response in patients. Immunosuppressant response could cause the effectiveness of botulinum toxin type A to be reduced over time, especially in long-term users. Currently, we do not find controlled studies demonstrating the clinical relevance of complexing proteins in patients. Dosage for incobotulinumtoxinA is generally believed to be 1:1 dose ratio with onabotulinumtoxinA. Recently, Dressler et al. has reconfirmed 1:1 dosage ratio based on LD50.2 Clinical studies by Sattler et al. and Prager and review articles by Carruthers et al. support a 1:1 dosage.3–5 However, both 1:1.5 and 1.5:1 were studied. 1:1.5 dosage was used by Prager and Rappl, with the higher dosage of onabotulinumtoxinA being shown to be nonsuperior to incobotulinumtoxinA.6 The opposite 1.5:1 dosage by Moers-Carpi et al. concluded a noninterchangeability of units between these two toxins, and that no fixed dose ratio exists in clinical practice.7 The relative disparity in overall experience for cosmetic efficacy led the authors to define the objective of this study as an evaluation of these two botulinum toxin type A products in a controlled manner addressing quantitative assessment of three areas of facial wrinkles using an identical dosage. We chose our controlled approach to be a prospective, split-face, randomized, double-blind study using a photographic upper face validated assessment scale for each of three wrinkle types: glabellar lines, crow’s feet, and forehead lines.
Eligible study participants were men and women aged 18 years or older. Exclusion criteria were previous treatment with a neuromodulator in the past 6 months, previous brow lift, currently pregnant or breastfeeding, a history of neurologic disease or deficit, an active facial skin infection, and allergy to neuromodulators. Subjects were randomized regarding which side of the face would be injected with onabotulinumtoxinA and incobotulinumtoxinA. In addition to the injector and patient being blind to the treatment for each side, the three-physician review panel was also blinded. A total dose of 22.5 units of onabotulinumtoxinA and 22.5 units of incobotulinumtoxinA was administered at baseline to the respective side of the face. One vial (100 MU) of onabotulinumtoxinA was reconstituted with 2.0 ml of 0.9% sterile saline solution. Similarly, one vial (100 MU) of incobotulinumtoxinA was reconstituted with 2.0 ml of 0.9% sterile saline solution. The injection pattern was the same for each patient (Fig. 1) and the dosages were compared with other study dosages according to location (Table 1).3,6–14 The duration of the study was 4 months. The follow-up visits were at 3 days, 2 weeks, 3 months, and 4 months after the initial treatment. At each of these visits, the investigator performed efficacy and safety assessments and photographs were taken. Also, at each visit during the study, adverse events were documented, including difficulty in swallowing, difficulty in speaking, difficulty in breathing, allergic reactions, dry mouth, tiredness, headaches, neck pain, eye problems such as
PATIENTS AND METHODS This study was a prospective, single-center, randomized, double-blind study. The study was approved by the Sarasota Memorial Hospital Institutional Review Board. Informed consent was obtained from each subject before all study-related procedures. The split-face study design ensured that any demographic bias was eliminated.
Fig. 1. Study injection sites of onabotulinumtoxinA and incobotulinumtoxinA.
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Plastic and Reconstructive Surgery • May 2015 Table 1. Comparison of Previous Study Injection Dosages Compared to Our Study
Reference Glabella lines Sattler et al., 20103 Prager et al., 20108 Carruthers et al., 20059 Prager et al., 20126 Moers-Carpi et al., 20127
Dosage Used in Prior Studies (units) 24 24 10, 20, 30, 40 30 (Ona) to 20 (Inco) 20 (Ona) to 30 (Inco) 20 20
Allergan, Inc., 201410 Merz North America, 201411 20 Lorenc et al., 201312 Forehead lines 6–15 Carruthers et al., 200813 17 Oliveira de Morais et al., 14 2012 10–20 for women Lorenc et al., 201312 and 20–40 for men Crow’s feet 24 Allergan, Inc., 201410 16–32 Lorenc et al., 201312
Dosage Used in This Study (units) 20
Statistical Analysis To assess group differences, a two-sample t test or modified t test for uneven variance was applied. The values were considered to be significant at a level of p < 0.05.
RESULTS 10
15
double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of the lids, and dry eyes. Flynn Validated Assessment Scale The parameters of data captured followed the established validated assessment scales for the upper face published by Flynn et al.15 The study included static and dynamic standardized digital photographs at each study visit of glabellar lines, forehead lines, and crow’s feet. Static lines were defined as those when no facial expression was present and dynamic lines were those when the patient was maximally contracting the specific muscle group in each of the three areas (i.e., frowning, smiling, and lifting the eyebrows). The scale is five points, ranging from 0 (no lines) to 4 (very severe). At the conclusion of the study, three independent physicians individually performed blind assessments of all the photographs for each side of the face of each subject and graded them numerically using the methodology and the photographic reference validated assessment scale. The scores from the three graders were averaged to a single score for each area and side of the face. The data were unmasked and grouped by toxin type. The average scores for each of the three wrinkle types were calculated for each toxin. Then, the three wrinkle scores were averaged for a combined score for total upper facial wrinkles for each toxin. This analysis was performed for static
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and dynamic wrinkles. The difference between the combined score at each posttreatment period (3 days, 2 weeks, 3 months, and 4 months) and the pretreatment score was made for each toxin, which represents the reduction in wrinkle score for each toxin at each time point.
There were 45 subjects enrolled, with ages ranging of 26 to 82 years (mean, 52.9 years), of which 41 were women and four were men. Irrespective of the exclusion criterion of no neuromodulator treatment in the prior 6 months, the population did have some subjects who presented with earlier history of neuromodulator injection: 23 subjects had prior onabotulinumtoxinA injections, six subjects had prior abobotulinumtoxinA (Dysport; Medicis Pharmaceutical, Scottsdale, Ariz.) injections, four had a history with both materials, 17 subjects had no history of neuromodulator use, and three subjects had data not reported. In the randomization, onabotulinumtoxinA was used on the right side of the face in 22 subjects and on the left side in 23 subjects, with the contralateral side given incobotulinumtoxinA. In the course of follow-up, the accountability of subjects was noted (Table 2), as were the age and sex distributions (Table 3). Results for Both Toxins over Baseline Representative before-and-after photographs of patients for each of the three dynamic wrinkle types are included (Fig. 2). The wrinkle score for each visit by wrinkle type and toxin for both static and dynamic wrinkles were tallied (Table 4). The data include p values for each visit compared with pretreatment wrinkle scores. As expected, the scores for the dynamic assessment condition were consistently greater than those seen for the static assessment condition. To summarize Table 4, examining the dynamic data by wrinkle type, we found that crow’s feet results show that both toxins were significant over baseline at 3 days and 2 weeks, whereas both fell below significance at 3 and 4 months. For dynamic forehead lines, both toxins were significant at all follow-up intervals. Dynamic glabella treatment results showed that both toxins were significant
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin Table 2. Accountability of Subjects Accountability of Subjects
Preoperative
3 Days
2 Wk
3 Mo
4 Mo
45 45
45 45
45 45
42 42
40 40
0 0
0 0
0 0
3 3
5 5
45 45
45 45
45 45
42 42
40 40
100 100
100 100
100 100
93 93
89 89
Enrolled and treated OnabotulinumtoxinA IncobotulinumtoxinA Unavailable/missed visits OnabotulinumtoxinA IncobotulinumtoxinA Available for analysis OnabotulinumtoxinA IncobotulinumtoxinA Accountability, % OnabotulinumtoxinA IncobotulinumtoxinA
Table 3. Age and Sex Distribution
No.
20–30 Yr
30–40 Yr
40–50 Yr
50–60 Yr
60–70 Yr
70–80 Yr
80–90 Yr
M 0
M 0
M 2
M 0
M 1
M 0
M 1
F 2
F 4
F 9
F 16
F 7
F 1
F 2
Total M 4
F 41
M, male; F, female.
at 3 days, 2 weeks, and 3 months, whereas at 4 months onabotulinumtoxinA remained significant over baseline (p < 0.046) and incobotulinumtoxinA fell below significance (p < 0.084). For all three dynamic wrinkles combined, both toxins were significant at all intervals. For static wrinkles by wrinkle type, the crow’s feet results were significant for both toxins at 3 days and 2 weeks, whereas both toxins fell below significance at 3 and 4 months. Static forehead results show both toxins significant at 3 days, 2 weeks, and 3 months, whereas both fell below significance at 4 months. The static glabella results show that both toxins were significant at 3 days and 2 weeks, whereas both fell below significance at 3 and 4 months. The combined static results showed that both toxins were significant over baseline at 3 days, 2 weeks, and 3 months, whereas both fell below significance at the 4-month interval. Comparison of OnabotulinumtoxinA to IncobotulinumtoxinA In the objective quantitative comparison between the toxins, the change from baseline score (reduction in wrinkles or wrinkle improvement) was documented (Table 5). The neuromodulator effect is shown to achieve the greatest difference from baseline in dynamic scoring of both groups at either 3 days or 2 weeks, decreasing thereafter. The data show no significant difference between the toxins for individual or combined static wrinkle reduction. The data do show a significant difference for combined dynamic wrinkles at 3 days, 2 weeks, 3 months,
and 4 months in favor of onabotulinumtoxinA versus incobotulinumtoxinA. Comparative Effect over Time The effect over time, for the most clinically relevant case, combined dynamic wrinkle reduction, can be seen graphically (Fig. 3), where the effect of both toxins diminishes over time but where onabotulinumtoxinA (in blue) constantly maintains a higher performance over incobotulinumtoxinA (in red) for 3 days (p < 0.010), 2 weeks (p < 0.008), 3 months (p < 0.013), and 4 months (p < 0.045). Adverse Events Patients were interviewed about adverse events during each of the follow-up visits. The interview inquired about the following: difficulty in swallowing, difficulty in speaking, difficulty in breathing, allergic reactions, dry mouth, tiredness, headaches, neck pain, and eye problems (e.g., double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of the lids, and dry eyes). No adverse events were reported by any of the patients during the follow-up period.
DISCUSSION Dosage for incobotulinumtoxinA is generally believed to be a 1:1 dose ratio with onabotulinumtoxinA, with the toxicity studies providing the most consistent comparison.2,16 Although toxicity dosage equivalence does not imply clinical efficacy dosage equivalence, there is a strong body of
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Plastic and Reconstructive Surgery • May 2015
Fig. 2. Representative before-and-after photographs of patients from each of the three dynamic wrinkle groups. (Left) Photographs obtained before treatment; (right) photographs obtained 2 weeks after treatment. (Above) Glabella treatment on a 43-yearold woman while frowning. (Center) Crow’s feet results from a 62-year-old woman while smiling. (Below) Forehead treatment on a 54-year-old woman while lifting her brows.
work regarding the 1:1 clinical dosage, with noted exceptions being both 1:1.5 and 1.5:1 dosages.3–7 Given the lack of compelling reason to differ, we chose a 1:1 ratio in our study. Glabella dosage was chosen to be 20 units, consistent with the U.S. Food and Drug Administration–approved indication for both toxins. With no U.S. Food and Drug Administration indication for forehead lines or crow’s feet at the time of the study design to provide dosage guidelines, we had selected 10 units for forehead and 15 units for crow’s feet from our practice experience, prior studies, peer discussion, and a desire for a conservative treatment plan. Several years of our own clinical experience with these dosage levels
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showed favorable patient satisfaction regarding a more natural appearance, without complete forehead freeze or excessive smile retardation. Of course, subsequent studies leading to the U.S. Food and Drug Administration approval of the crow’s feet indication for onabotulinumtoxinA have shown good efficacy at 24 units without substantial safety issues. With an overall conservative philosophy and favorable prior clinical experience for the authors at 10 units for forehead and 15 units for crow’s feet, especially in a mostly female population, we selected these values for this study. We note that in general our dosage was on the low side of the dosage range compared with the most relevant literature we found (Table 1).
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin Table 4. Wrinkle Score for Each Visit on a Scale from 0 (None) to 4 (Very Severe Wrinkles)
Dynamic Crow’s feet Ona Inco Forehead Ona Inco Glabella Ona Inco Combined Ona Inco Static Crow’s feet Ona Inco Forehead Ona Inco Glabella Ona Inco Combined Ona Inco
3 Days (n = 45)
2 Wk (n = 45)
3 Mo (n = 42)
4 Mo (n = 40)
Preinjection Wrinkle Score (n = 45)
Wrinkle Score
p
Wrinkle Score
p
Wrinkle Score
p
Wrinkle Score
p
2.47 2.49
1.77 1.87
0.0001 0.0001
1.92 1.99
0.0001 0.0001
2.32 2.39
0.2203 0.2966
2.53 2.56
0.64 0.6451
2.73 2.74
1.31 1.47
0.0001 0.0001
1.11 1.35
0.0001 0.0001
1.78 1.96
0.0001 0.0003
2.25 2.37
0.017 0.048
2.44 2.47
1.24 1.31
0.0001 0.0001
1.2 1.25
0.0001 0.0001
1.74 1.79
0.0016 0.0018
2.04 2.17
0.0466 0.0847
2.55 2.57
1.44 1.55
0.0001 0.0001
1.41 1.53
0.0001 0.0001
1.94 2.04
0.0001 0.0001
2.28 2.36
0.0157 0.0481
1.53 1.53
1.06 1.08
0.0001 0.0001
1.25 1.25
0.0005 0.0004
1.28 1.35
0.1039 0.1787
1.53 1.59
0.4982 0.6138
1.22 1.24
0.8 0.81
0.0001 0.0001
0.91 0.93
0.0001 0.0001
0.89 0.94
0.0167 0.0301
1.03 1.04
0.1165 0.1079
1.1 1.1
0.7 0.7
0.0001 0.0001
0.84 0.85
0.0004 0.0007
0.87 0.85
0.0994 0.078
0.92 0.9
0.1612 0.1354
1.28 1.29
0.85 0.86
0.0001 0.0001
1 1.01
0.0001 0.0001
1.01 1.04
0.0048 0.0102
1.16 1.18
0.1254 0.1508
Ona, onabotulinumtoxinA; Inco, incobotulinumtoxinA.
A prior study by Sattler et al. was a large, non–split-face study with 381 patients. This study compared onabotulinumtoxinA to incobotulinumtoxinA in treating glabellar lines at a total dosage of 24 units. This study did not find a significant difference between the two neuromodulators; however, it should be noted that the objective of this study was noninferiority with a primary measure of percent responders (oneline improvement on their four-line facial wrinkle scale).3 Carruthers et al. showed that 20, 30, and 40 units of onabotulinumtoxinA in the treatment of glabellar lines were significantly superior to 10 units in a parallel group study, but no significant difference was found among the 20-, 30-, and 40-unit groups, and an increasing effect for increasing dosage was not supported.9 This might suggest a saturation effect that limits sensitivity to differences between doses at the higher end of the dosage range. Additional limitations of the study pointed out by the authors was the relatively small number of 20 in each group and the fact that the starting wrinkle score happened to be significantly higher in one of the parallel groups (the 20-unit group), making it harder to be counted as a responder [scores had to reach 1 (mild lines), or 0 (no lines)] to qualify. Prager studied
incobotulinumtoxinA at 25 units, showing excellent efficacy but not in comparative study.4 Prager and Rappl studied 20 units of incobotulinumtoxinA versus 30 units of onabotulinumtoxinA, with no significant difference found, concluding there was no reason to increase either dosage to 30 units.6 Moers-Carpi et al. used the opposite dosage ratio, 20 units of onabotulinumtoxinA versus 30 units of incobotulinumtoxinA for glabellar lines, and had similar results, showing no significant difference between the toxins, concluding a noninterchangeability of dosage units.7 However, Carruthers et al. pointed out that the 2005 dose ranging study suggests that the Moers-Carpi finding may be because of a lack of sensitivity in the method.5 Prager et al. conducted a controlled, split-face, clinical comparison between onabotulinumtoxinA and incobotulinumtoxinA in the treatment of crow’s feet at a dosage of 24 units, full face, divided to 12 units for each toxin.8 No statistical significance was found between the toxins; however, the study was relatively small (n = 19 at 3 months). Our findings of greater efficacy for onabotulinumtoxinA over incobotulinumtoxinA for the same dosage may be partially attributable to our study comparing degree of response, rather than percentage of responders to a fixed endpoint.
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Plastic and Reconstructive Surgery • May 2015 Table 5. Change in Reduction in Wrinkle Score at Each Visit Compared with Pretreatment Score
Dynamic Crow’s feet Ona Inco Dif Forehead Ona Inco Dif Glabella Ona Inco Dif Combined Ona Inco Dif Static Crow’s feet Ona Inco Dif Forehead Ona Inco Dif Glabella Ona Inco Dif Combined Ona Inco Dif
3 Days (n = 45)
Preinjection Wrinkle Score (n = 45)
Wrinkle Score
2.47 2.49 −0.02
0.70 0.62 0.073
2.73 2.74 −0.01
1.42 1.27 0.150
2.44 2.47 −0.03
1.20 1.16 0.037
2.55 2.57 −0.02
1.11 1.02 0.09
1.53 1.53 0
0.47 0.45 0.013
1.22 1.24 −0.02
0.42 0.43 −0.007
1.1 1.1 0
0.40 0.40 0.000
1.28 1.29 −0.01
0.43 0.43 0.003
2 Wk (n = 45)
p
Wrinkle Score
0.071
0.55 0.50 0.043
0.043
1.62 1.39 0.233
0.226
1.24 1.22 0.013
0.010
1.14 1.04 0.10
0.210
0.27 0.28 −0.007
0.629
0.31 0.30 0.007
0.500
0.25 0.24 0.010
0.410
0.28 0.28 0.003
3 Mo (n = 42)
p
Wrinkle Score
0.240
0.13 0.09 0.047
0.006
0.94 0.76 0.173
0.375
0.72 0.71 0.010
0.008
0.60 0.52 0.08
0.715
0.28 0.21 0.063
0.372
0.37 0.34 0.033
0.285
0.28 0.30 −0.023
0.399
0.31 0.29 0.023
4 Mo (n = 40)
p
Wrinkle Score
p
0.191
−0.10 −0.10 0.000
0.500
0.012
0.43 0.32 0.110
0.070
0.425
0.41 0.33 0.083
0.067
0.013
0.24 0.18 0.06
0.045
0.037
0.01 −0.05 0.060
0.026
0.210
0.18 0.19 −0.010
0.645
0.814
0.22 0.23 −0.017
0.789
0.113
0.14 0.13 0.010
0.218
Ona, onabotulinumtoxinA; Inco, incobotulinumtoxinA; Dif, difference.
We believe a more significant element is found in our slightly lower dosage levels, which have likely increased clinical sensitivity to toxin differences by avoiding saturation.
Fig. 3. Mean reduction in combined wrinkle score for onabotulinumtoxinA (blue) versus incobotulinumtoxinA (red).
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Our study showed that onabotulinumtoxinA was statistically greater than incobotulinumtoxinA at reducing combined dynamic wrinkles at a 1:1 dose ratio at 3 days, 2 weeks, 3 months, and 4 months after injection. This might suggest that a higher dose ratio of incobotulinumtoxinA may be required to have the same effect as onabotulinumtoxinA or that the superiority finding is as valid at the slightly lower treatment dosage. One clinically relevant difference between the toxins is storage. Although onabotulinumtoxinA requires freezing before reconstitution, incobotulinumtoxinA can be stored on the shelf at room temperature, which can be advantageous in some practices. Both require refrigeration after reconstitution. Both manufacturers state that the toxins should be discarded 24 hours after reconstitution. However, storage longevity was not an element of this study. One limitation to our split-face study design was that the standard treatment for glabellar lines uses five spots, with one directly central; however,
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin to avoid product crossover in a split-face method, we eliminated the central spot and used four spots. Although the spacing was greater than the nominally expected 1-cm spread, we cannot be certain that we eliminated crossover.
CONCLUSIONS For identical dosage, both onabotulinumtoxinA and incobotulinumtoxinA are safe and effective in the treatment of glabellar lines, crow’s feet lines, and forehead lines; however, for our dosage levels, onabotulinumtoxinA was statistically greater in combined dynamic wrinkle reduction at 3 days, 2 weeks, 3 months, and 4 months. Ruth Hill Yeilding, M.D. YMD Eye & Face 328 West Morse Boulevard Winter Park, Fla. 32789 [email protected]
ACKNOWLEDGMENTS
The authors thank Randy Frey and Shirley McGarvey for manuscript review and Brad Haby Accelerated Vision for the statistical analysis. PATIENT CONSENT
Patients provided written consent for the use of their images. REFERENCES 1. Allergan, Inc. Q3 2013 earnings call transcript. Available at: http://seekingalpha.com/article/1784222-allergan-management-discusses-q3-2013-results-earnings-call-transcript. Accessed April 19, 2014. 2. Dressler D, Mander G, Fink K. Measuring the potency labeling of onabotulinumtoxinA and incobotulinumtoxinA in an LD50 assay. J Neural Transm. 2012;119:13–15. 3. Sattler G, Callander MJ, Grablowitz D, et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A
in the treatment of glabellar frown lines. Dermatol Surg. 2010;36(Suppl 4):2146–2154. 4. Prager W. Differential characteristics of incobotulinumtoxinA and its use in the management of glabellar frown lines. Clin Pharmacol. 2013;5:39–52. 5. Carruthers A, Kane MA, Flynn TC, et al. The convergence of medicine and neurotoxins: A focus on botulinum toxin type A and its application in aesthetic medicine—A global, evidence-based botulinum toxin consensus education initiative: Part I. Botulinum toxin in clinical and cosmetic practice. Dermatol Surg. 2013;39:493–509. 6. Prager W, Rappl T. Phase IV study comparing incobotulinumtoxinA and onabotulinumtoxinA using a 1:1.5 doseconversion ratio for the treatment of glabellar frown lines. J Cosmet Dermatol. 2012;11:267–271. 7. Moers-Carpi M, Dirschka T, Feller-Heppt G, et al. A randomised, double-blind comparison of 20 units of onabotulinumtoxinA with 30 units of incobotulinumtoxinA for glabellar lines. J Cosmet Laser Ther. 2012;14:296–303. 8. Prager W, Wissmüller E, Kollhorst B, Williams S, Zschocke I. Comparison of two botulinum toxin type A preparations for treating crow’s feet: A split-face, double-blind, proof-ofconcept study. Dermatol Surg. 2010;36(Suppl 4):2155–2160. 9. Carruthers A, Carruthers J, Said S. Dose-ranging study of botulinum toxin type A in the treatment of glabellar rhytids in females. Dermatol Surg. 2005;31:414–422. 10. Allergan, Inc. Botox cosmetic. Medication guide. Available at: http://www.botoxcosmetic.com. Accessed April 19, 2014. 11. Merz North America. Xeomin Official Site. Available at: http://www.xeomin.com. Accessed April 19, 2014. 12. Lorenc ZP, Kenkel JM, Fagien S, et al. Consensus panel’s assessment and recommendations on the use of 3 botulinum toxin type A products in facial aesthetics. Aesthet Surg J. 2013;33(Suppl):35S–40S. 13. Carruthers JD, Glogau RG, Blitzer A; Facial Aesthetics Consensus Group Faculty. Advances in facial rejuvenation: Botulinum toxin type a, hyaluronic acid dermal fillers, and combination therapies—Consensus recommendations. Plast Reconstr Surg. 2008;121(Suppl):5S–30S; quiz 31S. 14. Oliveira de Morais O, Matos Reis-Filho E, Vilela Pereira L, Martins Gomes C, Alves G. Comparison of four botulinum neurotoxin type A preparations in the treatment of hyperdynamic forehead lines in men: A pilot study. J Drugs Dermatol. 2012;11:216–219. 15. Flynn TC, Carruthers A, Carruthers J, et al. Validated assessment scales for the upper face. Dermatol Surg. 2012;38(Spec No):309–319. 16. Chung ME, Song DH, Park JH. Comparative study of biological activity of four botulinum toxin type A preparations in mice. Dermatol Surg. 2013;39:155–164.
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Background: The authors sought to compare the newest U.S. Food and Drug Administration–approved botulinum toxin type A product, incobotulinumtoxinA, to onabotulinumtoxinA for upper face wrinkles. This is the first prospective, split-face, randomized, double-blind study addressing three types of facial wrinkles using a 1:1 dose ratio. Methods: The study was designed, institutional review board approval was obtained, and 45 patients were enrolled. A three-judge independent reviewer panel compared photographs of patients to the upper face validated assessment scales, selecting a grade ranging from 0 (no lines) to 4 (very severe) for the degree of glabellar lines, crow’s feet, and forehead lines for each side of the face for photographs taken before treatment and 3 days, 2 weeks, 3 months, and 4 months after treatment. For toxin comparison, the difference in the magnitude of the degree of wrinkle scale at each period compared to before treatment was calculated and statistical analysis performed. Individual wrinkle types and all three wrinkle types combined were analyzed. Results: Both products offered significant reduction in individual and combined wrinkles at comparable time points; however, onabotulinumtoxinA had significantly greater combined dynamic wrinkle reduction at 3 days (p < 0.010), 2 weeks (p < 0.008), 3 months (p < 0.013), and 4 months (p < 0.045). Conclusions: For identical dosage, both onabotulinumtoxinA and incobotulinumtoxinA are safe and effective in reducing dynamic wrinkles in the upper face; however, for the authors’ dosages, onabotulinumtoxinA had statistically greater efficacy at 3 days, 2 weeks, 3 months, and 4 months. (Plast. Reconstr. Surg. 135: 1328, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.
P
hysician experience with one botulinum toxin type A, onabotulinumtoxinA (Botox; Allergan, Irvine, Calif.), is far greater than with the newest U.S. Food and Drug Administration–approved alternative incobotulinumtoxinA (Xeomin; distributed by Merz Aesthetics, Inc., and Merz Pharmaceuticals, LLC, Greensboro, From YMD Eye & Face; and Center for Sight. Received for publication April 24, 2014; accepted September 25, 2014. This trial is registered under the name “Split-Face Prospective Study Comparing Botox to Xeomin for the Treatment of Facial Wrinkles,” Clinical Trials.gov identification number NCT02122536 (https://clinicaltrials.gov/ct2/show/ NCT02122536). Copyright © 2015 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001255
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N.C.). OnabotulinumtoxinA was first used in U.S. Food and Drug Administration studies in 1978, and was approved by the U.S. Food and Drug Administration in 1988 for treatment of strabismus and blepharospasm. The first cosmetic use was published by Carruthers in 1992, and cosmetic U.S. Food and Drug Administration approval for reduction of moderate to severe glabella lines occurred in 2002. According to Allergan, Inc., the manufacturer of onabotulinumtoxinA, Disclosure: Dr. Fezza is a speaker, consultant, and on the advisory board of Allergan and on the advisory board of Merz. He is also a speaker for Lumenis. The other author has no conflicts of interest to declare. No external funding was received for this study.
www.PRSJournal.com
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin onabotulinumtoxinA remains the dominant neurotoxin in use today, with an estimated 82 percent share of the aesthetic neurotoxin market.1 IncobotulinumtoxinA received U.S. Food and Drug Administration approval for cervical dystonia and blepharospasm in 2010. Cosmetic approval for glabella lines came in 2011. Although onabotulinumtoxinA has a 900-kDa complexing protein, incobotulinumtoxinA is the only U.S. Food and Drug Administration–approved botulinum toxin type A product without complexing proteins. It is postulated that a botulinum toxin type A product without complexing protein would provide less of an immunosuppressant response in patients. Immunosuppressant response could cause the effectiveness of botulinum toxin type A to be reduced over time, especially in long-term users. Currently, we do not find controlled studies demonstrating the clinical relevance of complexing proteins in patients. Dosage for incobotulinumtoxinA is generally believed to be 1:1 dose ratio with onabotulinumtoxinA. Recently, Dressler et al. has reconfirmed 1:1 dosage ratio based on LD50.2 Clinical studies by Sattler et al. and Prager and review articles by Carruthers et al. support a 1:1 dosage.3–5 However, both 1:1.5 and 1.5:1 were studied. 1:1.5 dosage was used by Prager and Rappl, with the higher dosage of onabotulinumtoxinA being shown to be nonsuperior to incobotulinumtoxinA.6 The opposite 1.5:1 dosage by Moers-Carpi et al. concluded a noninterchangeability of units between these two toxins, and that no fixed dose ratio exists in clinical practice.7 The relative disparity in overall experience for cosmetic efficacy led the authors to define the objective of this study as an evaluation of these two botulinum toxin type A products in a controlled manner addressing quantitative assessment of three areas of facial wrinkles using an identical dosage. We chose our controlled approach to be a prospective, split-face, randomized, double-blind study using a photographic upper face validated assessment scale for each of three wrinkle types: glabellar lines, crow’s feet, and forehead lines.
Eligible study participants were men and women aged 18 years or older. Exclusion criteria were previous treatment with a neuromodulator in the past 6 months, previous brow lift, currently pregnant or breastfeeding, a history of neurologic disease or deficit, an active facial skin infection, and allergy to neuromodulators. Subjects were randomized regarding which side of the face would be injected with onabotulinumtoxinA and incobotulinumtoxinA. In addition to the injector and patient being blind to the treatment for each side, the three-physician review panel was also blinded. A total dose of 22.5 units of onabotulinumtoxinA and 22.5 units of incobotulinumtoxinA was administered at baseline to the respective side of the face. One vial (100 MU) of onabotulinumtoxinA was reconstituted with 2.0 ml of 0.9% sterile saline solution. Similarly, one vial (100 MU) of incobotulinumtoxinA was reconstituted with 2.0 ml of 0.9% sterile saline solution. The injection pattern was the same for each patient (Fig. 1) and the dosages were compared with other study dosages according to location (Table 1).3,6–14 The duration of the study was 4 months. The follow-up visits were at 3 days, 2 weeks, 3 months, and 4 months after the initial treatment. At each of these visits, the investigator performed efficacy and safety assessments and photographs were taken. Also, at each visit during the study, adverse events were documented, including difficulty in swallowing, difficulty in speaking, difficulty in breathing, allergic reactions, dry mouth, tiredness, headaches, neck pain, eye problems such as
PATIENTS AND METHODS This study was a prospective, single-center, randomized, double-blind study. The study was approved by the Sarasota Memorial Hospital Institutional Review Board. Informed consent was obtained from each subject before all study-related procedures. The split-face study design ensured that any demographic bias was eliminated.
Fig. 1. Study injection sites of onabotulinumtoxinA and incobotulinumtoxinA.
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Plastic and Reconstructive Surgery • May 2015 Table 1. Comparison of Previous Study Injection Dosages Compared to Our Study
Reference Glabella lines Sattler et al., 20103 Prager et al., 20108 Carruthers et al., 20059 Prager et al., 20126 Moers-Carpi et al., 20127
Dosage Used in Prior Studies (units) 24 24 10, 20, 30, 40 30 (Ona) to 20 (Inco) 20 (Ona) to 30 (Inco) 20 20
Allergan, Inc., 201410 Merz North America, 201411 20 Lorenc et al., 201312 Forehead lines 6–15 Carruthers et al., 200813 17 Oliveira de Morais et al., 14 2012 10–20 for women Lorenc et al., 201312 and 20–40 for men Crow’s feet 24 Allergan, Inc., 201410 16–32 Lorenc et al., 201312
Dosage Used in This Study (units) 20
Statistical Analysis To assess group differences, a two-sample t test or modified t test for uneven variance was applied. The values were considered to be significant at a level of p < 0.05.
RESULTS 10
15
double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of the lids, and dry eyes. Flynn Validated Assessment Scale The parameters of data captured followed the established validated assessment scales for the upper face published by Flynn et al.15 The study included static and dynamic standardized digital photographs at each study visit of glabellar lines, forehead lines, and crow’s feet. Static lines were defined as those when no facial expression was present and dynamic lines were those when the patient was maximally contracting the specific muscle group in each of the three areas (i.e., frowning, smiling, and lifting the eyebrows). The scale is five points, ranging from 0 (no lines) to 4 (very severe). At the conclusion of the study, three independent physicians individually performed blind assessments of all the photographs for each side of the face of each subject and graded them numerically using the methodology and the photographic reference validated assessment scale. The scores from the three graders were averaged to a single score for each area and side of the face. The data were unmasked and grouped by toxin type. The average scores for each of the three wrinkle types were calculated for each toxin. Then, the three wrinkle scores were averaged for a combined score for total upper facial wrinkles for each toxin. This analysis was performed for static
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and dynamic wrinkles. The difference between the combined score at each posttreatment period (3 days, 2 weeks, 3 months, and 4 months) and the pretreatment score was made for each toxin, which represents the reduction in wrinkle score for each toxin at each time point.
There were 45 subjects enrolled, with ages ranging of 26 to 82 years (mean, 52.9 years), of which 41 were women and four were men. Irrespective of the exclusion criterion of no neuromodulator treatment in the prior 6 months, the population did have some subjects who presented with earlier history of neuromodulator injection: 23 subjects had prior onabotulinumtoxinA injections, six subjects had prior abobotulinumtoxinA (Dysport; Medicis Pharmaceutical, Scottsdale, Ariz.) injections, four had a history with both materials, 17 subjects had no history of neuromodulator use, and three subjects had data not reported. In the randomization, onabotulinumtoxinA was used on the right side of the face in 22 subjects and on the left side in 23 subjects, with the contralateral side given incobotulinumtoxinA. In the course of follow-up, the accountability of subjects was noted (Table 2), as were the age and sex distributions (Table 3). Results for Both Toxins over Baseline Representative before-and-after photographs of patients for each of the three dynamic wrinkle types are included (Fig. 2). The wrinkle score for each visit by wrinkle type and toxin for both static and dynamic wrinkles were tallied (Table 4). The data include p values for each visit compared with pretreatment wrinkle scores. As expected, the scores for the dynamic assessment condition were consistently greater than those seen for the static assessment condition. To summarize Table 4, examining the dynamic data by wrinkle type, we found that crow’s feet results show that both toxins were significant over baseline at 3 days and 2 weeks, whereas both fell below significance at 3 and 4 months. For dynamic forehead lines, both toxins were significant at all follow-up intervals. Dynamic glabella treatment results showed that both toxins were significant
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin Table 2. Accountability of Subjects Accountability of Subjects
Preoperative
3 Days
2 Wk
3 Mo
4 Mo
45 45
45 45
45 45
42 42
40 40
0 0
0 0
0 0
3 3
5 5
45 45
45 45
45 45
42 42
40 40
100 100
100 100
100 100
93 93
89 89
Enrolled and treated OnabotulinumtoxinA IncobotulinumtoxinA Unavailable/missed visits OnabotulinumtoxinA IncobotulinumtoxinA Available for analysis OnabotulinumtoxinA IncobotulinumtoxinA Accountability, % OnabotulinumtoxinA IncobotulinumtoxinA
Table 3. Age and Sex Distribution
No.
20–30 Yr
30–40 Yr
40–50 Yr
50–60 Yr
60–70 Yr
70–80 Yr
80–90 Yr
M 0
M 0
M 2
M 0
M 1
M 0
M 1
F 2
F 4
F 9
F 16
F 7
F 1
F 2
Total M 4
F 41
M, male; F, female.
at 3 days, 2 weeks, and 3 months, whereas at 4 months onabotulinumtoxinA remained significant over baseline (p < 0.046) and incobotulinumtoxinA fell below significance (p < 0.084). For all three dynamic wrinkles combined, both toxins were significant at all intervals. For static wrinkles by wrinkle type, the crow’s feet results were significant for both toxins at 3 days and 2 weeks, whereas both toxins fell below significance at 3 and 4 months. Static forehead results show both toxins significant at 3 days, 2 weeks, and 3 months, whereas both fell below significance at 4 months. The static glabella results show that both toxins were significant at 3 days and 2 weeks, whereas both fell below significance at 3 and 4 months. The combined static results showed that both toxins were significant over baseline at 3 days, 2 weeks, and 3 months, whereas both fell below significance at the 4-month interval. Comparison of OnabotulinumtoxinA to IncobotulinumtoxinA In the objective quantitative comparison between the toxins, the change from baseline score (reduction in wrinkles or wrinkle improvement) was documented (Table 5). The neuromodulator effect is shown to achieve the greatest difference from baseline in dynamic scoring of both groups at either 3 days or 2 weeks, decreasing thereafter. The data show no significant difference between the toxins for individual or combined static wrinkle reduction. The data do show a significant difference for combined dynamic wrinkles at 3 days, 2 weeks, 3 months,
and 4 months in favor of onabotulinumtoxinA versus incobotulinumtoxinA. Comparative Effect over Time The effect over time, for the most clinically relevant case, combined dynamic wrinkle reduction, can be seen graphically (Fig. 3), where the effect of both toxins diminishes over time but where onabotulinumtoxinA (in blue) constantly maintains a higher performance over incobotulinumtoxinA (in red) for 3 days (p < 0.010), 2 weeks (p < 0.008), 3 months (p < 0.013), and 4 months (p < 0.045). Adverse Events Patients were interviewed about adverse events during each of the follow-up visits. The interview inquired about the following: difficulty in swallowing, difficulty in speaking, difficulty in breathing, allergic reactions, dry mouth, tiredness, headaches, neck pain, and eye problems (e.g., double vision, blurred vision, decreased eyesight, drooping eyelids, swelling of the lids, and dry eyes). No adverse events were reported by any of the patients during the follow-up period.
DISCUSSION Dosage for incobotulinumtoxinA is generally believed to be a 1:1 dose ratio with onabotulinumtoxinA, with the toxicity studies providing the most consistent comparison.2,16 Although toxicity dosage equivalence does not imply clinical efficacy dosage equivalence, there is a strong body of
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Plastic and Reconstructive Surgery • May 2015
Fig. 2. Representative before-and-after photographs of patients from each of the three dynamic wrinkle groups. (Left) Photographs obtained before treatment; (right) photographs obtained 2 weeks after treatment. (Above) Glabella treatment on a 43-yearold woman while frowning. (Center) Crow’s feet results from a 62-year-old woman while smiling. (Below) Forehead treatment on a 54-year-old woman while lifting her brows.
work regarding the 1:1 clinical dosage, with noted exceptions being both 1:1.5 and 1.5:1 dosages.3–7 Given the lack of compelling reason to differ, we chose a 1:1 ratio in our study. Glabella dosage was chosen to be 20 units, consistent with the U.S. Food and Drug Administration–approved indication for both toxins. With no U.S. Food and Drug Administration indication for forehead lines or crow’s feet at the time of the study design to provide dosage guidelines, we had selected 10 units for forehead and 15 units for crow’s feet from our practice experience, prior studies, peer discussion, and a desire for a conservative treatment plan. Several years of our own clinical experience with these dosage levels
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showed favorable patient satisfaction regarding a more natural appearance, without complete forehead freeze or excessive smile retardation. Of course, subsequent studies leading to the U.S. Food and Drug Administration approval of the crow’s feet indication for onabotulinumtoxinA have shown good efficacy at 24 units without substantial safety issues. With an overall conservative philosophy and favorable prior clinical experience for the authors at 10 units for forehead and 15 units for crow’s feet, especially in a mostly female population, we selected these values for this study. We note that in general our dosage was on the low side of the dosage range compared with the most relevant literature we found (Table 1).
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin Table 4. Wrinkle Score for Each Visit on a Scale from 0 (None) to 4 (Very Severe Wrinkles)
Dynamic Crow’s feet Ona Inco Forehead Ona Inco Glabella Ona Inco Combined Ona Inco Static Crow’s feet Ona Inco Forehead Ona Inco Glabella Ona Inco Combined Ona Inco
3 Days (n = 45)
2 Wk (n = 45)
3 Mo (n = 42)
4 Mo (n = 40)
Preinjection Wrinkle Score (n = 45)
Wrinkle Score
p
Wrinkle Score
p
Wrinkle Score
p
Wrinkle Score
p
2.47 2.49
1.77 1.87
0.0001 0.0001
1.92 1.99
0.0001 0.0001
2.32 2.39
0.2203 0.2966
2.53 2.56
0.64 0.6451
2.73 2.74
1.31 1.47
0.0001 0.0001
1.11 1.35
0.0001 0.0001
1.78 1.96
0.0001 0.0003
2.25 2.37
0.017 0.048
2.44 2.47
1.24 1.31
0.0001 0.0001
1.2 1.25
0.0001 0.0001
1.74 1.79
0.0016 0.0018
2.04 2.17
0.0466 0.0847
2.55 2.57
1.44 1.55
0.0001 0.0001
1.41 1.53
0.0001 0.0001
1.94 2.04
0.0001 0.0001
2.28 2.36
0.0157 0.0481
1.53 1.53
1.06 1.08
0.0001 0.0001
1.25 1.25
0.0005 0.0004
1.28 1.35
0.1039 0.1787
1.53 1.59
0.4982 0.6138
1.22 1.24
0.8 0.81
0.0001 0.0001
0.91 0.93
0.0001 0.0001
0.89 0.94
0.0167 0.0301
1.03 1.04
0.1165 0.1079
1.1 1.1
0.7 0.7
0.0001 0.0001
0.84 0.85
0.0004 0.0007
0.87 0.85
0.0994 0.078
0.92 0.9
0.1612 0.1354
1.28 1.29
0.85 0.86
0.0001 0.0001
1 1.01
0.0001 0.0001
1.01 1.04
0.0048 0.0102
1.16 1.18
0.1254 0.1508
Ona, onabotulinumtoxinA; Inco, incobotulinumtoxinA.
A prior study by Sattler et al. was a large, non–split-face study with 381 patients. This study compared onabotulinumtoxinA to incobotulinumtoxinA in treating glabellar lines at a total dosage of 24 units. This study did not find a significant difference between the two neuromodulators; however, it should be noted that the objective of this study was noninferiority with a primary measure of percent responders (oneline improvement on their four-line facial wrinkle scale).3 Carruthers et al. showed that 20, 30, and 40 units of onabotulinumtoxinA in the treatment of glabellar lines were significantly superior to 10 units in a parallel group study, but no significant difference was found among the 20-, 30-, and 40-unit groups, and an increasing effect for increasing dosage was not supported.9 This might suggest a saturation effect that limits sensitivity to differences between doses at the higher end of the dosage range. Additional limitations of the study pointed out by the authors was the relatively small number of 20 in each group and the fact that the starting wrinkle score happened to be significantly higher in one of the parallel groups (the 20-unit group), making it harder to be counted as a responder [scores had to reach 1 (mild lines), or 0 (no lines)] to qualify. Prager studied
incobotulinumtoxinA at 25 units, showing excellent efficacy but not in comparative study.4 Prager and Rappl studied 20 units of incobotulinumtoxinA versus 30 units of onabotulinumtoxinA, with no significant difference found, concluding there was no reason to increase either dosage to 30 units.6 Moers-Carpi et al. used the opposite dosage ratio, 20 units of onabotulinumtoxinA versus 30 units of incobotulinumtoxinA for glabellar lines, and had similar results, showing no significant difference between the toxins, concluding a noninterchangeability of dosage units.7 However, Carruthers et al. pointed out that the 2005 dose ranging study suggests that the Moers-Carpi finding may be because of a lack of sensitivity in the method.5 Prager et al. conducted a controlled, split-face, clinical comparison between onabotulinumtoxinA and incobotulinumtoxinA in the treatment of crow’s feet at a dosage of 24 units, full face, divided to 12 units for each toxin.8 No statistical significance was found between the toxins; however, the study was relatively small (n = 19 at 3 months). Our findings of greater efficacy for onabotulinumtoxinA over incobotulinumtoxinA for the same dosage may be partially attributable to our study comparing degree of response, rather than percentage of responders to a fixed endpoint.
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Plastic and Reconstructive Surgery • May 2015 Table 5. Change in Reduction in Wrinkle Score at Each Visit Compared with Pretreatment Score
Dynamic Crow’s feet Ona Inco Dif Forehead Ona Inco Dif Glabella Ona Inco Dif Combined Ona Inco Dif Static Crow’s feet Ona Inco Dif Forehead Ona Inco Dif Glabella Ona Inco Dif Combined Ona Inco Dif
3 Days (n = 45)
Preinjection Wrinkle Score (n = 45)
Wrinkle Score
2.47 2.49 −0.02
0.70 0.62 0.073
2.73 2.74 −0.01
1.42 1.27 0.150
2.44 2.47 −0.03
1.20 1.16 0.037
2.55 2.57 −0.02
1.11 1.02 0.09
1.53 1.53 0
0.47 0.45 0.013
1.22 1.24 −0.02
0.42 0.43 −0.007
1.1 1.1 0
0.40 0.40 0.000
1.28 1.29 −0.01
0.43 0.43 0.003
2 Wk (n = 45)
p
Wrinkle Score
0.071
0.55 0.50 0.043
0.043
1.62 1.39 0.233
0.226
1.24 1.22 0.013
0.010
1.14 1.04 0.10
0.210
0.27 0.28 −0.007
0.629
0.31 0.30 0.007
0.500
0.25 0.24 0.010
0.410
0.28 0.28 0.003
3 Mo (n = 42)
p
Wrinkle Score
0.240
0.13 0.09 0.047
0.006
0.94 0.76 0.173
0.375
0.72 0.71 0.010
0.008
0.60 0.52 0.08
0.715
0.28 0.21 0.063
0.372
0.37 0.34 0.033
0.285
0.28 0.30 −0.023
0.399
0.31 0.29 0.023
4 Mo (n = 40)
p
Wrinkle Score
p
0.191
−0.10 −0.10 0.000
0.500
0.012
0.43 0.32 0.110
0.070
0.425
0.41 0.33 0.083
0.067
0.013
0.24 0.18 0.06
0.045
0.037
0.01 −0.05 0.060
0.026
0.210
0.18 0.19 −0.010
0.645
0.814
0.22 0.23 −0.017
0.789
0.113
0.14 0.13 0.010
0.218
Ona, onabotulinumtoxinA; Inco, incobotulinumtoxinA; Dif, difference.
We believe a more significant element is found in our slightly lower dosage levels, which have likely increased clinical sensitivity to toxin differences by avoiding saturation.
Fig. 3. Mean reduction in combined wrinkle score for onabotulinumtoxinA (blue) versus incobotulinumtoxinA (red).
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Our study showed that onabotulinumtoxinA was statistically greater than incobotulinumtoxinA at reducing combined dynamic wrinkles at a 1:1 dose ratio at 3 days, 2 weeks, 3 months, and 4 months after injection. This might suggest that a higher dose ratio of incobotulinumtoxinA may be required to have the same effect as onabotulinumtoxinA or that the superiority finding is as valid at the slightly lower treatment dosage. One clinically relevant difference between the toxins is storage. Although onabotulinumtoxinA requires freezing before reconstitution, incobotulinumtoxinA can be stored on the shelf at room temperature, which can be advantageous in some practices. Both require refrigeration after reconstitution. Both manufacturers state that the toxins should be discarded 24 hours after reconstitution. However, storage longevity was not an element of this study. One limitation to our split-face study design was that the standard treatment for glabellar lines uses five spots, with one directly central; however,
Volume 135, Number 5 • Split-Face Comparison of Botox to Xeomin to avoid product crossover in a split-face method, we eliminated the central spot and used four spots. Although the spacing was greater than the nominally expected 1-cm spread, we cannot be certain that we eliminated crossover.
CONCLUSIONS For identical dosage, both onabotulinumtoxinA and incobotulinumtoxinA are safe and effective in the treatment of glabellar lines, crow’s feet lines, and forehead lines; however, for our dosage levels, onabotulinumtoxinA was statistically greater in combined dynamic wrinkle reduction at 3 days, 2 weeks, 3 months, and 4 months. Ruth Hill Yeilding, M.D. YMD Eye & Face 328 West Morse Boulevard Winter Park, Fla. 32789 [email protected]
ACKNOWLEDGMENTS
The authors thank Randy Frey and Shirley McGarvey for manuscript review and Brad Haby Accelerated Vision for the statistical analysis. PATIENT CONSENT
Patients provided written consent for the use of their images. REFERENCES 1. Allergan, Inc. Q3 2013 earnings call transcript. Available at: http://seekingalpha.com/article/1784222-allergan-management-discusses-q3-2013-results-earnings-call-transcript. Accessed April 19, 2014. 2. Dressler D, Mander G, Fink K. Measuring the potency labeling of onabotulinumtoxinA and incobotulinumtoxinA in an LD50 assay. J Neural Transm. 2012;119:13–15. 3. Sattler G, Callander MJ, Grablowitz D, et al. Noninferiority of incobotulinumtoxinA, free from complexing proteins, compared with another botulinum toxin type A
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