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Show A Direct Comparison of OnabotulinumtoxinA (Botox) and IncobotulinumtoxinA (Xeomin) in the Treatment of Benign Essential Blepharospasm: A Split-face Technique Julien Saad, BSc, MD, Alain Gourdeau, MD, FRCSC Background: Benign essential blepharospasm (BEB) is characterized by progressive involuntary contractions of the protractor muscles, sometimes leading to a debilitating closure of the lids. It is currently treated with the injection of botulinum neurotoxin A (BoNT/A). The purpose of this study was to compare 2 BoNT/A preparations (i.e., Xeomin and Botox) in the treatment of BEB. Methods: This was a prospective, randomized, double-blinded split-face technique in 48 patients already treated by Botox for BEB. Patients received the same medication to either side of the face for 4 injections, and were then evaluated using subjective and objective measures. Bleph-arospasm Disability Index (BSDI) and Jankovic Rating Scale (JRS) were assessed using a repeated-measures analysis of variance (ANOVA) and paired t test. Patient preference and objective comparison of residual orbicularis strength and spasm were compared using a multinomial logistic regres-sion model, a repeated-measures ANOVA, and a paired t test. Results: A paired t test showed no preference between Xeomin and Botox (P = 0.7205) and demonstrated a ten-dency toward not having a preference for either medication (P = 0.0301 vs Botox and P = 0.0039 vs Xeomin). The regression model showed no effect of time on patient pref-erence (P = 0.4217). The ANOVA for BSDI scores did not reveal any difference between the 2 medications as com-pared with baseline (P = 0.8161), nor did it demonstrate an effect of time on BSDI scores (P = 0.6108). A paired t test found no difference between the 2 scores (P = 0.1909) at baseline. There was no difference in JRS scores for either medication when compared with baseline (P = 0.2314), nor was there an effect of time on such scores (P = 0.4951). There was also no difference between the 2 medications according to paired t test (P = 0.3224) at baseline. Baseline residual orbicularis strength was similar between the 2 medications (paired t test; P = 0.3228). ANOVA shows an effect of time on orbicularis strength (P = 0.0055), but no difference was seen at any of the 5 visits (P . 0.05). Base-line spasm scores were similar between Botox and Xeomin (paired Student t test; P = 0.3228). The ANOVA shows no difference between both medications at any point in time (P = 0.4408), and that time had no effect on the efficacy of either treatment (P = 0.3268). Conclusion: No difference between Xeomin and Botox was detected in either subjective or objective measures for the treatment of BEB. Journal of Neuro-Ophthalmology 2014;34:233-236 doi: 10.1097/WNO.0000000000000110 © 2014 by North American Neuro-Ophthalmology Society Benign essential blepharospasm (BEB) is characterized by involuntary progressive contractions involving the principal protractors of the lids, and when severe, can lead to complete occlusion of the eye (1). Symptoms typically begin between the fifth and seventh decade, with females being more affected than males in a 3:1 ratio (2). The neurological circuit controlling the eye blink includes a sensory and a motor pathway, with BEB possessing numerous possible triggers, and a likely multifactorial etiology (3). Spontaneous remission of BEB is rare, with most patients requiring treatment for many years. Treatment consists of reducing involuntary contractions, primarily with botulinum neurotoxin A (BoNT/A) injections (4,5). BoNT/A inhibits the fusion of cholinergic vesicles in the presynaptic membranes of the neuromuscular junctions, which causes a temporary focal muscle paralysis (6). One of the most commonly used neurotoxins is Botox (Vistabel, onabotulinumtoxinA; Allergan Inc). Botox preparations are accompanied by complexing proteins, which allow for greater stability in the digestive tract and increased absorp-tion (7). These proteins do not improve storage life, nor do they affect the diffusion of the medication once injected (8). Département d'ophtalmologie (JS, AG), Faculté de médecine, Uni-versité Laval, Quebec City, Canada; and Centre universitaire d'oph-talmologie et Centre de recherche du CHU de Québec (JS, AG), Hôpital de l'Enfant-Jésus, Quebec City, Canada. Supported by research funds provided by Centre universitaire d'ophtalmologie, CHU de Québec, Quebec, Canada. The authors report no conflicts of interest. Address correspondence to Julien Saad, BSc, MD, Hôpital Saint- Sacrement, 1050 chemin Ste-Foy, Quebec, QC, G1S 4L8, E-mail: julien.saad@gmail.com Saad and Gourdeau: J Neuro-Ophthalmol 2014; 34: 233-236 233 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Some studies have demonstrated that neutralizing antibod-ies to these complexing proteins are found in the circula-tion, which may lead to a secondary resistance (8). Xeomin (Bocouture, incobotulinumtoxinA; Merz Phar-maceuticals GmbH) is the first BoNT/A not associated with complexing proteins. It also has a long shelf life of 4 years, is stable at room temperature, and possesses the same diffusion pattern as Botox (9). Many studies have demon-strated a noninferiority of Xeomin to Botox for BEB (10,11), and also for many other pathologies including focal dystonia, spasticity, hemifacial spasm, and hypersalivation (12). To the best of our knowledge, there has not been a prospective, randomized split-face comparison of these 2 medications for the treatment of BEB. The purpose of this study was to evaluate and compare Botox with Xeomin in the treatment of BEB in the same population, using a split-face technique in patients with bilateral symmetric BEB. METHODS Study Design A randomized, double-blind prospective study in which 48 patients treated for bilateral, symmetrical BEB were enrolled between February and March 2012. All patients were previously treated and controlled with Botox at the Neuro-Ophthalmology Clinic at Hôpital de l'Enfant-Jésus in Quebec City, Quebec. The patients were randomized so that half received Xeomin on the right side and Botox on the left side of their faces, and vice versa for the other half. The study adhered to the tenets of the Declaration of Helsinki and was approved by the institutional review board and ethics committee of l'Hôpital de l'Enfant-Jésus. Written consent was obtained from all patients before enrollment. Study Protocol Patients were examined and treated by a single investigator (A.G.) and questioned by either the research nurse or medical resident. All were masked to the randomization. At each visit, the patient would answer the Blepharospasm Disability Index (BSDI) and choose a preferred treatment side based on better control of spasms or lesser side effects. After the questionnaire, the patients then underwent a slit-lamp examination, an assessment of orbicularis strength and spasm, as well as an evaluation using the Jankovic Rating Scale (JRS) by the same investigator (A.G.). The patients were then injected with Xeomin to either the right or left side of the face, with Botox to the other side for 4 consecutive treatments. There was no washout period before enrollment in this study; any residual effect of Botox was thought to have worn off after the first injection of Xeomin. The medications were dispensed by the hospital's pharmacy department in syringes labeled with the patient's ID number and the side to be injected. The patients were interviewed and assessed at each of 4 treatment visits, as well as the first appointment after their last injection of Xeomin. Dosage The patients enrolled in this study had previously found stability and control with Botox, using the same number of units during the previous 2 visits, and having a steady interval between visits. Many studies that compared the efficacy of Xeomin with Botox have found that a sub-stitution of 1:1 was sufficient (9,11), therefore the same number of units and interval of treatment were continued throughout the study, substituting 1 unit of Botox for 1 unit of Xeomin. Statistical Methods All analyses have been performed using SAS software (SAS Inst, NC, release 9.3, 2012). Side preference, residual orbicularis strength, and an objective comparison of spasm were assessed by evaluating the probability of each of the 3 possible answers; Xeomin being more effective, Botox being more effective, or equal efficacy. The effect of time on preference was evaluated using a repeated-measures multi-nomial logistic regression model. The JRS was scored objectively on a scale of 0-4 for both severity and frequency of spasms. This was performed by the principle investigator for each side of the face, and at each of the 5 visits. The sum of the 2 scores (0-8) were then tabulated, with a higher score correlating to poorer control of spasms. The BSDI assesses functional impairment while perform-ing 6 daily activities ("driving a vehicle", "reading", "watching TV", "shopping", "walking", "doing everyday activities") TABLE 1. Demographic and treatment data of patients injected with Botox vs Xeomin All Enrolled Patients (n = 48) Excluding Deceased Patient (n = 47) Mean SD Range Mean SD Range Sex (male/female) 24/24 24/23 Age at enrollment, years 70.2 12.1 44.5-92 69.7 11.8 44.5-88.2 Age at onset of symptoms, years 56.8 15.0 6.0-80.6 56.7 15.1 6.0-80.6 Duration of treatment before study, years 17.0 10.5 3.0-42.3 16.6 10.3 3.0-42.3 Units used per side 19.9 4.9 7.5-30 20.0 4.9 7.5-30 234 Saad and Gourdeau: J Neuro-Ophthalmol 2014; 34: 233-236 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (11). Each activity was rated on a scale of 0-4 with the possibility of rating an activity as "nonapplicable". The sum of all scores were added and then divided by the number of applicable activities. The mean BSDI and JRS scores for each side of the face were compared at the first visit (i.e., before receiving the first Xeomin injection) using a paired t test. The scores from subsequent visits were then compared with baseline scores looking for a difference between the 2 medications at any of the visits, as well as for an effect of time on the efficacy of either medication using a repeated-measures analysis of variance (ANOVA). The baseline score served as a covariable, and the medication and visit served as the repeated measures for these analyses. The residual orbicularis strength and spasm were assessed at each visit using a Likert scale of 5 points (0 to +4 for spasm and 0 to 24 for strength). The means of each score were calculated for each medication at each of the 5 visits. Baseline scores (i.e., before the first Xeomin injection) were compared using a paired Student t test, and subsequent visits were compared with baseline using a repeated-measures ANOVA looking for difference between the 2 medications and for an effect of time on treatment. Baseline scores served as a covariable, and the medication and visit were used as the repeated measures. RESULTS Forty-five of the 48 enrolled patients completed the study (Table 1). One patient died after the first injection, unre-lated to the medication, and the other 2 withdrew from the study after the third injection. Missing data were imputed using the "Hot Deck" method. The probability of a patient preferring either medication or having no preference at all were as follows: PBotox = 0.2549 (confidence interval [CI], 0.1602-0.3495), PXeomin = 0.1652 (CI, 0.1652-0.2731), and Pno preference = 0.5799 (CI, 0.4454-0.7144). When comparing the probability of each occurrence, we found a significant trend toward having no preference as compared with preferring Botox (P = 0.0301) or Xeomin (P = 0.0039), but no preference between the 2 medications (P = 0.7205). There was also no effect of time on the patients' preference (P = 0.4217). Comparing the BSDI scores for both medications, we averaged the sums for each patient at each of the 5 visits and calculated a mean score for each medication at each visit (Table 2). Xeomin scores tended to be lower than the Botox score, but baseline scores were not significantly different (P = 0.1909). Furthermore, there was no difference detected with respect to baseline scores for either medication (P = 0.8161), nor was there an effect of time (P = 0.6108). The mean JRS scores were calculated at each of 5 visits for Xeomin and Botox (Table 2). There was no significant difference between the 2 medications at baseline (P = 0.3224). The ANOVA showed no difference between the 2 treat-ments as compared with baseline (P = 0.2314) and showed no effect of time on JRS scores (P = 0.4951). The mean scores for residual orbicularis strength at each visit were determined (Table 2). The paired Student t test indicates no significant difference between the 2 medications at the initial visit (P = 0.3228). However, the ANOVA shows a significant difference in strength between the 2 medications, which varied from one visit to the other (P = 0.0055). Further analyses found no significant difference at any of the visits using a paired t tests (P = 0.1590 at Visit 3 and P = 0.0706 at Visit 4). The mean scores for spasms on a rating scale from 0 to +4 at each visit are shown in Table 2. The paired Student t test showed no significant difference between the 2 med-ications at the initial visit (P = 0.3228). There was also no difference between both medications at any point in time (P = 0.4408), nor did time have an effect on the efficacy of both treatments (P = 0.3268). Furthermore, there were instances where the investigator noted a slight difference between the 2 sides, but not enough to attribute a different score on the predetermined scale. A multinomial logistic regression model, much like that used for patient preference, was used to determine whether a slight difference exists. No difference was noted between the 2 medications for orbicularis strength (P = 0.2960) or spasms (P = 0.5181). DISCUSSION BEB can be a debilitating disease, with up to two-thirds of patients becoming functionally blind (13). The purpose of TABLE 2. Comparison of all scores (± 1.96 · standard error) for both medications Mean BSDI Mean JRS Residual Strength Residual Spasm Xeomin Botox Xeomin Botox Xeomin Botox Xeomin Botox Visit 1 4.70 ± 1.40 5.19 ± 1.43 2.81 ± 0.34 2.83 ± 0.35 21.04 ± 0.21 21.03 ± 0.21 1.41 ± 0.20 1.42 ± 0.20 Visit 2 3.34 ± 1.32 3.81 ± 1.35 2.16 ± 0.37 2.23 ± 0.37 21.14 ± 0.22 21.13 ± 0.21 1.26 ± 0.21 1.27 ± 0.21 Visit 3 4.89 ± 1.55 5.02 ± 1.52 2.30 ± 0.40 2.37 ± 0.39 21.20 ± 0.23 21.26 ± 0.22 1.38 ± 0.22 1.38 ± 0.21 Visit 4 4.15 ± 1.42 4.62 ± 1.43 2.30 ± 0.35 2.40 ± 0.36 21.17 ± 0.21 21.08 ± 0.20 1.31 ± 0.19 1.37 ± 0.19 Visit 5 3.79 ± 1.42 4.19 ± 1.56 2.64 ± 0.39 2.64 ± 0.39 21.19 ± 0.20 21.20 ± 0.18 1.44 ± 0.20 1.47 ± 0.22 BSDI, Blepharospasm Disability Index; JRS, Jankovic Rating Scale. Saad and Gourdeau: J Neuro-Ophthalmol 2014; 34: 233-236 235 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. this study was to determine whether there was a difference in efficacy and patient preference between Xeomin and Botox. To the best of our knowledge, this study is the first using a prospective, randomized, double-blinded split-face technique for the comparison of these 2 medications. Fur-thermore, using 4 injections of the same medication to either side, we eliminated any potential residual effect of Botox received before the study at Visits 2 to 4. Subjectively, no significant difference was noted. Using the BSDI, we were unable to detect any difference between the 2 medications. A possible explanation for the lack of difference on the BSDI is that although the index is sensitive enough when comparing BONT/A with placebo, it may be less useful when comparing the 2 agents (14). A 1-point improvement on this scale constitutes a 25% dif-ference in symptoms, which may be too great to be noted by the patient. It also does not take into account the impor-tance of each activity in an individual's daily life. However, in our study, we asked the patients about their preference, if any, between the two, and no preference was found. Using objective measures, the JRS results failed to demonstrate any difference between Xeomin and Botox, as did the global scores for spasms. Once again, the JRS may not be sensitive enough to demonstrate a difference between the 2 agents, as opposed to comparing with placebo (14). However, a different scale used to assess for spasms also indicated that no significant difference exists between the 2 medications. Using the regression model, we eliminated the possibility of there being a subtle difference in spasm, not detected by the JRS. The residual orbicularis strength as assessed by the investigator did show some difference over time, likely because of the differences seen in Visits 3 and 4. 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