Liquid Formulation of AbobotulinumtoxinA Exhibits a Favorable Efficacy and Safety Profile in Moderate to Severe Glabellar Lines: A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trial

Liquid Formulation of AbobotulinumtoxinA Exhibits a Favorable Efficacy and Safety Profile in... Abstract Background In most countries, approved botulinum toxin type A formulations require reconstitution before injection. Objectives To evaluate the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection, ASI) in subjects with moderate to severe glabellar lines (GL). Methods In this Phase II, double-blind, placebo-controlled, randomized study, 176 female subjects (aged 30 to 60 years) were randomized into five treatment groups: ASI 20, 50, or 75 U, reconstituted abobotulinumtoxinA (aboBoNT-A) 50 U, and placebo. GL severity was assessed at maximum frown using a 4-point grading scale. Responders were subjects with severity grade of moderate [2] or severe [3] at baseline improving to none [0] or mild [1], evaluated at each time-point by Investigator’s Live Assessment (ILA) or Subject’s Self-Assessment (SSA). Safety profiles were also determined. Results Baseline characteristics were similar across groups. Responder rates on Day 29 by ILA were significantly greater for ASI 20, 50, and 75 U versus placebo (88.9%, 91.4%, and 87.9% vs. 0%, respectively; P < 0.0001). Similar results were observed by SSA. A greater proportion of responders was observed in ASI groups vs placebo from Day 8 to 113 for ILA and SSA (P < 0.001). AboBoNT-A responder rate on Day 29 for ILA was 77.1% (P < 0.1006 vs ASI 50 U); with comparable results by SSA. The ASI safety profile was comparable to that of aboBoNT-A. Conclusions Ready-to-use liquid formulation of abobotulinumtoxinA was shown to be efficacious, with comparable results to reconstituted abobotulinumtoxinA, and to have a favorable safety profile in subjects with severe to moderate GL. Level of Evidence: 1 It is widely recognized by both clinicians and patients that glabellar lines (GL) have an important role in self-perception and emotional wellbeing, and the minimally invasive treatment of GL with botulinum toxin type A (BoNT-A) has been well established.1 The efficacy and safety of abobotulinumtoxinA for use in improving the appearance of moderate to severe GL has been evaluated in previous double-blind, randomized, placebo-controlled clinical studies.2-6 These studies demonstrated that abobotulinumtoxinA was well tolerated and reduced the severity of GL for up to five months. Currently available BoNT-A preparations include abobotulinumtoxinA (phase III; Dysport, Ipsen Ltd., Slough, UK; Azzalure, Galderma Ltd., Lausanne, Switzerland), onabotulinumtoxinA (phase III; Botox, Allergan, Inc., Irvine, CA), incobotulinumtoxinA (phase III; Bocouture/Xeomin, Merz Pharmaceuticals, Inc., Frankfurt, Germany) and Neuronox®/Meditoxin (phase III; Medy-Tox, Inc., Seoul, South Korea).7 However, all currently approved BoNT-A preparations in Europe and North America are not available in liquid formulation and therefore require reconstitution with sodium chloride prior to injection.6-8 There are several potential challenges associated with reconstituted preparations. When reconstitution is required, healthcare professionals have to spend time on preparation, which detracts from time spent with the patient. In addition, in a healthcare setting, reconstitution errors may occur when medications require preparation and reconstitution.9,10 Errors may occur in the dilution of toxins which could result in under or over-dosing.10-12 Additionally, this may have economic consequences due to product waste.9,13 Even for experienced injectors, reconstitution can allow for some variability in injection doses. Therefore a ready-to-use liquid formulation of BoNT-A will facilitate and standardize injection practice, ensuring that appropriate doses and concentrations are administered and thus preventing reconstitution errors. The aim of the present study was to assess the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection; ASI) in the treatment of moderate to severe GL after a single injection. In addition, the relative safety and efficacy of ASI was compared with the approved dose of reconstituted abobotulinumtoxinA (aboBoNT-A) for improving the appearance of GL. METHODS Objectives The primary objective was to assess the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA, ASI, at various doses (20, 50, or 75 units [U]) compared with placebo, for improvement of the appearance of moderate to severe GL after a single treatment. The standard dry formulation of aboBoNT-A served as an active comparator in this study, which was considered the secondary objective. Ethics The present study was conducted under the provisions of the Declaration of Helsinki, with the consent of the Independent Ethics Committee (IEC) and in accordance with informed consent regulations and the International Conference on Harmonisation (ICH) Consolidated Guideline on Good Clinical Practice.14 This study also adhered to all local regulatory requirements and has been registered with ClinicalTrials.gov, number NCT01333397. All subjects provided written informed consent prior to entering the study (before initiation of any study-related procedure and administration of treatment), which was personally signed and dated by the subject. Study Design This study was a phase II, randomized, multicenter, double-blind, placebo and active comparator controlled study conducted at eight centers in France and Germany. Enrollment took place between March and the end of June 2011. An overview of the study design is shown in Figure 1. Figure 1. View largeDownload slide Study design. aboBoNT-A, abobotulinumtoxinA; AE, adverse event; ASI, abobotulinumtoxinA solution for injection. * Day 4 follow up monitoring of AEs and concomitant medications via telephone contact. Figure 1. View largeDownload slide Study design. aboBoNT-A, abobotulinumtoxinA; AE, adverse event; ASI, abobotulinumtoxinA solution for injection. * Day 4 follow up monitoring of AEs and concomitant medications via telephone contact. At baseline (BL) subjects were randomized 1:1:1:1:1 to placebo, ASI (20, 50, or 75 U) or aboBoNT-A 50 U. Computer-generated randomization lists were created by a sponsor statistician independent from the study using a validated in-house system developed with SAS software (SAS Institute, Inc., Cary, NC). The randomization schedule is generated using the SAS procedure PLAN. Treatment numbers were assigned when subjects entered the study using a 24-h interactive voice response system from an external contract research organization. Inclusion Criteria The study included female subjects, aged 30 to 60 years (inclusive) with moderate to severe GL at maximum frown at BL (Day 1, pre-treatment), as assessed by the investigator’s and subjects’ assessment using a validated 4-point photographic scale. In addition, all subjects were required to be naïve to previous treatment with any serotype of botulinum toxin (BoNT) and either of non-childbearing potential or if female of childbearing potential must return a negative outcome from a pregnancy test. The rationale for a female-only study was to have a homogenous study population. Subjects were excluded from entering the study if they had received any prior treatment with fillers (eg, collagen-type implants), skin abrasions or photorejuvenation within 12 months of enrollment or any previous injections with silicone in the upper face. This study also excluded subjects who had any planned facial cosmetic surgery during the study period or had a history of ablative skin resurfacing of the area to be treated during the study. Treatment The manufacturing process for BoNT-A is identical in the lyophilized and liquid formulation products. The currently marketed products aboBoNT-A 500 U and aboBoNT-A 125 U are freeze-dried preparations of Clostridium BoNT-A hemagglutinin complex (BoNT-A-HAC) formulated with lactose (bulking agent) and human serum albumin (HSA) in a glass vial. ASI consists of BoNT-A-HAC and excipients (L-histidine 1.55 mg, sucrose 4.00 mg, sodium chloride 8.76 mg, polysorbate-80 0.10 mg, hydrochloric acid to pH 6.5, water for injection and nitrogen). The liquid formulation does not contain HSA, lactose or any excipient from animal origin. The ASI formulation was supplied as a liquid in a 1 mL pre-filled syringe containing 500 U (nominal) of BoNT-A-HAC and all subjects receiving ASI were treated with the same batch. In order to achieve the required doses of 20, 50, and 75 U in 0.25 mL, the respective volumes of active ASI formulation (0.15, 0.4, and 0.6 mL) were diluted to a final concentration of 79, 200, and 300 U/mL using a 0 U/mL placebo containing only the excipients of ASI (ie, without the toxin). The aboBoNT-A dry formulation consisted of a white, lyophilized powder containing 125 U of BoNT-A-HAC which was reconstituted with 0.63 mL sterile, preservative-free saline (sodium chloride for injection 0.9%) to achieve a concentration of 200 U/mL. Units of the toxin were similar in both formulation, thus units of the liquid formulation correspond to those of the reconstituted preparation. The placebo was supplied for administration as a liquid in a 1 mL pre-filled syringe containing only the excipients of ASI. All syringes used for each treatment were prepared by an independent nurse or pharmacist and were indistinguishable to the injector; equal volumes of ASI, reconstituted aboBoNT-A or placebo were injected into each subject. For each treatment group, the total treatment dose on Day 1 was divided into five injections (0.05 mL per injection; total injection volume of 0.25 mL), each of which was administered into the following pre-defined sites across the glabellar region: a single injection into the procerus muscle inferior to the line joining the eyebrows and superior to the root of the nose; each corrugator muscle was injected directly above the inner canthus and above the bony orbital rim; and each lateral corrugator/orbicularis muscle was injected directly above the pupil, approximately 1 cm above the bony orbital rim. The subjects were required to attend office follow-up visits on Days 8, 15, 29, 57, 85, and 113. All subjects who had attended the Day 113 visit were considered to have completed the study. In addition, subjects were contacted on Day 4 post-injection for a follow-up interview. Assessments At screening, BL and at each scheduled post-treatment visit, the investigator used a validated 4-point photographic scale to assess glabellar line severity at maximum frown and at rest.15 The scale represents the severity of GL (Grade 0, none; Grade 1, mild; Grade 2, moderate; Grade 3, severe). Investigators were fully trained on the use of the photographic scale and were provided with a written description of each set of photographs to standardise assessments among investigators. In addition, at screening, BL and at each scheduled post-treatment visit, subjects were asked to assess their GL at maximum frown, using a 4-point categorical scale (Grade 0, no wrinkles; Grade 1, mild wrinkles; Grade 2, moderate wrinkles; Grade 3, severe wrinkles), with reference to the same photographic scale used by investigators. This occurred prior to and independently of the investigator’s assessment. Treatment emergent adverse events (TEAEs) were monitored on Day 1 post treatment, Day 4 post treatment (telephone follow-up) and at each visit following treatment. Endpoints Co-primary efficacy endpoints: The proportion of responders in the Investigator’s Live Assessment (ILA) of GL at maximum frown at Day 29, defined as a subject with severity grade of moderate [2] or severe [3] at maximum frown at BL improving to a severity grade of none [0] or mild [1]. The proportion of responders in the Subject’s Self-Assessment (SSA) of GL at maximum frown at Day 29, as defined for the ILA. Secondary efficacy endpoints included: The proportion of responders at maximum frown at all other post-treatment visits (Days 8, 15, 57, 85, and 113) as assessed by the ILA and SSA The proportion of subjects assessed as responders at maximum frown at Day 29 who remain responders on Day 113 The proportion of subjects with a reduction of two or more grades in the severity of GL at maximum frown at all post-treatment visits, as measured by the ILA and SSA Safety assessments, which were made throughout the study to monitor TEAEs Statistical Analysis Statistical analyses were performed in accordance with ICH E9 guidelines.14 Efficacy analyses were based on the intent-to-treat (ITT) population and safety analysis was based on the safety population. Both are defined as all randomized subjects who received study treatment, regardless of the actual amount injected. The proportions of responders with 95% CI were summarized by treatment group and differences were compared using a Chi-square test. A type I error rate equal to 0.0085 was used for the primary efficacy analysis, and 0.05 for other efficacy analysis. Adverse events were coded using the MedDRA version 14.0 (MedDRA MSSO, McLean, VA). RESULTS Study Population A total of 176 female subjects were randomized into the placebo and four active treatment groups. Of the 176 subjects enrolled, 174 completed the study; two subjects were lost to follow-up (one each from the placebo and the 75 U ASI group). All subjects were included in the ITT and safety populations. Demographic data and other baseline characteristics are shown in Table 1. Subjects had a mean age (range) of 47.3 (30-60) years and mean BMI (range) of 22.2 (16.7-48.1) kg/m2. Overall, demographic characteristics were similar across the treatment groups. At maximum frown, severe or moderate GL were reported for all subjects by ILA, and for all subjects (except for one case of mild GL) reported by SSA. In the ILA and SSA of maximum frown at BL, 60.0% and 45.7% of subjects in the placebo group had severe GL; while, in the abobotulinumtoxinA groups (ASI and aboBoNT-A) 38.9% to 48.6% and 33.3% to 54.3% of subjects had severe GL by ILA and SSA, respectively. Therefore, there are slight differences in the percentage of subjects with severe GL across treatment groups. Table 1. Baseline Demographics and Subject Characteristics Characteristic  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  Mean age, years ±SD  46.8 ± 6.4  46.7 ± 8.4  48.1 ± 6.9  47.9 ± 6.0  47.0 ± 6.6  Range  31-59  30-60  34-59  35-58  30-58  Mean BMI, kg/m2  21.65  22.26  22.57  22.29  22.10  Range  17.0-29.7  18.6-33.2  18.4-48.1  19.1-32.0  16.7-29.0  Investigators’ live assessment of GL at maximum frown, n (%)  Severe  21 (60.0)  14 (38.9)  15 (42.8)  15 (42.8)  17 (48.6)  Moderate  14 (40.0)  22 (61.1)  20 (57.1)  20 (57.1)  18 (51.4)  Investigators’ live assessment of GL at rest, n (%)  Severe  4 (11.4)  3 (8.3)  2 (5.7)  4 (11.4)  5 (14.3)  Moderate  14 (40.0)  14 (38.9)  11 (31.4)  10 (28.6)  14 (40.0)  Mild  17 (48.6)  17 (47.2)  22 (62.9)  21 (60.0)  13 (37.1)  None  0 (0)  2 (5.6)  0 (0)  0 (0)  3 (8.6)  Subjects’ aelf-assessment of GL at maximum frown, n (%)  Severe  16 (45.7)  12 (33.3)  18 (51.4)  14 (40.0)  19 (54.3)  Moderate  19 (54.3)  24 (66.7)  16 (45.7)  21 (60.0)  16 (45.7)  Mild  0 (0)  0 (0)  1 (2.9)  0 (0)  0 (0)  Characteristic  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  Mean age, years ±SD  46.8 ± 6.4  46.7 ± 8.4  48.1 ± 6.9  47.9 ± 6.0  47.0 ± 6.6  Range  31-59  30-60  34-59  35-58  30-58  Mean BMI, kg/m2  21.65  22.26  22.57  22.29  22.10  Range  17.0-29.7  18.6-33.2  18.4-48.1  19.1-32.0  16.7-29.0  Investigators’ live assessment of GL at maximum frown, n (%)  Severe  21 (60.0)  14 (38.9)  15 (42.8)  15 (42.8)  17 (48.6)  Moderate  14 (40.0)  22 (61.1)  20 (57.1)  20 (57.1)  18 (51.4)  Investigators’ live assessment of GL at rest, n (%)  Severe  4 (11.4)  3 (8.3)  2 (5.7)  4 (11.4)  5 (14.3)  Moderate  14 (40.0)  14 (38.9)  11 (31.4)  10 (28.6)  14 (40.0)  Mild  17 (48.6)  17 (47.2)  22 (62.9)  21 (60.0)  13 (37.1)  None  0 (0)  2 (5.6)  0 (0)  0 (0)  3 (8.6)  Subjects’ aelf-assessment of GL at maximum frown, n (%)  Severe  16 (45.7)  12 (33.3)  18 (51.4)  14 (40.0)  19 (54.3)  Moderate  19 (54.3)  24 (66.7)  16 (45.7)  21 (60.0)  16 (45.7)  Mild  0 (0)  0 (0)  1 (2.9)  0 (0)  0 (0)  All participants were female (race, n = 176 [100%] Caucasian; ethnicity, n = 5 [2.8%] Hispanic/Latina, n = 171 [97.2%] not Hispanic/Latina). Investigators assessment of GL was made using a validated 4-point photographic scale where 0=none and 3=severe (Honeck scale).15 aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; BMI, body mass index; GL, glabellar lines; SD, standard deviation. View Large Subjects in the aboBoNT-A 50 U group had more severe lines at maximum frown, as per ILA and SSA, and less mild lines at rest, compared with all ASI doses. Efficacy Co-Primary Efficacy Endpoints: Proportion of Responders at Day 29, as Measured by the ILA and SSA of GL at Maximum Frown As shown in Figure 2A and Supplemental Table 1A, the proportion of responders at Day 29 in the ILA of GL at maximum frown was significantly greater in all three ASI dose groups compared with the placebo group (88-91% vs 0%; P < 0.0001). Similarly, the proportion of responders at Day 29 in the SSA of GL at maximum frown was significantly higher in each of the ASI dose groups compared with the placebo group (82-92% vs 2.9%; P < 0.0001) (Figure 2B, Supplemental Table 1B). These results therefore demonstrated the efficacy of ASI at Day 29 versus the placebo group. Figure 2. View largeDownload slide Proportion of responders (95% CI) at each time point for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. Day 29 = primary endpoint. A responder at maximum frown is defined as a subject having a severity grade of none or mild at maximum frown on the visit day and a severity grade of moderate or severe at maximum frown at screening or baseline visit. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Figure 2. View largeDownload slide Proportion of responders (95% CI) at each time point for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. Day 29 = primary endpoint. A responder at maximum frown is defined as a subject having a severity grade of none or mild at maximum frown on the visit day and a severity grade of moderate or severe at maximum frown at screening or baseline visit. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Responders at Other Time-Points, as Measured by the ILA and SSA of GL at Maximum Frown The proportion of responders in the ILA of GL at maximum frown were significantly higher in all three ASI dose groups compared with placebo group at each time-point (Day 8 to Day 113) throughout the study (all P < 0.0001 vs. placebo, except ASI 20 U at Day 113 [P = 0.0035]) (Figure 2A, Supplemental Table 1A). These results were comparable to those observed for the proportions of responders receiving each ASI dose in the SSA of GL at maximum frown throughout the study (all P ≤ 0.0001 vs. placebo, except ASI 50 U at Day 113 [P = 0.0002]) (Figure 2B, Supplemental Table 1B). Proportion of Responders on Day 29 who Remained Responders on Day 113 The proportion of responders at maximum frown on Day 29 who remained responders on Day 113 was 25.0%, 46.9%, and 65.5% in the ASI 20 U, ASI 50 U, and ASI 75 U groups, respectively, for the ILA of GL; and 36.4%, 40.0%, and 63.0% in the same respective groups for the SSA of GL. These results suggested a dose–response relationship for the duration of efficacy of ASI, which is not unexpected. The Proportion of Subjects with a Reduction of Two or More Grades in the Severity of GL as Measured by the ILA and SSA at Maximum Frown As shown in Figure 3A and Supplemental Table 2A, a significantly greater proportion of subjects in the ASI groups had a two or more grade reduction in GL severity at maximum frown compared with the placebo group on Days 8 to 113 (P < 0.0001 to 0.0241 vs placebo), by ILA. Comparable results were seen for the SSA (P < 0.0001 to 0.0393 vs placebo), while only ASI 20 U was not significant compared with placebo at Day 113 (P = 0.0853) (Figure 3B, Supplemental Table 2B). Figure 3. View largeDownload slide Proportion of subjects (95% CI) with a reduction of two or more grades from baseline in GL severity for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. AboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Figure 3. View largeDownload slide Proportion of subjects (95% CI) with a reduction of two or more grades from baseline in GL severity for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. AboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Comparison of ASI and aboBoNT-A 50 U At Day 29, the proportion of responders in the ILA of GL at maximum frown was 14.3% higher in the ASI 50 U group than in the aboBoNT-A 50 U group; however, this increase was not statistically significant (91.4% vs 77.1%; 95% CI, −2.4, 31.0; P = 0.1006) (Figure 2A, Supplemental Table 1A). Additionally, the proportion of responders in the SSA of GL at maximum frown was 2.8% higher in the ASI 50 U group compared with the aboBoNT-A 50 U group (85.7% vs 82.9%; 95% CI, −14.2, 19.9; P = 0.7426) (Figure 2B, Supplemental Table 1B). The proportion of responders in the ILA of GL at maximum frown at Days 8 and 15 was higher in the ASI 50 U and 75 U groups compared with the aboBoNT-A 50 U group (80.0% and 82.9% vs 57.1% at Day 8, respectively; 94.3% and 91.4% vs 73.5% at Day 15, respectively). There were no noteworthy differences at Days 57 and 85 for all three ASI dose groups; whilst at Day 113, the responder rate was higher in the ASI 75 U group than the aboBoNT-A 50 U (55.9% vs 31.4%, respectively) (Figure 2A, Supplemental Table 1A). In addition, no marked differences were observed in the responder rates for SSA of GL at maximum frown for the three ASI doses at any time-point throughout the study, when compared with the aboBoNT-A 50 U group, except the ASI 75 U group which had a higher responder rate at Day 113 (52.9% vs 28.6%, respectively) (Figure 2B, Supplemental Table 1B). Safety Details of TEAEs are summarized in Table 2. Approximately a third of subjects in each group had at least one TEAE, ranging from 28.6% in the aboBoNT-A 50 U group to 41.7% in the ASI 20 U group and 34.3% in the placebo group (Table 2). Overall, the frequency of TEAEs in the aboBoNT-A/ASI groups did not appear to be dose related. Of these adverse events, the incidence of Investigator-assessed treatment-related TEAEs were similar across the groups; 16.7%, 11.4%, and 11.4% in the ASI 20 U, 50 U and 75 U groups, respectively, 5.7% in the aboBoNT-A 50 U group and 14.3% in the placebo group. There were no deaths, withdrawals due to TEAEs, treatment-related serious adverse events (SAEs) or severe treatment-related TEAEs. Two SAEs were reported during the study (vertigo and headache) by one subject in the ASI 20 U group and were not considered to be related to treatment by the Investigator. In addition, no TEAEs considered treatment-related were remote from the injection site. Table 2. Summary of Treatment-Emergent Adverse Events (Safety Population) Number of subjects reporting at least one event, n (%)  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  TEAEs (occurring in ≥5% subjects)  12 (34.3)  15 (41.7)  10 (28.6)  11 (31.4)  10 (28.6)   Headache  4 (11.4)  3 (8.3)  3 (8.6)  2 (5.7)  3 (8.6)   Nasopharyngitis  4 (11.4)  0  1 (2.9)  1 (2.9)  2 (5.7)   Back pain  0  1 (2.8)  0  0  2 (5.7)   Eyelid ptosis  0 (0)  1 (2.8)  0 (0)  2 (5.7)  0 (0)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)  Severe TEAEs  0  1 (2.8)  0  0  0  At least one related TEAEs  5 (14.3)  6 (16.7)  4 (11.4)  4 (11.4)  2 (5.7)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)   Eyelid ptosis  0  1 (2.8)  0  2 (5.7)  0   Headache  1 (2.9)  1 (2.8)  1 (2.9)  2 (5.7)  0   Injection site hemorrhage  0  0  1 (2.9)  0  0   Nasal congestion  0  0  1 (2.9)  0  0   Ecchymosis  0  1 (2.8)  0  0  0   Injection site swelling  0  1 (2.8)  0  0  0   Rhinorrhea  0  1 (2.8)  0  0  0  Number of subjects reporting at least one event, n (%)  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  TEAEs (occurring in ≥5% subjects)  12 (34.3)  15 (41.7)  10 (28.6)  11 (31.4)  10 (28.6)   Headache  4 (11.4)  3 (8.3)  3 (8.6)  2 (5.7)  3 (8.6)   Nasopharyngitis  4 (11.4)  0  1 (2.9)  1 (2.9)  2 (5.7)   Back pain  0  1 (2.8)  0  0  2 (5.7)   Eyelid ptosis  0 (0)  1 (2.8)  0 (0)  2 (5.7)  0 (0)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)  Severe TEAEs  0  1 (2.8)  0  0  0  At least one related TEAEs  5 (14.3)  6 (16.7)  4 (11.4)  4 (11.4)  2 (5.7)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)   Eyelid ptosis  0  1 (2.8)  0  2 (5.7)  0   Headache  1 (2.9)  1 (2.8)  1 (2.9)  2 (5.7)  0   Injection site hemorrhage  0  0  1 (2.9)  0  0   Nasal congestion  0  0  1 (2.9)  0  0   Ecchymosis  0  1 (2.8)  0  0  0   Injection site swelling  0  1 (2.8)  0  0  0   Rhinorrhea  0  1 (2.8)  0  0  0  Safety population defined as all randomized subjects who received study treatment, regardless of injection volume. Events presented are TEAEs that occurred in >5% (n = 2) of subjects in at least one active group and related TEAEs that occurred in more subjects receiving active treatment than placebo. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; GL, glabellar lines; TEAE, treatment-emergent adverse event. View Large Injection site adverse reactions occurred in a small number of subjects in all treatment groups, including the placebo group with no dose response relationship. In total, treatment-related eyelid ptosis was observed in three subjects, one treated with ASI 20 U and two with ASI 75 U, all of which were local to the injection site and considered related to treatment. No concomitant medication was given for the events, two out of the three subjects recovered without sequelae, one within 3 weeks (ASI 75 U group) and the other in 6 weeks (ASI 20 U group), and one patient was lost to follow-up while the event was ongoing (ASI 75 U group). All headaches related to treatment were of mild intensity and patients recovered within 5 days. No concomitant medication was required for any related headache. Few additional subjects in the ASI groups reported treatment-related AEs (one subject in the ASI 50 U experienced nasal congestion; one subject in the 20 U ASI group had ecchymosis at the base of the nose and internal edges of each eyebrow; one subject in the 20 U ASI group had rhinorrhea), which resolved without any concomitant medication. DISCUSSION The safety and efficacy of abobotulinumtoxinA for the improvement in the appearance of GL has already been well established,1,3-5 and 50 U (Dysport/Azzalure) is the recommended dose for the improvement in the appearance of GL.2,6 The present study was designed to investigate the efficacy and safety of different doses of a new ready-to-use liquid formulation of abobotulinumtoxinA, ASI compared with placebo for the improvement in the appearance of GL. This study also aimed to assess the relative efficacy and safety of the different doses of ASI compared with the optimal dose of aboBoNT-A (50 U) when used to improve the appearance of moderate to severe GL. The primary objective was to assess the response to three different doses of ASI, each compared with placebo, in patients with moderate to severe GLs at maximum frown, as assessed according to ILA and SSA. The results showed that a significantly greater proportion of subjects had an improvement in the appearance of moderate to severe GL at Day 29 compared with placebo, both at maximum frown in all ASI groups for ILA and SSA (P < 0.0001 for all). In addition, this increase was observed at all post-treatment time-points, whether measured by the ILA or by the SSA (P < 0.0001 to 0.0035). Notably, the proportion of subjects who were responders on Day 29 and who remained so on Day 113 was similar for the ILA and SSA at maximum frown. Although the study was not powered to detect differences between active treatment groups, some indication of dose–response was observed in the proportion of responders using the ILA at maximum frown and in the proportion of subjects with two or more grades improvement in GL at maximum frown. Additionally, a higher proportion of subjects experiencing maintained BoNT-A effects was observed as ASI dose increased. This result suggested that the higher the dose of ASI, the longer the duration of action. Although a dose–response relationship may not be obvious for ASI at Day 29, after this peak response it is evident that higher ASI doses resulted in slower decreases in the proportion of responders from Day 57 to Day 113 for the ILA at maximum frown. These results were comparable to those reported for aboBoNT-A by Monheit et al (n = 279 in aboBoNT-A groups), which showed a higher responder rate at maximum frown on Day 30 in the 75 U group when compared with the 50 U group (85% vs 77%, respectively)1,5; however, Ascher et al (n = 102 in aboBoNT-A groups) showed no difference in responder rate for the same doses at maximum frown on Day 30 (76% vs 76%, respectively).1,4 This lower power may be accounted for by the difference in cohort size. In addition, both previous studies reported 50 U as the optimal dose for aboBoNT-A in the treatment of GL.4,5 Analysis of the co-primary endpoints showed that the proportion of subjects at Day 29 was greater than placebo for all ASI groups for the ILA and the SSA. A significantly greater proportion of subjects in all ASI groups compared with placebo had a reduction of two or more grades in GL severity on Days 8 to 113, as measured by the ILA at maximum frown. Comparable results were observed in the SSA for all doses and time-points, except in the ASI 20 U group on Day 113, which was not significantly different to the placebo group. There were no significant differences in the proportions of responders according to the ILA of GL at maximum frown between the ASI 50 U and the aboBoNT-A 50 U groups at Day 29. The proportion of responders at maximum frown by ILA tend to be slightly lower in the aboBoNT-A group compared with the ASI group at the same dose (50 U) at each time-point, most notably from Day 8 to Day 29. These differences were maintained from Day 57 to Day 113, but with a slightly decreased magnitude. A similar, but more sustained, effect was also observed with ASI 75 U compared with aboBoNT-A 50 U by ILA at maximum frown. For the SSA, no marked differences were identified in the proportion of responders in the ASI groups compared with aboBoNT-A 50 U at any time point for the SSA at maximum frown, except for the ASI 75 U group at Day 113. The results of the present study were comparable to those of a recent study that confirmed the safety and efficacy of MT10109L (Neuronox Aqua, Medy Tox, Inc.), a liquid formulation of BoNT-A for use in the management of glabellar frown lines.16 Approximately one third of subjects in each group had at least one TEAE. The incidence and type of TEAEs were similar across the active treatment groups. The incidence of treatment-related TEAEs in the ASI groups was similar to that of the placebo group and there were no deaths, withdrawals due to AE, treatment-related SAEs or treatment-related severe TEAEs reported throughout the study. Overall, a favorable safety profile was observed with ASI and aboBoNT-A, with no notable tolerance differences between the two formulations. No new or unexpected safety issues emerged from this study. The dose of ASI and aboBoNT-A, the dose per muscle, and the route of administration planned for the present study were the same as in other previous studies and were consistent with the currently approved prescribing information for the treatment of GL.2,6 Additionally, the doses selected for this study were based on the efficacy and clinical safety data from previous studies.4,5,17,18 The number of chosen injection sites for this study was also based on efficacy and safety findings from a previous study,17 and was consistent with the number of injections approved in the current Dysport/Azzalure prescribing information.2,6 In order to properly assess the safety and efficacy of the new formulation in this subject population, only subjects who were naïve to any previous treatment with any BoNT serotype for any indication were included in this study. This ensured that the expectations of each individual subject for the treatment effect would not impact their interpretation of the response. The inclusion of a placebo group in this study allowed for robust assessment of the treatment effect of the new liquid formulation. The recognized limitations of the present study included a mild imbalance of baseline severity at maximum frown. This may have contributed to the small differences between different active treatment groups. It may be beneficial to stratify subjects based on baseline severity at maximum frown. In addition, all participants in the present study were female; therefore, males should be included in further studies. CONCLUSIONS The results of the present study demonstrated that a novel, ready-to-use liquid formulation of abobotulinumtoxinA, ASI, at 20, 50, and 75 U was associated with significant improvements in the appearance of GL at maximum frown compared with placebo at Day 29. In addition, the efficacy of ASI in the treatment of GL was considered to be clinically comparable to that of aboBoNT-A at each time-point. ASI was well tolerated and exhibited a similar safety profile to that of aboBoNT-A. Supplementary Material This article contains supplementary material located online at www.aestheticsurgeryjournal.com. Disclosures Dr Ascher served as a consultant for and has received research grant support from Allergan, (Irvine, CA, USA); Ipsen (Paris, France); and Merz (Frankfurt, Germany). Dr Ascher is an instructor and investigator for Ipsen. Dr Kestemont received honoraria from Galderma (Lausanne, Switzerland) for participating in courses and workshops. Dr Boineau has served as a consultant and speaker for Galderma. Dr Stein has received lecture fees, training fees, and meeting sponsorship from Ipsen. Dr Heckmann received honoraria from Allergan, Ipsen, and Evolus (Pune, India) for conducting clinical trials in the field of botulinum toxin research. Dr Pavicic received compensation from Ipsen for conducting a clinical trial, outside of the current study. Dr Pavicic is a consultant and speaker for Merz, Galderma, Dermaceutics (Dublin, Ireland), Beiersdorf (Hamburg, Germany), and Cynosure (Westford, MA, USA). Dr Rzany is an advisor and speaker for Ipsen, Galderma, and Merz. Drs Volteau and Picaut are employees of Ipsen. Dr Tse was an employee of Ipsen at the time of the study. All non- Ipsen authors also received compensation from Ipsen for conducting this clinical trial. Drs Bodokh and Dendorfer declared no further disclosures. Funding This study was sponsored by Ipsen (Paris, France), which provided funding to the investigational centers involved. Editorial support was provided by Watermeadow Medical and funded by Ipsen. REFERENCES 1. Rzany B Ascher B Monheit G. Treatment of glabellar lines with botulinum toxin type A (Speywood Unit): a clinical overview. J Eur Acad Dermatol Venereol . 2010; 24 Suppl 1: 1- 14. Google Scholar CrossRef Search ADS PubMed  2. Ipsen Biopharm Ltd. Dysport Full Perscribing Information. 2016; https://www.dysport.com/pdfs/Dysport_Full_Pres cribing_Information.pdf. Accessed December 6, 2016. 3. Brandt F Swanson N Baumann L Huber B. Randomized, placebo-controlled study of a new botulinum toxin type a for treatment of glabellar lines: efficacy and safety. Dermatol Surg . 2009; 35( 12): 1893- 1901. Google Scholar CrossRef Search ADS PubMed  4. Ascher B Zakine B Kestemont P Baspeyras M Bougara A Santini J. A multicenter, randomized, double-blind, placebo-controlled study of efficacy and safety of 3 doses of botulinum toxin A in the treatment of glabellar lines. J Am Acad Dermatol . 2004; 51( 2): 223- 233. Google Scholar CrossRef Search ADS PubMed  5. Monheit G Carruthers A Brandt F Rand R. A randomized, double-blind, placebo-controlled study of botulinum toxin type A for the treatment of glabellar lines: determination of optimal dose. Dermatol Surg . 2007; 33( 1 Spec No.): S51- S59. Google Scholar CrossRef Search ADS PubMed  6. electronic Medicines Compendium. Azzalure Summary of Product Characteristics. 2015; https://www.medicines.org.uk/emc/medicine/21985%20-%20companyDetails. Accessed December 6, 2016. 7. Walker TJ Dayan SH. Comparison and overview of currently available neurotoxins. J Clin Aesthet Dermatol . 2014; 7( 2): 31- 39. Google Scholar PubMed  8. electronic Medicines Compendium. Dysport 300 units Summary of Product Characteristics. 2016; https://www.medicines.org.uk/emc/medicine/870/SPC/Dysport+300+units,+Dysport+500+units/. Accessed December 6, 2016. 9. Carey WD. Incorrect reconstitution of incobotulinumtoxinA leads to loss of neurotoxin. J Drugs Dermatol . 2014; 13( 6): 735- 738. Google Scholar PubMed  10. Berdot S Sabatier B Gillaizeau F Caruba T Prognon P Durieux P. Evaluation of drug administration errors in a teaching hospital. BMC Health Serv Res . 2012; 12: 60. Google Scholar CrossRef Search ADS PubMed  11. Allergan Inc. BOTOX® Dilution, Reconstitution and Injection Guide. 2015. https://hcp.botoxcosmetic.com/~/media/Unique%20Sites/BotoxCosmeticHCP/Files/PDFs/Dilution_Reconstitution_Injection_Guide.pdf. Accessed December 6, 2016. 12. Anderson J Hilmas CJ. Botulinum Toxin. In: Gupta RC, ed. Handbook of Toxicology of Chemical Warfare Agents . San Diego, USA: Academic Press; 2015: 361- 386. Google Scholar CrossRef Search ADS   13. Niamtu J3rd. Neurotoxin waste from drawing product through the vial stopper. J Clin Aesthet Dermatol . 2014; 7: 33- 37. Google Scholar PubMed  14. European Medicines Agency. Statistical principles for clinical trials - ICH Harmonised Tripartite Guideline 1998. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf. Accessed December 6, 2016. 15. Honeck P Weiss C Sterry W Rzany B; Gladys study group. Reproducibility of a four-point clinical severity score for glabellar frown lines. Br J Dermatol . 2003; 149( 2): 306- 310. Google Scholar CrossRef Search ADS PubMed  16. Kim JE Song EJ Choi GS Lew BL Sim WY Kang H. The efficacy and safety of liquid-type botulinum toxin type A for the management of moderate to severe glabellar frown lines. Plast Reconstr Surg . 2015; 135( 3): 732- 741. Google Scholar CrossRef Search ADS PubMed  17. Rzany B Ascher B Fratila A Monheit GD Talarico S Sterry W. Efficacy and safety of 3- and 5-injection patterns (30 and 50 U) of botulinum toxin A (Dysport) for the treatment of wrinkles in the glabella and the central forehead region. Arch Dermatol . 2006; 142( 3): 320- 326. Google Scholar CrossRef Search ADS PubMed  18. EU Clinical Trials Register. 2007-005958-23 A Phase II, Randomised, Double-Blind Study to Compare the Safety and Efficacy of One Treatment Cycle of Clostridium Botulinum Type A Toxin (50 Units) When Reconstituted from Either a 125 Unit or a 500 Unit Presentation for the Treatment of Glabellar Lines. 2007; https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-005958-23/DE. Accessed December 6, 2016. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Aesthetic Surgery Journal Oxford University Press

Liquid Formulation of AbobotulinumtoxinA Exhibits a Favorable Efficacy and Safety Profile in Moderate to Severe Glabellar Lines: A Randomized, Double-Blind, Placebo- and Active Comparator-Controlled Trial

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Oxford University Press
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© 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com
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1090-820X
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1527-330X
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10.1093/asj/sjw272
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Abstract

Abstract Background In most countries, approved botulinum toxin type A formulations require reconstitution before injection. Objectives To evaluate the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection, ASI) in subjects with moderate to severe glabellar lines (GL). Methods In this Phase II, double-blind, placebo-controlled, randomized study, 176 female subjects (aged 30 to 60 years) were randomized into five treatment groups: ASI 20, 50, or 75 U, reconstituted abobotulinumtoxinA (aboBoNT-A) 50 U, and placebo. GL severity was assessed at maximum frown using a 4-point grading scale. Responders were subjects with severity grade of moderate [2] or severe [3] at baseline improving to none [0] or mild [1], evaluated at each time-point by Investigator’s Live Assessment (ILA) or Subject’s Self-Assessment (SSA). Safety profiles were also determined. Results Baseline characteristics were similar across groups. Responder rates on Day 29 by ILA were significantly greater for ASI 20, 50, and 75 U versus placebo (88.9%, 91.4%, and 87.9% vs. 0%, respectively; P < 0.0001). Similar results were observed by SSA. A greater proportion of responders was observed in ASI groups vs placebo from Day 8 to 113 for ILA and SSA (P < 0.001). AboBoNT-A responder rate on Day 29 for ILA was 77.1% (P < 0.1006 vs ASI 50 U); with comparable results by SSA. The ASI safety profile was comparable to that of aboBoNT-A. Conclusions Ready-to-use liquid formulation of abobotulinumtoxinA was shown to be efficacious, with comparable results to reconstituted abobotulinumtoxinA, and to have a favorable safety profile in subjects with severe to moderate GL. Level of Evidence: 1 It is widely recognized by both clinicians and patients that glabellar lines (GL) have an important role in self-perception and emotional wellbeing, and the minimally invasive treatment of GL with botulinum toxin type A (BoNT-A) has been well established.1 The efficacy and safety of abobotulinumtoxinA for use in improving the appearance of moderate to severe GL has been evaluated in previous double-blind, randomized, placebo-controlled clinical studies.2-6 These studies demonstrated that abobotulinumtoxinA was well tolerated and reduced the severity of GL for up to five months. Currently available BoNT-A preparations include abobotulinumtoxinA (phase III; Dysport, Ipsen Ltd., Slough, UK; Azzalure, Galderma Ltd., Lausanne, Switzerland), onabotulinumtoxinA (phase III; Botox, Allergan, Inc., Irvine, CA), incobotulinumtoxinA (phase III; Bocouture/Xeomin, Merz Pharmaceuticals, Inc., Frankfurt, Germany) and Neuronox®/Meditoxin (phase III; Medy-Tox, Inc., Seoul, South Korea).7 However, all currently approved BoNT-A preparations in Europe and North America are not available in liquid formulation and therefore require reconstitution with sodium chloride prior to injection.6-8 There are several potential challenges associated with reconstituted preparations. When reconstitution is required, healthcare professionals have to spend time on preparation, which detracts from time spent with the patient. In addition, in a healthcare setting, reconstitution errors may occur when medications require preparation and reconstitution.9,10 Errors may occur in the dilution of toxins which could result in under or over-dosing.10-12 Additionally, this may have economic consequences due to product waste.9,13 Even for experienced injectors, reconstitution can allow for some variability in injection doses. Therefore a ready-to-use liquid formulation of BoNT-A will facilitate and standardize injection practice, ensuring that appropriate doses and concentrations are administered and thus preventing reconstitution errors. The aim of the present study was to assess the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA (abobotulinumtoxinA solution for injection; ASI) in the treatment of moderate to severe GL after a single injection. In addition, the relative safety and efficacy of ASI was compared with the approved dose of reconstituted abobotulinumtoxinA (aboBoNT-A) for improving the appearance of GL. METHODS Objectives The primary objective was to assess the efficacy and safety of a ready-to-use liquid formulation of abobotulinumtoxinA, ASI, at various doses (20, 50, or 75 units [U]) compared with placebo, for improvement of the appearance of moderate to severe GL after a single treatment. The standard dry formulation of aboBoNT-A served as an active comparator in this study, which was considered the secondary objective. Ethics The present study was conducted under the provisions of the Declaration of Helsinki, with the consent of the Independent Ethics Committee (IEC) and in accordance with informed consent regulations and the International Conference on Harmonisation (ICH) Consolidated Guideline on Good Clinical Practice.14 This study also adhered to all local regulatory requirements and has been registered with ClinicalTrials.gov, number NCT01333397. All subjects provided written informed consent prior to entering the study (before initiation of any study-related procedure and administration of treatment), which was personally signed and dated by the subject. Study Design This study was a phase II, randomized, multicenter, double-blind, placebo and active comparator controlled study conducted at eight centers in France and Germany. Enrollment took place between March and the end of June 2011. An overview of the study design is shown in Figure 1. Figure 1. View largeDownload slide Study design. aboBoNT-A, abobotulinumtoxinA; AE, adverse event; ASI, abobotulinumtoxinA solution for injection. * Day 4 follow up monitoring of AEs and concomitant medications via telephone contact. Figure 1. View largeDownload slide Study design. aboBoNT-A, abobotulinumtoxinA; AE, adverse event; ASI, abobotulinumtoxinA solution for injection. * Day 4 follow up monitoring of AEs and concomitant medications via telephone contact. At baseline (BL) subjects were randomized 1:1:1:1:1 to placebo, ASI (20, 50, or 75 U) or aboBoNT-A 50 U. Computer-generated randomization lists were created by a sponsor statistician independent from the study using a validated in-house system developed with SAS software (SAS Institute, Inc., Cary, NC). The randomization schedule is generated using the SAS procedure PLAN. Treatment numbers were assigned when subjects entered the study using a 24-h interactive voice response system from an external contract research organization. Inclusion Criteria The study included female subjects, aged 30 to 60 years (inclusive) with moderate to severe GL at maximum frown at BL (Day 1, pre-treatment), as assessed by the investigator’s and subjects’ assessment using a validated 4-point photographic scale. In addition, all subjects were required to be naïve to previous treatment with any serotype of botulinum toxin (BoNT) and either of non-childbearing potential or if female of childbearing potential must return a negative outcome from a pregnancy test. The rationale for a female-only study was to have a homogenous study population. Subjects were excluded from entering the study if they had received any prior treatment with fillers (eg, collagen-type implants), skin abrasions or photorejuvenation within 12 months of enrollment or any previous injections with silicone in the upper face. This study also excluded subjects who had any planned facial cosmetic surgery during the study period or had a history of ablative skin resurfacing of the area to be treated during the study. Treatment The manufacturing process for BoNT-A is identical in the lyophilized and liquid formulation products. The currently marketed products aboBoNT-A 500 U and aboBoNT-A 125 U are freeze-dried preparations of Clostridium BoNT-A hemagglutinin complex (BoNT-A-HAC) formulated with lactose (bulking agent) and human serum albumin (HSA) in a glass vial. ASI consists of BoNT-A-HAC and excipients (L-histidine 1.55 mg, sucrose 4.00 mg, sodium chloride 8.76 mg, polysorbate-80 0.10 mg, hydrochloric acid to pH 6.5, water for injection and nitrogen). The liquid formulation does not contain HSA, lactose or any excipient from animal origin. The ASI formulation was supplied as a liquid in a 1 mL pre-filled syringe containing 500 U (nominal) of BoNT-A-HAC and all subjects receiving ASI were treated with the same batch. In order to achieve the required doses of 20, 50, and 75 U in 0.25 mL, the respective volumes of active ASI formulation (0.15, 0.4, and 0.6 mL) were diluted to a final concentration of 79, 200, and 300 U/mL using a 0 U/mL placebo containing only the excipients of ASI (ie, without the toxin). The aboBoNT-A dry formulation consisted of a white, lyophilized powder containing 125 U of BoNT-A-HAC which was reconstituted with 0.63 mL sterile, preservative-free saline (sodium chloride for injection 0.9%) to achieve a concentration of 200 U/mL. Units of the toxin were similar in both formulation, thus units of the liquid formulation correspond to those of the reconstituted preparation. The placebo was supplied for administration as a liquid in a 1 mL pre-filled syringe containing only the excipients of ASI. All syringes used for each treatment were prepared by an independent nurse or pharmacist and were indistinguishable to the injector; equal volumes of ASI, reconstituted aboBoNT-A or placebo were injected into each subject. For each treatment group, the total treatment dose on Day 1 was divided into five injections (0.05 mL per injection; total injection volume of 0.25 mL), each of which was administered into the following pre-defined sites across the glabellar region: a single injection into the procerus muscle inferior to the line joining the eyebrows and superior to the root of the nose; each corrugator muscle was injected directly above the inner canthus and above the bony orbital rim; and each lateral corrugator/orbicularis muscle was injected directly above the pupil, approximately 1 cm above the bony orbital rim. The subjects were required to attend office follow-up visits on Days 8, 15, 29, 57, 85, and 113. All subjects who had attended the Day 113 visit were considered to have completed the study. In addition, subjects were contacted on Day 4 post-injection for a follow-up interview. Assessments At screening, BL and at each scheduled post-treatment visit, the investigator used a validated 4-point photographic scale to assess glabellar line severity at maximum frown and at rest.15 The scale represents the severity of GL (Grade 0, none; Grade 1, mild; Grade 2, moderate; Grade 3, severe). Investigators were fully trained on the use of the photographic scale and were provided with a written description of each set of photographs to standardise assessments among investigators. In addition, at screening, BL and at each scheduled post-treatment visit, subjects were asked to assess their GL at maximum frown, using a 4-point categorical scale (Grade 0, no wrinkles; Grade 1, mild wrinkles; Grade 2, moderate wrinkles; Grade 3, severe wrinkles), with reference to the same photographic scale used by investigators. This occurred prior to and independently of the investigator’s assessment. Treatment emergent adverse events (TEAEs) were monitored on Day 1 post treatment, Day 4 post treatment (telephone follow-up) and at each visit following treatment. Endpoints Co-primary efficacy endpoints: The proportion of responders in the Investigator’s Live Assessment (ILA) of GL at maximum frown at Day 29, defined as a subject with severity grade of moderate [2] or severe [3] at maximum frown at BL improving to a severity grade of none [0] or mild [1]. The proportion of responders in the Subject’s Self-Assessment (SSA) of GL at maximum frown at Day 29, as defined for the ILA. Secondary efficacy endpoints included: The proportion of responders at maximum frown at all other post-treatment visits (Days 8, 15, 57, 85, and 113) as assessed by the ILA and SSA The proportion of subjects assessed as responders at maximum frown at Day 29 who remain responders on Day 113 The proportion of subjects with a reduction of two or more grades in the severity of GL at maximum frown at all post-treatment visits, as measured by the ILA and SSA Safety assessments, which were made throughout the study to monitor TEAEs Statistical Analysis Statistical analyses were performed in accordance with ICH E9 guidelines.14 Efficacy analyses were based on the intent-to-treat (ITT) population and safety analysis was based on the safety population. Both are defined as all randomized subjects who received study treatment, regardless of the actual amount injected. The proportions of responders with 95% CI were summarized by treatment group and differences were compared using a Chi-square test. A type I error rate equal to 0.0085 was used for the primary efficacy analysis, and 0.05 for other efficacy analysis. Adverse events were coded using the MedDRA version 14.0 (MedDRA MSSO, McLean, VA). RESULTS Study Population A total of 176 female subjects were randomized into the placebo and four active treatment groups. Of the 176 subjects enrolled, 174 completed the study; two subjects were lost to follow-up (one each from the placebo and the 75 U ASI group). All subjects were included in the ITT and safety populations. Demographic data and other baseline characteristics are shown in Table 1. Subjects had a mean age (range) of 47.3 (30-60) years and mean BMI (range) of 22.2 (16.7-48.1) kg/m2. Overall, demographic characteristics were similar across the treatment groups. At maximum frown, severe or moderate GL were reported for all subjects by ILA, and for all subjects (except for one case of mild GL) reported by SSA. In the ILA and SSA of maximum frown at BL, 60.0% and 45.7% of subjects in the placebo group had severe GL; while, in the abobotulinumtoxinA groups (ASI and aboBoNT-A) 38.9% to 48.6% and 33.3% to 54.3% of subjects had severe GL by ILA and SSA, respectively. Therefore, there are slight differences in the percentage of subjects with severe GL across treatment groups. Table 1. Baseline Demographics and Subject Characteristics Characteristic  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  Mean age, years ±SD  46.8 ± 6.4  46.7 ± 8.4  48.1 ± 6.9  47.9 ± 6.0  47.0 ± 6.6  Range  31-59  30-60  34-59  35-58  30-58  Mean BMI, kg/m2  21.65  22.26  22.57  22.29  22.10  Range  17.0-29.7  18.6-33.2  18.4-48.1  19.1-32.0  16.7-29.0  Investigators’ live assessment of GL at maximum frown, n (%)  Severe  21 (60.0)  14 (38.9)  15 (42.8)  15 (42.8)  17 (48.6)  Moderate  14 (40.0)  22 (61.1)  20 (57.1)  20 (57.1)  18 (51.4)  Investigators’ live assessment of GL at rest, n (%)  Severe  4 (11.4)  3 (8.3)  2 (5.7)  4 (11.4)  5 (14.3)  Moderate  14 (40.0)  14 (38.9)  11 (31.4)  10 (28.6)  14 (40.0)  Mild  17 (48.6)  17 (47.2)  22 (62.9)  21 (60.0)  13 (37.1)  None  0 (0)  2 (5.6)  0 (0)  0 (0)  3 (8.6)  Subjects’ aelf-assessment of GL at maximum frown, n (%)  Severe  16 (45.7)  12 (33.3)  18 (51.4)  14 (40.0)  19 (54.3)  Moderate  19 (54.3)  24 (66.7)  16 (45.7)  21 (60.0)  16 (45.7)  Mild  0 (0)  0 (0)  1 (2.9)  0 (0)  0 (0)  Characteristic  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  Mean age, years ±SD  46.8 ± 6.4  46.7 ± 8.4  48.1 ± 6.9  47.9 ± 6.0  47.0 ± 6.6  Range  31-59  30-60  34-59  35-58  30-58  Mean BMI, kg/m2  21.65  22.26  22.57  22.29  22.10  Range  17.0-29.7  18.6-33.2  18.4-48.1  19.1-32.0  16.7-29.0  Investigators’ live assessment of GL at maximum frown, n (%)  Severe  21 (60.0)  14 (38.9)  15 (42.8)  15 (42.8)  17 (48.6)  Moderate  14 (40.0)  22 (61.1)  20 (57.1)  20 (57.1)  18 (51.4)  Investigators’ live assessment of GL at rest, n (%)  Severe  4 (11.4)  3 (8.3)  2 (5.7)  4 (11.4)  5 (14.3)  Moderate  14 (40.0)  14 (38.9)  11 (31.4)  10 (28.6)  14 (40.0)  Mild  17 (48.6)  17 (47.2)  22 (62.9)  21 (60.0)  13 (37.1)  None  0 (0)  2 (5.6)  0 (0)  0 (0)  3 (8.6)  Subjects’ aelf-assessment of GL at maximum frown, n (%)  Severe  16 (45.7)  12 (33.3)  18 (51.4)  14 (40.0)  19 (54.3)  Moderate  19 (54.3)  24 (66.7)  16 (45.7)  21 (60.0)  16 (45.7)  Mild  0 (0)  0 (0)  1 (2.9)  0 (0)  0 (0)  All participants were female (race, n = 176 [100%] Caucasian; ethnicity, n = 5 [2.8%] Hispanic/Latina, n = 171 [97.2%] not Hispanic/Latina). Investigators assessment of GL was made using a validated 4-point photographic scale where 0=none and 3=severe (Honeck scale).15 aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; BMI, body mass index; GL, glabellar lines; SD, standard deviation. View Large Subjects in the aboBoNT-A 50 U group had more severe lines at maximum frown, as per ILA and SSA, and less mild lines at rest, compared with all ASI doses. Efficacy Co-Primary Efficacy Endpoints: Proportion of Responders at Day 29, as Measured by the ILA and SSA of GL at Maximum Frown As shown in Figure 2A and Supplemental Table 1A, the proportion of responders at Day 29 in the ILA of GL at maximum frown was significantly greater in all three ASI dose groups compared with the placebo group (88-91% vs 0%; P < 0.0001). Similarly, the proportion of responders at Day 29 in the SSA of GL at maximum frown was significantly higher in each of the ASI dose groups compared with the placebo group (82-92% vs 2.9%; P < 0.0001) (Figure 2B, Supplemental Table 1B). These results therefore demonstrated the efficacy of ASI at Day 29 versus the placebo group. Figure 2. View largeDownload slide Proportion of responders (95% CI) at each time point for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. Day 29 = primary endpoint. A responder at maximum frown is defined as a subject having a severity grade of none or mild at maximum frown on the visit day and a severity grade of moderate or severe at maximum frown at screening or baseline visit. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Figure 2. View largeDownload slide Proportion of responders (95% CI) at each time point for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. Day 29 = primary endpoint. A responder at maximum frown is defined as a subject having a severity grade of none or mild at maximum frown on the visit day and a severity grade of moderate or severe at maximum frown at screening or baseline visit. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Responders at Other Time-Points, as Measured by the ILA and SSA of GL at Maximum Frown The proportion of responders in the ILA of GL at maximum frown were significantly higher in all three ASI dose groups compared with placebo group at each time-point (Day 8 to Day 113) throughout the study (all P < 0.0001 vs. placebo, except ASI 20 U at Day 113 [P = 0.0035]) (Figure 2A, Supplemental Table 1A). These results were comparable to those observed for the proportions of responders receiving each ASI dose in the SSA of GL at maximum frown throughout the study (all P ≤ 0.0001 vs. placebo, except ASI 50 U at Day 113 [P = 0.0002]) (Figure 2B, Supplemental Table 1B). Proportion of Responders on Day 29 who Remained Responders on Day 113 The proportion of responders at maximum frown on Day 29 who remained responders on Day 113 was 25.0%, 46.9%, and 65.5% in the ASI 20 U, ASI 50 U, and ASI 75 U groups, respectively, for the ILA of GL; and 36.4%, 40.0%, and 63.0% in the same respective groups for the SSA of GL. These results suggested a dose–response relationship for the duration of efficacy of ASI, which is not unexpected. The Proportion of Subjects with a Reduction of Two or More Grades in the Severity of GL as Measured by the ILA and SSA at Maximum Frown As shown in Figure 3A and Supplemental Table 2A, a significantly greater proportion of subjects in the ASI groups had a two or more grade reduction in GL severity at maximum frown compared with the placebo group on Days 8 to 113 (P < 0.0001 to 0.0241 vs placebo), by ILA. Comparable results were seen for the SSA (P < 0.0001 to 0.0393 vs placebo), while only ASI 20 U was not significant compared with placebo at Day 113 (P = 0.0853) (Figure 3B, Supplemental Table 2B). Figure 3. View largeDownload slide Proportion of subjects (95% CI) with a reduction of two or more grades from baseline in GL severity for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. AboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Figure 3. View largeDownload slide Proportion of subjects (95% CI) with a reduction of two or more grades from baseline in GL severity for the Investigators’ Live Assessment of GL at (A) maximum frown and (B) Subjects’ Self-Assessment of GL at maximum frown. AboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; CI, confidence interval; GL, glabellar lines. Comparison of ASI and aboBoNT-A 50 U At Day 29, the proportion of responders in the ILA of GL at maximum frown was 14.3% higher in the ASI 50 U group than in the aboBoNT-A 50 U group; however, this increase was not statistically significant (91.4% vs 77.1%; 95% CI, −2.4, 31.0; P = 0.1006) (Figure 2A, Supplemental Table 1A). Additionally, the proportion of responders in the SSA of GL at maximum frown was 2.8% higher in the ASI 50 U group compared with the aboBoNT-A 50 U group (85.7% vs 82.9%; 95% CI, −14.2, 19.9; P = 0.7426) (Figure 2B, Supplemental Table 1B). The proportion of responders in the ILA of GL at maximum frown at Days 8 and 15 was higher in the ASI 50 U and 75 U groups compared with the aboBoNT-A 50 U group (80.0% and 82.9% vs 57.1% at Day 8, respectively; 94.3% and 91.4% vs 73.5% at Day 15, respectively). There were no noteworthy differences at Days 57 and 85 for all three ASI dose groups; whilst at Day 113, the responder rate was higher in the ASI 75 U group than the aboBoNT-A 50 U (55.9% vs 31.4%, respectively) (Figure 2A, Supplemental Table 1A). In addition, no marked differences were observed in the responder rates for SSA of GL at maximum frown for the three ASI doses at any time-point throughout the study, when compared with the aboBoNT-A 50 U group, except the ASI 75 U group which had a higher responder rate at Day 113 (52.9% vs 28.6%, respectively) (Figure 2B, Supplemental Table 1B). Safety Details of TEAEs are summarized in Table 2. Approximately a third of subjects in each group had at least one TEAE, ranging from 28.6% in the aboBoNT-A 50 U group to 41.7% in the ASI 20 U group and 34.3% in the placebo group (Table 2). Overall, the frequency of TEAEs in the aboBoNT-A/ASI groups did not appear to be dose related. Of these adverse events, the incidence of Investigator-assessed treatment-related TEAEs were similar across the groups; 16.7%, 11.4%, and 11.4% in the ASI 20 U, 50 U and 75 U groups, respectively, 5.7% in the aboBoNT-A 50 U group and 14.3% in the placebo group. There were no deaths, withdrawals due to TEAEs, treatment-related serious adverse events (SAEs) or severe treatment-related TEAEs. Two SAEs were reported during the study (vertigo and headache) by one subject in the ASI 20 U group and were not considered to be related to treatment by the Investigator. In addition, no TEAEs considered treatment-related were remote from the injection site. Table 2. Summary of Treatment-Emergent Adverse Events (Safety Population) Number of subjects reporting at least one event, n (%)  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  TEAEs (occurring in ≥5% subjects)  12 (34.3)  15 (41.7)  10 (28.6)  11 (31.4)  10 (28.6)   Headache  4 (11.4)  3 (8.3)  3 (8.6)  2 (5.7)  3 (8.6)   Nasopharyngitis  4 (11.4)  0  1 (2.9)  1 (2.9)  2 (5.7)   Back pain  0  1 (2.8)  0  0  2 (5.7)   Eyelid ptosis  0 (0)  1 (2.8)  0 (0)  2 (5.7)  0 (0)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)  Severe TEAEs  0  1 (2.8)  0  0  0  At least one related TEAEs  5 (14.3)  6 (16.7)  4 (11.4)  4 (11.4)  2 (5.7)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)   Eyelid ptosis  0  1 (2.8)  0  2 (5.7)  0   Headache  1 (2.9)  1 (2.8)  1 (2.9)  2 (5.7)  0   Injection site hemorrhage  0  0  1 (2.9)  0  0   Nasal congestion  0  0  1 (2.9)  0  0   Ecchymosis  0  1 (2.8)  0  0  0   Injection site swelling  0  1 (2.8)  0  0  0   Rhinorrhea  0  1 (2.8)  0  0  0  Number of subjects reporting at least one event, n (%)  Placebo (n = 35)  ASI 20 U (n = 36)  ASI 50 U (n = 35)  ASI 75 U (n = 35)  aboBoNT-A 50 U (n = 35)  TEAEs (occurring in ≥5% subjects)  12 (34.3)  15 (41.7)  10 (28.6)  11 (31.4)  10 (28.6)   Headache  4 (11.4)  3 (8.3)  3 (8.6)  2 (5.7)  3 (8.6)   Nasopharyngitis  4 (11.4)  0  1 (2.9)  1 (2.9)  2 (5.7)   Back pain  0  1 (2.8)  0  0  2 (5.7)   Eyelid ptosis  0 (0)  1 (2.8)  0 (0)  2 (5.7)  0 (0)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)  Severe TEAEs  0  1 (2.8)  0  0  0  At least one related TEAEs  5 (14.3)  6 (16.7)  4 (11.4)  4 (11.4)  2 (5.7)   Injection site pain  1 (2.9)  2 (5.6)  1 (2.9)  2 (5.7)  1 (2.9)   Eyelid ptosis  0  1 (2.8)  0  2 (5.7)  0   Headache  1 (2.9)  1 (2.8)  1 (2.9)  2 (5.7)  0   Injection site hemorrhage  0  0  1 (2.9)  0  0   Nasal congestion  0  0  1 (2.9)  0  0   Ecchymosis  0  1 (2.8)  0  0  0   Injection site swelling  0  1 (2.8)  0  0  0   Rhinorrhea  0  1 (2.8)  0  0  0  Safety population defined as all randomized subjects who received study treatment, regardless of injection volume. Events presented are TEAEs that occurred in >5% (n = 2) of subjects in at least one active group and related TEAEs that occurred in more subjects receiving active treatment than placebo. aboBoNT-A, abobotulinumtoxinA; ASI, abobotulinumtoxinA solution for injection; GL, glabellar lines; TEAE, treatment-emergent adverse event. View Large Injection site adverse reactions occurred in a small number of subjects in all treatment groups, including the placebo group with no dose response relationship. In total, treatment-related eyelid ptosis was observed in three subjects, one treated with ASI 20 U and two with ASI 75 U, all of which were local to the injection site and considered related to treatment. No concomitant medication was given for the events, two out of the three subjects recovered without sequelae, one within 3 weeks (ASI 75 U group) and the other in 6 weeks (ASI 20 U group), and one patient was lost to follow-up while the event was ongoing (ASI 75 U group). All headaches related to treatment were of mild intensity and patients recovered within 5 days. No concomitant medication was required for any related headache. Few additional subjects in the ASI groups reported treatment-related AEs (one subject in the ASI 50 U experienced nasal congestion; one subject in the 20 U ASI group had ecchymosis at the base of the nose and internal edges of each eyebrow; one subject in the 20 U ASI group had rhinorrhea), which resolved without any concomitant medication. DISCUSSION The safety and efficacy of abobotulinumtoxinA for the improvement in the appearance of GL has already been well established,1,3-5 and 50 U (Dysport/Azzalure) is the recommended dose for the improvement in the appearance of GL.2,6 The present study was designed to investigate the efficacy and safety of different doses of a new ready-to-use liquid formulation of abobotulinumtoxinA, ASI compared with placebo for the improvement in the appearance of GL. This study also aimed to assess the relative efficacy and safety of the different doses of ASI compared with the optimal dose of aboBoNT-A (50 U) when used to improve the appearance of moderate to severe GL. The primary objective was to assess the response to three different doses of ASI, each compared with placebo, in patients with moderate to severe GLs at maximum frown, as assessed according to ILA and SSA. The results showed that a significantly greater proportion of subjects had an improvement in the appearance of moderate to severe GL at Day 29 compared with placebo, both at maximum frown in all ASI groups for ILA and SSA (P < 0.0001 for all). In addition, this increase was observed at all post-treatment time-points, whether measured by the ILA or by the SSA (P < 0.0001 to 0.0035). Notably, the proportion of subjects who were responders on Day 29 and who remained so on Day 113 was similar for the ILA and SSA at maximum frown. Although the study was not powered to detect differences between active treatment groups, some indication of dose–response was observed in the proportion of responders using the ILA at maximum frown and in the proportion of subjects with two or more grades improvement in GL at maximum frown. Additionally, a higher proportion of subjects experiencing maintained BoNT-A effects was observed as ASI dose increased. This result suggested that the higher the dose of ASI, the longer the duration of action. Although a dose–response relationship may not be obvious for ASI at Day 29, after this peak response it is evident that higher ASI doses resulted in slower decreases in the proportion of responders from Day 57 to Day 113 for the ILA at maximum frown. These results were comparable to those reported for aboBoNT-A by Monheit et al (n = 279 in aboBoNT-A groups), which showed a higher responder rate at maximum frown on Day 30 in the 75 U group when compared with the 50 U group (85% vs 77%, respectively)1,5; however, Ascher et al (n = 102 in aboBoNT-A groups) showed no difference in responder rate for the same doses at maximum frown on Day 30 (76% vs 76%, respectively).1,4 This lower power may be accounted for by the difference in cohort size. In addition, both previous studies reported 50 U as the optimal dose for aboBoNT-A in the treatment of GL.4,5 Analysis of the co-primary endpoints showed that the proportion of subjects at Day 29 was greater than placebo for all ASI groups for the ILA and the SSA. A significantly greater proportion of subjects in all ASI groups compared with placebo had a reduction of two or more grades in GL severity on Days 8 to 113, as measured by the ILA at maximum frown. Comparable results were observed in the SSA for all doses and time-points, except in the ASI 20 U group on Day 113, which was not significantly different to the placebo group. There were no significant differences in the proportions of responders according to the ILA of GL at maximum frown between the ASI 50 U and the aboBoNT-A 50 U groups at Day 29. The proportion of responders at maximum frown by ILA tend to be slightly lower in the aboBoNT-A group compared with the ASI group at the same dose (50 U) at each time-point, most notably from Day 8 to Day 29. These differences were maintained from Day 57 to Day 113, but with a slightly decreased magnitude. A similar, but more sustained, effect was also observed with ASI 75 U compared with aboBoNT-A 50 U by ILA at maximum frown. For the SSA, no marked differences were identified in the proportion of responders in the ASI groups compared with aboBoNT-A 50 U at any time point for the SSA at maximum frown, except for the ASI 75 U group at Day 113. The results of the present study were comparable to those of a recent study that confirmed the safety and efficacy of MT10109L (Neuronox Aqua, Medy Tox, Inc.), a liquid formulation of BoNT-A for use in the management of glabellar frown lines.16 Approximately one third of subjects in each group had at least one TEAE. The incidence and type of TEAEs were similar across the active treatment groups. The incidence of treatment-related TEAEs in the ASI groups was similar to that of the placebo group and there were no deaths, withdrawals due to AE, treatment-related SAEs or treatment-related severe TEAEs reported throughout the study. Overall, a favorable safety profile was observed with ASI and aboBoNT-A, with no notable tolerance differences between the two formulations. No new or unexpected safety issues emerged from this study. The dose of ASI and aboBoNT-A, the dose per muscle, and the route of administration planned for the present study were the same as in other previous studies and were consistent with the currently approved prescribing information for the treatment of GL.2,6 Additionally, the doses selected for this study were based on the efficacy and clinical safety data from previous studies.4,5,17,18 The number of chosen injection sites for this study was also based on efficacy and safety findings from a previous study,17 and was consistent with the number of injections approved in the current Dysport/Azzalure prescribing information.2,6 In order to properly assess the safety and efficacy of the new formulation in this subject population, only subjects who were naïve to any previous treatment with any BoNT serotype for any indication were included in this study. This ensured that the expectations of each individual subject for the treatment effect would not impact their interpretation of the response. The inclusion of a placebo group in this study allowed for robust assessment of the treatment effect of the new liquid formulation. The recognized limitations of the present study included a mild imbalance of baseline severity at maximum frown. This may have contributed to the small differences between different active treatment groups. It may be beneficial to stratify subjects based on baseline severity at maximum frown. In addition, all participants in the present study were female; therefore, males should be included in further studies. CONCLUSIONS The results of the present study demonstrated that a novel, ready-to-use liquid formulation of abobotulinumtoxinA, ASI, at 20, 50, and 75 U was associated with significant improvements in the appearance of GL at maximum frown compared with placebo at Day 29. In addition, the efficacy of ASI in the treatment of GL was considered to be clinically comparable to that of aboBoNT-A at each time-point. ASI was well tolerated and exhibited a similar safety profile to that of aboBoNT-A. Supplementary Material This article contains supplementary material located online at www.aestheticsurgeryjournal.com. Disclosures Dr Ascher served as a consultant for and has received research grant support from Allergan, (Irvine, CA, USA); Ipsen (Paris, France); and Merz (Frankfurt, Germany). Dr Ascher is an instructor and investigator for Ipsen. Dr Kestemont received honoraria from Galderma (Lausanne, Switzerland) for participating in courses and workshops. Dr Boineau has served as a consultant and speaker for Galderma. Dr Stein has received lecture fees, training fees, and meeting sponsorship from Ipsen. Dr Heckmann received honoraria from Allergan, Ipsen, and Evolus (Pune, India) for conducting clinical trials in the field of botulinum toxin research. Dr Pavicic received compensation from Ipsen for conducting a clinical trial, outside of the current study. Dr Pavicic is a consultant and speaker for Merz, Galderma, Dermaceutics (Dublin, Ireland), Beiersdorf (Hamburg, Germany), and Cynosure (Westford, MA, USA). Dr Rzany is an advisor and speaker for Ipsen, Galderma, and Merz. Drs Volteau and Picaut are employees of Ipsen. Dr Tse was an employee of Ipsen at the time of the study. All non- Ipsen authors also received compensation from Ipsen for conducting this clinical trial. Drs Bodokh and Dendorfer declared no further disclosures. Funding This study was sponsored by Ipsen (Paris, France), which provided funding to the investigational centers involved. Editorial support was provided by Watermeadow Medical and funded by Ipsen. REFERENCES 1. Rzany B Ascher B Monheit G. Treatment of glabellar lines with botulinum toxin type A (Speywood Unit): a clinical overview. J Eur Acad Dermatol Venereol . 2010; 24 Suppl 1: 1- 14. 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Reproducibility of a four-point clinical severity score for glabellar frown lines. Br J Dermatol . 2003; 149( 2): 306- 310. Google Scholar CrossRef Search ADS PubMed  16. Kim JE Song EJ Choi GS Lew BL Sim WY Kang H. The efficacy and safety of liquid-type botulinum toxin type A for the management of moderate to severe glabellar frown lines. Plast Reconstr Surg . 2015; 135( 3): 732- 741. Google Scholar CrossRef Search ADS PubMed  17. Rzany B Ascher B Fratila A Monheit GD Talarico S Sterry W. Efficacy and safety of 3- and 5-injection patterns (30 and 50 U) of botulinum toxin A (Dysport) for the treatment of wrinkles in the glabella and the central forehead region. Arch Dermatol . 2006; 142( 3): 320- 326. Google Scholar CrossRef Search ADS PubMed  18. EU Clinical Trials Register. 2007-005958-23 A Phase II, Randomised, Double-Blind Study to Compare the Safety and Efficacy of One Treatment Cycle of Clostridium Botulinum Type A Toxin (50 Units) When Reconstituted from Either a 125 Unit or a 500 Unit Presentation for the Treatment of Glabellar Lines. 2007; https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-005958-23/DE. Accessed December 6, 2016. © 2017 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com

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Aesthetic Surgery JournalOxford University Press

Published: Feb 1, 2018

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