International Consensus Recommendations on the Aesthetic Usage of Ready-to-Use AbobotulinumtoxinA (Alluzience).

Alluzience (abobotulinumtoxinA RTU; Ipsen, Paris, France and Galderma SA, Lausanne, Switzerland) is the first ready-to-use (RTU) botulinum toxin type A liquid solution approved for the treatment of glabellar lines in Europe. In this article, the authors provide consensus recommendations on the aesthetic usage of abobotulinumtoxinA RTU. Members of the International Board on Alluzience convened to develop consensus on the treatment of glabellar lines as well as other facial wrinkles based on their own extensive experience. Consensus recommendations were developed to provide practical guidelines for injection of abobotulinumtoxinA RTU. General guidance on proper assessment, treatment planning, and patient education is provided, as well as specific injection guidelines per indication. Indications covered include glabellar lines, crow's feet, horizontal forehead lines, lateral eyebrow lift, lower eyelid wrinkles, bunny lines, drooping nasal tip, perioral wrinkles, drooping mouth corners, masseter hypertrophy, hollow cheek lines, dimpled chin, and platysmal bands. These guidelines provide a practical framework to support routine injection of facial muscles with Alluzience.

Efficacy and Safety of AbobotulinumtoxinA for the Treatment of Glabellar Lines in Chinese Patients: A Pivotal, Phase 3, Randomized, Double-Blind and Open-Label Phase Study.

BACKGROUND: Various botulinumtoxinA formulations are approved for glabellar lines treatment worldwide, including abobotulinumtoxinA (Dysport®). OBJECTIVES: Assess abobotulinumtoxinA superiority versus placebo and non-inferiority versus active comparator (onabotulinumtoxinA; Botox®), for the treatment of Chinese patients with moderate/severe glabellar lines. METHODS: Phase 3, randomized study (NCT02450526) comprising a double-blind (cycle 1) phase and an open-label (cycles 2-5) phase. Patients received abobotulinumtoxinA 50 units or matching placebo (5:1), active comparator (onabotulinumtoxinA 20 units) or matching placebo (5:1). In cycles 2-5, eligible patients were retreated with abobotulinumtoxinA only. Responders had glabellar lines of none/mild severity. PRIMARY ENDPOINT: responder rates at cycle 1, day 29 at maximum frown with abobotulinumtoxinA versus placebo (for superiority; by investigator's live assessment [ILA] and subject's self-assessment [SSA]), and versus active comparator (for non-inferiority; by ILA). Treatment-emergent adverse events were recorded. RESULTS: Overall, 520 patients were randomized. Superiority and non-inferiority, respectively, were demonstrated for abobotulinumtoxinA versus placebo (ILA, SSA; both p < 0.0001) and abobotulinumtoxinA versus active comparator. AbobotulinumtoxinA efficacy was maintained over open-label cycles; median time to onset of efficacy was 2.0 days. After 6 months, 17% of patients treated with abobotulinumtoxinA remained responders. AbobotulinumtoxinA was well-tolerated. Safety results were in line with the known profile of abobotulinumtoxinA; adverse events rate decreased with repeated treatment. CONCLUSIONS: After a single injection, abobotulinumtoxinA demonstrated superiority versus placebo and non-inferiority versus onabotulinumtoxinA for the treatment of moderate-to-severe glabellar lines in Chinese patients. Multiple injections of abobotulinumtoxinA demonstrated efficacy and safety in the treatment of glabellar lines in Chinese patients. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Botulinum toxin injections can be used to smooth frown lines that appear between the eyebrows (known as glabellar lines) in patients who have moderate or severe frown lines. This study looked at how injections of a botulinum toxin (abobotulinumtoxinA [aboBoNT-A]) could help with smoothing frown lines in patients from China compared with an injection of another botulinum toxin called onabotulinumtoxinA (onaBoNT-A) or placebo (saltwater, no treatment). The study included 520 patients from China, 18­65 years old, who had moderate or severe frown lines. All patients received a first injection of either aboBoNT-A, onaBoNT-A, or saltwater, and were studied for 12 weeks. After the first injection, patients could receive up to four more injections of aboBoNT-A, given at 12-week intervals, if their frown lines became moderate or severe again. Most patients (92%) had not previously received any botulinum toxin injections. The results showed that single and repeat injections of aboBoNT-A helped to smooth moderate and severe frown lines. The researchers found that after a single injection, aboBoNT-A was superior to no treatment and was similar to onaBoNT-A. Patients recorded a response to aboBoNT-A after 2 days and the response lasted for 6 months in 17% of patients. The effect on frown lines was maintained after repeat injections and aboBoNT-A was well tolerated by patients. These results suggest that aboBoNT-A is a suitable treatment for smoothing frown lines in patients from China with moderate to severe frown lines.

Efficacy and safety of abobotulinumtoxinA for upper limb spasticity in children with cerebral palsy: a randomized repeat-treatment study.

AIM: To assess the efficacy and safety of repeat abobotulinumtoxinA injections in reducing upper limb spasticity in children with cerebral palsy (CP). METHOD: This was a double-blind, repeat-cycle study (NCT02106351) in children with CP (2-17y). Children were randomized to receive 2U/kg (control), 8U/kg, or 16U/kg abobotulinumtoxinA injections into the target muscle group (wrist or elbow flexors) and additional muscles alongside occupational therapy via a home-exercise therapy program (HETP; minimum five 15min sessions/wk). Children received 8U/kg or 16U/kg plus HETP in cycles 2 to 4. RESULTS: During cycle 1, 210 children (126 males, 84 females; mean age [SD] 9y [4y 5mo], range 2-17y; n=70/group) had at least one upper limb abobotulinumtoxinA injection and 209 complied with the HETP. At week 6 of cycle 1, children in the 8U/kg or 16U/kg groups had significantly lower Modified Ashworth scale scores versus the 2U/kg group (primary outcome: treatment differences of -0.4 [p=0.012] and -0.7 [p<0.001] respectively). All groups improved on Physician Global Assessment and children in all groups achieved their treatment goals at least as expected. Therapeutic benefits were sustained during cycles 2 to 4; muscular weakness was the only treatment-related adverse event reported in at least one child/group (4.3% and 5.7% vs 1.4% respectively). INTERPRETATION: Treatment with 8U/kg or 16U/kg abobotulinumtoxinA significantly reduced upper limb spasticity versus the 2U/kg control dose. Therapeutic benefits of abobotulinumtoxinA plus HETP were sustained with repeat treatment cycles. WHAT THIS PAPER ADDS: AbobotulinumtoxinA injections significantly reduced upper limb spasticity in children with cerebral palsy. Children treated with abobotulinumtoxinA and targeted home exercises showed global improvement and goal attainment. Benefits were sustained over 1 year with repeat cycles of abobotulinumtoxinA and home exercises. AbobotulinumtoxinA injections into the upper limb were well tolerated over 1 year.

Liquid Formulation of AbobotulinumtoxinA: A 6-Month, Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of a Single Treatment, Ready-to-Use Toxin for Moderate-to-Severe Glabellar Lines.

BACKGROUND: Safety and efficacy of botulinum toxin A for glabellar line (GL) treatment are well established. Currently approved formulations require reconstitution before injection. OBJECTIVES: The authors sought to assess 6-month efficacy, safety, and patient satisfaction of new ready-to-use abobotulinumtoxinA solution for injection (ASI) in patients with moderate-to-severe GL at maximum frown. METHODS: The authors conducted a phase 3, double-blind, randomized, placebo-controlled trial (NCT02353871). Patients (N = 185) were randomized (2:1) to receive ASI 50 U or placebo. GL severity was evaluated at days 8, 15, 29, 57, 85, 113, 148, and 183 employing a 4-point scale for investigator's live assessment (ILA) and subject's self-assessment (SSA). Primary endpoint was ILA of GL at maximum frown at day 29, and secondary endpoints were ILA and SSA of GL at maximum frown (all time points), patient satisfaction with GL appearance, time to onset, and duration of action. RESULTS: Responder rates were significantly higher for ASI vs placebo (88.3% vs 1.4%; P < 0.0001) at day 29 by ILA and all time points by ILA (P < 0.0001-0.0441) and SSA (P < 0.0001-0.0036). Sixty percent of patients reported onset of treatment response on or before day 3 (P < 0.0001 vs placebo), and in 5% of patients, efficacy by ILA lasted 6 months (day 183; P = 0.0441 vs placebo). Patient satisfaction rates were significantly higher for ASI vs placebo at all visits (P < 0.0001). Safety was comparable with the known abobotulinumtoxinA profile. CONCLUSIONS: ASI was significantly efficacious for improving moderate or severe GL vs placebo by investigator and patient assessment. ASI was associated with high patient satisfaction, a long duration of action, and comparable safety profile to abobotulinumtoxinA.

Significantly Increased Patient Satisfaction Following Liquid Formulation AbobotulinumtoxinA Treatment in Glabellar Lines: FACE-Q Outcomes From a Phase 3 Clinical Trial.

BACKGROUND: The FACE-Q patient-reported outcome assesses patient experiences/outcomes with aesthetic facial procedure. A recent trial of abobotulinumtoxinA (ASI, liquid formulation) was the first to our knowledge to assess satisfaction with FACE-Q after glabellar line (GL) injection. OBJECTIVES: The authors sought to evaluate patient satisfaction with ASI for GL treatment employing 3 FACE-Q scales: facial appearance, psychological well-being, and aging appearance. METHODS: This was a Phase 3, randomized, double-blind, placebo-controlled trial (NCT02353871) of ASI 50 units in adults with moderate-to-severe GL with 6-month follow-up. RESULTS: Significantly greater least squares mean changes from baseline were associated with ASI treatment (N = 125) vs placebo (N = 59) for satisfaction with facial appearance at all visits until day 148 (5 months; P < 0.0001-0.0037), psychological well-being at all visits (P < 0.0001-0.0279), and aging appearance at all visits except day 148 (P < 0.0001-0.0409). Significant differences (ASI vs placebo) were observed at all visits for individual items: "how rested your face looks" (P < 0.0001-0.0415), "I feel okay about myself" (P = 0.0011-0.0399), and "I feel attractive" (P < 0.0001-0.0102). Maximal least squares mean (standard error) changes in aging appearance score were -1.4 (0.3; ASI) and -0.3 (0.4; placebo). Investigators' live assessment of GL at maximum frown significantly correlated with improvements in FACE-Q facial appearance and psychological scales (all patients: r = -0.41 and r = -0.36 [both P < 0.0001], respectively). CONCLUSIONS: Significant improvements in patient satisfaction with aging, facial appearance, and, importantly, psychological well-being were demonstrated with ASI employing FACE-Q scales up to 5 to 6 months post-injection. Results support a long duration of efficacy with ASI and use of FACE-Q in future trials and clinical practice.

Effects of repeated abobotulinumtoxinA injections in upper limb spasticity.

INTRODUCTION: The efficacy of single injections of abobotulinumtoxinA (Dysport) is established in adults with upper limb spasticity. In this study we assessed the effects of repeated injections of abobotulinumtoxinA over 1 year. METHODS: Patients (n = 258, safety population) received 500 U, 1,000 U, or 1,500 U (1,500-U dose included 500-U shoulder injections) for up to 4 or 5 treatment cycles. Assessments included treatment-emergent adverse events (TEAEs), muscle tone, passive and active range of motion (XV1, XA ), angle of catch (XV3 ), Disability Assessment Scale (DAS) score, Modified Frenchay Scale (MFS) score, and Physician Global Assessment (PGA) score. RESULTS: The incidence of TEAEs decreased across cycles. Muscle tone reduction and XV1 remained stable across cycles, whereas XV3 and XA continued to improve at the finger, wrist, and elbow flexors. DAS and PGA improved across cycles. MFS improved best with 1,500 U. DISCUSSION: A favorable safety profile and continuous improvements in active movements and perceived and active function were associated with repeated abobotulinumtoxinA injections in upper limb muscles. Muscle Nerve 57: 245-254, 2018.

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.

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.

Efficacy and safety of two administration modes of an intra-detrusor injection of 750 units dysport® (abobotulinumtoxinA) in patients suffering from refractory neurogenic detrusor overactivity (NDO): A randomised placebo-controlled phase IIa study.

AIMS: Assess the efficacy and safety of abobotulinumtoxinA (Dysport®) in adult patients with neurogenic detrusor overactivity (NDO). METHODS: This Phase IIa, international, multicentre, double-blind, randomised, placebo controlled, pilot study enrolled 47 patients with NDO and urinary incontinence resulting from spinal cord injury (SCI) or multiple sclerosis (MS). Patients were treated with 15 intra-detrusor injections of Dysport 750 U or the equivalent placebo (n = 16 and 7) or 30 injections of Dysport 750 U or the equivalent placebo (n = 17 and 7). Primary endpoint was change from baseline in mean number of daily incontinence episode frequency (IEF) at day 84. Secondary endpoints included change from baseline in urodynamic parameters and quality of life (QOL). A safety assessment was also conducted. RESULTS: Adjusted mean changes from baseline in IEF were -3.2 (-76%) and -1.7 (-15%) for 15 injections Dysport and placebo groups, respectively, (P = 0.1103) and -3.2 (-88%) and -2.6 (-73%) for 30 injections Dysport and placebo groups, respectively, (P = 0.0686). Statistically significant improvements in maximum cystometric capacity, maximum detrusor pressure and volume at first contraction were reported in the Dysport groups compared with placebo (P < 0.05). Improvements in QOL were reported. Three muscle weakness episodes were reported as serious adverse events in two tetraplegic and one paraplegic patient, all in the 15 injections Dysport group. CONCLUSIONS: Both 15 and 30 injections administration modes of Dysport decreased daily IEF and resulted in significant improvements in urodynamic parameters in NDO patients with MS or SCI. Reduction to 15 injection sites did not appear to be associated with any impact on efficacy. Neurourol. Urodynam. 36:457-462, 2017. © 2016 Wiley Periodicals, Inc.

Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial.

BACKGROUND: Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. OBJECTIVES: The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. METHODS: This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores. RESULTS: At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. CONCLUSIONS: Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

AbobotulinumtoxinA (Dysport) dosing in cervical dystonia: an exploratory analysis of two large open-label extension studies.

Treatment with botulinum toxin-A is recommended as first-line treatment for cervical dystonia (CD). In clinical practice many factors appear to influence dose adjustment and the retreatment regimen; however, there is little information available in the literature regarding the evolution of dosing over treatment cycles. We report on two similarly designed, long-term, multicenter, open-label extension studies of Dysport for the treatment of CD, which followed 500 U fixed-dose placebo-controlled trials. Both studies specified a fixed 500 U dose for the first open-label treatment cycle, with dose adjustment in subsequent treatment cycles according to the clinical response. These analyses include 218 patients who entered the two studies; doses in the subsequent treatment cycles ranged between 250 and 1,000 U. During open-label treatment, all treatment cycles resulted in improvements in mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores. However, increasing the dose of Dysport above the initial 500 U dose was not observed to result in an incremental improvement in response as measured by the TWSTRS. No individual patient characteristic was found to reliably predict the use of higher doses at each treatment cycle. Dysport was generally well tolerated with no major differences in the incidence of adverse events (AEs) observed with different doses. Dysphagia was considered an AE of special interest and dysphagia data from the open-label studies were combined with two Phase II studies. Analysis of this enhanced database indicates that unilateral injections of >150 U into the sternocleidomastoid muscle is associated with a higher dysphagia risk. Thus, limiting the dose in the sternocleidomastoid may help reduce the incidence of dysphagia.

Immunoresistance in cervical dystonia patients after treatment with abobotulinumtoxinA.

Formation of antibodies against botulinum toxin type A has been observed following treatment of Cervical Dystonia (CD). We present the immunological findings from two 12-week Phase III prospective, randomized, double-blind, single-dose, placebo-controlled studies (Study 1, n = 116; Study 2, n = 136). Patients in both studies were administered abobotulinumtoxinA 500U or placebo intramuscularly at baseline. Patients could receive up to three or four additional treatments (250-1000U) in an open-label follow-up period. Blood samples were collected at baseline and during treatment to test for antibodies to abobotulinumtoxinA using a radioimmunoprecipitation assay (Study 2 only) and a mouse protection assay. Loss of response was predefined using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score at 4 weeks following injection. No subjects in Study 1 and one individual in Study 2 developed neutralizing antibodies (nABs) during the double-blind treatment phase; the individual who developed immunoresistance had received botulinum toxin type A treatment prior to the study and did not respond to treatment. Two subjects demonstrated a change in nAB status during open-label treatment and overall responsiveness was maintained in these patients. In conclusion, the development of immunoresistance was rare and, in the presence of circulating nABs, patients may still gain benefit from intramuscular abobotulinumtoxinA treatment.

When can maximal efficacy occur with repeat botulinum toxin injection in upper limb spastic paresis?

Repeated injection cycles with abobotulinumtoxinA, a botulinum toxin type A, are recommended in current clinical guidelines as a treatment option for adults with upper limb spastic paresis. However, the magnitude of the maximal therapeutic effect of repeated abobotulinumtoxinA treatment across different efficacy parameters and the number of injection cycles required to reach maximal effect remain to be elucidated. Here, we present a post hoc exploratory analysis of a randomized, double-blind, placebo-controlled trial (12-24 weeks; NCT01313299) and open-label extension study (up to 12 months; NCT0131331), in patients aged 18-80 years with hemiparesis for ≥6 months after stroke/traumatic brain injury. Two inferential methods were used to assess the changes in efficacy parameters after repeat abobotulinumtoxinA treatment cycles: Mixed Model Repeated Measures analysis and Non-Linear Random Coefficients analysis. Using the latter model, the expected maximal effect size (not placebo-controlled) and the number of treatment cycles to reach 90% of this maximal effect were estimated. Treatment responses in terms of passive and perceived parameters (i.e. modified Ashworth scale in primary target muscle group, disability assessment scale for principal target for treatment or limb position, and angle of catch at fast speed) were estimated to reach near-maximal effect in two to three cycles. Near-maximal treatment effect for active parameters (i.e. active range of motion against the resistance of extrinsic finger flexors and active function, assessed by the Modified Frenchay Scale) was estimated to be reached one to two cycles later. In contrast to most parameters, active function showed greater improvements at Week 12 (estimated maximal change from baseline-modified Frenchay Scale overall score: +0.8 (95% confidence interval, 0.6; 1.0) than at Week 4 (+0.6 [95% confidence interval, 0.4; 0.8]). Overall, the analyses suggest that repeated treatment cycles with abobotulinumtoxinA in patients chronically affected with upper limb spastic paresis allow them to relearn how to use the affected arm with now looser antagonists. Future studies should assess active parameters as primary outcome measures over repeated treatment cycles, and assess efficacy at the 12-week time-point of each cycle, as the benefits of abobotulinumtoxinA may be underestimated in the studies of insufficient duration. Abbreviated summary In this post hoc analysis of repeated abobotulinumtoxinA injection cycles in upper limb spastic paresis, Gracies et al. used statistical modelling to elucidate the maximal therapeutic effect of abobotulinumtoxinA. Notably, the number of injections required to reach this maximal effect was higher for active (e.g. active function) compared with passive (e.g. tone) parameters.

The Effect of Repeated abobotulinumtoxinA (Dysport®) Injections on Walking Velocity in Persons with Spastic Hemiparesis Caused by Stroke or Traumatic Brain Injury.

BACKGROUND: Botulinum toxin (BoNT) injections were shown to improve muscle tone of limbs in patients with spasticity. However, limited data are available regarding the effects of repeated BoNT injections on walking ability. OBJECTIVE: To assess changes in walking velocity (WV), step length, and cadence under different test conditions after repeated treatment with abobotulinumtoxinA (aboBoNT-A; Dysport) in spastic lower limb muscles. DESIGN: Secondary analysis of an open-label, multiple-cycle extension (National Clinical Trials number NCT01251367) to a phase III, double-blind, randomized, placebo-controlled, single-treatment cycle study, in adults with chronic hemiparesis (NCT01249404). SETTING: Fifty-two centers across Australia, Belgium, the Czech Republic, France, Hungary, Italy, Poland, Portugal, Russia, Slovakia, and the United States. PATIENTS: 352 Ambulatory adults (18-80 years) with spastic hemiparesis and gait dysfunction caused by stroke or traumatic brain injury, with a comfortable barefoot WV of 0.1 to 0.8 m/s. INTERVENTIONS: Up to four aboBoNT-A treatment cycles, administered to spastic lower limb muscles. MAIN OUTCOME MEASUREMENTS: Changes from baseline in comfortable and maximal barefoot and with shoes WV (m/s), step length (m/step), and cadence (steps/minutes). RESULTS: At Week 12 after four injections, WV improved by 0.08 to 0.10 m/s, step length by 0.03 to 0.04 m/step, and cadence by 3.9 to 6.2 steps/minutes depending on test condition (all P < .0001 to .0003 vs baseline). More patients (7% to 17%) became unlimited community ambulators (WV ≥0.8 m/s) across test conditions compared with baseline, with 39% of 151 patients classified as unlimited community ambulators in at least one test condition and 17% in all four test conditions. CONCLUSIONS: Clinically meaningful and statistically significant improvements in WV, step length, and cadence under all four test conditions were observed in patients with spastic hemiparesis after each aboBoNT-A treatment cycle.

Histomorphology and vascular lesions in dorsal rat skin used as injection sites for a subcutaneous toxicity study.

Subcutaneous injection of pharmaceutical compounds into the dorsal skin of rats is common in preclinical and nonclinical studies. However, no detailed histologic description of this anatomic location has been published to date. Following the observation of vascular lesions in the dorsum of rats in a thirteen-week toxicity study, a complementary study was performed on untreated Sprague-Dawley rats to evaluate the normal histology of the skin and subcutis, the potential effect of chronic subcutaneous injection on the morphology of the skin and its vasculature, and the spontaneous vascular pathology in the areas used as injection sites in the principal study. This study showed that saline injection did not fundamentally alter the morphology of the injection sites used for the principal study. Skin thickness was greater in males than in females. Although acellular intimal thickening occurred spontaneously in the dorsal skin of untreated males and females, only males had a spontaneous incidence of intimal hyperplasia. No site predilection for intimal lesions was apparent for either sex. Saline injection, or the physical trauma of injection, may induce intimal hyperplasia; males appear more likely to develop the lesion than do females. It is possible that acellular intimal thickening can progress to intimal hyperplasia under appropriate conditions.

Abobotulinumtoxina injections in shoulder muscles to improve adult upper limb spasticity: Results from a phase 4 real-world study and a phase 3 open-label trial.

Botulinum toxins, such as abobotulinumtoxinA, are used to treat spasticity (muscle overactivity) in arm muscles. Spasticity in shoulder muscles occurs in many patients following a stroke. Shoulder spasticity can be painful and limit limb movement. This paper compares the results from patients who did and those who did not receive abobotulinumtoxinA injections in shoulder muscles (among other arm muscles) in 2 studies. In both studies, the results showed that more patients receiving treatment in shoulder muscles chose pain as a key goal for treatment and had reduced pain following treatment compared with patients not treated in the shoulder. In addition, patients receiving shoulder injections showed further improvement in arm movement compared with those not receiving shoulder injections. Overall, these results suggest that abobotulinumtoxinA treatment in shoulder muscles may improve outcomes for patients with arm spasticity involving the shoulder.

Duration of Symptom Relief Between Injections for AbobotulinumtoxinA (Dysport®) in Spastic Paresis and Cervical Dystonia: Comparison of Evidence From Clinical Studies.

Background: Botulinum toxin-A is a well-established treatment for adult and pediatric spastic paresis and cervical dystonia. While guidelines and approved labels indicate that treatment should not occur more frequently than every 12 weeks, studies and real-world evidence show that the timing of symptom recurrence between treatments may vary. Methods: We report retreatment criteria and response duration (retreatment intervals) from four pivotal, double-blind, placebo-controlled studies with open-label extensions involving patients treated with abobotulinumtoxinA (aboBoNTA) for upper limb (NCT01313299) or lower limb (NCT01249404) spastic paresis in adults, lower limb spastic paresis in children (NCT01249417), and cervical dystonia in adults (NCT00257660). We review results in light of recently available preclinical data. Results: In spastic paresis, 24.0-36.9% of upper limb patients treated with aboBoNTA and 20.1-32.0% of lower limb patients did not require retreatment before 16 weeks. Moreover, 72.8-93.8% of aboBoNTA-treated pediatric patients with lower limb spastic paresis did not require retreatment before 16 weeks (17.7-54.0% did not require retreatment before 28 weeks). In aboBoNTA-treated patients with cervical dystonia, 72.6-81.5% did not require retreatment before 16 weeks. Conclusion: AboBoNTA, when dosed as recommended, offers symptom relief beyond 12 weeks to many patients with spastic paresis and cervical dystonia. From recently available preclinical research, the amount of active neurotoxin administered with aboBoNTA might be a factor in explaining this long duration of response.

Efficacy and Safety of AbobotulinumtoxinA for the Treatment of Hemiparesis in Adults with Lower Limb Spasticity Previously Treated With Other Botulinum Toxins: A Secondary Analysis of a Randomized Controlled Trial.

OBJECTIVE: To examine the safety and efficacy of abobotulinumtoxinA in patients previously treated with botulinum toxin type A (BoNT-A) products other than abobotulinumtoxinA. DESIGN: Secondary analysis from a phase 3, double-blind, single-cycle, randomized, placebo-controlled study. SETTING: Fifty-two centers (11 countries). PATIENTS: Adults with spastic hemiparesis were randomized (1:1:1) to receive abobotulinumtoxinA 1000 U, 1500 U, or placebo in their affected lower limb. MAIN OUTCOME MEASUREMENTS: Muscle tone (6-point Modified Ashworth Scale [MAS], 0-5) for the gastrocnemius-soleus complex (GSC); proportion of MAS responders (≥1-point improvement); angle of catch (XV3 ) and spasticity grade (Y) for the GSC and soleus. Assessments were at weeks 1, 4, and 12 post-injection. Only descriptive statistics are presented. RESULTS: Of 388 patients, 84 received previous BoNT-A treatment (abobotulinumtoxinA 1000 U: N = 30; abobotulinumtoxinA 1500 U: N = 28; placebo: N = 26). At week 4, mean (SD) changes in MAS score in the GSC were - 0.8 (1.1), -0.9 (1.0), and - 0.4 (0.7) for abobotulinumtoxinA 1000 U, 1500 U, and placebo, respectively. Greater MAS responder rates were observed for abobotulinumtoxinA versus placebo at all time points. Mean (SD) changes (week 4) for abobotulinumtoxinA 1000 U, 1500 U, and placebo for XV3 were: GSC, 8° (21), 6° (10) and 1° (7); soleus, 11° (21), 5° (9) and 0° (8), respectively; for Y: GSC, -0.4 (0.7), -0.6 (0.8) and - 0.0 (0.9); soleus, -0.5 (0.7), -0.5 (0.7) and - 0.1 (0.6), respectively. Safety data and adverse events were consistent with the overall known profile of abobotulinumtoxinA. CONCLUSIONS: Patients previously treated with other BoNT-As showed improved muscle tone and spasticity at week 4 following abobotulinumtoxinA injection versus placebo. These findings suggest that abobotulinumtoxinA, at the recommended doses, has a good safety and efficacy profile in adults with lower limb spasticity who were previously treated with other BoNT-A products.