AIM OF THE STUDY:SPACE, a prospective, non-interventional, open-label, multinational study, investigated physicians' and subjects' assessment of safety, efficacy, and health-related quality of life (HRQoL) following botulinum neurotoxin type A (BoNT-A) treatment to understand real-world clinical usage for the management of focal and multifocal spasticity.CLINICAL RATIONALE FOR THE STUDY:Treatment guidelines recommend the use of BoNT-A for the management of spasticity in adults. This study assessed how physicians use BoNT-A therapy in real-world clinical practice, and provided evidence on long-term safety and efficacy over a period of up to 2 years.MATERIALS AND METHODS:BoNT treatment-naïve adults with spasticity of any aetiology received any BoNT-A formulation at their physician's discretion, and were observed for ≤ 8 treatment cycles (≤ 2 years). Daily practice information, physician's global assessments of tolerability and efficacy, and HRQoL were documented. Incidences of adverse drug reactions or all adverse events were documented for non-Mexican subjects and for Mexican subjects, respectively, due to protocol differences based on local regulatory requirements.RESULTS:A total of 701 subjects were enrolled (safety population; nine countries). Physicians rated the tolerability of BoNT-A as 'very good' or 'good' for 88.2-97.4% of subjects throughout the study (subject numbers declined throughout this non-interventional study). Adverse drug reactions were reported for 16/600 (2.7%) of the non-Mexican subjects, with two considered to be 'definitely related' to treatment (injection-site haematoma, n = 1; botulism, n = 1). For 687 subjects, efficacy was rated 'very good' or 'good' by most physicians and subjects. Improvements in HRQoL were observed.CONCLUSIONS AND CLINICAL IMPLICATIONS:Throughout this 2-year study, BoNT-A treatment was generally well-tolerated, effective, and associated with an improved HRQoL. This study makes a valuable contribution to the broader understanding of how physicians use BoNT-A therapy to manage spasticity in real-world clinical practice.

Abstract Background We evaluated quality of life among subjects with upper- and lower-limb spasticity who received escalating doses of incobotulinumtoxinA (total body doses up to 800 U) in the prospective, single-arm, dose-titration TOWER study. Methods In this exploratory trial, subjects (N = 155; 18–80 years of age) with upper- and lower-limb spasticity due to cerebral causes who were deemed to require total body doses of up to 800 U incobotulinumtoxinA received three consecutive injection cycles of incobotulinumtoxinA (400, 600, and up to 800 U), each with 12 to 16 weeks’ follow-up. QoL was assessed using the EuroQol 5-dimensions questionnaire, three-level (EQ-5D), before and 4 weeks post-injection in each injection cycle and at the end of injection cycle 3. Results The mean EQ-5D visual analog scale scores of 155 participants continuously improved from study baseline to 4 weeks post-injection in all injection cycles (mean [standard deviation] change 6.7 [14.1], 9.6 [16.3], and 8.6 [17.0] for injection cycles 1, 2, and 3, respectively; p < 0.0001 for all, paired sample t-test). In general, among those with a change in the EQ-5D rating of their condition, the proportion of subjects with ‘improvement’ was greater than that with ‘worsening’ for individual EQ-5D dimensions across all injection cycles. At the end of injection cycle 3, the proportion of subjects rating their condition as ‘normal’ increased from study baseline for all dimensions, and there was a ≥ 46% reduction in the proportion of subjects with a rating of ‘severe impairment’. Conclusion These preliminary results suggest that escalating incobotulinumtoxinA doses up to 800 U are associated with improvement in quality of life ratings in subjects with multifocal upper- and lower-limb spasticity, and form a basis for future comparator studies. Trial registration ClinicalTrials.gov, NCT01603459 . Date of registration: May 22, 2012.

Objective: In this post-hoc analysis, the effectiveness of incobotulinumtoxinA for treating key clinical patterns of lower limb (LL) spasticity (eg, pes equinovarus) is assessed. Background: Botulinum toxin A formulations, including incobotulinumtoxinA, have been shown to be safe and effective for the treatment of upper limb (UL) spasticity. Design/Methods: In the TOWER study (NCT01603459), escalating fixed total doses of incobotulinumtoxinA (400, 600 and 600­–800U, respectively) were used to treat 155 adult subjects (18–80 years) with UL and LL spasticity. Muscle tone was assessed using the Ashworth Scale (AS); additional outcome measures included AS responder rates (defined as patients with ≥1 point improvement at 4-weeks) and Resistance to Passive Movement Scale (REPAS) Results: In treatment cycle 1, 109 subjects received LL treatment for any clinical pattern. Pes equinovarus was the most frequently treated pattern (N=100); however, a total of 9 different LL clinical patterns were treated during the study. The mean ± standard deviation [SD] dose for pes equinovarus was 166.3±94.9 U during the first cycle. At the 4-week follow-up visit, the mean improvement (± SD) in ankle joint AS score was −0.63±0.76 in subjects treated for pes equinovarus and −0.16±0.63 in subjects not treated for this pattern. A significant effect of pes equinovarus dose on AS improvement was revealed using multiple regression analysis, adjusting for AS baseline value ( P =0.0096). AS responder rates were 55.0% in treated subjects and 12.7% in untreated subjects ( P P =0.0022). Conclusions: Results support the safety and effectiveness of incobotulinumtoxinA for the treatment of LL spasticity. Study Supported by: Merz Pharmaceuticals GmbH Disclosure: Dr. Simpson has received personal compensation for activities with Merz, Allergan, Ipsen, Endo, Insys, MundiPharma, Takeda, and Teva CNS as a consultant. Dr. Wissel has received personal compensation for activities with Allergan, Ipsen, Merz, and Medtronic. Dr. Bensmail has received personal compensation for activities with Medtronic, Allergan, Ipsen, Merz, and Almirall as a consultant, member of a scientific advisory board, a speaker or other activities. Dr. Scheschonka has received personal compensation for activities with Merz as an employee. Dr. Faltau-Baque has received personal compensation for activities with Merz as an employee. Dr. Simon has received personal compensation for activities with Merz Pharmaceuticals as an employee.

Objective: The Titration study in IOWer and uppER-limb spasticity (TOWER) study (NCT01603459), evaluated incobotulinumtoxinA for upper- and lower-limb spasticity. This post hoc analysis assessed shoulder spasticity in patients who received injections into the shoulder. Methods: Subjects received 3 injection cycles with escalating incobotulinumtoxinA doses on the same side (400, 600, 600-800 U; <= 600 U per limb including optional shoulder dose, planned range 100-250 U). Joint function was assessed with the Ashworth Scale shoulder sumscore (AS-SSS) in subjects treated in the shoulder vs those who were not. Safety was assessed in subjects treated in the shoulder, and in those who had upper-limb treatment without shoulder treatment. Results: The proportion of subjects receiving shoulder treatment increased with escalating dose at each cycle (n= 84/140 (60.0%) by cycle 3; mean (standard deviation (SD)) shoulder dose 118.4 U (SD 60.2)). From baseline to 4-weeks post-injection, mean AS-SSS improved by -1.1 (SD 1.9), -1.7 (SD 1.8) and -1.7 (1.8) in cycles 1, 2 and 3, respectively, in subjects treated in the shoulder, and -0.5 (SD 1.3), -0.8 (SD 1.6) and -0.9 (SD 1.4) in subjects who were not. A significant dose effect on AS-SSS was observed in cycle 3 (p = 0.0081). No unexpected safety concerns were reported. Conclusion: The results demonstrate an improvement in shoulder spasticity and safety following incobotulinumtoxinA treatment.

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.

Effective treatment of disabling, multifocal upper- and/or lower limb spasticity may require botulinum neurotoxin doses higher than those indicated currently. TOWER (NCT01603459) previously investigated the safety and efficacy of escalating incobotulinumtoxinA doses (400– ≤ 800U) in adults with upper- and lower limb spasticity due to stroke or other cerebral causes (Wissel. Neurology, 2017). Here, we report further data regarding the impact of escalating doses on multi-pattern treatment and muscle dosing. Treatment comprised three injection cycles (ICs) with escalating total doses on the same body side, each followed by 12–16 weeks' observation: IC1, 400U into the upper limb and/or lower limb; IC2, 600U into the upper limb and/or lower limb; and IC3, 600–800U into the upper and lower limbs (maximum 600U per limb). At screening, investigators selected a target clinical pattern for treatment in all ICs. Other patterns were treated at the investigator's discretion. In total, 155 patients (mean [SD] age, 53.7 [13.1] years) were enrolled, with spasticity due to stroke (85.2%) or other cerebral causes (14.8%). The number of clinical patterns and muscles treated increased with escalating dose at each IC. In IC1, IC2 and IC3, respectively, 608, 743 and 811 clinical patterns and 46, 49 and 53 different muscles were treated in 155, 152 and 140 patients. The number of patients treated for the most frequently injected clinical patterns in the upper (flexed elbow) and lower limb (pes equinovarus), respectively, increased from 75.5% and 56.8% of patients in IC1 to 88.6% and 87.1% in IC3. Escalating incobotulinumtoxinA doses enabled a more comprehensive multi-pattern treatment approach, with an increase of approximately 33% in clinical patterns and more muscles treated with the highest dose (600–800U) versus the initial dose (400U) in patients with upper- and lower limb spasticity.

To evaluate the efficacy and safety of incobotulinumtoxinA to treat shoulder spasticity using a post-hoc analysis.

Objective: To evaluate safety (primary objective) and efficacy of increasing doses (400 U up to 800 U) of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) for patients with limb spasticity.Methods: In this prospective, single-arm, dose-titration study (NCT01603459), patients (18-80 years) with spasticity due to cerebral causes, who were clinically deemed to require total doses of 800 U incobotulinumtoxinA, received 3 consecutive injection cycles (ICs) with 400 U, 600 U, and 600-800 U incobotulinumtoxinA, respectively, each followed by 12-16 weeks' observation. Outcomes included adverse events (AEs), antibody testing, Resistance to Passive Movement Scale (REPAS; based on the Ashworth Scale), and Goal Attainment Scale.Results: In total, 155 patients were enrolled. IncobotulinumtoxinA dose escalation did not lead to an increased incidence of treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). No treatment-related serious AEs occurred. The most frequent AEs overall were falls (7.7%), nasopharyngitis, arthralgia, and diarrhea (6.5% each). Five patients (3.2%) discontinued due to AEs. No patient developed secondary nonresponse due to neutralizing antibodies. Mean (SD) REPAS score improvements from each injection to 4 weeks postinjection increased throughout the study (IC1: -4.6 [ 3.9]; IC2: -5.9 [ 4.2]; IC3: -7.1 [ 4.8]; p, 0.0001 for all). The proportion of patients achieving >= 3 (of 4) treatment goals also increased (IC1: 25.2%; IC2: 50.7%; IC3: 68.6%).Conclusion: Escalating incobotulinumtoxinA doses (400 U up to 800 U) did not compromise safety or tolerability, enabled treatment in a greater number ofmuscles/spasticity patterns, and was associated with increased treatment efficacy, improved muscle tone, and goal attainment.

April 18, 2016April 5, 2016Free AccessEscalating Doses of IncobotulinumtoxinA (400U-800U) Lead to Increasing Improvements in Disability Due to Multifocal Upper- and Lower-Limb Spasticity (P3.295)David Simpson, Djamel Bensmail, Bruce Rubin, Astrid Scheschonka, Olivier Simon, and Jörg WisselAuthors Info & AffiliationsApril 5, 2016 issue86 (16_supplement)https://doi.org/10.1212/WNL.86.16_supplement.P3.295 Letters to the Editor

PM&RVolume 8, Issue 9S p. S281-S281 Neurological Rehabilitation Poster 370 An International, Observational Study of Botulinum Toxin Type A in Spasticity – SPAsticity in PractiCE (SPACE) Jörg Wissel MD, FRCP, Jörg Wissel MD, FRCPSearch for more papers by this authorJulian P. Harriss MD, MS, Julian P. Harriss MD, MSSearch for more papers by this authorOlivier Simon MD, Olivier Simon MDSearch for more papers by this authorKati Sternberg Dr, Kati Sternberg DrSearch for more papers by this authorNicolas Roche MD, PhD, Nicolas Roche MD, PhDSearch for more papers by this authorCarlos Cantú-Brito MD, PhD, Carlos Cantú-Brito MD, PhDSearch for more papers by this authorSvetlana E. Khatkova MD, PHD, Svetlana E. Khatkova MD, PHDSearch for more papers by this authorPatrik Säterö MD, Patrik Säterö MDSearch for more papers by this author Jörg Wissel MD, FRCP, Jörg Wissel MD, FRCPSearch for more papers by this authorJulian P. Harriss MD, MS, Julian P. Harriss MD, MSSearch for more papers by this authorOlivier Simon MD, Olivier Simon MDSearch for more papers by this authorKati Sternberg Dr, Kati Sternberg DrSearch for more papers by this authorNicolas Roche MD, PhD, Nicolas Roche MD, PhDSearch for more papers by this authorCarlos Cantú-Brito MD, PhD, Carlos Cantú-Brito MD, PhDSearch for more papers by this authorSvetlana E. Khatkova MD, PHD, Svetlana E. Khatkova MD, PHDSearch for more papers by this authorPatrik Säterö MD, Patrik Säterö MDSearch for more papers by this author First published: 24 September 2016 https://doi.org/10.1016/j.pmrj.2016.07.297Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume8, Issue9S2016 AAPM&R Annual Assembly AbstractsSeptember 2016Pages S281-S281 RelatedInformation

OBJECTIVE:This educational paper aims to describe, in adult patients, the different aspects of muscle overactivity after a central nervous system lesion, including spasticity, spastic dystonia and spastic co-contraction, the assessment of their symptoms and consequences, and therapeutic options.DISCUSSION AND CONCLUSION:Clinical evaluation involves the assessment of passive range of motion, angle of catch or clonus, active range of motion, rapid alternating movements and functional consequences. A number of scales have been developed to assess patients with spastic paresis, involving both patient and caregivers. Not all persons with spasticity require treatment, which is considered only when muscle overactivity is disabling or problematic. A list of personal objectives may be proposed for each patient, which will drive assessment and treatment. Prior to treatment the patient must be informed of the intended benefits and possible adverse events. Clinical evaluation may be supported by the use of transient neuromuscular blocks and/or instrumental analysis. Physical therapies usually represent the mainstay of treatment. Self-rehabilitation with stretching and active exercises, intramuscular injections of botulinum toxin, alcohol or phenol injections, oral or intrathecal drugs, and surgery comprise the treatment options available to the clinician. Follow-up must be scheduled in order to assess the benefits of treatment and possible adverse events.