Modelling Long-Term Outcomes and Risk of Death for Patients with Post-Stroke Spasticity Receiving Abobotulinumtoxina Treatment and Rehabilitation Therapy.

OBJECTIVE: Stroke is associated with a high risk of death and cardiovascular events. Rehabilitation therapy is critical for functional recovery, to reduce hospital readmissions, all-cause and cardiovascular mortality, and stroke recurrence (long-term outcomes). Post-stroke spasticity may prevent effective recovery by restricting mobility. AbobotulinumtoxinA is an adjunctive therapy to physical therapy for post-stroke spasticity, but its long-term effects are unknown. The objective was to model the long-term clinical and economic outcomes of abobotulinumtoxinA for post-stroke spasticity. METHODS: Effects of abobotulinumtoxinA on treating post-stroke spasticity and evidence linking functional outcomes with long-term outcomes were collected in a focused literature review. A model was developed to estimate health benefits on long-term outcomes, direct medical costs, life- and qualityadjusted life-years for abobotulinumtoxinA injections plus rehabilitation therapy compared with rehabilitation therapy alone, from a UK perspective over a 10-year time-period. RESULTS: AbobotulinumtoxinA + rehabilitation therapy led to a risk reduction of 8.8% for all-cause mortality, and an increase of 13% in life-years and 59% in quality-adjusted life-years compared with rehabilitation therapy alone. AbobotulinumtoxinA + rehabilitation therapy was considered cost-effective compared with rehabilitation therapy alone (incremental cost-effectiveness ratio: £24,602). CONCLUSION: AbobotulinumtoxinA + rehabilitation therapy may improve long-term outcomes, including post-stroke survival, while being cost-effective for the treatment of post-stroke spasticity.

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.

Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis.

OBJECTIVE: The aim of this study is to evaluate a novel composite measure of active range of motion (XA) and determine whether this measure correlates with active function. DESIGN: Post hoc analysis of two randomized, placebo-controlled, double-blind studies with open-label extensions exploring changes in active function with abobotulinumtoxinA. SETTING: Tertiary rehabilitation centers in Australia, Europe, and the United States. SUBJECTS: Adults with upper (n = 254) or lower (n = 345) limb spastic paresis following stroke or brain trauma. INTERVENTIONS: AbobotulinumtoxinA (⩽5 treatment cycles) in the upper or lower limb. MAIN MEASURES: XA was used to calculate a novel composite measure (CXA), defined as the sum of XA against elbow, wrist, and extrinsic finger flexors (upper limb) or soleus and gastrocnemius muscles (lower limb). Active function was assessed by the Modified Frenchay Scale and 10-m comfortable barefoot walking speed in the upper limb and lower limb, respectively. Correlations between CXA and active function at Weeks 4 and 12 of open-label cycles were explored. RESULTS: CXA and active function were moderately correlated in the upper limb (P < 0.0001-0.0004, r = 0.476-0.636) and weakly correlated in the lower limb (P < 0.0001-0.0284, r = 0.186-0.285) at Weeks 4 and 12 of each open-label cycle. Changes in CXA and active function were weakly correlated only in the upper limb (Cycle 2 Week 12, P = 0.0160, r = 0.213; Cycle 3 Week 4, P = 0.0031, r = 0.296). Across cycles, CXA improvements peaked at Week 4, while functional improvements peaked at Week 12. CONCLUSION: CXA is a valid measure for functional impairments in spastic paresis. CXA improvements following abobotulinumtoxinA injection correlated with and preceded active functional improvements.

Early AbobotulinumtoxinA (Dysport®) in Post-Stroke Adult Upper Limb Spasticity: ONTIME Pilot Study.

The ONTIME study investigated whether early post-stroke abobotulinumtoxinA injection delays appearance or progression of upper limb spasticity (ULS) symptoms. ONTIME (NCT02321436) was a 28-week, exploratory, double-blind, randomized, placebo-controlled study of abobotulinumtoxinA 500U in patients with ULS (Modified Ashworth Scale [MAS] score ≥ 2) 2⁻12 weeks post-stroke. Patients were either symptomatic or asymptomatic (only increased MAS) at baseline. Primary efficacy outcome measure: time between injection and visit at which re-injection criteria were met (MAS ≥ 2 and ≥1, sign of symptomatic spasticity: pain, involuntary movements, impaired active or passive function). Forty-two patients were randomized (abobotulinumtoxinA 500U: n = 28; placebo: n = 14) with median 5.86 weeks since stroke. Median time to reach re-injection criteria was significantly longer for abobotulinumtoxinA (156 days) than placebo (32 days; log-rank: p = 0.0176; Wilcoxon: p = 0.0480). Eleven (39.3%) patients receiving abobotulinumtoxinA did not require re-injection for ≥28 weeks versus two (14.3%) in placebo group. In this exploratory study, early abobotulinumtoxinA treatment significantly delayed time to reach re-injection criteria compared with placebo in patients with post-stroke ULS. These findings suggest an optimal time for post-stroke spasticity management and help determine the design and sample sizes for larger confirmatory studies.

Effect of early use of AbobotulinumtoxinA after stroke on spasticity progression: Protocol for a randomised controlled pilot study in adult subjects with moderate to severe upper limb spasticity (ONTIME pilot).

INTRODUCTION: Approximately 15 million people suffer a stroke annually, up to 40% of which may develop spasticity, which can result in impaired limb function, pain and associated involuntary movements affecting motor control.Robust clinical data on spasticity progression, associated symptoms development and functional impairment is scarce. Additionally, maximal duration of muscle tone reduction following botulinum toxin type A (BoNT-A) injections remains undetermined. The ONTIME pilot study aims to explore these issues and evaluate whether abobotulinumtoxinA 500 U (Dysport®; Ipsen) administered intramuscularly within 12 weeks following stroke delays the appearance or progression of symptomatic (disabling) upper limb spasticity (ULS). METHODS: ONTIME is a 28-week, phase 4, randomised, double-blind, placebo-controlled, exploratory pilot study initiated at four centres across Malaysia, the Philippines, Singapore and Thailand. Subjects (n = 42) with moderate to severe ULS (modified Ashworth scale [MAS] score ≥2) in elbow flexors or pronators, wrist flexors, or finger flexors will be recruited. Subjects will be randomised 2:1 to abobotulinumtoxinA 500 U or placebo (single dose 2-12 weeks after first-ever stroke).Primary efficacy will be measured by time between initial injection and visit at which reinjection criteria (MAS score ≥2 in the primary targeted muscle group and appearance or reappearance of symptomatic ULS) are met. Follow-up visits will be 4-weekly to a maximum of 28 weeks. DISCUSSION: This pilot study will facilitate the design and sample size calculation of further confirmatory studies, and is expected to provide insights into the optimal management of post-stroke patients, including timing of BoNT-A therapy and follow-up duration.

An international survey of patients living with spasticity.

PURPOSE: To better understand patient perspectives on the life impact of spasticity. METHODS: Global Internet survey (April 2014-May 2015) of 281 people living with spasticity. RESULTS: Respondents indicated that spasticity has a broad impact on their daily-life: 72% reported impact on quality of life, 44% reported loss of independence and 44% reported depression. Most respondents (64%) were cared for by family members, of whom half had stopped working or reduced their hours. Overall, 45% reported dissatisfaction with the information provided at diagnosis; main reasons were "not enough information" (67%) and "technical terminology" (36%). Respondents had high treatment expectations; 63% expected to be free of muscle spasm, 41% to take care of themselves and 36% to return to a normal routine. However, 33% of respondents had not discussed these expectations with their physician. The most common treatments were physiotherapy (75%), botulinum neurotoxin (BoNT, 73%) and oral spasmolytics (57%). Of those treated with BoNT, 47% waited >1 year from spasticity onset to treatment. CONCLUSIONS: This survey emphasises the broad impact of spasticity and highlights unmet needs in the patient journey. Improvements with regards to communication and the therapeutic relationship would be especially welcomed by patients, and would help manage treatment expectations. Implications of Rehabilitation Spasticity has broad impact on the lives of patients and their families that extends beyond the direct physical disability. Patients with spasticity need to be well informed about their condition and treatments available and should be given the opportunity to discuss their expectations. Physicians need to be aware of the patient's individual needs and expectations in order to better help them achieve their therapeutic goals.

Impact of integrated upper limb spasticity management including botulinum toxin A on patient-centred goal attainment: rationale and protocol for an international prospective, longitudinal cohort study (ULIS-III).

OBJECTIVES: Describe the rationale and protocol for the Upper Limb International Spasticity (ULIS)-III study, which aims to evaluate the impact of integrated spasticity management, involving multiple botulinum toxin A (BoNT-A) injection cycles and concomitant therapies, on patient-centred goal attainment. Outline novel outcome assessment methods for ULIS-III and report initial evaluation data from goal setting in early stages of the study. DESIGN: Large international longitudinal cohort study of integrated upper limb spasticity management, including BoNT-A. PARTICIPANTS AND SETTING: ULIS-III is a 2-year study expected to enrol >1000 participants at 58 study centres across 14 countries. INTERVENTIONS: The study design is non-interventional and intended to reflect real-life clinical practice. It will describe injection practices and additional treatment strategies, and record clinical decision-making in a serial approach to long-term spasticity management. OUTCOME MEASURES: ULIS-III will use a goal-directed approach to selection of targeted standardised measures to capture the diversity of presentation, goals and outcomes. ULIS-III will implement the Upper Limb Spasticity Index, a battery of assessments including a structured approach to goal attainment scaling (Goal Attainment Scaling-Evaluation of Outcomes for Upper Limb Spasticity tool), alongside a limited set of standardised measures, chosen according to patients' selected goal areas. Concomitant therapy inputs, patient satisfaction with engagement in goal setting, health economic end points and health-related quality of life data will also be captured. RESULTS OF INITIAL EVALUATION OF GOAL QUALITY: Recruitment started in January 2015. By June 2015, 58 sites had been identified and initial data collected for 79 patients across 13 sites in 3 countries. Goal setting data were quality-checked and centres rated on the basis of function-related and Specific, Measurable, Achievable, Realistic, Timed (SMART) characteristics of goal statements. Overall, 11/13 centres achieved the highest rating (A++). CONCLUSIONS: ULIS-III will provide valuable information regarding treatment of and outcomes from real-life upper limb spasticity management worldwide. TRIAL REGISTRATION NUMBER: NCT02454803; Pre-results.

Factors influencing goal attainment in patients with post-stroke upper limb spasticity following treatment with botulinum toxin A in real-life clinical practice: sub-analyses from the Upper Limb International Spasticity (ULIS)-II Study.

In this post-hoc analysis of the ULIS-II study, we investigated factors influencing person-centred goal setting and achievement following botulinum toxin-A (BoNT-A) treatment in 456 adults with post-stroke upper limb spasticity (ULS). Patients with primary goals categorised as passive function had greater motor impairment (p < 0.001), contractures (soft tissue shortening [STS]) (p = 0.006) and spasticity (p = 0.02) than those setting other goal types. Patients with goals categorised as active function had less motor impairment (0.0001), contracture (p < 0.0001), spasticity (p < 0.001) and shorter time since stroke (p = 0.001). Patients setting goals for pain were older (p = 0.01) with more contractures (p = 0.008). The proportion of patients achieving their primary goal was not impacted by timing of first-ever BoNT-A injection (medium-term (≤1 year) vs. longer-term (>1 year)) post-stroke (80.0% vs. 79.2%) or presence or absence of severe contractures (76.7% vs. 80.6%), although goal types differed. Earlier BoNT-A intervention was associated with greater achievement of active function goals. Severe contractures impacted negatively on goal achievement except in pain and passive function. Goal setting by patients with ULS is influenced by impairment severity, age and time since stroke. Our findings resonate with clinical experience and may assist patients and clinicians in selecting realistic, achievable goals for treatment.