Claire Vilain

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

Efficacy and safety of abobotulinumtoxinA in spastic lower limb: Randomized trial and extension

Objective: To demonstrate single abobotulinumtoxinA injection efficacy in lower limb vs placebo for adults with chronic hemiparesis and assess long-term safety and efficacy of repeated injections. Methods: In a multicenter, double-blind, randomized, placebo-controlled, single-cycle study followed by a 1-year open-label, multiple-cycle extension, adults ≥6 months after stroke/brain injury received one lower limb injection (abobotulinumtoxinA 1,000 U, abobotulinumtoxinA 1,500 U, placebo) followed by ≤4 open-label cycles (1,000, 1,500 U) at ≥12-week intervals. Efficacy measures included Modified Ashworth Scale (MAS) in gastrocnemius–soleus complex (GSC; double-blind primary endpoint), physician global assessment (PGA), and comfortable barefoot walking speed. Safety was the open-label primary endpoint. Results: After a single injection, mean (95% confidence interval) MAS GSC changes from baseline at week 4 (double-blind, n = 381) were as follows: −0.5 (−0.7 to −0.4) (placebo, n = 128), −0.6 (−0.8 to −0.5) (abobotulinumtoxinA 1,000 U, n = 125; p = 0.28 vs placebo), and −0.8 (−0.9 to −0.7) (abobotulinumtoxinA 1,500 U, n = 128; p = 0.009 vs placebo). Mean week 4 PGA scores were as follows: 0.7 (0.5, 0.9) (placebo), 0.9 (0.7, 1.1) (1,000 U; p = 0.067 vs placebo), and 0.9 (0.7, 1.1) (1,500 U; p = 0.067); walking speed was not significantly improved vs placebo. At cycle 4, week 4 (open-label), mean MAS GSC change reached −1.0. Incremental improvements in PGA and walking speed occurred across open-label cycles; by cycle 4, week 4, mean PGA was 1.9, and walking speed increased +25.3% (17.5, 33.2), with 16% of participants walking >0.8 m/s (associated with community mobility; 0% at baseline). Tolerability was good and consistent with the known abobotulinumtoxinA safety profile. Conclusions: In chronic hemiparesis, single abobotulinumtoxinA (Dysport Ipsen) administration reduced muscle tone. Repeated administration over a year was well-tolerated and improved walking speed and likelihood of achieving community ambulation. Clinicaltrial.gov identifiers: NCT01249404, NCT01251367. Classification of evidence: The double-blind phase of this study provides Class I evidence that for adults with chronic spastic hemiparesis, a single abobotulinumtoxinA injection reduces lower extremity muscle tone.

Efficacy and Safety of AbobotulinumtoxinA (Dysport) for the Treatment of Hemiparesis in Adults With Upper Limb Spasticity Previously Treated With Botulinum Toxin: Subanalysis From a Phase 3 Randomized Controlled Trial

To assess the efficacy and safety of abobotulinumtoxinA in adults with upper limb spasticity previously treated with botulinum toxin A (BoNT‐A).

Dose-Dependent Effects of AbobotulinumtoxinA (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study

AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence‐based information on optimal dosing for clinical use is limited.

Development of a Pediatric Goal-Centered Upper Limb Spasticity Home Exercise Therapy Program for Use in a Phase-III Trial of Abobotulinumtoxina (Dysport®)

Abstract Aims: To create a standardized home exercise therapy program that could be implemented by international sites to provide a consistent level of therapeutic intervention for pediatric patients participating in an ongoing Phase-III, randomized, controlled trial of repeat abobotulinumtoxinA injections for pediatric upper limb spasticity (NCT02106351). Methods: Physical therapists, occupational therapists, and medical doctors worked collaboratively to design an exercise therapy program to be implemented in the home setting. In this article, we describe the development process and the finalized program that is currently being used in the Phase-III trial. Results: The final program is presented as a “toolbox” for therapists, and includes a standardized step-wise process for choosing the most appropriate exercises and functional activities to achieve the agreed treatment goals of each abobotulinumtoxinA injection. The core toolbox includes: a clear protocol for clinicians, information sheets, signature of commitment forms, exercise score charts, and the library of exercises and functional activities that therapists choose from to aid the patient in achieving their treatment goals. Conclusions: Implementation of this home therapy program provides a standardized background of good practice against which to test the efficacy of abobotulinumtoxinA. Preliminary data show that the program is readily accepted by patients and their families.

Investigation of mixed model repeated measures analyses and non-linear random coefficient models in the context of long-term efficacy data

The longitudinal data from 2 published clinical trials in adult subjects with upper limb spasticity (a randomized placebo-controlled study [NCT01313299] and its long-term open-label extension [NCT01313312]) were combined. Their study designs involved repeat intramuscular injections of abobotulinumtoxinA (Dysport®), and efficacy endpoints were collected accordingly. With the objective of characterizing the pattern of response across cycles, Mixed Model Repeated Measures analyses and Non-Linear Random Coefficient (NLRC) analyses were performed and their results compared. The Mixed Model Repeated Measures analyses, commonly used in the context of repeated measures with missing dependent data, did not involve any parametric shape for the curve of changes over time. Based on clinical expectations, the NLRC included a negative exponential function of the number of treatment cycles, with its asymptote and rate included as random coefficients in the model. Our analysis focused on 2 specific efficacy parameters reflecting complementary aspects of efficacy in the study population. A simulation study based on a similar study design was also performed to further assess the performance of each method under different patterns of response over time. This highlighted a gain of precision with the NLRC model, and most importantly the need for its assumptions to be verified to avoid potentially biased estimates. These analyses describe a typical situation and the conditions under which non-linear mixed modeling can provide additional insights on the behavior of efficacy parameters over time. Indeed, the resulting estimates from the negative exponential NLRC can help determine the expected maximal effect and the treatment duration required to reach it.

Poster 292 Improvement of Spasticity Following AbobotulinumtoxinA (Dysport®) Injections in Shoulder Muscles in Hemiparetic Patients with Upper Limb Spasticity–Sub-Analysis of a Prospective, Long-Term, Open-Label Study with Single and Repeated Injection Cycles

Participants: A total of 134 patients (abobotulinumtoxinA, n1⁄489; placebo, n1⁄445) were randomized and 129 (abobotulinumtoxinA, n1⁄484; placebo, n1⁄445) completed the W4 primary endpoint evaluation. Interventions: CD patients were randomized (2:1) to abobotulinumtoxinA or placebo. Toxin-naı̈ve abobotulinumtoxinA patients received 500 units/2 mL in 2 affected neck muscles. AbobotulinumtoxinA CD subjects who had previously received botulinum treatment (non-naı̈ve) received 250-500 units/2 mL (2.5:1 abobotulinumtoxinA: previous onabotulinumtoxinA [Botox ] dose) into muscles injected during prior treatments. Main Outcome Measures: The primary endpoint was change from baseline to Week 4 (W4) in Toronto Western Spasmodic Torticollis Rating Oasis, The Online Abstract Submission System Scale (TWSTRS) total score. Safety was assessed over the 12-week study period. Results: Versus placebo, abobotulinumtoxinA patients experienced significantly greater changes from baseline in TWSTRS score at W4 (-2.5 versus -10.8, P<.001; based upon the modified intent-to-treat population). Adverse events (AEs) occurred in 41% and 22% of abobotulinumtoxinA and placebo patients, respectively. Dysphagia was reported in 9% of treated patients. Other AEs in treated patients were muscle weakness, neck pain, and headache, none of which were reported with placebo. Conclusions: Data from this study indicate a 2 mL dilution of abobotulinumtoxinA was significantly more effective than placebo in CD patients. No unexpected AEs were observed relative to previous studies that used the 1 mL dilution volume in this patient population. Level of Evidence: Level II

Poster 308 Improvement of Spasticity, Active Movements and Active Function after Repeated Injections of AbobotulinumtoxinA (Dysport) in Adults with Spastic Paresis in the Upper Limb: Results of a Phase III Open-Label Extension Study

Disclosures: George Francis: I Have No Relevant Financial Relationships To Disclose Case/Program Description: Sacral neoplasms often present as large masses refractory to chemotherapy and radiation, requiring a sacrectomy. Multiple sacral nerve roots and vessels may be compromised, resulting in immobility, pressure ulcers, orthostasis, and neurogenic bowel and bladder. Our goal is to review the rehabilitative needs and outcomes post-sacrectomy via two inpatient case presentations. A 58-year-old woman with a solitary fibrous tumor underwent an en bloc resection involving a subtotal sacrectomy from S2 to coccyx, an L5-S1 laminectomy, ligation of her bilateral S2-5 nerve roots, neurolysis of bilateral S1 and sciatic nerve roots, and bilateral gluteal flap closures. Post-operatively, activity precautions included no walking initially and no hip flexion for two weeks. She required tilt table treatments and was ambulating at post-op Day 8. The rehabilitation challenges included: training on the management of her neurogenic bowel and bladder, controlling her neuropathic and somatic pain, and mobilizing her despite the hip restrictions. The second case includes a 67-year-old male with a sacral chordoma who underwent a two-stage surgery. Stage one involved preparation for the en bloc resection of the sacral tumor. One day later, stage two involved an L5-S1 laminectomy, ligation of the S2-5 nerve roots, en bloc resection of the sacral, bilateral S1 root and sciatic neurolysis, and bilateral gluteus muscle flaps for closure. His rehabilitation challenges included: severe protein malnutrition, orthostatic hypotension, delayed wound healing, fluid collection, uncontrolled pain, and neurogenic bowel and bladder. Setting: Tertiary cancer center. Results: Highly functional outcomes are seen in these patients, including independent bowel and bladder management and return to pre-operative ambulatory status. Discussion: Rehabilitation interventions for these patients include: medical stabilization, pain management, wound healing, transfers, mobility, and neurogenic bowel and bladder management. Conclusions: These are highly complex surgical patients with extensive rehabilitation needs that require the management by a physiatrist. Level of Evidence: Level V