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)

Abstract

IntroductionApproximately 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).MethodsONTIME 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.DiscussionThis 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.

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

“…Full details of the ONTIME study (NCT02321436) protocol have been published [ 35 ]. ONTIME was conducted in accordance with the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice Guidelines, and local regulatory requirements, with approval from relevant independent ethics committee/institutional review boards.…”

“…Doses were administered per muscle according to investigators’ judgements. Recommended dosing regimens were previously published [ 35 ]. Most patients participated in occupational and physiotherapy practices.…”

“…Secondary assessments included change in muscle tone (MAS) in PTMG, assessed at baseline and each subsequent visit. Active motor function in affected UL was evaluated using Fugl–Meyer assessment (total score, 0–66) for: upper extremity (scored 0–36), wrist (0–10), hand (0–14), and in terms of coordination/speed (0–6) [ 35 , 38 ]. Global assessment of change was investigator-evaluated (5-point Likert scale, ranging from ‘much better’ to ‘much worse’).…”

“…The study schedule has been published previously [ 35 ]. The first visit recorded patient demographics, type of stroke, medical and surgical history, and severity of stroke-induced disability (modified Rankin Scale).…”

The Effectiveness of Botulinum Toxin Type A (BoNT-A) Treatment in Brazilian Patients with Chronic Post-Stroke Spasticity: Results from the Observational, Multicenter, Prospective BCause Study

“…Treatment with BoNT-A is often deferred until the patient shows clinical signs of spasticity, usually at least 3 months post-stroke [13]. However, recent studies have demonstrated that treatment with BoNT-A as early as 2-12 weeks following stroke may prevent the development of spasticity and improve muscle tone, thus improving prognosis [13][14][15][16].…”