[ARTICLE] 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) – Full Text

Abstract

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.

1. Introduction

An estimated 15 million people suffer a stroke annually [1]; of whom, up to 40% develop post-stroke spasticity, a state of velocity-dependent increase in tonic stretch reflexes (‘muscle tone’) with exaggerated tendon jerks [2] most commonly affecting upper limbs [3]; [4]; [5]; [6] ;  [7]. Post-stroke spasticity impedes active and passive functioning of affected limb(s), impairs activities of daily living and requires long-term treatment; associated healthcare costs are up to four-fold greater than for stroke survivors without spasticity [7]. Furthermore, spasticity may involve pain and involuntary movements, interfering with dressing, gait, balance and walking speed, and can disrupt rehabilitation [8]. Without functional improvement, secondary musculoskeletal complications such as contractures and deformity may develop [9].

Data on the proportion of patients with post-stroke spasticity developing disability are scarce. One survey (N = 140) reported a prevalence of 17% spasticity and 4% disabling spasticity with a year [4]. Upper limb involvement and age <65 years were associated with disabling spasticity in this study [4]. In other studies, over a third of individuals developed spasticity within a year, including 20% with severe spasticity [10] ;  [11], suggesting higher rates of disabling spasticity than those reported by Lundström et al. [4].

Studies evaluating the timeframe for developing spasticity symptoms post-stroke are also few, with small cohorts (around 100 patients), but suggest the prevalence and severity of spasticity increases within a year post-stroke [5]; [6]; [10]; [11]; [12] ;  [13]. Certain studies indicate that spasticity symptoms and muscle tone changes are apparent in up to 25% of stroke victims within 2 weeks [3]; [5] ;  [14]. One study reported increased muscle tone as an early risk factor for developing severe disabling spasticity, particularly if it affected more than two joints, or was associated with a modified Ashworth scale (MAS) score ≥2 in one affected joint within 6 weeks post-stroke [14]. Indeed, spasticity may persist [15], and the severity of upper limb spasticity (ULS) may increase over time, most commonly affecting anti-gravity muscles, during the first 2 weeks and at 3 months post-stroke [5].

AbobotulinumtoxinA is an effective focal intervention for reducing ULS [16] and coupled with neurorehabilitation is recommended in standard clinical practice [17] ;  [18]. Treatment with botulinum toxin A (BoNT-A) is generally delayed in post-stroke spasticity until patients show clinical signs of increased muscle tone, usually about 3 months following stroke [19], despite evidence that symptoms begin much earlier.

Recent studies aimed to evaluate whether earlier post-stroke treatment with BoNT-A may prevent disabling spasticity development [15]; [19] ;  [20] and demonstrate that BoNT-A administered within 3 months provides sustained improvement in muscle tone. However, there is a paucity of robust clinical data on spasticity progression timeframes, associated symptom development, functional impairment, and maximal duration of muscle tone reduction with BoNT-A.

The ONTIME pilot study explores these foregoing issues to establish whether treatment with abobotulinumtoxinA (Dysport®) within 2–12 weeks post-stroke might delay symptomatic or disabling spasticity development, and to assess the duration of this effect. Importantly, this study incorporates composite measure of active and passive functionality, involuntary movements and pain.

Fig. 1

Continue —> 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)

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