Posts Tagged abobotulinumtoxinA

[ARTICLE] Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – Full Text

Abstract

Background

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.

Objective

To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS.

Design

Secondary analysis of a phase 3 study (NCT01313299).

Setting

Multicenter, international, double-blind, placebo-controlled clinical trial.

Participants

A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose).

Methods

The overall effect of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects.

Main Outcome Measures

Angle of arrest (XV1) and angle of catch (XV3) were assessed with the Tardieu scale, and active range of motion (XA).

Results

At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (XV1, XV3, XA) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in XV3 and XA, suggesting a dose-dependent effect.

Conclusions

Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints.

Introduction

Upper limb spasticity (ULS) is a common symptom after stroke and traumatic brain injury (TBI) and is associated with impaired self-care and additional burden of care [1-5]. Among several treatment strategies, guidelines recommend intramuscular botulinum toxin injections as a first-line treatment for adults with ULS [6-11].

Botulinum toxin type A (BoNT-A) injections may target upper extremity muscle groups from the shoulder, to decrease adductor and internal rotation tone, to the elbow, wrist, fingers, and thumb, to decrease flexor tone [12,13]. Specific muscle selection is based on the pattern of muscle overactivity, functional deficits, and patient goals [6]. These goals include increased passive and active range of motion, improved function (feeding and dressing), easier care (palmar and axillary hygiene), and reduction of pain [13].

Evidence-based information on optimal dosing for clinical use is relatively sparse. Dosing is not interchangeable between different BoNT-A products; therefore, improving our understanding of product-specific dosing will minimize confusion among injectors and improve the quality of patient care [13].

Among BoNT-A formulations, abobotulinumtoxinA (Dysport; Galderma Laboratories, LP, Fort Worth, TX) has been shown to decrease muscle tone (as measured by the Modified Ashworth Scale [MAS]) [13-17] and pain [18] and to facilitate goal attainment [19] in adults with ULS. A recent systematic review [13] of 12 randomized controlled trials (RCTs) in ULS concluded that abobotulinumtoxinA (total dose range, 500-1500 U) was generally well-tolerated, with “strong evidence” to support reduced muscle tone.

This paper presents the results of a secondary analysis from a recently published large international clinical trial, demonstrating improved active range of motion after abobotulinumtoxinA treatment in adults with hemiparesis and ULS >6 months after stroke or TBI [20]. This phase 3, randomized, double-blind, placebo-controlled study demonstrated that a total dose of either 500 U or 1000 U abobotulinumtoxinA injected in the upper extremity also resulted in decreased muscle tone and improvements in global physician-assessed clinical benefit compared with placebo.

Apart from a systematic measurement of active range of motion (XA) against finger, wrist, and elbow flexors, another unique aspect of the trial was the assessment of spasticity at the finger, wrist, and elbow flexor groups with the Tardieu scale (TS) [21,22]. The TS is a standardized evaluation used to assess the angle of arrest at slow speed (ie, passive range of motion, XV1) and the angle of catch at fast speed (XV3). The trial demonstrated improvements for finger, wrist, and elbow joints at week 4 in XV3 at both abobotulinumtoxinA doses and in XA at 1000 U; for the 500-U dose, improvements in XA were seen in the finger flexors. Both doses were associated with a favorable safety profile [20]. This analysis aims to provide a detailed description of improvements in spasticity and the active range of motion for individual muscle groups by dose and to provide information on muscle-specific dosing, which can be used in future recommendations for injectors.

Continue —> Dose-Dependent Effects of Abobotulinumtoxina (Dysport) on Spasticity and Active Movements in Adults With Upper Limb Spasticity: Secondary Analysis of a Phase 3 Study – ScienceDirect

 

Figure 1. Change from baseline of Tardieu scale parameters and of active range of motion week 4 postinjection in (A) extrinsic finger flexors, (B) wrist flexors, and (C) elbow flexors. Dose groups were as follows (lowest to highest dose): 500 U/non-PTMG, 500 U/PTMG, 1000 U/non-PTMG, and 1000 U/PTMG. Standard deviations and mean change from baseline values are detailed in Table 3. PTMG = primary targeted muscle group; XV1 = passive range of motion; XV3 = angle of catch at fast speed; XA = active range of motion.

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[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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[ARTICLE] Safety and efficacy of incobotulinumtoxinA as a potential treatment for poststroke spasticity – Full Text HTML/PDF

Abstract: Spasticity is a common disabling symptom for several neurological conditions. Botulinum toxin type A injection represents the gold standard treatment for focal spasticity after stroke showing efficacy, reversibility, and low prevalence of complications. In recent years, incobotulinumtoxinA, a new Botulinum toxin type A free of complexing proteins, has been used for treating several movement disorders with safety and efficacy. IncobotulinumtoxinA is currently approved for treating spasticity of the upper limb in stroke survivors, even if several studies described the use also in lower limb muscles. In the present review article, we examine the safety and effectiveness of incobotulinumtoxinA for the treatment of spasticity after stroke.

Introduction

Spasticity with muscle paresis and loss of dexterity represents one of the most common and discomforting complications affecting stroke survivors. It can have a disabling effect on stroke patients through pain and reduced mobility, affecting quality of life, and can be highly detrimental to daily functioning. Previous studies, based on the estimates of health care professionals, suggested that the prevalence of poststroke spasticity was ~60%, even if this value can be lower than the real value considering the difficulties in measuring spasticity routinely in rehabilitative settings.1

In a recent study, conducted in a clinical setting, 39% of patients with first-ever stroke were spastic after 12 months.2 Lundström et al reported that an estimated prevalence of spasticity 1 year after the first-ever stroke was 17% and that it was more prevalent in the upper limb than in the lower limb.3

In another study, spasticity was present in only 19% of the 95 subjects investigated 3 months after stroke.4 The same group of authors reported that 13 subjects out of 63 displayed spasticity after 18 months of stroke.5

There is no consensus concerning the number of patients developing spasticity. The discrepancies about the prevalence of spasticity onset after stroke might be related to various study settings and samples as well as the difficulty to measure and to identify its early development, discriminating between spastic-dystonia, muscle contracture, increase of stiffness, and other biomechanical factors. It is known that spastic hypertone can be responsible for motor impairments and activity limitations as well as for forced limb posture and pain at rest and during passive movements. The degree of spasticity may change according to the position of the patients, the task being performed, and the presence of aggravating factors such as pressure ulcers, skin infections, or urinary tract infections. Therefore, considering the variability of clinical features of stroke survivors, the assessment of spasticity is difficult as well as the need for treatment. In fact, for example, it has also been suggested that for stroke patients, the overactivity of leg extensor muscles enables them to support their body, standing position, and stance phase of gait cycle but interferes with knee flexion during the swing phase, so in this case, a botulinum toxin (BoNT) injection into rectus femoris or vastus intermedius muscles can be useful to reduce this impairment.6

Spasticity is also divided into generalized and focal when few muscles are involved. This type of classification can influence the choice of treatment considering not only the therapy but also the aim to improve limb posture and body image, to apply splinting, to consent hygiene, to increase passive articular range of motion, to walk and stand, to decrease pain and discomfort, to reduce the burden of care, or to prevent contracture. The purpose of this review article is to evaluate the effectiveness of the employment of incobotulinumtoxinA, a recent marked formulation of botulinum toxin type A (BoNT-A), to reduce spasticity in stroke survivors through an analysis of published clinical studies.

Continue (HTML) —-> Source: Safety and efficacy of incobotulinumtoxinA as a potential treatment fo | NDT

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[ARTICLE] Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial

Summary

Background

Resistance from antagonistic muscle groups might be a crucial factor reducing function in chronic hemiparesis. The resistance due to spastic co-contraction might be reduced by botulinum toxin injections. We assessed the effects of abobotulinumtoxinA injection in the upper limb muscles on muscle tone, spasticity, active movement, and function.

Methods

In this randomised, placebo-controlled, double-blind study, we enrolled adults (aged 18–80 years) at least 6 months after stroke or brain trauma from 34 neurology or rehabilitation clinics in Europe and the USA. Eligible participants were randomly allocated in a 1:1:1 ratio with a computer-generated list to receive a single injection session of abobotulinumtoxinA 500 U or 1000 U or placebo into the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. Patients and investigators were masked to treatment allocation. The primary endpoint was the change in muscle tone (Modified Ashworth Scale [MAS]) in the PTMG from baseline to 4 weeks. Secondary endpoints were Physician Global Assessment (PGA) at week 4 and change from baseline to 4 weeks in the perceived function (Disability Assessment Scale [DAS]) in the principal target of treatment, selected by the patient together with physician from four functional domains (dressing, hygiene, limb position, and pain). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01313299.

Findings

243 patients were randomly allocated to placebo (n=81), abobotulinumtoxinA 500 U (n=81), or abobotulinumtoxinA 1000 U (n=81). Mean change in MAS score from baseline at week 4 in the PTMG was −0·3 (SD 0·6) in the placebo group (n=79), −1·2 (1·0) in the abobotulinumtoxinA 500 U group (n=80; difference −0·9, 95% CI −1·2 to −0·6; p<0·0001 vs placebo), and −1·4 (1·1) in the abobotulinumtoxinA 1000 U group (n=79; −1·1, −1·4 to −0·8; p<0·0001 vs placebo). Mean PGA score at week 4 was 0·6 (SD 1·0) in the placebo group (n=78), 1·4 (1·1) in the abobotulinumtoxinA 500 U group (n=80; p=0·0003 vs placebo), and 1·8 (1·1) in the abobotulinumtoxinA 1000 U group (n=78; p<0·0001 vs placebo). Mean change from baseline at week 4 in DAS score for the principal target of treatment was −0·5 (0·7) in the placebo group (n=79), −0·7 (0·8) in the abobotulinumtoxinA 500 U group (n=80; p=0·2560 vs placebo), and −0·7 (0·7) in the abobotulinumtoxinA 1000 U group (n=78; p=0·0772 vs placebo). Three serious adverse events occurred in each group and none were treatment related; two resulted in death (from pulmonary oedema in the placebo group and a pre-existing unspecified cardiovascular disorder in the abobotulinumtoxinA 500 U group). Adverse events that were thought to be treatment related occurred in two (2%), six (7%), and seven (9%) patients in the placebo, abobotulinumtoxinA 500 U, and abobotulinumtoxinA 1000 U groups, respectively. The most common treatment-related adverse event was mild muscle weakness. All adverse events were mild or moderate.

Interpretation

AbobotulinumtoxinA at doses of 500 U or 1000 U injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures.

http://www.sciencedirect.com/science/article/pii/S1474442215002161

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[ARTICLE] Abobotulinumtoxina (Dysport®): Doses Used to Treat Upper Limb Muscles of Adults with Spasticity Participating in a Phase III Randomized, Double-Blind Placebo- Controlled Study

Abstract

Introduction/Background: In a Phase III, randomized, double-blind placebo-controlled study conducted in 34 sites from 9 countries, two doses of abobotulinumtoxinA (Dysport®) 500 and 1000 units (U) were shown to be efficacious on muscle tone for the treatment of hemiparetic adults post stroke or traumatic brain injury (TBI) with a favourable safety profile.1.

Materials and Methods: 243 patients received abobotulinumtoxinA 500 or 1000 U or placebo by intramuscular injection into their primary targeted muscle group (PTMG, selected from extrinsic finger flexors, wrist flexors and elbow flexors) and at least two other upper limb muscles, including shoulder muscles. Treatment was administered in a volume of 5.0 mL using electrostimulation. Doses administered to upper limb muscles are reported here.

Results: For the abobotulinumtoxinA 500 U group, mean (SD) doses (U) administered in fingers flexors were: 93.5 (17.0) for flexor digitorium profundus (FDP), 95.4 (14.3) for flexor digitorium superficialis (FDS) and 76.9 (26.8) for other finger flexors (flexor pollis longus, adductor pollicis); in wrist flexors: 92.2 (18.1) for flexor carpi radialis (FCR) and 89.9 (25.7) for flexor carpi ulnaris (FCU); in elbow flexors: 88.3 (28.5) for brachioradialis, 148.5 (60.2) for brachialis and 108.6 (49.5) for other elbow muscles (biceps brachii, pronator teres) and 122.2 (44.1) in shoulder muscles (triceps brachii, pectoralis major, subscapularis, latissimus dorsi). For the abobotulinumtoxinA 1000 U group, doses administered were 195.5 (25.9) for FDP, 196.8 (28.4) for FDS, 157.0 (53.3) for other finger flexors, 178.1 (45.5) for FCR, 171.2 (45.2) for FCU, 172.1 (44.8) for brachioradialis, 321.4 (103.2) for brachialis, 216.5 (92.2) for other elbow muscles and 300.0 (129.1) in shoulder muscles.

Conclusion: In this Phase III worldwide study in hemiparetic patients with upper limb spasticity post stroke/TBI, mean doses administered were 76.9–196.8 U for muscles in the finger flexors, 89.9-178.1 U for muscles in wrist flexors, 88.3–321.4 U for muscles in the elbow flexors and 122.2–300.0 U in shoulder muscles. Total dose administered (in the PTMG and at least 2 upper limb muscles) was 500 or 1000 U, which was previously shown to improve muscle tone in this patient population.

via DIAL : Abobotulinumtoxina (Dysport®): Doses Used to Treat Upper Limb Muscles of Adults with Spasticity Participating in a Phase III Randomized, Double-Blind Placebo- Controlled Study.

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[Systematic Literature Review]. AbobotulinumtoxinA in Clinical Trials for Adult Upper Limb Spasticity.

…On the basis of data extracted from 12 randomized clinical studies, a strong evidence base (9/12 studies) exists for the use of ABO to reduce ULS caused by stroke…

http://journals.lww.com/ajpmr/Abstract/publishahead/Systematic_Literature_Review_of_AbobotulinumtoxinA.99185.aspx

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