Early Use of Botulinum Toxin in Spasticity Post Stroke. (EUBoSS)

Is it Clinically Effective to Treat Arm Flexor Spasticity, With Botulinum Toxin - Type A (BoNTA) and Physiotherapy, as Soon as Signs of Abnormal Muscle Activity Are Observed?

Patients who survive a stroke are often left with an arm that cannot be used. One reason for this is that the muscles affected by the stroke become overactive. This is known as spasticity. Such unwanted muscle overactivity, if left untreated or poorly managed, can lead to limb deformities. For example, the wrist and fingers in the arm affected by spasticity become stiff and curl into a fist and the hand cannot be used for any functional purpose. Palm hygiene can become difficult and patients find this deformity unsightly and painful. Botulinum toxin (BT) has been shown to reduce muscle overactivity and is licensed for this purpose. In current practice this treatment is often used as a last line of defence. Although BT can reduce the muscle overactivity, when injected using current protocols, it seems to have little impact on the recovery of function and/or treating the limb deformities and pain. If BT can be given in the early stages of a stroke, i.e. as soon as the muscle overactivity is observed, then we will be able to treat spasticity and may prevent the limb deformities and pain from developing. We may also be able to assist the recovery of arm movement in some of the patients who would otherwise not have regained this. In addition to benefiting the patient, the prevention of secondary complications by early treatment may reduce the costs of long term care to the NHS . We hope to discover if our plan of providing early treatment with BT is more effective than the current approach. If we demonstrate that the treatment is effective we will be able to introduce this new method almost immediately within the NHS through our collaboration with doctors and therapists who are actively treating patients with this condition.

Study Overview

• Status: Completed
• Conditions: Stroke; Muscle Spasticity; Contracture
• Intervention / Treatment: Drug: Placebo; Drug: onabotulinumtoxinA

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B18 7QH
      • Sandwell and West Birmingham NHS TRUST

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Over 18 years of age.
2. Patients with stroke due to a primary cerebral haemorrhage/infarction, subarachnoid haemorrhage producing an upper motor syndrome affecting one body side which results in a hemiplegia
3. Capable of providing informed consent directly or indirectly, or, consent obtainable from next of kin or legal representative
4. No useful arm function (i.e. less than or equal to 2 on the grasp subsection of the Action Research Arm Test) at onset of spasticity

Exclusion Criteria:

1. Significant musculoskeletal conditions that affected upper limb function prior to the stroke
2. Unconscious or moribund during the screening period
3. Recovery of useful arm function (a score of 3 or more in the grasp section of the Action Research Arm Test) prior to injections
4. Patients with contraindications to electrical stimulation including active implants (e.g. cardiac assist devices), metal implants at site of stimulation, scar tissue/cancerous tissue at site of stimulation, uncontrolled epilepsy, deep vein thrombosis in limb / muscle being stimulated and pregnancy (or planned pregnancy)
5. Previous upper motor neurone syndrome or hypertonicity due to multiple sclerosis, spinal cord injury or other neurological disorder
6. Patients with a known hypersensitivity to any botulinum toxin or to any of the excipients of BOTOX® (i.e. Human serum albumin)
7. Patients with myasthenia gravis or Eaton Lambert Syndrome or other neuromuscular junction or myopathic disorder
8. Patients with infection at the proposed injection site(s)
9. Patients who are pregnant or may become pregnant at the time of the proposed injections and for the duration of the study
10. Current treatment with any antispasticity agent or previous injection with BOTOX

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Botulinum Toxin - Type A (onabotulinumtoxinA); Botulinum Toxin - Type A. One set of injections of up to 200 Units of Botox (Allergan). Injected to Biceps, Brachialis, Flexor Dig Superficialis, Flexor Dig Profundus, Flexor Carpi Radialis and Flexor Carpi Ulnaris.	Drug: onabotulinumtoxinA; Other Names: Botox; Botulinum toxin type-A
Placebo Comparator: 0.9% NaCl Saline Injection; Saline - Injected to Biceps, Brachialis, Flexor Dig Superficialis, Flexor Dig Profundus, Flexor Carpi Radialis and Flexor Carpi Ulnaris.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Action Research Arm Test	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Spasticity	In reducing focal spasticity in the arm as measured by surface electromyography (EMG) response of the wrist and elbow flexors to an externally imposed perturbation	6 Months
Strength and Fatigue	Strength and fatigue as measured by maximum isometric strength and the rate of force production in the wrist and elbow joints	6 Months
Stiffness and passive range of movement.	Range of movement and force required to produce the same with a custom built device	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life	EuroQol EQ-5D	6 Months
Care Giver Strain Index		6 Months

Collaborators and Investigators

• Sponsor: Sandwell & West Birmingham Hospitals NHS Trust
• Collaborators: Stroke Research Network; Keele University
• Investigators: Study Chair: Anand D Pandyan, PhD, Keele University; Principal Investigator: Stephen G Sturman, MB ChB, SWBH NHS Trust

Publications and helpful links

General Publications

• Lindsay C, Simpson J, Ispoglou S, Sturman SG, Pandyan AD. The early use of botulinum toxin in post-stroke spasticity: study protocol for a randomised controlled trial. Trials. 2014 Jan 8;15:12. doi: 10.1186/1745-6215-15-12.
• Lindsay C, Humphreys I, Phillips C, Pandyan A. Estimating the cost consequence of the early use of botulinum toxin in post-stroke spasticity: Secondary analysis of a randomised controlled trial. Clin Rehabil. 2023 Mar;37(3):373-380. doi: 10.1177/02692155221133522. Epub 2022 Nov 3.
• Lindsay C, Ispoglou S, Helliwell B, Hicklin D, Sturman S, Pandyan A. Can the early use of botulinum toxin in post stroke spasticity reduce contracture development? A randomised controlled trial. Clin Rehabil. 2021 Mar;35(3):399-409. doi: 10.1177/0269215520963855. Epub 2020 Oct 11.

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: June 18, 2013
• First Submitted That Met QC Criteria: June 19, 2013
• First Posted (Estimate): June 20, 2013

Study Record Updates

• Last Update Posted (Estimate): November 18, 2014
• Last Update Submitted That Met QC Criteria: November 17, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Early treatment of spasticity.; Post stroke spasticity.
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Stroke; Muscle Spasticity; Contracture; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: PB-PG-0808-16319; 2010-021257-39 (EudraCT Number); ISRCTN57435427 (Registry Identifier: ISRCTN)