Comparing Lower-concentration Dysport Treatment Targeted to the Neuromuscular Junction With Current Clinical Practice (NMJ)

A Phase III Prospective, Multi-center, Randomised, Evaluator-blinded Study to Compare Neuromuscular Junction (NMJ) Targeted Technique for Dysport Injections in Upper Limb Spasticity Post Stroke or Traumatic Brain Injury to the Technique Used in Current Clinical Practice

The aim of the study was to compare Dysport treatment results (as assessed by Modified Ashworth Scale (MAS) in the elbow joint 4 weeks post treatment) following two treatment techniques: the current clinical practice injection technique using high-concentration dilution (300 U/mL Dysport) versus the neuromuscular junction (NMJ)-targeted injection technique using low-concentration dilution (100 U/mL Dysport). The hypothesis was that one high-volume, low-concentration injection located centrally in the area/band of the NMJ zones would be as effective as the technique used in current medical practice.

Study Overview

• Status: Terminated
• Conditions: Arm Spasticity
• Intervention / Treatment: Biological: Botulinum toxin type A

Detailed Description

This was a randomised, evaluator-blinded, comparative, parallel group, multicentre study, conducted in four countries (Denmark, Finland, Norway and Sweden). For each subject, the primary efficacy assessments using MAS were performed by the same blinded evaluator, and every effort was made at each site to ensure that the MAS evaluator was the same person throughout the study. Dysport doses were to follow clinical practice for subjects suffering from upper limb spasticity position pattern type 1, 3 or 4 post stroke or traumatic brain injury.

The hypothesis for this study was that one low-concentration botulinum neurotoxin type A (BoNT-A) injection per muscle, centrally located in the area/band of the NMJ zones, would spread to and block the surrounding NMJ zones and be as effective as the technique used today in clinical practice. The possibility to reduce the number of injection points would decrease the risk of injection discomfort, pain and injection site bleeding for the patient. A simplified injection technique with one injection per muscle and in a defined location would also benefit physicians.

At Baseline (Visit 1), subjects were randomised to one of two treatment groups:

• Group 1: Current clinical practice technique and high-concentration dilution: Dysport 300 U/mL.
• Group 2: NMJ targeted technique and low-concentration dilution: Dysport 100 U/mL.

Each subject visited the clinic on at least three occasions:

• Baseline (Visit 1): Screening, randomisation and Dysport treatment.
• Week 4 (Visit 2): Treatment follow-up, 4 weeks after Dysport treatment.
• Week 12 (Visit 3): Treatment and study follow-up, 12 weeks after Dysport treatment.

For subjects not receiving any post study BoNT-A injection at Week 12 due to remaining treatment effect, an extra visit (Visit 4) for study follow-up was to take place at the next routine visit planned for a new BoNT-A injection, at the latest 24 weeks post study injection.

The duration of each subject's study period was at a minimum 12 weeks and maximum 24 weeks. The overall duration of the study was planned to be approximately 36 months.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark, 9000
    • Aalborg Sygehus Nord
  • Glostrup, Denmark, 2600
    • Glostrup Hospital
  • Hammel, Denmark, 8450
    • Regionshospitalet Hammel
  • København NV, Denmark, 2400
    • Bispebjerg Hospital
  • Roskilde, Denmark, 4000
    • Roskilde Hospital
  • Vejle, Denmark, 7100
    • Vejle Hospital
  • Viborg, Denmark, 8800
    • Regionshopsitalet Viborg
• Finland
  • Joensuu, Finland, 80210
    • North Karelia Central Hospital
  • Jyväskylä, Finland, 40503
    • Central Hospital of Central Finland
• Norway
  • Bergen, Norway, 5021
    • Haukeland University Hospital
  • Skien, Norway, , 3700
    • Sykehuset Telemark HF
• Sweden
  • Eskilstuna, Sweden, 631-88
    • Mälarsjukhuset MSE
  • Göteborg, Sweden
    • Sahlgrenska University Hospital
  • Halmstad, Sweden, 30185
    • Hallands Sjukhus, Neurology Clinic
  • Härnösand, Sweden, 87182
    • Sundsvall-Härnösand, Rehabilitation Medicine
  • Nyköping, Sweden, 61185
    • Nyköpings Lasarett,
  • Stockholm, Sweden, 114 33
    • Neurology Clinic Stockholm
  • Stockholm, Sweden, 18288
    • Danderyds Hospital,
  • Sävar, Sweden, 91831
    • Neurorehab Sävar
  • Visby, Sweden, 62184
    • Rehabilitation Center Gotland
  • Ystad, Sweden, 27133
    • Ystad Lasarett
  • Örnsköldsvik, Sweden, 891 89
    • Örnsköldsviks Sjukhus, Neurology Clinic
  • Östersund, Sweden, 83102
    • Östersunds Rehabilitation Center

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:

• Provision of written informed consent prior to any study related procedures.
• Subjects male or female, aged 18 years or older.
• Upper limb spasticity post stroke or traumatic brain injury.
• Spasticity position pattern type 1, 3 or 4.
• Elbow flexor muscles spasticity MAS 2 to 3.
• At least 2 consecutive previous treatment cycles of BoNT-A for current diagnosis.
• The latest treatment cycle demonstrating good treatment efficacy where the Dysport dose administered was considered to be adequate according to Investigator judgement.
• Need of the same treatment modality in muscle (m.) brachialis, m. biceps brachii, m. brachioradialis, m. flexor carpi ulnaris, m. flexor carpi radialis as the previous treatment cycle.
• Last BoNT-A treatment 12-24 weeks ago.

Exclusion Criteria:

• Poor response to BoNT-A treatment, according to Investigator.
• Need of Dysport doses >800 U in the upper limb.
• Concomitant treatment with BoNT-A for other indications than spasticity.
• Any elbow flexor contracture prohibiting MAS evaluation and/or elbow flexion improvement of at least 1 step on the MAS.
• Cutaneous or joint inflammation in the affected upper limb.
• Was likely to start other spasticity treatment during the study.
• Was likely to start physiotherapy treatment during the study.
• Other ongoing neurological disorder (e.g., myasthenia gravis).
• History of dysphagia or aspiration.
• Use of agents interfering with neuromuscular transmission (e.g., aminoglycosides).
• Treated with an investigational medicinal product within 30 days before start of the study.
• Known sensitivity to BoNT-A or any components of Dysport.
• Was at risk of pregnancy or was lactating. Females of childbearing potential must have provided a negative pregnancy test (urinary human chorionic gonadotropin (U-hCG)) at Visit 1 and must have been using adequate contraception. Non-childbearing potential was defined as post-menopause for at least one year, surgical sterilisation or hysterectomy at least three months before the start of the study.
• Had a history of, or known current, problems with alcohol or drug abuse.
• Had a mental condition rendering the subject unable to understand the nature, scope and possible consequences of the study, and/or evidence of an uncooperative attitude.
• Had abnormal Baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the investigator, might have jeopardised the subject's safety or decreased the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: NMJ Targeted; NMJ targeted technique and low-concentration dilution (Dysport 100 U/mL). The same number and sites of injections/deposits per muscle were given as per prestudy. With a Dysport dilution of 300 U/mL the volume to be injected varied between 0.1 mL and 0.7 mL per muscle. The dose and the choice of muscles involved in the elbow flexion were the same as for the last prestudy treatment.	Biological: Botulinum toxin type A; Other Names: AbobotulinumtoxinA (Dysport®)
ACTIVE_COMPARATOR: Current Clinical Practice; Current clinical practice technique and high-concentration dilution (Dysport 300 U/mL). A single injection per muscle was given in the midline of the band of NMJ zones. With a Dysport dilution of 100 U/mL the volume to be injected varied between 0.4 mL and 2.0 mL per muscle. The dose and the choice of muscles involved in the elbow flexion were the same as for the last prestudy treatment.	Biological: Botulinum toxin type A; Other Names: AbobotulinumtoxinA (Dysport®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4	A clinically relevant change was one level decrease on the MAS scale. Subjects meeting the defined decrease at Week 4 were considered as responders in the primary efficacy analysis.	Baseline to Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 and Week 12	Increased muscle tone in elbow flexors was assessed using the MAS. Scale ranges from 0 (no increase in muscle tone) to 4 (affected part rigid in flexion or extension).	Baseline to Week 12
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12	A clinically relevant change was one level decrease on the MAS scale. Subjects meeting the defined decrease at Week 12 were considered as responders.	Baseline to Week 12
Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject	Pain assessment using the VAS. The VAS was a 10 cm straight horizontal line scoring scale. Score range on VAS was from 0 to 10 where 0 indicated no pain and 10 indicated worst pain imaginable.	Baseline, Week 4 and Week 12
Injection Site Pain Measured by VAS at Day 1.	Pain assessment using the VAS. The VAS was a 100 mm straight horizontal line scoring scale. Score range on VAS was from 0 to 100 where 0 indicated no pain and 100 indicated worst pain imaginable.	Baseline
Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS)	At Baseline, an agreed primary goal related to elbow flexion in one of the following categories was determined: active function, impairment, involuntary movement, mobility, pain passive function or other. Each goal was usually rated -1, unless the subject was as bad as he/she could be in that particular goal area, in which case the Baseline score was -2. The evaluator rated the outcome score at Week 4 or Week 12, depending on the time point defined at the baseline visit (Visit 1), using the GAS five-point scale (-2, -1, 0, +1 and +2).	Up to Week 12
Subject Global Evaluation of Treatment Effect	Comparison of treatment effect between previous (prestudy) and study treatment cycles assessed by the subject at the end of study (Week 12 up to Week 24 (Visit 3 or Visit 4)). Categorised as follows: Much worse / Worse / Same / Better / Much better.	Up to Week 24
Investigator Preference of Injection Technique	When all patients at the site had completed the study (last subject last visit) a global assessment of the injection technique was to be made by the Investigators. The following question was answered: "Based on your experience during this study, which injection technique do you prefer?"	Following last visit of the last subject at each site

Collaborators and Investigators

• Sponsor: Ipsen

Publications and helpful links

General Publications

• Rekand T, Biering-Sorensen B, He J, Vilholm OJ, Christensen PB, Ulfarsson T, Belusa R, Strom T, Myrenfors P, Maisonobe P, Dalager T. Botulinum toxin treatment of spasticity targeted to muscle endplates: an international, randomised, evaluator-blinded study comparing two different botulinum toxin injection strategies for the treatment of upper limb spasticity. BMJ Open. 2019 May 5;9(5):e024340. doi: 10.1136/bmjopen-2018-024340.

Study record dates

Study Major Dates

• Study Start: September 1, 2012
• Primary Completion (ACTUAL): March 1, 2015
• Study Completion (ACTUAL): March 1, 2015

Study Registration Dates

• First Submitted: September 6, 2012
• First Submitted That Met QC Criteria: September 6, 2012
• First Posted (ESTIMATE): September 10, 2012

Study Record Updates

• Last Update Posted (ACTUAL): September 27, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Botulinum toxin; Dysport; neuromuscular junction; Modified Ashworth Scale; arm spasticity; upper limb spasticity
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Muscle Spasticity; 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: A-99-52120-162; 2011-005375-16 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).