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

Phase 3

Terminated

Conditions: Arm Spasticity

Interventions: Biological: Botulinum toxin type A

Registration Number: NCT01682148

Lead Sponsor: Ipsen

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 100

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NMJ Targeted	Botulinum toxin type A	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.
Current Clinical Practice	Botulinum toxin type A	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4	Baseline to 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.

Secondary Outcome Measures

Name	Time	Method
Subject Global Evaluation of Treatment Effect	Up to Week 24	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.
Injection Site Pain Measured by VAS at Day 1.	Baseline	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.
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 and Week 12	Baseline to 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).
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12	Baseline to 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.
Investigator Preference of Injection Technique	Following last visit of the last subject at each site	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?"
Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject	Baseline, Week 4 and Week 12	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.
Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS)	Up to Week 12	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).

Trial Locations

Locations (23): Sahlgrenska University Hospital
🇸🇪
Göteborg, Sweden
Danderyds Hospital,
🇸🇪
Stockholm, Sweden
Östersunds Rehabilitation Center
🇸🇪
Östersund, Sweden
Nyköpings Lasarett,
🇸🇪
Nyköping, Sweden
Neurology Clinic Stockholm
🇸🇪
Stockholm, Sweden
Mälarsjukhuset MSE
🇸🇪
Eskilstuna, Sweden
Hallands Sjukhus, Neurology Clinic
🇸🇪
Halmstad, Sweden
Sundsvall-Härnösand, Rehabilitation Medicine
🇸🇪
Härnösand, Sweden
Neurorehab Sävar
🇸🇪
Sävar, Sweden
Aalborg Sygehus Nord
🇩🇰
Aalborg, Denmark
Regionshospitalet Hammel
🇩🇰
Hammel, Denmark
Glostrup Hospital
🇩🇰
Glostrup, Denmark
Bispebjerg Hospital
🇩🇰
København NV, Denmark
Roskilde Hospital
🇩🇰
Roskilde, Denmark
Vejle Hospital
🇩🇰
Vejle, Denmark
Regionshopsitalet Viborg
🇩🇰
Viborg, Denmark
Haukeland University Hospital
🇳🇴
Bergen, Norway
North Karelia Central Hospital
🇫🇮
Joensuu, Finland
Central Hospital of Central Finland
🇫🇮
Jyväskylä, Finland
Sykehuset Telemark HF
🇳🇴
Skien, Norway
Rehabilitation Center Gotland
🇸🇪
Visby, Sweden
Ystad Lasarett
🇸🇪
Ystad, Sweden
Örnsköldsviks Sjukhus, Neurology Clinic
🇸🇪
Örnsköldsvik, Sweden