Clinical trial NCT01682148: Comparing Lower-concentration Dysport Treatment Targeted to the Neuromuscular Junction With Current Clinical Practice
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Arm Spasticity
Keywords: Dysport
arm spasticity
Modified Ashworth Scale
neuromuscular junction
Botulinum toxin
upper limb spasticity
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2012-09-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4
timeFrame: Baseline to Week 4
Secondary outcomes:
measure: Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 and Week 12
timeFrame: Baseline to Week 12
measure: Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12
timeFrame: Baseline to Week 12
measure: Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject
timeFrame: Baseline, Week 4 and Week 12
measure: Injection Site Pain Measured by VAS at Day 1.
timeFrame: Baseline
measure: Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS)
timeFrame: Up to Week 12
measure: Subject Global Evaluation of Treatment Effect
timeFrame: Up to Week 24
measure: Investigator Preference of Injection Technique
timeFrame: Following last visit of the last subject at each site
Other outcomes:
Locations:
city: Aalborg
country: Denmark
facility: Aalborg Sygehus Nord
city: Glostrup
country: Denmark
facility: Glostrup Hospital
city: Hammel
country: Denmark
facility: Regionshospitalet Hammel
city: København NV
country: Denmark
facility: Bispebjerg Hospital
city: Roskilde
country: Denmark
facility: Roskilde Hospital
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Viborg
country: Denmark
facility: Regionshopsitalet Viborg
city: Joensuu
country: Finland
facility: North Karelia Central Hospital
city: Jyväskylä
country: Finland
facility: Central Hospital of Central Finland
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Skien
country: Norway
facility: Sykehuset Telemark HF
city: Eskilstuna
country: Sweden
facility: Mälarsjukhuset MSE
city: Göteborg
country: Sweden
facility: Sahlgrenska University Hospital
city: Halmstad
country: Sweden
facility: Hallands Sjukhus, Neurology Clinic
city: Härnösand
country: Sweden
facility: Sundsvall-Härnösand, Rehabilitation Medicine
city: Nyköping
country: Sweden
facility: Nyköpings Lasarett,
city: Stockholm
country: Sweden
facility: Neurology Clinic Stockholm
city: Stockholm
country: Sweden
facility: Danderyds Hospital,
city: Sävar
country: Sweden
facility: Neurorehab Sävar
city: Visby
country: Sweden
facility: Rehabilitation Center Gotland
city: Ystad
country: Sweden
facility: Ystad Lasarett
city: Örnsköldsvik
country: Sweden
facility: Örnsköldsviks Sjukhus, Neurology Clinic
city: Östersund
country: Sweden
facility: Östersunds Rehabilitation Center
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.