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

Primary Purpose

Arm Spasticity

Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Botulinum toxin type A
Sponsored by
Ipsen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Arm Spasticity focused on measuring Dysport, arm spasticity, Modified Ashworth Scale, neuromuscular junction, Botulinum toxin, upper limb spasticity

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Aalborg Sygehus Nord
  • Glostrup Hospital
  • Regionshospitalet Hammel
  • Bispebjerg Hospital
  • Roskilde Hospital
  • Vejle Hospital
  • Regionshopsitalet Viborg
  • North Karelia Central Hospital
  • Central Hospital of Central Finland
  • Haukeland University Hospital
  • Sykehuset Telemark HF
  • Mälarsjukhuset MSE
  • Sahlgrenska University Hospital
  • Hallands Sjukhus, Neurology Clinic
  • Sundsvall-Härnösand, Rehabilitation Medicine
  • Nyköpings Lasarett,
  • Neurology Clinic Stockholm
  • Danderyds Hospital,
  • Neurorehab Sävar
  • Rehabilitation Center Gotland
  • Ystad Lasarett
  • Örnsköldsviks Sjukhus, Neurology Clinic
  • Östersunds Rehabilitation Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

NMJ Targeted

Current Clinical Practice

Arm Description

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 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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
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.
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.
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).
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.
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?"

Full Information

First Posted
September 6, 2012
Last Updated
September 15, 2022
Sponsor
Ipsen
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1. Study Identification

Unique Protocol Identification Number
NCT01682148
Brief Title
Comparing Lower-concentration Dysport Treatment Targeted to the Neuromuscular Junction With Current Clinical Practice
Acronym
NMJ
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

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Terminated
Why Stopped
The study was terminated early due to slow recruitment.
Study Start Date
September 2012 (undefined)
Primary Completion Date
March 2015 (Actual)
Study Completion Date
March 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ipsen

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Arm Spasticity
Keywords
Dysport, arm spasticity, Modified Ashworth Scale, neuromuscular junction, Botulinum toxin, upper limb spasticity

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
NMJ Targeted
Arm Type
Experimental
Arm Description
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.
Arm Title
Current Clinical Practice
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Botulinum toxin type A
Other Intervention Name(s)
AbobotulinumtoxinA (Dysport®)
Primary Outcome Measure Information:
Title
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4
Description
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.
Time Frame
Baseline to Week 4
Secondary Outcome Measure Information:
Title
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 and Week 12
Description
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).
Time Frame
Baseline to Week 12
Title
Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12
Description
A clinically relevant change was one level decrease on the MAS scale. Subjects meeting the defined decrease at Week 12 were considered as responders.
Time Frame
Baseline to Week 12
Title
Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject
Description
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.
Time Frame
Baseline, Week 4 and Week 12
Title
Injection Site Pain Measured by VAS at Day 1.
Description
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.
Time Frame
Baseline
Title
Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS)
Description
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).
Time Frame
Up to Week 12
Title
Subject Global Evaluation of Treatment Effect
Description
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.
Time Frame
Up to Week 24
Title
Investigator Preference of Injection Technique
Description
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?"
Time Frame
Following last visit of the last subject at each site

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ipsen Medical Director
Organizational Affiliation
Ipsen
Official's Role
Study Director
Facility Information:
Facility Name
Aalborg Sygehus Nord
City
Aalborg
ZIP/Postal Code
9000
Country
Denmark
Facility Name
Glostrup Hospital
City
Glostrup
ZIP/Postal Code
2600
Country
Denmark
Facility Name
Regionshospitalet Hammel
City
Hammel
ZIP/Postal Code
8450
Country
Denmark
Facility Name
Bispebjerg Hospital
City
København NV
ZIP/Postal Code
2400
Country
Denmark
Facility Name
Roskilde Hospital
City
Roskilde
ZIP/Postal Code
4000
Country
Denmark
Facility Name
Vejle Hospital
City
Vejle
ZIP/Postal Code
7100
Country
Denmark
Facility Name
Regionshopsitalet Viborg
City
Viborg
ZIP/Postal Code
8800
Country
Denmark
Facility Name
North Karelia Central Hospital
City
Joensuu
ZIP/Postal Code
80210
Country
Finland
Facility Name
Central Hospital of Central Finland
City
Jyväskylä
ZIP/Postal Code
40503
Country
Finland
Facility Name
Haukeland University Hospital
City
Bergen
ZIP/Postal Code
5021
Country
Norway
Facility Name
Sykehuset Telemark HF
City
Skien
ZIP/Postal Code
, 3700
Country
Norway
Facility Name
Mälarsjukhuset MSE
City
Eskilstuna
ZIP/Postal Code
631-88
Country
Sweden
Facility Name
Sahlgrenska University Hospital
City
Göteborg
Country
Sweden
Facility Name
Hallands Sjukhus, Neurology Clinic
City
Halmstad
ZIP/Postal Code
30185
Country
Sweden
Facility Name
Sundsvall-Härnösand, Rehabilitation Medicine
City
Härnösand
ZIP/Postal Code
87182
Country
Sweden
Facility Name
Nyköpings Lasarett,
City
Nyköping
ZIP/Postal Code
61185
Country
Sweden
Facility Name
Neurology Clinic Stockholm
City
Stockholm
ZIP/Postal Code
114 33
Country
Sweden
Facility Name
Danderyds Hospital,
City
Stockholm
ZIP/Postal Code
18288
Country
Sweden
Facility Name
Neurorehab Sävar
City
Sävar
ZIP/Postal Code
91831
Country
Sweden
Facility Name
Rehabilitation Center Gotland
City
Visby
ZIP/Postal Code
62184
Country
Sweden
Facility Name
Ystad Lasarett
City
Ystad
ZIP/Postal Code
27133
Country
Sweden
Facility Name
Örnsköldsviks Sjukhus, Neurology Clinic
City
Örnsköldsvik
ZIP/Postal Code
891 89
Country
Sweden
Facility Name
Östersunds Rehabilitation Center
City
Östersund
ZIP/Postal Code
83102
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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/).
IPD Sharing URL
https://vivli.org/members/ourmembers/
Citations:
PubMed Identifier
31061021
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.
Results Reference
derived

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

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