Arm Spasticity
Conditions
Keywords
Dysport, arm spasticity, Modified Ashworth Scale, neuromuscular junction, Botulinum toxin, upper limb spasticity
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.
Interventions
BIOLOGICALBotulinum toxin type A
Sponsors
Ipsen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| 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. |
| 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? |
| 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). |
Countries
Denmark, Finland, Norway, Sweden
Participant flow
Recruitment details
From September 2012, subjects were recruited across 20 sites in four countries: Denmark (5 sites), Finland (2 sites), Norway (2 sites) and Sweden (11 sites). Due to slow recruitment, the study was terminated early.
Pre-assignment details
272 subjects were planned to be randomised (136 subjects in each group). In total, 100 subjects were enrolled and 88 (44 subjects in each group) were randomised and received study medication; 12 subjects were screening failures.
Participants by arm
| Arm | Count |
|---|---|
| NMJ Targeted NMJ targeted technique and low-concentration dilution (Dysport 100 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. | 44 |
| Current Clinical Practice Current clinical practice technique and high-concentration dilution (Dysport 300 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. | 44 |
| Total | 88 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | NMJ Targeted | Current Clinical Practice | Total |
|---|---|---|---|
| Age, Customized | 57.1 years STANDARD_DEVIATION 11.4 | 60.3 years STANDARD_DEVIATION 14.4 | 58.7 years STANDARD_DEVIATION 13 |
| Region of Enrollment Denmark | 20 Participants | 19 Participants | 39 Participants |
| Region of Enrollment Finland | 5 Participants | 5 Participants | 10 Participants |
| Region of Enrollment Norway | 2 Participants | 3 Participants | 5 Participants |
| Region of Enrollment Sweden | 17 Participants | 17 Participants | 34 Participants |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 30 Participants |
| Sex: Female, Male Male | 30 Participants | 28 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 44 | 9 / 44 |
| serious Total, serious adverse events | 2 / 44 | 2 / 44 |
Outcome results
Primary
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.
Time frame: Baseline to Week 4
Population: The primary analysis was based on both the ITT and Per Protocol (PP) populations. The ITT population was all treated subjects having at least one Baseline assessment of the primary efficacy parameter. The PP population was all subjects in the ITT population for whom no major protocol violations or deviations occurred until Week 4 (Visit 2).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NMJ Targeted (ITT Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 | 25 responders |
| Current Clinical Practice (ITT Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 | 32 responders |
| NMJ Targeted (PP Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 | 17 responders |
| Current Clinical Practice (PP Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the Modified Ashworth Scale (MAS) at Week 4 | 20 responders |
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.098695% CI: [-0.363, 0.0284]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.568295% CI: [-0.363, 0.0284]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.85435% CI: [-0.363, 0.0284]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.916795% CI: [-0.363, 0.0284]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.605295% CI: [-0.1948, 0.3362]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.536995% CI: [-0.1948, 0.3362]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.773295% CI: [-0.1948, 0.3362]Generalised linear model
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.175895% CI: [-0.1948, 0.3362]Generalised linear model
Secondary
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).
Time frame: Up to Week 12
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter. Only subjects with non-missing values were included in the analysis. Only overall GAS score data are summarised below.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NMJ Targeted (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of -1 | 9 Participants |
| NMJ Targeted (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of +1 | 9 Participants |
| NMJ Targeted (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of 0 | 11 Participants |
| NMJ Targeted (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of +2 | 1 Participants |
| NMJ Targeted (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of -2 | 3 Participants |
| Current Clinical Practice (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of +2 | 1 Participants |
| Current Clinical Practice (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of -2 | 1 Participants |
| Current Clinical Practice (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of -1 | 15 Participants |
| Current Clinical Practice (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of 0 | 18 Participants |
| Current Clinical Practice (ITT Population) | Achievement of the Primary Goal Measured by Goal Attainment Scale (GAS) | Overall GAS score of +1 | 6 Participants |
p-value: 0.5747Mann-Whitney U-test
Secondary
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.
Time frame: Baseline to Week 12
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter. Only subjects with non-missing values were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NMJ Targeted (ITT Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12 | 13 responders |
| Current Clinical Practice (ITT Population) | Change From Baseline for Elbow Flexors Muscle Tone as Measured by the MAS at Week 12 | 19 responders |
Comparison: A responder was defined as a subject with at least one level decrease on the MAS scale.p-value: 0.2495% CI: [-0.3531, 0.0884]Generalised linear model
Secondary
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).
Time frame: Baseline to Week 12
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter. Only subjects with non-missing values were included in this analysis.~CCP=Current Clinical Practice; N'=number of subjects with data at each time point for each treatment group; NMJ=neuromuscular junction.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| NMJ Targeted (ITT Population) | 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 4 | -0.5 units on a scale |
| NMJ Targeted (ITT Population) | 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 | 0.0 units on a scale |
| Current Clinical Practice (ITT Population) | 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 4 | -1.0 units on a scale |
| Current Clinical Practice (ITT Population) | 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 | 0.0 units on a scale |
Secondary
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.
Time frame: Baseline, Week 4 and Week 12
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter.~CCP=Current Clinical Practice; N'=number of subjects with data at each time point for each treatment group; NMJ=neuromuscular junction.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| NMJ Targeted (ITT Population) | Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject | Week 4 | -5.80 Change in VAS from Baseline | Standard Deviation 23.07 |
| NMJ Targeted (ITT Population) | Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject | Week 12 | -0.03 Change in VAS from Baseline | Standard Deviation 26.02 |
| Current Clinical Practice (ITT Population) | Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject | Week 4 | -4.35 Change in VAS from Baseline | Standard Deviation 12.29 |
| Current Clinical Practice (ITT Population) | Change From Baseline of Spasticity Related Pain Measured by Visual Analogue Scale (VAS), Assessed by the Subject | Week 12 | 0.03 Change in VAS from Baseline | Standard Deviation 20.67 |
Comparison: Mean change in VAS from Baseline to Week 4.p-value: 0.9448ANOVA
Comparison: Mean change in VAS from Baseline to Week 12.p-value: 0.5458ANOVA
Secondary
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.
Time frame: Baseline
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter. Only subjects with non-missing values were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NMJ Targeted (ITT Population) | Injection Site Pain Measured by VAS at Day 1. | 25.67 mm | Standard Deviation 25.37 |
| Current Clinical Practice (ITT Population) | Injection Site Pain Measured by VAS at Day 1. | 30.68 mm | Standard Deviation 27.33 |
p-value: 0.4006ANOVA
Secondary
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?
Time frame: Following last visit of the last subject at each site
Population: The question on preferred injection technique was answered by 3 of the 20 Investigators.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NMJ Targeted (ITT Population) | Investigator Preference of Injection Technique | NMJ Targeted | 1 Investigators |
| NMJ Targeted (ITT Population) | Investigator Preference of Injection Technique | Current Clinical Practice | 2 Investigators |
Secondary
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.
Time frame: Up to Week 24
Population: ITT population: all treated subjects having at least one Baseline assessment of the primary efficacy parameter. Only subjects with non-missing values were included in the analysis. If a subject had more than one evaluation entry, the last one was used.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| NMJ Targeted (ITT Population) | Subject Global Evaluation of Treatment Effect | Better | 11 Participants |
| NMJ Targeted (ITT Population) | Subject Global Evaluation of Treatment Effect | Worse | 7 Participants |
| NMJ Targeted (ITT Population) | Subject Global Evaluation of Treatment Effect | No Change From Baseline | 18 Participants |
| NMJ Targeted (ITT Population) | Subject Global Evaluation of Treatment Effect | Much Worse | 1 Participants |
| NMJ Targeted (ITT Population) | Subject Global Evaluation of Treatment Effect | Much Better | 3 Participants |
| Current Clinical Practice (ITT Population) | Subject Global Evaluation of Treatment Effect | Much Worse | 0 Participants |
| Current Clinical Practice (ITT Population) | Subject Global Evaluation of Treatment Effect | Much Better | 2 Participants |
| Current Clinical Practice (ITT Population) | Subject Global Evaluation of Treatment Effect | Better | 16 Participants |
| Current Clinical Practice (ITT Population) | Subject Global Evaluation of Treatment Effect | No Change From Baseline | 20 Participants |
| Current Clinical Practice (ITT Population) | Subject Global Evaluation of Treatment Effect | Worse | 2 Participants |
p-value: 0.1802Mann-Whitney U-test