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

• Sponsor: Ipsen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01682148
• Collaborator: (none)
• Enrollment: 100
• Locations: 23
• Arms: 2
• Duration (Months): 29.9
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Arm Spasticity	Biological: Botulinum toxin type A	Phase 3

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 Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Sep 1, 2012
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

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®)

Outcome Measures

Primary Outcome Measures

1. 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

1. 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).

2. 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.

3. 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.

4. 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.

5. 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).

6. 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.

7. 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?"

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aalborg Sygehus Nord	Aalborg		Denmark	9000
2	Glostrup Hospital	Glostrup		Denmark	2600
3	Regionshospitalet Hammel	Hammel		Denmark	8450
4	Bispebjerg Hospital	København NV		Denmark	2400
5	Roskilde Hospital	Roskilde		Denmark	4000
6	Vejle Hospital	Vejle		Denmark	7100
7	Regionshopsitalet Viborg	Viborg		Denmark	8800
8	North Karelia Central Hospital	Joensuu		Finland	80210
9	Central Hospital of Central Finland	Jyväskylä		Finland	40503
10	Haukeland University Hospital	Bergen		Norway	5021
11	Sykehuset Telemark HF	Skien		Norway	, 3700
12	Mälarsjukhuset MSE	Eskilstuna		Sweden	631-88
13	Sahlgrenska University Hospital	Göteborg		Sweden
14	Hallands Sjukhus, Neurology Clinic	Halmstad		Sweden	30185
15	Sundsvall-Härnösand, Rehabilitation Medicine	Härnösand		Sweden	87182
16	Nyköpings Lasarett,	Nyköping		Sweden	61185
17	Neurology Clinic Stockholm	Stockholm		Sweden	114 33
18	Danderyds Hospital,	Stockholm		Sweden	18288
19	Neurorehab Sävar	Sävar		Sweden	91831
20	Rehabilitation Center Gotland	Visby		Sweden	62184
21	Ystad Lasarett	Ystad		Sweden	27133
22	Örnsköldsviks Sjukhus, Neurology Clinic	Örnsköldsvik		Sweden	891 89
23	Östersunds Rehabilitation Center	Östersund		Sweden	83102

Sponsors and Collaborators

• Ipsen

Investigators

• Study Director: Ipsen Medical Director, Ipsen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT01682148
• Other Study ID Numbers: A-99-52120-162; 2011-005375-16
• First Posted: Sep 10, 2012
• Last Update Posted: Aug 6, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Ipsen: Dysport; arm spasticity; Modified Ashworth Scale; neuromuscular junction; Botulinum toxin; upper limb spasticity
• Additional relevant MeSH terms: Muscle Spasticity; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA

Study Results

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 Detail	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.

Arm/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	Neuromuscular junction (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.	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.
Period Title: Overall Study
STARTED	44	44
COMPLETED	40	41
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	NMJ Targeted	Current Clinical Practice	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	44	44	88
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (11.4)	60.3 (14.4)	58.7 (13.0)
Sex: Female, Male (Count of Participants)
Female	14 31.8%	16 36.4%	30 34.1%
Male	30 68.2%	28 63.6%	58 65.9%
Region of Enrollment (Count of Participants)
Sweden	17 38.6%	17 38.6%	34 38.6%
Norway	2 4.5%	3 6.8%	5 5.7%
Finland	5 11.4%	5 11.4%	10 11.4%
Denmark	20 45.5%	19 43.2%	39 44.3%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted (ITT Population)	Current Clinical Practice (ITT Population)	NMJ Targeted (PP Population)	Current Clinical Practice (PP Population)
Arm/Group Description	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.	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.	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.	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.
Measure Participants	44	44	25	29
Number [responders]	25	32	17	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a responder rate (π) of 63% in the reference group, a clinically relevant delta (Δ) of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.0986
	Comments	Based on a generalised linear model including factors for treatment.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.1673
	Confidence Interval	(2-Sided) 95%; -0.3630 to 0.0284
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.5682
	Comments	Based on a generalised linear model including factors for spasticity pattern.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.1673
	Confidence Interval	(2-Sided) 95%; -0.3630 to 0.0284
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.8543
	Comments	Based on a generalised linear model including factors for country.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.1673
	Confidence Interval	(2-Sided) 5%; -0.3630 to 0.0284
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.9167
	Comments	Based on a generalised linear model including factors for MAS at Baseline.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.1673
	Confidence Interval	(2-Sided) 95%; -0.3630 to 0.0284
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (PP Population), Current Clinical Practice (PP Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.6052
	Comments	Based on a generalised linear model including factors for treatment.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.0707
	Confidence Interval	(2-Sided) 95%; -0.1948 to 0.3362
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (PP Population), Current Clinical Practice (PP Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.5369
	Comments	Based on a generalised linear model including factors for spasticity pattern.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.0707
	Confidence Interval	(2-Sided) 95%; -0.1948 to 0.3362
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (PP Population), Current Clinical Practice (PP Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.7732
	Comments	Based on a generalised linear model including factors for country.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.0707
	Confidence Interval	(2-Sided) 95%; -0.1948 to 0.3362
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (PP Population), Current Clinical Practice (PP Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Based on a π of 63% in the reference group, a clinically relevant Δ of 17%, α=2.5% (one sided) and power=80%, the sample size estimate yielded 122 valid subjects per group. Including a 10% addition for premature withdrawals, 136 subjects per group were necessary to be randomised in the study (i.e., a total of 272 subjects).
Statistical Test of Hypothesis	p-Value	0.1758
	Comments	Based on a generalised linear model including factors for MAS at Baseline.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	0.0707
	Confidence Interval	(2-Sided) 95%; -0.1948 to 0.3362
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	40	43
Baseline to Week 4	-0.5	-1.0
Baseline to Week 12	0.0	0.0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	39	39
Number [responders]	13	19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	A responder was defined as a subject with at least one level decrease on the MAS scale.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2400
	Comments	Based on a generalised linear model including factors for treatment, spasticity pattern, country and MAS baseline score.
	Method	Generalised linear model
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	-0.1324
	Confidence Interval	(2-Sided) 95%; -0.3531 to 0.0884
	Parameter Dispersion	Type: Value:
	Estimation Comments	Difference of the two clinical success rates (NMJ Targeted minus Current Clinical Practice).

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	44	44
Week 4	-5.80 (23.07)	-4.35 (12.29)
Week 12	-0.03 (26.02)	0.03 (20.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	Mean change in VAS from Baseline to Week 4.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9448
	Comments
	Method	ANOVA
	Comments	Analysis of variance (ANOVA) included factors for treatment, spasticity pattern and country, and Baseline VAS as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments	Mean change in VAS from Baseline to Week 12.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5458
	Comments
	Method	ANOVA
	Comments	ANOVA included factors for treatment, spasticity pattern and country, and Baseline VAS as a covariate.

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	36	37
Mean (Standard Deviation) [mm]	25.67 (25.37)	30.68 (27.33)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4006
	Comments
	Method	ANOVA
	Comments	ANOVA included factors for treatment, spasticity pattern and country.

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	33	41
Overall GAS score of -2	3 6.8%	1 2.3%
Overall GAS score of -1	9 20.5%	15 34.1%
Overall GAS score of 0	11 25%	18 40.9%
Overall GAS score of +1	9 20.5%	6 13.6%
Overall GAS score of +2	1 2.3%	1 2.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5747
	Comments
	Method	Mann-Whitney U-test
	Comments

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	NMJ Targeted	Current Clinical Practice
Arm/Group Description	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.	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.
Measure Participants	40	40
Much Better	3 6.8%	2 4.5%
Better	11 25%	16 36.4%
No Change From Baseline	18 40.9%	20 45.5%
Worse	7 15.9%	2 4.5%
Much Worse	1 2.3%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	NMJ Targeted (ITT Population), Current Clinical Practice (ITT Population)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1802
	Comments
	Method	Mann-Whitney U-test
	Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The question on preferred injection technique was answered by 3 of the 20 Investigators.

Arm/Group Title	Number of Investigators Who Responded
Arm/Group Description	Investigator preference for using the NMJ Targeted versus the Current Clinical Practice technique was requested at each of the 20 sites (20 Investigators).
Measure Participants	3
NMJ Targeted	1
Current Clinical Practice	2

Adverse Events

Time Frame	Adverse events (AEs) were monitored from informed consent to the time when the subject's participation in the study ended (Week 12 to Week 24 (Visit 3 or Visit 4)). AEs were elicited by direct, non-leading questioning at each clinic visit or by spontaneous reports.
Adverse Event Reporting Description	The safety population was defined as all subjects who received at least one dose of study medication. The safety population was analysed using subjects as treated. If a subject experienced more than one event in a System Organ Class (SOC), the subject was counted only once in that SOC.
Arm/Group Title	NMJ Targeted		Current Clinical Practice
Arm/Group Description	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.		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 .
All Cause Mortality
	NMJ Targeted		Current Clinical Practice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	NMJ Targeted		Current Clinical Practice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/44 (4.5%)		2/44 (4.5%)
Infections and infestations
Cystitis	1/44 (2.3%)		0/44 (0%)
Urinary tract infection	0/44 (0%)		1/44 (2.3%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/44 (2.3%)		0/44 (0%)
Nervous system disorders
Epilepsy	0/44 (0%)		1/44 (2.3%)
Other (Not Including Serious) Adverse Events
	NMJ Targeted		Current Clinical Practice
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/44 (29.5%)		9/44 (20.5%)
Gastrointestinal disorders
Vomiting	1/44 (2.3%)		0/44 (0%)
Diarrhoea	0/44 (0%)		1/44 (2.3%)
Dysphagia	0/44 (0%)		1/44 (2.3%)
Gastritis	0/44 (0%)		1/44 (2.3%)
General disorders
Fatigue	1/44 (2.3%)		1/44 (2.3%)
Influenza like illness	0/44 (0%)		1/44 (2.3%)
Injection site hypersensitivity	0/44 (0%)		1/44 (2.3%)
Infections and infestations
Eye infection	1/44 (2.3%)		0/44 (0%)
Upper respiratory tract infection	1/44 (2.3%)		0/44 (0%)
Urinary tract infection	0/44 (0%)		3/44 (6.8%)
Nasopharyngitis	0/44 (0%)		1/44 (2.3%)
Injury, poisoning and procedural complications
Contusion	1/44 (2.3%)		0/44 (0%)
Fall	1/44 (2.3%)		0/44 (0%)
Muscle strain	1/44 (2.3%)		0/44 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	2/44 (4.5%)		0/44 (0%)
Back pain	1/44 (2.3%)		0/44 (0%)
Bursitis	1/44 (2.3%)		0/44 (0%)
Nervous system disorders
Headache	3/44 (6.8%)		0/44 (0%)
Epilepsy	1/44 (2.3%)		1/44 (2.3%)
Neuralgia	1/44 (2.3%)		0/44 (0%)
Migraine	1/44 (2.3%)		0/44 (0%)
Syncope	1/44 (2.3%)		0/44 (0%)
Psychiatric disorders
Depression	1/44 (2.3%)		0/44 (0%)
Reproductive system and breast disorders
Epididymitis	1/44 (2.3%)		1/44 (2.3%)
Acquired hydrocele	0/44 (0%)		1/44 (2.3%)
Skin and subcutaneous tissue disorders
Pain of skin	0/44 (0%)		1/44 (2.3%)

Limitations/Caveats

Due to slow recruitment, the study was terminated early. Therefore, fewer subjects than planned were enrolled.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor required reasonable opportunity to review any abstract, presentation or paper before the material was submitted for publication or communicated. This also applied to any amendments that were requested by referees or journal editors. The Sponsor committed to comment on the draft documents within the time period agreed in the contractual arrangements between the Sponsor and authors or their institution. Delays were also possible if publication would adversely affect patentability.