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Clinical Trial Results:
A phase III, randomised, double blind and open label phase, active and placebo controlled study comparing the short term efficacy of two formulations of clostridium botulinum type A toxin (Dysport and Dysport NG) to placebo, and assessing the short and long term efficacy and safety of Dysport NG following repeated treatments of subjects with cervical dystonia (CD).

Summary
EudraCT number	2010-019907-43
Trial protocol	PT CZ DE BE AT HU
Global end of trial date	04 Jun 2013

Results information
Results version number	v1(current)
This version publication date	02 Jun 2016
First version publication date	02 Jun 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

Y-52-52120-134

ISRCTN number

US NCT number

NCT01261611

WHO universal trial number (UTN)

Sponsor organisation name

Ipsen Innovation

Sponsor organisation address

5 Avenue du Canada, Les Ulis, France, 91940

Public contact

Medical Director, Neurology., Ipsen Innovation, clinical.trials@ipsen.com

Scientific contact

Medical Director, Neurology., Ipsen Innovation, clinical.trials@ipsen.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

20 May 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

01 May 2012

Global end of trial reached?

Yes

Global end of trial date

04 Jun 2013

Was the trial ended prematurely?

Main objective of the trial

The primary study objectives will be assessed in terms of improvement of the subject’s CD at a pre-defined time point after treatment. The primary study objectives are to demonstrate the superiority of Dysport NG to placebo in terms of efficacy and to test the non-inferior efficacy of Dysport NG, when compared to Dysport, in CD subjects. In addition to testing for the primary study objectives, the superiority in terms of efficacy of Dysport versus placebo, will be assessed.

Protection of trial subjects

This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.

Background therapy

Evidence for comparator

A large body of evidence demonstrates the safety and efficacy of Dysport across several clinical indications.This study was the first use of Dysport NG in humans with CD. The active substance (BTX-A-HAC) in Dysport NG was the same as in the currently marketed Dysport product and had the same mechanism of action. Dysport NG was, therefore, expected to have the same efficacy and safety profile in humans as Dysport, with the advantage of eliminating the potential risk of transmission of infective agents, by the substitution of plant and synthetic products for human and animal-derived products. However, due to the change of excipient, thorough assessment of the safety and efficacy of Dysport NG is necessary. Previous clinical studies indicate that the maximum effect of Dysport and maximum improvements in CD are observed approximately 4 weeks post treatment, after which there is a gradual return to baseline disease status. The Week 4 follow up visit after the first treatment cycle was therefore, chosen as the primary time point of interest. Retreatment is necessary in order to maintain the beneficial effect and the long term treatment of CD. Previously conducted long term studies demonstrate the maintenance of the therapeutic effect of Dysport following repeated treatments, with a favourable short and long term safety and immunogenicity profile.

Actual start date of recruitment

27 Apr 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 2

Country: Number of subjects enrolled

Russian Federation: 36

Country: Number of subjects enrolled

Ukraine: 62

Country: Number of subjects enrolled

Poland: 68

Country: Number of subjects enrolled

Portugal: 12

Country: Number of subjects enrolled

Austria: 9

Country: Number of subjects enrolled

Belgium: 9

Country: Number of subjects enrolled

Czech Republic: 58

Country: Number of subjects enrolled

France: 31

Country: Number of subjects enrolled

Germany: 38

Country: Number of subjects enrolled

Hungary: 44

Worldwide total number of subjects

369

EEA total number of subjects

269

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

328

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Patients recruited at 61 centres in Australia, Austria, Belgium, Czech Republic, France, Germany, Hungary, Poland, Portugal, Russia and Ukraine.

Screening details

382 subjects screened, 369 randomised due to 13 screen failures.

Period 1 title

Treatment Cycle 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

Dysport NG

Arm description

Up to 5 treatment cycles of Dysport NG

Arm type

Experimental

Investigational medicinal product name

Dysport NG

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

500U (1ml) administered as intramuscular injection on day 1 of treatment cycle 1.

Dysport

Arm description

1 treatment cycle of Dysport

Arm type

Active comparator

Investigational medicinal product name

Dysport

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

Dysport 500U (1ml) injected as intramuscular injection on day 1 of treatment cycle 1.

Placebo

Arm description

1 treatment cycle of placebo.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

1ml administered as, intramuscular injection on day 1 of treatment cycle 1.

Number of subjects in period 1	Dysport NG	Dysport	Placebo
Started	156	159	54
Completed	152	156	52
Not completed	4	3	2
Protocol violation	-	-	2
Adverse event	-	1	-
Withdrawal by Subject	3	2	-
Lost to follow-up	1	-	-

Period 2 title

Treatment Cycle 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Dysport NG

Arm description

Up to 5 treatment cycles of Dysport NG

Arm type

Experimental

Investigational medicinal product name

Dysport NG

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

500U (1ml) administered as intramuscular injection on day 1 of treatment cycle 2.

Number of subjects in period 2 ^[1]	Dysport NG
Started	359
Completed	346
Not completed	13
Protocol Violations	2
Not otherwise specified	2
Withdrawal by Subject	4
Completed study	4
Adverse Events	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Of 360 subjects who completed double blind period (Dysport NG / Dysport / Placebo arms) 359 subjects entered open label period (only one arm: Dysport NG). One subject was never retreated and then stayed at cycle 1 during all the study.

Period 3 title

Treatment Cycle 3

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Dysport NG

Arm description

Up to 5 treatment cycles of Dysport NG

Arm type

Experimental

Investigational medicinal product name

Dysport NG

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

250U (0.5ml), 500U (1ml) or 750U (1.5ml) administered as intramuscular injection on day 1 of treatment cycle 3.

Number of subjects in period 3	Dysport NG
Started	346
Completed	316
Not completed	30
Lost to Follow-up	1
Withdrawal by Subject	4
Completed study	24
Adverse Events	1

Period 4 title

Treatment Cycle 4

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Dysport NG

Arm description

Up to 5 treatment cycles of Dysport NG

Arm type

Experimental

Investigational medicinal product name

Dysport NG

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

250U (0.5ml), 500U (1ml), 750U (1.5ml) or 1000U (2ml) administered as intramuscular injection on day 1 of treatment cycle 4.

Number of subjects in period 4	Dysport NG
Started	316
Completed	220
Not completed	96
Lost to Follow-up	2
Not otherwise specified	3
Withdrawal by Subject	3
Adverse Events	1
Completed study	87

Period 5 title

Treatment Cycle 5

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Dysport NG

Arm description

Up to 5 treatment cycles of Dysport NG

Arm type

Experimental

Investigational medicinal product name

Dysport NG

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intramuscular use

Dosage and administration details

250U (0.5ml), 500U (1ml), 750U (1.5ml) or 1000U (2ml) administered as intramuscular injection on day 1 of treatment cycle 5.

Number of subjects in period 5	Dysport NG
Started	220
Completed	217
Not completed	3
Lost to Follow-up	1
Withdrawal by Subject	1
Adverse Events	1

Baseline characteristics

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Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Reporting group title

Dysport

Reporting group description

1 treatment cycle of Dysport

Reporting group title

Placebo

Reporting group description

1 treatment cycle of placebo.

Reporting group values	Dysport NG	Dysport	Placebo	Total
Number of subjects	156	159	54	369
Age categorical
Units: Subjects
Age continuous
ITT population was all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered.
Units: years
arithmetic mean (standard deviation)	51.6 ± 12.4	49.1 ± 12	49.7 ± 10.8	-
Gender categorical
ITT population
Units: Subjects
Female	100	101	34	235
Male	56	58	20	134
Race (NIH/OMB)
ITT population
Units: Subjects
Asian	0	0	1	1
Black or African American	0	1	1	2
White	154	154	49	357
Unknown or Not Reported	2	4	3	9
Time since diagnosis of CD, years
Units: years
arithmetic mean (standard deviation)	7.13 ± 7.95	6.88 ± 7.49	6.25 ± 7.31	-
Baseline TWSTRS score
Units: unit on scale
arithmetic mean (standard deviation)	44.56 ± 9.2	46.23 ± 8.82	47.02 ± 9.19	-

End points

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Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Reporting group title

Dysport

Reporting group description

1 treatment cycle of Dysport

Reporting group title

Placebo

Reporting group description

1 treatment cycle of placebo.

Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Reporting group title

Dysport NG

Reporting group description

Up to 5 treatment cycles of Dysport NG

Subject analysis set title

Dysport NG

Subject analysis set type

Intention-to-treat

Subject analysis set description

All doses

Primary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle

End point description

TWSTRS is comprised of three different components namely severity, disability and pain. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS total score is the sum of the 3 component scores ranging from 0 to a maximum of 85. Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Primary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-12.46 (-14.3 to -10.62)	-13.99 (-15.78 to -12.21)	-3.93 (-6.74 to -1.12)

LS mean difference - Dysport NG vs Placebo

Comparison groups

Dysport NG v Placebo

Number of subjects included in analysis

210

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

ANCOVA

Confidence interval

Notes
[1] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed.

LS mean difference - Dysport vs Placebo

Comparison groups

Dysport v Placebo

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

< 0.0001

Method

ANCOVA

Confidence interval

Notes
[2] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed.

LS mean difference - Dysport NG vs Dysport

Comparison groups

Dysport NG v Dysport

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

non-inferiority ^[3]

Method

Parameter type

LS mean difference

Point estimate

1.532

Confidence interval

level

95%

sides

2-sided

lower limit

-0.819

upper limit

3.883

Notes
[3] - An ANCOVA on the change from baseline with treatment, baseline TWSTRS total score, BTX status at baseline and pooled centre as explanatory variables had been performed. The non-inferiority margin was 3 points.

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle

End point description

TWSTRS Severity scores range from 0 (absence of severity) to 35 (maximum severity). Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-6.2 (-7 to -5.4)	-6.6 (-7.3 to -5.8)	-1.9 (-3.1 to -0.6)

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle

End point description

TWSTRS Disability scores range from 0 (no disability) to 30 (maximum disability). Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-3.3 (-4.1 to -2.6)	-3.9 (-4.7 to -3.2)	-0.8 (-1.9 to 0.4)

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle

End point description

TWSTRS Pain scores range from 0 (no pain) to 20 (maximum pain).

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-3.1 (-3.7 to -2.51)	-3.44 (-4.03 to -2.86)	-1.21 (-2.12 to -0.29)

No statistical analyses for this end point

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle

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End point title

Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle

End point description

The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain). Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-14.8 (-19 to -10.7)	-19.2 (-23.3 to -15.2)	-3.4 (-9.8 to 3)

No statistical analyses for this end point

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle

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End point title

Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle

End point description

The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no symptoms) to 100mm (worst possible symptoms). Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	159	54
Units: units on a scale
least squares mean (confidence interval 95%)	-18.7 (-22.7 to -14.7)	-23.6 (-27.5 to -19.7)	-3.3 (-9.4 to 2.8)

No statistical analyses for this end point

Secondary: Percentage of Treatment Responders Following First Treatment Cycle

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End point title

Percentage of Treatment Responders Following First Treatment Cycle

End point description

Analysis based on number of subjects in the Intent to Treat (ITT) population.

End point type

Secondary

End point timeframe

Baseline and Week 4

End point values	Dysport NG	Dysport	Placebo
Number of subjects analysed	156	156	54
Units: percentage of participants
number (not applicable)	45.8	55.8	20.8

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5

End point description

The change in TWSTRS total score is the score at week 4 minus the score at baseline. Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-15.35 (-16.36 to -14.34)
Cycle 3 (n=346)	-14.85 (-15.86 to -13.84)
Cycle 4 (n=316)	-15.58 (-16.61 to -14.55)
Cycle 5 (n=220)	-15.28 (-16.42 to -14.14)

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5

End point description

TWSTRS Severity scores range from 0 (absence of severity) to 35 (maximum severity). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	349
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-7.2 (-7.6 to -6.7)
Cycle 3 (n=346)	-7.1 (-7.5 to -6.6)
Cycle 4 (n=316)	-7.3 (-7.7 to -6.8)
Cycle 5 (n=220)	-7 (-7.5 to -6.4)

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5

End point description

TWSTRS Disability scores range from 0 (no disability) to 30 (maximum disability). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-4.7 (-5.2 to -4.3)
Cycle 3 (n=346)	-4.6 (-5 to -4.1)
Cycle 4 (n=316)	-5 (-5.5 to -4.5)
Cycle 5 (n=220)	-4.9 (-5.5 to -4.3)

No statistical analyses for this end point

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5

End point description

TWSTRS Pain scores range from 0 (no pain) to 20 (maximum pain). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-3.45 (-3.8 to -3.1)
Cycle 3 (n=346)	-3.21 (-3.57 to -2.85)
Cycle 4 (n=316)	-3.34 (-3.69 to -2.98)
Cycle 5 (n=220)	-3.41 (-3.79 to -3.04)

No statistical analyses for this end point

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5

End point description

The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain).

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-20.1 (-22.5 to -17.6)
Cycle 3 (n=346)	-17.8 (-20.4 to -15.2)
Cycle 4 (n=316)	-18 (-20.5 to -15.4)
Cycle 5 (n=220)	-16.1 (-19.3 to -12.8)

No statistical analyses for this end point

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5

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End point title

Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5

End point description

The assessment was made on a continuous 100-mm horizontal line with a scale of 0 mm (no symptoms) to 100 mm (worst possible symptoms). Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: units on a scale
arithmetic mean (confidence interval 95%)
Cycle 2 (n=359)	-24 (-26.4 to -21.7)
Cycle 3 (n=346)	-18.9 (-21.4 to -16.4)
Cycle 4 (n=316)	-21 (-23.5 to -18.5)
Cycle 5 (n=220)	-18.2 (-21.2 to -15.2)

No statistical analyses for this end point

Secondary: Percentage of Treatment Responders for Treatment Cycles 2 to 5

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End point title

Percentage of Treatment Responders for Treatment Cycles 2 to 5

End point description

Analysis based on number (n) of subjects in the Intent to Treat (ITT) population in each Cycle.

End point type

Secondary

End point timeframe

Treatment cycle Baseline and Week 4

End point values	Dysport NG
Number of subjects analysed	359
Units: percentage of participants
number (not applicable)
Cycle 2 (n=359)	58.5
Cycle 3 (n=346)	56.8
Cycle 4 (n=316)	63.5
Cycle 5 (n=220)	57.5

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

2 years

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.0

Reporting group title

Dysport NG, 250 U

Reporting group description

Reporting group title

Dysport NG, 500 U

Reporting group description

Reporting group title

Dysport NG, 750 U

Reporting group description

Reporting group title

Dysport NG, 1000 U

Reporting group description

Reporting group title

Dysport, 500 U

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	Dysport NG, 250 U	Dysport NG, 500 U	Dysport NG, 750 U	Dysport NG, 1000 U	Dysport, 500 U	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 4 (0.00%)	16 / 363 (4.41%)	3 / 210 (1.43%)	1 / 57 (1.75%)	3 / 156 (1.92%)	0 / 55 (0.00%)
number of deaths (all causes)	0	2	0	0	0	0
number of deaths resulting from adverse events	0	2	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	0 / 57 (0.00%)	1 / 156 (0.64%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	0 / 57 (0.00%)	1 / 156 (0.64%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion malignant
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	0 / 57 (0.00%)	1 / 156 (0.64%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Clavicle fracture
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic dissection
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	1 / 210 (0.48%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paget-Schroetter syndrome
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	1 / 210 (0.48%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis haemorrhagic
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	1 / 57 (1.75%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	1 / 57 (1.75%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal perforation
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	1 / 210 (0.48%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine polyp
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	0 / 57 (0.00%)	1 / 156 (0.64%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Completed suicide
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid cyst
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Proctitis infectious
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal abscess
subjects affected / exposed	0 / 4 (0.00%)	1 / 363 (0.28%)	0 / 210 (0.00%)	0 / 57 (0.00%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia streptococcal
subjects affected / exposed	0 / 4 (0.00%)	0 / 363 (0.00%)	0 / 210 (0.00%)	0 / 57 (0.00%)	1 / 156 (0.64%)	0 / 55 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Dysport NG, 250 U	Dysport NG, 500 U	Dysport NG, 750 U	Dysport NG, 1000 U	Dysport, 500 U	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	59 / 363 (16.25%)	29 / 210 (13.81%)	7 / 57 (12.28%)	15 / 156 (9.62%)	1 / 55 (1.82%)
Gastrointestinal disorders
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	38 / 363 (10.47%)	20 / 210 (9.52%)	5 / 57 (8.77%)	11 / 156 (7.05%)	0 / 55 (0.00%)
occurrences all number	0	54	25	5	11	0
Musculoskeletal and connective tissue disorders
Muscular weakness
subjects affected / exposed	1 / 4 (25.00%)	11 / 363 (3.03%)	13 / 210 (6.19%)	6 / 57 (10.53%)	0 / 156 (0.00%)	0 / 55 (0.00%)
occurrences all number	1	15	14	6	0	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	21 / 363 (5.79%)	9 / 210 (4.29%)	2 / 57 (3.51%)	4 / 156 (2.56%)	1 / 55 (1.82%)
occurrences all number	0	26	9	2	4	1

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Were there any global substantial amendments to the protocol? Yes

25 Jun 2012

Protocol Amendment 5 (Substantial): The protocol was amended to update the contact information for the Sponsor’s Medical and Clinical contacts, remove the pharmacovigilance/emergency contact details from the US, to replace Ipsen Pharma with Kymos Pharma as a CRO for processing binding antibody samples and ensure consistency across all studies with regard to the IB used for assessment of expectedness.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle

Primary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle

Secondary: Percentage of Treatment Responders Following First Treatment Cycle

Secondary: Percentage of Treatment Responders Following First Treatment Cycle

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5

Secondary: Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5

Secondary: Percentage of Treatment Responders for Treatment Cycles 2 to 5

Secondary: Percentage of Treatment Responders for Treatment Cycles 2 to 5

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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