Study Comparing Short Term Efficacy of Dysport and Dysport NG to Placebo, and to Assess Efficacy and Safety of Dysport NG of Subjects With Cervical Dystonia

• Sponsor: Ipsen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01261611
• Collaborator: (none)
• Enrollment: 382
• Locations: 57
• Arms: 3
• Duration (Months): 26
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate how well a new drug called Dysport NG works and how safe it is, when it is used for the treatment of cervical dystonia. Dysport NG will be compared to an approved drug called Dysport.

Condition or Disease	Intervention/Treatment	Phase
Cervical Dystonia	Biological: Botulinum toxin type A; Biological: Botulinum toxin type A; Drug: Placebo	Phase 3

Detailed Description

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.

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.

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 382 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dysport NG 500U (1mL) administered as intramuscular injection on day 1 of treatment cycle 1 and 2. 250U (0.5mL), 500U (1mL) or 750U (1.5mL) administered as intramuscular injection on day 1 of treatment cycle 3. 250U (0.5mL), 500U (1mL), 750U (1.5mL) or 1000U (2mL) administered as intramuscular injection on day 1 of treatment cycle 4 and 5.	Biological: Botulinum toxin type A; I.M. (in the muscle) injection on day 1 of up to 5 treatment cycles.; Other Names: AbobotulinumtoxinA (DysportRU®)
Active Comparator: Dysport 500U (1mL) injected as intramuscular injection on day 1 of treatment cycle 1.	Biological: Botulinum toxin type A; I.M. injection on day 1 of treatment cycle 1.; Other Names: AbobotulinumtoxinA (Dysport®)
Placebo Comparator: Placebo 1mL administered as, intramuscular injection on day 1 of treatment cycle 1.	Drug: Placebo; I.M. injection on day 1 of treatment cycle 1.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle [Baseline and Week 4]

   TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.

Secondary Outcome Measures

1. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle [Baseline and Week 4]

   TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.

2. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle [Baseline and Week 4]

   TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.

3. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle [Baseline and Week 4]

   TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.

4. Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle [Baseline and Week 4]

   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).

5. Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle [Baseline and Week 4]

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

6. Percentage of Treatment Responders Following First Treatment Cycle [Baseline and Week 4]

   A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.

7. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

   TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.

8. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

   TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.

9. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

   TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.

10. Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

    TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.

11. Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

    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).

12. Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

    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).

13. Percentage of Treatment Responders for Treatment Cycles 2 to 5 [Treatment cycle Baseline and Week 4]

    A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Dystonia with at least 18 months duration since onset.

• Previously untreated with Botulinum toxin-A (BTX-A) or -B or a minimum of 14 weeks since the last injection.

• TWSTRS score at baseline of: Total score ≥ 30, Severity Sub-Scale score ≥ 15, Disability Sub-Scale score ≥ 3, Pain Sub-Scale score ≥ 2.

Exclusion Criteria:

• Known hypersensitivity to Botulinum toxin (BTX) or related compounds or any component in the study drug formulation (including cow milk protein).

• Pure anterocollis or pure retrocollis.

• In apparent remission from Cervical Dystonia.

• Known clinically significant underlying swallowing or respiratory abnormality which might be exacerbated by BTX treatment.

• Previous poor response to BTX treatment or known presence of BTX neutralising antibodies.

• Previous phenol or alcohol injections into the neck muscles.

• Previous myotomy or denervation surgery involving the neck or shoulder region.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Monash Medical Centre	Clayton		Australia
2	Austin Hospital	Heidelberg		Australia
3	Department of Neurosciences Alfred Hospital	Prahran		Australia
4	Westmead Hospital	Westmead		Australia
5	Univ.-Klinik für Neurologie	Innsbruck		Austria
6	Univ.-Klinik für Neurologie	Wien		Austria
7	AZ St. Jan	Brugge		Belgium
8	Universitair Ziekenhuis Antwerpen	Edegem		Belgium
9	AZ Sint Lucas	Gent		Belgium
10	Centre Hospitalier Universitaire de Liège	Liège		Belgium
11	HH Ziekenhuis	Roeselare		Belgium
12	Fakultni nemocnice Brno	Brno		Czechia
13	Pardubicka krajska nemocnice	Pardubice		Czechia
14	RESEARCH SITE s.r.o.	Plzen		Czechia
15	Vseobecna fakultni nemocnice v Praze	Praha		Czechia
16	CHU Amiens	Amiens		France
17	Hopital Neurologique	Bron		France
18	CHU Caremeau	Nîmes		France
19	CHU Bordeaux	Pessac		France
20	CHU Strasbourg	Strasbourg		France
21	Hopital Purpan	Toulouse		France
22	Neurologische Klinik u. Poliklinik	Berlin		Germany
23	Neurologische Klinik u. Poliklinik	Bonn		Germany
24	Neurologische Klinik	Düsseldorf		Germany
25	Neurologische Klinik	Halle		Germany
26	Neurologische Klinik	Hannover		Germany
27	Neurologische Klinik	Leipzig		Germany
28	Neurologische Klinik	München		Germany
29	Neurologische Klinik	Tübingen		Germany
30	Neurologische Klinik	Wiesbaden		Germany
31	Neurologische Klinik	Würzburg		Germany
32	Semmelweis Egyetem	Budapest		Hungary
33	Jósa András Oktató Kórház Nonprofit Kft.	Nyíregyháza		Hungary
34	Pécsi Tudományegyetem	Pécs		Hungary
35	Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ	Szeged		Hungary
36	Pomorskie Centrum Traumatologii im. M. Kopernika w Gdansku	Gdansk		Poland
37	Specjalistyczna Praktyka Lekarska	Katowice		Poland
38	Malopolskie Centrum Medyczne	Krakow		Poland
39	Gabinet Lekarski	Lodz		Poland
40	Niepubliczny Zaklad Opieki Zdrowotnej	Poznan		Poland
41	Samodzielny Publiczny Centralny Szpital Kliniczny	Warszawa		Poland
42	Hospital Santa Maria	Lisboa		Portugal
43	Hospital Geral de Santo Antonio	Porto		Portugal
44	Research Medical Complex "Vashe Zdorovie"	Kazan		Russian Federation
45	Research Center of Neurology of RAMS	Moscow		Russian Federation
46	Nizhniy Novgorod Research Institute for Traumatology and Orthopaedics	Nizhniy Novgorod		Russian Federation
47	Samara Regional Clinical Hospital	Samara		Russian Federation
48	Smolensk State Medical Academy Smolensk Regional Clinical Hospital	Smolensk		Russian Federation
49	Russian Medical Military Academy n.a. S.M.Kirov	St. Petersburg		Russian Federation
50	Bukovinian Medical State University	Chernivtsi		Ukraine
51	Ukrainian State Institute of Medical and Social Problems of Disability	Dnipropetrovsk		Ukraine
52	Donetsk Railroad Clinical Hospital	Donetsk		Ukraine
53	Institute of Neurology, Psychiatry and Narcology AMS of Ukraine	Kharkiv		Ukraine
54	Lviv Regional Clinical Hospital	Lviv		Ukraine
55	Municipal Institution "Odesa Regional Clinical Hospital"	Odessa		Ukraine
56	Uzhgorod National University	Uzhgorod		Ukraine
57	Vinnytsya National Medical University	Vinnytsya		Ukraine

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: NCT01261611
• Other Study ID Numbers: Y-52-52120-134; 2010-019907-43
• First Posted: Dec 16, 2010
• Last Update Posted: Sep 24, 2019
• Last Verified: Sep 1, 2019

• Additional relevant MeSH terms: Dystonia; Dystonic Disorders; Torticollis; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA

Study Results

Participant Flow

Recruitment Details	Subjects recruited at 61 centres in Australia (2 subjects), Austria (9 subjects), Belgium (9 subjects), Czech Republic (58 subjects), France (31 subjects), Germany (38 subjects), Hungary (44 subjects), Poland (68 subjects), Portugal (12 subjects), Russia (36 subjects) and Ukraine (62 subjects).
Pre-assignment Detail	382 subjects screened, 369 randomised due to 13 screen failures.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	Up to 5 treatment cycles of Dysport NG	1 treatment cycle of Dysport	1 treatment cycle of placebo
Period Title: Treatment Cycle 1
STARTED	156	159	54
COMPLETED	152	156	52
NOT COMPLETED	4	3	2
Period Title: Treatment Cycle 1
STARTED	359	0	0
COMPLETED	346	0	0
NOT COMPLETED	13	0	0
Period Title: Treatment Cycle 1
STARTED	346	0	0
COMPLETED	316	0	0
NOT COMPLETED	30	0	0
Period Title: Treatment Cycle 1
STARTED	316	0	0
COMPLETED	220	0	0
NOT COMPLETED	96	0	0
Period Title: Treatment Cycle 1
STARTED	220	0	0
COMPLETED	217	0	0
NOT COMPLETED	3	0	0

Baseline Characteristics

Arm/Group Title	Dysport NG	Dysport	Placebo	Total
Arm/Group Description	500U (1mL) administered as intramuscular injection on day 1 of treatment cycle 1 and 2. 250U (0.5mL), 500U (1mL) or 750U (1.5mL) administered as intramuscular injection on day 1 of treatment cycle 3. 250U (0.5mL), 500U (1mL), 750U (1.5mL) or 1000U (2mL) administered as intramuscular injection on day 1 of treatment cycle 4 and 5. Botulinum type A toxin (Dysport NG): I.M. (in the muscle) injection on day 1 of up to 5 treatment cycles.	500U (1mL) injected as intramuscular injection on day 1 of treatment cycle 1. Botulinum type A toxin (Dysport®): I.M. injection on day 1 of treatment cycle 1.	1mL administered as, intramuscular injection on day 1 of treatment cycle 1. Placebo: I.M. injection on day 1 of treatment cycle 1.	Total of all reporting groups
Overall Participants	156	159	54	369
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.6 (12.4)	49.1 (12.0)	49.7 (10.8)	50.3 (12.1)
Sex: Female, Male (Count of Participants)
Female	100 64.1%	101 63.5%	34 63%	235 63.7%
Male	56 35.9%	58 36.5%	20 37%	134 36.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 1.9%	1 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 0.6%	1 1.9%	2 0.5%
White	154 98.7%	154 96.9%	49 90.7%	357 96.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1.3%	4 2.5%	3 5.6%	9 2.4%
Time since diagnosis of CD, years (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.13 (7.95)	6.88 (7.49)	6.25 (7.31)	6.84 (7.63)
Baseline Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total score (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	44.56 (9.20)	46.23 (8.82)	47.02 (9.19)	45.64 (9.06)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle
Description	TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the Intent to Treat (ITT) population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-12.46	-13.99	-3.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dysport NG, Placebo
	Comments	A pre-specified analysis of the LS mean difference between the Dysport NG and Placebo arms was performed. A total of 210 subjects were included in the analysis.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	An ANCOVA on the change from baseline, baseline TWSTRS Total score, baseline BTX status and pooled centre as explanatory variables was performed.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dysport, Placebo
	Comments	A pre-specified analysis of the LS mean difference between the Dysport and Placebo arms was performed. A total of 213 subjects were included in the analysis.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	An ANCOVA on the change from baseline, baseline TWSTRS Total score, baseline BTX status and pooled centre as explanatory variables was performed.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Dysport NG, Dysport
	Comments	A pre-specified analysis of the LS mean difference between the Dysport NG and Dysport arms was performed. A total of 315 subjects were included in the analysis.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	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.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.532
	Confidence Interval	(2-Sided) 95%; -0.819 to 3.883
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-6.2	-6.6	-1.9

3. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-3.3	-3.9	-0.8

4. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-3.10	-3.44	-1.21

5. Secondary Outcome

Title	Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle
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).
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-14.8	-19.2	-3.4

6. Secondary Outcome

Title	Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle
Description	The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no symptoms) to 100 mm (worst possible symptoms).
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	152	156	53
Least Squares Mean (95% Confidence Interval) [Units on a scale]	-18.7	-23.6	-3.3

7. Secondary Outcome

Title	Percentage of Treatment Responders Following First Treatment Cycle
Description	A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered). The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG	Dysport	Placebo
Arm/Group Description	500U	500U
Measure Participants	153	156	53
Number [Percentage of participants]	45.8 29.4%	55.8 35.1%	20.8 38.5%

8. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5
Description	TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-15.35
Cycle 3	-14.85
Cycle 4	-15.58
Cycle 5	-15.28

9. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-7.2
Cycle 3	-7.1
Cycle 4	-7.3
Cycle 5	-7.0

10. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-4.7
Cycle 3	-4.6
Cycle 4	-5.0
Cycle 5	-4.9

11. Secondary Outcome

Title	Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5
Description	TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-3.45
Cycle 3	-3.21
Cycle 4	-3.34
Cycle 5	-3.41

12. Secondary Outcome

Title	Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5
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).
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-20.1
Cycle 3	-17.8
Cycle 4	-18.0
Cycle 5	-16.1

13. Secondary Outcome

Title	Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5
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).
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	-24.0
Cycle 3	-18.9
Cycle 4	-21.0
Cycle 5	-18.2

14. Secondary Outcome

Title	Percentage of Treatment Responders for Treatment Cycles 2 to 5
Description	A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. 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, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.
Time Frame	Treatment cycle Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Analysis based on number (n) of subjects in the ITT population (all randomised subjects who received at least one injection of study treatment regardless of the amount of study treatment administered) in each cycle. The ITT population was analysed using subjects as randomised. Missing data were not imputed.

Arm/Group Title	Dysport NG
Arm/Group Description	All doses
Measure Participants	359
Cycle 2	58.5 37.5%
Cycle 3	56.8 36.4%
Cycle 4	63.5 40.7%
Cycle 5	57.5 36.9%

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	Analysis based on number of subjects in the safety population (all randomised subjects who received at least one injection of study treatment). One subject was randomised to Dysport 500 U but actually received placebo; therefore, this subject was counted in the placebo group for the safety population analysis (n=55 not n=54). Data are broken down by dose across all treatment cycles and the denominator (total number of patients at risk) for each group could not be reported in participant flow.
Arm/Group Title	Dysport NG, 250U		Dysport NG, 500U		Dysport NG, 750U		Dysport NG, 1000U		Dysport, 500U		Placebo
Arm/Group Description	Subjects in the safety population were analysed as treated.		Subjects in the safety population were analysed as treated.		Subjects in the safety population were analysed as treated.		Subjects in the safety population were analysed as treated.		The safety population was analysed using subjects as treated. One subject was randomised to Dysport 500 U but actually received placebo; therefore, this subject was counted in the placebo group for the safety population, and the Dysport group for the ITT population.		The safety population was analysed using subjects as treated. One subject was randomised to Dysport 500 U but actually received placebo; therefore, this subject was counted in the placebo group for the safety population, and the Dysport group for the ITT population.
All Cause Mortality
	Dysport NG, 250U		Dysport NG, 500U		Dysport NG, 750U		Dysport NG, 1000U		Dysport, 500U		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Dysport NG, 250U		Dysport NG, 500U		Dysport NG, 750U		Dysport NG, 1000U		Dysport, 500U		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		16/363 (4.4%)		3/210 (1.4%)		1/57 (1.8%)		3/156 (1.9%)		0/55 (0%)
Cardiac disorders
Acute coronary syndrome	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Endocrine disorders
Thyroid cyst	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Gastrointestinal disorders
Gastric ulcer haemorrhage	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Dysphagia	0/4 (0%)		0/363 (0%)		1/210 (0.5%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Gastritis haemorrhagic	0/4 (0%)		0/363 (0%)		0/210 (0%)		1/57 (1.8%)		0/156 (0%)		0/55 (0%)
Gastrooesphageal reflux disease	0/4 (0%)		0/363 (0%)		0/210 (0%)		1/57 (1.8%)		0/156 (0%)		0/55 (0%)
Rectal perforation	0/4 (0%)		0/363 (0%)		1/210 (0.5%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Hepatobiliary disorders
Cholelithiasis	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Infections and infestations
Pneumonia streptococcal	0/4 (0%)		0/363 (0%)		0/210 (0%)		0/57 (0%)		1/156 (0.6%)		0/55 (0%)
Proctitis infectious	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Vaginal abscess	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Injury, poisoning and procedural complications
Clavicle fracture	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Fibula fracture	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Meniscus injury	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Upper limb fracture	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Lung adenocarcinoma	0/4 (0%)		0/363 (0%)		0/210 (0%)		0/57 (0%)		1/156 (0.6%)		0/55 (0%)
Malignant pleural effusion	0/4 (0%)		0/363 (0%)		0/210 (0%)		0/57 (0%)		1/156 (0.6%)		0/55 (0%)
Pericardial effusion malignant	0/4 (0%)		0/363 (0%)		0/210 (0%)		0/57 (0%)		1/156 (0.6%)		0/55 (0%)
Nervous system disorders
Cerebrovascular accident	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Psychiatric disorders
Alcohol withdrawal syndrome	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Completed suicide	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Reproductive system and breast disorders
Uterine polyp	0/4 (0%)		0/363 (0%)		0/210 (0%)		0/57 (0%)		1/156 (0.6%)		0/55 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Vascular disorders
Paget-Schroetter syndrome	0/4 (0%)		1/363 (0.3%)		0/210 (0%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Aortic dissection	0/4 (0%)		0/363 (0%)		1/210 (0.5%)		0/57 (0%)		0/156 (0%)		0/55 (0%)
Other (Not Including Serious) Adverse Events
	Dysport NG, 250U		Dysport NG, 500U		Dysport NG, 750U		Dysport NG, 1000U		Dysport, 500U		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		59/363 (16.3%)		29/210 (13.8%)		7/57 (12.3%)		15/156 (9.6%)		1/55 (1.8%)
Gastrointestinal disorders
Dysphagia	0/4 (0%)	0	38/363 (10.5%)	54	20/210 (9.5%)	25	5/57 (8.8%)	5	11/156 (7.1%)	11	0/55 (0%)	0
Infections and infestations
Nasopharyngitis	0/4 (0%)	0	21/363 (5.8%)	26	9/210 (4.3%)	9	2/57 (3.5%)	2	4/156 (2.6%)	4	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Muscular weakness	1/4 (25%)	1	11/363 (3%)	15	13/210 (6.2%)	14	6/57 (10.5%)	6	0/156 (0%)	0	0/55 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.