Efficacy and Safety Dose Titration Study of Botulinum Toxin Type A to Treat Spasticity in the Leg and Arm

Sponsor

Merz Pharmaceuticals GmbH (Industry)

Overall Status

Completed

CT.gov ID

NCT01603459

Collaborator

(none)

155

Enrollment

Locations

Arm

Duration (Months)

4.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether injections with increasing doses (up to 800 units) of Botulinum toxin type A into muscles of the leg and/or arm are safe and effective in treating patients with spasticity on one body side due to cerebral causes.

Condition or Disease	Intervention/Treatment	Phase
Spasticity of the Upper and Lower Limb Due to Cerebral Causes	Drug: IncobotulinumtoxinA	Phase 3

Detailed Description

A dose-titration approach will be used over three injection cycles, with a flexible observation period after injections of 12-16 weeks and a total duration of up to 48 weeks. Cycle 1 and 2: upper and/or lower limb to be treated; Cycle 3: upper and lower limb to be treated.

Study Design

Study Type:

Interventional

Actual Enrollment :

155 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Prospective, Open-label, Non-randomized, Single-arm, Multi-center Dose Titration Study to Investigate the Safety and Efficacy of NT 201 in Subjects Deemed to Require Total Body Doses of 800 U of NT 201 During the Course of the Study for the Treatment of Upper and Lower Limb Spasticity of the Same Body Side Due to Cerebral Causes

Study Start Date :

May 1, 2012

Actual Primary Completion Date :

Sep 1, 2014

Actual Study Completion Date :

Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IncobotulinumtoxinA (Xeomin) (up to 800 Units) IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection	Drug: IncobotulinumtoxinA Subjects to receive up to 3 injection cycle, with the dose titrated from 400 units to up to 800 units. For each injection session: solution prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400-800 units, volume 2.0 mL per 100 units; Mode of administration: intramuscular injection.

Arm

Intervention/Treatment

Experimental: IncobotulinumtoxinA (Xeomin) (up to 800 Units)

IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection

Drug: IncobotulinumtoxinA

Subjects to receive up to 3 injection cycle, with the dose titrated from 400 units to up to 800 units. For each injection session: solution prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400-800 units, volume 2.0 mL per 100 units; Mode of administration: intramuscular injection.

Outcome Measures

Primary Outcome Measures

Occurrence of Treatment-Emergent Adverse Events (AEs), AEs of Special Interest (AESIs), and Serious AEs (SAEs) by Injection Cycle, Overall and Related to the Administration of Study Medication [From baseline to week 36-48]
Treatment-emergent Adverse Events (TEASs) are events observed from the time point of first injection until 16 weeks after last injection. Values reported here refer to the number of subjects affected.
Investigator's Global Assessment of Tolerability in Subjects [Up to Week 48]
A 4-point Likert scale was used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor.

Secondary Outcome Measures

Ashworth Scale (AS) Scores of the Target Joint Selected at Study Baseline Visit [From Cycle Baseline to Week 4 of Each Cycle]
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Ashworth Scale (AS) Scores of Every Joint Affected by Clinical Patterns of Spasticity [From Cycle Baseline to Week 4 of Each Cycle]
Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Resistance to Passive Movement Scale (REPAS) Scores of Treated Side [From Cycle Baseline to Week 4 of Each Cycle]
The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Functional Ambulation Classification (FAC) Scale Scores [From Cycle Baseline to Week 4 of Each Cycle]
The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Change of Functional Ambulation Classification (FAC) Score From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Goal Attainment Scale (GAS) Scores for Upper and Lower Limb, Respectively [From Cycle Baseline Visit to Week 12-16, 24-32 and 36-48]
Change in goal attainment T-scores from respective injection cycle baseline visit. GAS measures the extent to which subject's individual goals are achieved in course of intervention. Subject and treating team have to identify 2 personal goals for each treated limb at each injection cycle. Investigator rates the GAS score for each injection cycle. Degree of goal attainment is rated on 5-point scale (-2, -1, 0, +1, +2; study baseline set to -1) and in order to account for interindividual differences in the number of goals, ratings are computed with the Kiresuk formula (Kiresuk & Sherman, Community Mental Health Journal. 1968;4(6):443-53) resulting in T-scores measuring the degree of goal attainment at each visit. A score of 50 indicates that the individual has reached the expected level of achievement for all goals. The size of change from measurement to measurement indicates incremental change towards or away from goal attainment. Positive values indicate a higher goal attainment.
Disability Assessment Scale (DAS) Scores in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb [From Cycle Baseline to Week 4 of Each Cycle]
The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value.
Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Injection Cycle Baseline Visits to Respective Control Visits [Week 4 of Each Cycle]
The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit. [From Study Baseline to Week 12-16, 24-32 and 36-48]
The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Global Assessment of Efficacy Scores [Week 12-16, 24-32 and 36-48]
Investigator assessment. The global assessment of efficacy will be assessed by the investigator, the subject, and the caregiver using a 4-point Likert scale with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor.
EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores [From Cycle Baseline to Week 4 of Each Cycle]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems.
Visual Analogue Scale (VAS) of EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores [From Cycle Baseline to Week 4 of Each Cycle]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values represent better outcome).
Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits [From Cycle Baseline to Week 4 of Each Cycle]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values represent better outcome).
Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles [From Study Baseline to Week 4, 16-20 and 28-36]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Positive values indicate improvement
Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit [From Study Baseline to Week 12-16, 24-32 and 36-48]
The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Positive values indicate improvement.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Upper and lower limb spasticity of the same body side due to cerebral causes
Time since event leading to spasticity in the target body side greater than 12 weeks
Need for 800 units Botulinum toxin type A

Exclusion Criteria:

Body weight below 50kg
Fixed contractures of the target joint
Generalized disorders of muscle activity like Myasthenia gravis that preclude use of Botulinum toxin type A
Infection at the injection site

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Merz Investigational Site # 001197	Doral	Florida	United States	33172
2	Merz Investigational Site # 001235	Indianapolis	Indiana	United States	46202
3	Merz Investigational Site # 001191	New York	New York	United States	10029
4	Merz Investigational Site #001238	Charlotte	North Carolina	United States	28203
5	Merz Investigational Site # 001232	Cleveland	Ohio	United States	44195
6	Merz Investigational Site #001237	Milwaukee	Wisconsin	United States	53226
7	Merz Investigational Site # 001203	Calgary, AB		Canada	T2N 2T9
8	Merz Investigational site #001195	Edmonton, AB		Canada	T5G 0B7
9	Merz Investigational Site # 033018	Garches		France	92380
10	Merz Investigational Site #033049	Montpellier		France	34295
11	Merz Investigational Site # 033050	Nimes		France	30029
12	Merz Investigational Site #049191	Aachen		Germany	52074
13	Merz Investigational Site #049297	Bad Aibling		Germany	83043
14	Merz Investigational Site #049022	Beelitz-Heilstätten		Germany	14547
15	Merz Investigational Site #049298	Berlin		Germany	10178
16	Merz Investigational Site # 049153	Gießen		Germany	35385
17	Merz Investigational Site #049295	Göttingen		Germany	37075
18	Merz Investigational Site #049300	Nümbrecht		Germany	51588
19	Merz Investigational Site #049296	Tübingen		Germany	72076
20	Merz Investigational Site # 039005	Lecco		Italy	23845
21	Merz Investigational Site # 039010	Milano		Italy	20122
22	Merz Investigational Site # 039015	Milano		Italy	20157
23	Merz Investigational Site # 039017	Novara		Italy	28100
24	Merz Investigational Site #039013	Passignano sul Trasimeno		Italy	06065
25	Merz Investigational Site #039016	San Giovanni Rotondo		Italy	71013
26	Merz Investigational Site #039014	Verona		Italy	37134
27	Merz Investigational Site #047001	Bergen		Norway	5053
28	Merz Investigational Site # 351001	Lisboa		Portugal	1649-028
29	Merz Investigational Site # 351003	Lisbon		Portugal	1150-199
30	Merz Investigational Site #034007	Madrid		Spain	28046
31	Merz Investigational Site #034025	Malaga		Spain	29009
32	Merz Investigational Site #034022	Manresa		Spain	08242
33	Merz Investigational Site #034024	Santander		Spain	39008

Sponsors and Collaborators

Merz Pharmaceuticals GmbH

Investigators

Study Director: Medical Expert, Merz Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Merz Pharmaceuticals GmbH

ClinicalTrials.gov Identifier:

NCT01603459

Other Study ID Numbers:

MRZ60201_3053_1
2010-020886-26

First Posted:

May 22, 2012

Last Update Posted:

Apr 26, 2017

Last Verified:

Mar 1, 2017

Additional relevant MeSH terms:

Muscle Spasticity

incobotulinumtoxinA

Study Results

Participant Flow

Recruitment Details	The clinical study was conducted at 30 sites located in Canada, France, Germany, Italy, Norway, Portugal, Spain, and the United States of America.
Pre-assignment Detail

Arm/Group Title	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
Arm/Group Description	IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA: Subjects to receive up to 3 injection cycle, with the dose titrated from 400 units to up to 800 units. For each injection session: solution prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400-800 units, volume 2.0 mL per 100 units; Mode of administration: Intramuscular injection.
Period Title: Overall Study
STARTED	155
COMPLETED	137
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
Arm/Group Description	IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA: Subjects to receive up to 3 injection cycle, with the dose titrated from 400 units to up to 800 units. For each injection session: solution prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400-800 units, volume 2.0 mL per 100 units; Mode of administration: Intramuscular injection.
Overall Participants	155
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.7 (13.1)
Sex: Female, Male (Count of Participants)
Female	51 32.9%
Male	104 67.1%

Outcome Measures

1. Secondary Outcome

Title	Ashworth Scale (AS) Scores of the Target Joint Selected at Study Baseline Visit
Description	The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
The full analysis set (FAS) is the subset of all subjects who were exposed to study medication at least once. Only subjects treated in the target joint in the respective cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	154	151	148	140	138
Mean (Standard Deviation) [units on a scale]	3.0 (0.7)	2.1 (0.9)	2.7 (0.7)	2.0 (0.9)	2.6 (0.8)	1.7 (1.0)

2. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Injection Cycle Baseline Visits to Respective Control Visits
Description	The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS), observed cases, only subjects treated in the target joint in the respective cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	148	138
Mean (Standard Deviation) [units on a scale]	-0.8 (0.9)	-0.8 (0.8)	-0.9 (0.9)

3. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Study Baseline Visit to Control Visits of Injection Cycles
Description	The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS), observed cases, only subjects treated in the target joint in the respective cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	148	138
Mean (Standard Deviation) [units on a scale]	-0.8 (0.9)	-1.0 (0.9)	-1.3 (1.0)

4. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS), observed cases, only subjects treated in the target joint in the respective cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Timeframe 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	151	140	137
Mean (Standard Deviation) [units on a scale]	-0.2 (0.7)	-0.3 (0.8)	-0.7 (0.9)

5. Secondary Outcome

Title	Ashworth Scale (AS) Scores of Every Joint Affected by Clinical Patterns of Spasticity
Description	Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective pattern in the respective injection cycle.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	155	152	152	140	140
Internally rotated/extended/adducted shoulder	2.7 (0.6)	2.2 (0.8)	2.5 (0.8)	2.0 (0.9)	2.5 (0.8)	1.9 (0.9)
Flexed elbow	2.6 (0.7)	1.9 (0.9)	2.4 (0.7)	1.7 (0.9)	2.4 (0.8)	1.4 (0.9)
Extended elbow	2.7 (0.5)	1.8 (0.9)	2.5 (0.6)	2.1 (0.7)	2.6 (0.6)	1.7 (0.8)
Pronated forearm	2.7 (0.7)	1.6 (0.9)	2.4 (0.8)	1.7 (1.0)	2.5 (0.7)	1.4 (0.8)
Flexed wrist	2.7 (0.8)	1.8 (1.0)	2.4 (0.9)	1.5 (1.0)	2.4 (0.8)	1.4 (1.0)
Clenched fist	2.9 (0.7)	2.0 (0.9)	2.7 (0.8)	1.8 (0.9)	2.5 (0.7)	1.5 (0.9)
Thumb in palm	2.4 (0.9)	1.5 (1.1)	2.3 (0.9)	1.4 (1.0)	2.2 (0.8)	1.3 (1.0)
Flexed hip	1.8 (0.8)	1.4 (0.9)
Adducted thigh	1.8 (0.5)	1.5 (0.6)	2.0 (1.2)	1.9 (0.9)	2.3 (0.8)	2.0 (0.6)
Internally rotated hip	3.0 (NA)	2.0 (NA)	2.0 (1.4)	2.0 (1.4)	2.7 (0.6)	1.7 (0.6)
Flexed knee	2.4 (0.7)	2.0 (0.7)	2.4 (0.6)	1.8 (0.7)	2.5 (0.7)	1.8 (1.0)
Extended knee	2.6 (0.7)	2.3 (0.9)	2.1 (0.8)	1.8 (0.9)	2.2 (0.8)	1.5 (0.8)
Pes equinovarus	2.8 (0.7)	2.1 (0.9)	2.6 (0.8)	1.9 (1.0)	2.5 (0.8)	1.6 (0.9)
Pes equinovalgus	2.8 (0.4)	2.4 (1.3)	2.6 (0.8)	1.9 (0.7)	2.3 (0.9)	2.0 (1.1)
Extended hallux	1.7 (1.1)	0.9 (0.7)	1.8 (0.8)	0.9 (0.7)	1.9 (0.9)	1.1 (0.8)
Flexed toes	1.8 (0.9)	1.3 (0.8)	1.6 (0.9)	1.1 (0.8)	1.9 (0.9)	1.1 (0.8)

6. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Injection Cycle Baseline Visits to Respective Control Visits
Description	Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective pattern of respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Internally rotated/extended/adducted shoulder	-0.5 (0.8)	-0.6 (0.8)	-0.5 (0.8)
Flexed elbow	-0.7 (0.8)	-0.7 (0.8)	-0.9 (0.9)
Extended elbow	-0.9 (0.8)	-0.5 (0.9)	-0.8 (0.8)
Pronated forearm	-1.1 (0.6)	-0.7 (0.7)	-1.0 (0.8)
Flexed wrist	-0.9 (0.8)	-0.9 (0.8)	-1.0 (0.9)
Clenched fist	-0.9 (0.8)	-0.9 (0.8)	-1.1 (0.8)
Thumb in palm	-0.9 (1.0)	-0.9 (1.1)	-0.9 (1.0)
Flexed hip	-0.4 (0.9)
Aducted thigh	-0.3 (0.5)	-0.1 (0.7)	-0.1 (1.0)
Internally rotated hip	-1.0 (NA)	0.0 (0.0)	-1.0 (1.0)
Flexed knee	-0.4 (0.5)	-0.6 (0.6)	-0.8 (0.9)
Extended knee	-0.4 (0.5)	-0.4 (0.7)	-0.7 (0.9)
Pes equinovarus	-0.7 (0.8)	-0.7 (0.8)	-0.8 (0.8)
Pes equinovalgus	-0.4 (1.1)	-0.7 (0.7)	-0.3 (0.7)
Extended hallux	-0.8 (0.9)	-0.9 (1.0)	-0.8 (1.3)
Flexed toes	-0.5 (0.8)	-0.5 (0.8)	-0.8 (0.7)

7. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Study Baseline Visit to Control Visits of Injection Cycles
Description	Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective pattern of respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Internally rotated/extended/adducted shoulder	-0.5 (0.8)	-0.6 (0.9)	-0.5 (1.0)
Flexed elbow	-0.7 (0.8)	-0.9 (0.8)	-1.2 (0.9)
Extended elbow	-0.9 (0.8)	-0.7 (0.8)	-0.9 (1.0)
Pronated forearm	-1.1 (0.6)	-1.0 (0.9)	-1.1 (0.9)
Flexed wrist	-0.9 (0.8)	-1.1 (0.9)	-1.2 (1.1)
Clenched fist	-0.9 (0.8)	-1.1 (0.9)	-1.4 (0.9)
Thumb in palm	-0.9 (1.0)	-1.0 (1.2)	-1.1 (1.3)
Flexed hip	-0.6 (1.5)
Adducted thigh	-0.3 (0.5)	-0.1 (0.7)	-0.6 (0.8)
Internally rotated hip	-1.0 (NA)	-0.5 (0.7)	-0.7 (1.5)
Flexed knee	-0.4 (0.5)	-0.4 (0.8)	-0.4 (1.2)
Extended knee	-0.4 (0.5)	-0.4 (0.6)	-0.6 (0.6)
Pes equinovarus	-0.7 (0.8)	-0.8 (0.9)	-1.1 (0.9)
Pes equinovalgus	-0.4 (1.1)	-0.9 (0.6)	-0.4 (0.7)
Extended hallux	-0.8 (0.9)	-0.9 (1.1)	-0.2 (1.3)
Flexed toes	-0.5 (0.8)	-0.5 (0.7)	-0.6 (0.8)

8. Secondary Outcome

Title	Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	Clinical pattern treated at corresponding cycle of the same body side as the selected target joint. The AS is a well known and commonly used scale in clinical trials with spasticity. It was considered to be the best clinical tool for measuring resistance to movement. It was used to categorize the severity of spasticity by judging resistance to passive movement. It is a 5-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension).
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective pattern of respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Internally rotated/extended/adducted shoulder	-0.0 (0.7)	0.0 (0.9)	-0.3 (0.9)
Flexed elbow	-0.2 (0.7)	-0.3 (0.8)	-0.8 (0.9)
Extended elbow	-0.2 (0.7)	-0.1 (0.9)	-0.2 (0.8)
Pronated forearm	-0.3 (0.9)	-0.1 (0.7)	-0.7 (1.0)
Flexed wrist	-0.2 (0.7)	-0.2 (1.0)	-0.7 (1.0)
Clenched fist	-0.2 (0.7)	-0.3 (0.7)	-0.8 (0.9)
Thumb in palm	-0.2 (0.9)	-0.3 (0.9)	-0.8 (1.1)
Flexed hip	-0.2 (1.0)	-0.3 (1.4)
Adducted thigh	0 (0)	-0.3 (0.5)	-0.4 (0.8)
Internally rotated hip	-0.5 (0.7)	0.3 (0.6)	0.0 (1.0)
Flexed knee	0.1 (0.9)	0.4 (1.2)	-0.4 (1.1)
Extended knee	-0.1 (0.4)	0.1 (0.5)	-0.4 (0.7)
Pes equinovarus	-0.1 (0.6)	-0.2 (0.7)	-0.7 (0.9)
Pes equinovalgus	-0.2 (0.4)	-0.1 (0.6)	-0.4 (0.5)
Extended hallux	0.0 (1.2)	0.6 (1.3)	-0.2 (1.0)
Flexed toes	-0.0 (0.7)	0.2 (0.7)	-0.4 (0.7)

9. Secondary Outcome

Title	Resistance to Passive Movement Scale (REPAS) Scores of Treated Side
Description	The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	155	152	149	140	138
Mean (Standard Deviation) [units on a scale]	24.8 (6.7)	20.2 (7.1)	24.0 (7.0)	18.1 (7.6)	22.9 (7.2)	15.7 (7.6)

10. Secondary Outcome

Title	Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Injection Cycle Baseline Visits to Respective Control Visits
Description	The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mean (Standard Deviation) [units on a scale]	-4.6 (3.9)	-5.9 (4.2)	-7.1 (4.8)

11. Secondary Outcome

Title	Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Study Baseline Visit to Control Visits of Injection Cycles
Description	The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
The full analysis set is the subset of all subjects who were exposed to study medication at least once.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mean (Standard Deviation) [units on a scale]	-4.6 (3.9)	-6.7 (4.6)	-9.0 (5.5)

12. Secondary Outcome

Title	Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	The REPAS is a summary 26-item test used to assess resistance to passive movement in all four limbs of the body. It provides a global evaluation of spasticity status, as well as per hemibody and per limb. 16 items describe the condition of both upper limbs, 10 that of both lower limbs. Each item is rated by using the Ashworth Scale. The sum of the values represent the REPAS score which may range from zero (no resistance for any item) to 104 (limbs rigid for all items). Here, the hemi-REPAS was evaluated, i.e. the maximum value for the treated body side was 52.
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
The full analysis set is the subset of all subjects who were exposed to study medication at least once.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	152	140	137
Mean (Standard Deviation) [units on a scale]	-0.8 (4.2)	-1.9 (4.7)	-5.5 (5.3)

13. Secondary Outcome

Title	Functional Ambulation Classification (FAC) Scale Scores
Description	The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	155	152	149	140	138
Mean (Standard Deviation) [units on a scale]	3.5 (1.4)	3.7 (1.3)	3.7 (1.3)	3.8 (1.3)	3.8 (1.3)	3.9 (1.2)

14. Secondary Outcome

Title	Change of Functional Ambulation Classification (FAC) Score From Injection Cycle Baseline Visits to Respective Control Visits
Description	The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mean (Standard Deviation) [units on a scale]	0.1 (0.5)	0.1 (0.4)	0.1 (0.4)

15. Secondary Outcome

Title	Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Control Visits of Injection Cycles
Description	The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mean (Standard Deviation) [units on a scale]	0.1 (0.5)	0.3 (0.6)	0.4 (0.7)

16. Secondary Outcome

Title	Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	The FAC examines the independence and ambulation of subjects whereby supervision/physical assistance from 1 person is allowed. Subjects are classified to following categories: Level 0: no functional ambulation; Level 1: Ambulator-dependent for physical assistance (Level II); Level 2: Ambulator-dependent for physical assistance (Level I); Level 3: Ambulator-dependent for supervision; Level 4: Ambulator-independent, level surface only; Level 5: Ambulator-independent.
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	152	140	137
Mean (Standard Deviation) [units on a scale]	0.2 (0.5)	0.3 (0.6)	0.4 (0.8)

17. Secondary Outcome

Title	Goal Attainment Scale (GAS) Scores for Upper and Lower Limb, Respectively
Description	Change in goal attainment T-scores from respective injection cycle baseline visit. GAS measures the extent to which subject's individual goals are achieved in course of intervention. Subject and treating team have to identify 2 personal goals for each treated limb at each injection cycle. Investigator rates the GAS score for each injection cycle. Degree of goal attainment is rated on 5-point scale (-2, -1, 0, +1, +2; study baseline set to -1) and in order to account for interindividual differences in the number of goals, ratings are computed with the Kiresuk formula (Kiresuk & Sherman, Community Mental Health Journal. 1968;4(6):443-53) resulting in T-scores measuring the degree of goal attainment at each visit. A score of 50 indicates that the individual has reached the expected level of achievement for all goals. The size of change from measurement to measurement indicates incremental change towards or away from goal attainment. Positive values indicate a higher goal attainment.
Time Frame	From Cycle Baseline Visit to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	140	138	135
Upper limb	7.178 (9.254)	10.601 (9.211)	13.028 (8.765)
Lower limb	8.222 (9.649)	10.914 (9.251)	13.579 (10.196)

18. Secondary Outcome

Title	Disability Assessment Scale (DAS) Scores in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb
Description	The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	143	143	151	143	140	128
Mean (Standard Deviation) [units on a scale]	2.6 (0.5)	2.0 (0.7)	2.4 (0.6)	1.7 (0.7)	2.2 (0.6)	1.5 (0.7)

19. Secondary Outcome

Title	Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Injection Cycle Baseline Visits to Respective Control Visits
Description	The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Time Frame	Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	143	143	128
Mean (Standard Deviation) [units on a scale]	-0.6 (0.7)	-0.7 (0.7)	-0.7 (0.8)

20. Secondary Outcome

Title	Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Study Baseline Visit to Control Visits of Injection Cycles
Description	The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	143	143	128
Mean (Standard Deviation) [units on a scale]	-0.6 (0.7)	-0.9 (0.8)	-1.0 (0.9)

21. Primary Outcome

Title	Occurrence of Treatment-Emergent Adverse Events (AEs), AEs of Special Interest (AESIs), and Serious AEs (SAEs) by Injection Cycle, Overall and Related to the Administration of Study Medication
Description	Treatment-emergent Adverse Events (TEASs) are events observed from the time point of first injection until 16 weeks after last injection. Values reported here refer to the number of subjects affected.
Time Frame	From baseline to week 36-48

Outcome Measure Data

Analysis Population Description
Safety evaluation set (SES) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Any TEAE	56	57	36
Any related TEAE	7	8	4
Any TEAE of special interest	6	8	7
Any related TEAE of special interest	2	4	3
Any serious TEAE	4	11	3
Any related serious TEAE	0	0	0

22. Primary Outcome

Title	Investigator's Global Assessment of Tolerability in Subjects
Description	A 4-point Likert scale was used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor.
Time Frame	Up to Week 48

Outcome Measure Data

Analysis Population Description
Safety evaluation set (SES) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Very good	121	111	117
Good	29	26	20
Moderate	3	3	1
Poor	0	2	0
Missing	2	10	2

23. Secondary Outcome

Title	Change of Disability Assessment Scale (DAS) Score in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit.
Description	The Disability Assessment Scale consists of the four domains hygiene, dressing, limb position, and pain which are assessed on a 4-point scale with the values 0 (=no disability), 1 (=mild disability), 2 (=moderate disability), and 3 (=severe disability). One of the domains will be selected per subject per injection cycle. Arithmetic means are built on each patient's target domain value change.
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	151	140	127
Mean (Standard Deviation) [units on a scale]	-0.2 (0.6)	-0.3 (0.7)	-0.9 (0.9)

24. Secondary Outcome

Title	Global Assessment of Efficacy Scores
Description	Investigator assessment. The global assessment of efficacy will be assessed by the investigator, the subject, and the caregiver using a 4-point Likert scale with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor.
Time Frame	Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	152	140
Frequency 1 (very good)	7	21	38
Frequency 2 (good)	79	89	87
Frequency 3 (moderate)	63	28	11
Frequency 4 (poor)	3	3	1
Missing	3	11	3

25. Secondary Outcome

Title	EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	155	152	149	140	138
Mobility: Frequency 1	12	27	14	24	19	20
Mobility: Frequency 2	139	125	136	122	119	116
Mobility: Frequency 3	4	3	2	3	2	2
Self-care: Frequency 1	30	31	30	24	24	22
Self-care: Frequency 2	96	100	101	104	101	107
Self-care: Frequency 3	29	24	21	20	15	9
Usual activities: Frequency 1	11	19	16	21	15	17
Usual activities: Frequency 2	113	108	119	110	113	111
Usual activities: Frequency 3	31	28	17	17	12	10
Pain/discomfort: Frequency 1	53	73	56	74	57	77
Pain/discomfort: Frequency 2	85	75	88	70	79	58
Pain/discomfort: Frequency 3	17	7	8	5	4	3
Anxiety/depression: Frequency 1	72	82	83	93	78	85
Anxiety/depression: Frequency 2	69	67	63	49	57	49
Anxiety/depression: Frequency 3	14	6	6	7	5	4

26. Secondary Outcome

Title	Visual Analogue Scale (VAS) of EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values represent better outcome).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 1 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 2 Control Visit 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 3 Baseline Visit	IncobotulinumtoxinA(Xeomin): Injection Cycle 3 Control Visit 1
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	155	152	149	140	138
Mean (Standard Deviation) [units on a scale]	59.9 (18.9)	66.7 (17.6)	67.2 (17.0)	69.9 (16.6)	67.1 (17.9)	68.9 (17.7)

27. Secondary Outcome

Title	Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mobility: Frequency -1	18	11	6
Mobility: Frequency 0	135	136	128
Mobility: Frequency 1	2	2	4
Self-care: Frequency -1	19	7	11
Self-care: Frequency 0	123	127	121
Self-care: Frequency 1	13	14	6
Usual activities: Frequency -2	0	0	1
Usual activities: Frequency -1	20	18	7
Usual activities: Frequency 0	126	116	126
Usual activities: Frequency 1	9	14	4
Pain/discomfort: Frequency -2	1	2	0
Pain/discomfort: Frequency -1	39	30	29
Pain/discomfort: Frequency 0	105	105	102
Pain/discomfort: Frequency 1	9	12	7
Pain/discomfort: Frequency 2	1	0	0
Anxiety/depression:Frequency -2	0	0	1
Anxiety/depression:Frequency -1	27	18	17
Anxiety/depression: Frequency 0	119	121	111
Anxiety/depression: Frequency 1	9	9	9
Anxiety/depression: Frequency 2	0	1	0

28. Secondary Outcome

Title	Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values represent better outcome).
Time Frame	From Cycle Baseline to Week 4 of Each Cycle

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	149	138
Mean (Standard Deviation) [units on a scale]	6.7 (14.1)	2.4 (12.4)	1.7 (12.4)

29. Secondary Outcome

Title	Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 1 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 2 Control Visit. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to Cycle 3 Control Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	155	149	138
Mobility: Frequency -1	18	16	14
Mobility: Frequency 0	135	127	118
Mobility: Frequency 1	2	5	5
Self-care: Frequency -1	19	20	25
Self-care: Frequency 0	123	110	100
Self-care: Frequency 1	13	18	13
Usual activities: Frequency -2	0	1	1
Usual activities: Frequency -1	20	31	31
Usual activities: Frequency 0	126	103	98
Usual activities: Frequency 1	9	13	8
Pain/discomfort: Frequency -2	1	3	3
Pain/discomfort: Frequency -1	39	40	42
Pain/discomfort: Frequency 0	105	93	85
Pain/discomfort: Frequency 1	9	13	8
Pain/discomfort: Frequency 2	1	0	0
Anxiety/depression:Frequency -2	0	7	6
Anxiety/depression:Frequency -1	27	28	32
Anxiety/depression:Frequency 0	119	100	85
Anxiety/depression:Frequency 1	9	14	15
Anxiety/depression:Frequency 2	0	0	0

30. Secondary Outcome

Title	Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Positive values indicate improvement
Time Frame	From Study Baseline to Week 4, 16-20 and 28-36

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Injection Cycle 1	IncobotulinumtoxinA (Xeomin): Injection Cycle 2	IncobotulinumtoxinA (Xeomin): Injection Cycle 3
Arm/Group Description	Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	154	148	137
Mean (Standard Deviation) [units on a scale]	6.7 (14.1)	9.6 (16.3)	8.6 (17.0)

31. Secondary Outcome

Title	Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Frequency -2/-1= improvement by two/one categories; 0 = no change; +1/+2 worsening by one/two categories.
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	152	140	137
Mobility: Frequency -1	10	13	16
Mobility: Frequency 0	137	121	116
Mobility: Frequency 1	5	5	4
Self-care: Frequency -1	20	24	30
Self-care: Frequency 0	120	99	97
Self-care: Frequency 1	12	17	10
Usual activities: Frequency -2	1	1	1
Usual activities: Frequency -1	21	26	33
Usual activities: Frequency 0	125	106	96
Usual activities: Frequency 1	5	7	7
Pain/discomfort: Frequency -2	0	0	3
Pain/discomfort: Frequency -1	32	35	40
Pain/discomfort: Frequency 0	100	89	81
Pain/discomfort: Frequency 1	20	15	13
Pain/discomfort: Frequency 2	0	1	0
Anxiety/depression: Frequency -2	2	4	5
Anxiety/depression: Frequency -1	29	28	30
Anxiety/depression: Frequency 0	108	91	89
Anxiety/depression: Frequency 1	12	17	13
Anxiety/depression: Frequency 2	1	0	0

32. Secondary Outcome

Title	Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit
Description	The EQ-5D is a common quality of life questionnaire to be filled out by the subject. It evaluates the general impact of a subject's health in 5 dimensions, i.e., on the ability to perform daily physical activities as well as on pain perception and mood. Each dimension is scored on 1 out of 3 categories specific to each dimension, generally meaning: 1= no problem; 2 = moderate problems; 3 = severe problems). In addition, the subject was to indicate on a visual analogue scale, ranging from 0 to 100, how good or bad their own health was on the examination day (higher values indicate better outcome). This table: Positive values indicate improvement.
Time Frame	From Study Baseline to Week 12-16, 24-32 and 36-48

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - only subjects treated in the respective injection cycle were analyzed.

Arm/Group Title	IncobotulinumtoxinA (Xeomin): Time Frame 1	IncobotulinumtoxinA (Xeomin): Time Frame 2	IncobotulinumtoxinA (Xeomin): Time Frame 3
Arm/Group Description	Time frame 1 is from Study Baseline to Cycle 2 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 400 units Intramuscular injection.	Time frame 2 is from Study Baseline to Cycle 3 Baseline. Subjects to receive IncobotulinumtoxinA fixed total body dose of 600 units Intramuscular injection.	Time frame 3 is from Study Baseline to End of Cycle 3 Visit. Subjects to receive IncobotulinumtoxinA total body dose of 800 units Intramuscular injection.
Measure Participants	151	139	136
Mean (Standard Deviation) [units on a scale]	7.1 (16.3)	6.9 (15.8)	10.5 (17.5)

Adverse Events

	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
Time Frame	From the time point of first injection until 16 weeks after last injection
Adverse Event Reporting Description

Arm/Group Title	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
Arm/Group Description	IncobotulinumtoxinA (Xeomin, also known as "NT 201" or "Botulinum toxin type A (150 kiloDalton), free from complexing proteins") (active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection. IncobotulinumtoxinA: Subjects to receive up to 3 injection cycle, with the dose titrated from 400 units to up to 800 units. For each injection session: solution prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl), 400-800 units, volume 2.0 mL per 100 units; Mode of administration: Intramuscular injection.
All Cause Mortality
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
	Affected / at Risk (%)	# Events
Total	17/155 (11%)
Cardiac disorders
Cardiac failure	1/155 (0.6%)
Gastrointestinal disorders
Abdominal pain	1/155 (0.6%)
Hepatobiliary disorders
Cholecystitis	1/155 (0.6%)
Infections and infestations
Pneumonia	2/155 (1.3%)
Bronchopneumonia	1/155 (0.6%)
Meningitis bacterial	1/155 (0.6%)
Sepsis	1/155 (0.6%)
Sinusitis	1/155 (0.6%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/155 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	1/155 (0.6%)
Nervous system disorders
Convulsion	4/155 (2.6%)
Epilepsy	3/155 (1.9%)
Cerebral infarction	2/155 (1.3%)
Ischemic stroke	1/155 (0.6%)
Other (Not Including Serious) Adverse Events
	IncobotulinumtoxinA (Xeomin) (up to 800 Units)
	Affected / at Risk (%)	# Events
Total	34/155 (21.9%)
Gastrointestinal disorders
Diarrhoea	10/155 (6.5%)	13
Infections and infestations
Nasopharyngitis	10/155 (6.5%)	13
Injury, poisoning and procedural complications
Fall	12/155 (7.7%)	17
Musculoskeletal and connective tissue disorders
Arthralgia	10/155 (6.5%)	12
Musculoskeletal pain	8/155 (5.2%)	8

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

Publication of study information usually requires agreement with the sponsor. In case of justified doubts by the sponsor, the Investigator will consider these doubts in the publication as long as the scientific neutrality is not affected.

Results Point of Contact

Name/Title	Public Disclosure Manager
Organization	Merz Pharmaceuticals GmbH
Phone	+49 69 1503 1
Email	clinicaltrials@merz.de

Responsible Party:

Merz Pharmaceuticals GmbH

ClinicalTrials.gov Identifier:

NCT01603459

Other Study ID Numbers:

MRZ60201_3053_1
2010-020886-26

First Posted:

May 22, 2012

Last Update Posted:

Apr 26, 2017

Last Verified:

Mar 1, 2017

Efficacy and Safety Dose Titration Study of Botulinum Toxin Type A to Treat Spasticity in the Leg and Arm

Study Details

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Primary Outcome Measures

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Adverse Events

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