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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Spasticity of the Upper and Lower Limb Due to Cerebral Causes

Intervention / Treatment
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* Drug: IncobotulinumtoxinA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IncobotulinumtoxinA (Xeomin) (up to 800 Units)<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | From baseline to week 36-48 | 
| Investigator's Global Assessment of Tolerability in Subjects | A 4-point Likert scale was used with the ratings 1 = very good, 2 = good, 3 = moderate, and 4 = poor. | Up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ashworth Scale (AS) Scores of the Target Joint Selected at Study Baseline Visit | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Ashworth Scale (AS) Score of the Target Joint Selected at Study Baseline Visit From Injection Cycle Baseline Visits to Respective Control Visits | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| 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 | 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). | From Study Baseline to Week 4, 16-20 and 28-36 | 
| 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 | 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). | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| Ashworth Scale (AS) Scores of Every Joint Affected by Clinical Patterns of Spasticity | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Ashworth Scale (AS) Score of Every Joint Affected by Clinical Patterns of Spasticity From Injection Cycle Baseline Visits to Respective Control Visits | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| 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 | 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). | From Study Baseline to Week 4, 16-20 and 28-36 | 
| 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 | 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). | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| Resistance to Passive Movement Scale (REPAS) Scores of Treated Side | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Injection Cycle Baseline Visits to Respective Control Visits | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Resistance to Passive Movement Scale (REPAS) Score of Treated Side From Study Baseline Visit to Control Visits of Injection Cycles | 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. | From Study Baseline to Week 4, 16-20 and 28-36 | 
| 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 | 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. | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| Functional Ambulation Classification (FAC) Scale Scores | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Functional Ambulation Classification (FAC) Score From Injection Cycle Baseline Visits to Respective Control Visits | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Control Visits of Injection Cycles | 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. | From Study Baseline to Week 4, 16-20 and 28-36 | 
| Change of Functional Ambulation Classification (FAC) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit | 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. | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| Goal Attainment Scale (GAS) Scores for Upper and Lower Limb, Respectively | 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. | From Cycle Baseline Visit to Week 12-16, 24-32 and 36-48 | 
| Disability Assessment Scale (DAS) Scores in a Selected Principal Therapeutic Target Domain Affecting the Upper Limb | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| 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 | 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. | Week 4 of Each Cycle | 
| 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 | 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. | From Study Baseline to Week 4, 16-20 and 28-36 | 
| 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. | 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. | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| Global Assessment of Efficacy Scores | 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. | Week 12-16, 24-32 and 36-48 | 
| EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Visual Analogue Scale (VAS) of EuroQoL 5-Dimensions Questionnaire (EQ-5D) Scores | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits | 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. | From Cycle Baseline to Week 4 of Each Cycle | 
| Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Injection Cycle Baseline Visits to Respective Control Visits | 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). | From Cycle Baseline to Week 4 of Each Cycle | 
| Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles | 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. | From Study Baseline to Week 4, 16-20 and 28-36 | 
| Change in Visual Analogue Scale of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Control Visits of Injection Cycles | 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 | From Study Baseline to Week 4, 16-20 and 28-36 | 
| Change of EuroQoL 5-dimensions Questionnaire (EQ-5D) Score From Study Baseline Visit to Injection Cycle Baseline Visits and End of Cycle 3 Visit | 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. | From Study Baseline to Week 12-16, 24-32 and 36-48 | 
| 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 | 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. | From Study Baseline to Week 12-16, 24-32 and 36-48 |