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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merz Pharmaceuticals GmbH
ClinicalTrials.gov Identifier:
NCT01603459
First received: April 17, 2012
Last updated: March 27, 2017
Last verified: March 2017
  Purpose
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 Intervention Phase
Spasticity of the Upper and Lower Limb Due to Cerebral Causes Drug: IncobotulinumtoxinA Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
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

Resource links provided by NLM:


Further study details as provided by Merz Pharmaceuticals GmbH:

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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.


Enrollment: 155
Study Start Date: May 2012
Study Completion Date: September 2014
Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.


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.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01603459

  Show 33 Study Locations
Sponsors and Collaborators
Merz Pharmaceuticals GmbH
Investigators
Study Director: Medical Expert Merz Pharmaceuticals
  More Information

Publications:
Responsible Party: Merz Pharmaceuticals GmbH
ClinicalTrials.gov Identifier: NCT01603459     History of Changes
Other Study ID Numbers: MRZ60201_3053_1
2010-020886-26 ( EudraCT Number )
Study First Received: April 17, 2012
Results First Received: July 26, 2016
Last Updated: March 27, 2017

Additional relevant MeSH terms:
Muscle Spasticity
Muscular Diseases
Musculoskeletal Diseases
Muscle Hypertonia
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Botulinum Toxins
incobotulinumtoxinA
Botulinum Toxins, Type A
abobotulinumtoxinA
onabotulinumtoxinA
Acetylcholine Release Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Neuromuscular Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on June 28, 2017