IncobotulinumtoxinA (Xeomin) for Upper Limb Spasticity

Study Overview
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Brief Summary
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This study will investigate the efficacy and safety of incobotulinumtoxinA (Xeomin) in the treatment of arm tightness (upper limb spasticity) using two different dilutions of incobotulinumtoxinA (Xeomin).

Detailed Description
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IncobotulinumtoxinA (Xeomin) is a botulinum toxin type A preparation free of complexing proteins. Injected into a muscle, incobotulinumtoxinA causes a reversible local weakening of the muscle for several months, and may improve an impaired muscle function by lessening the muscle tightness within few days. IncobotulinumtoxinA is widely used for various severe neurological conditions. There is some evidence that the treatment effect may be influenced by the amount of the solvent in which incobotulinumtoxinA is diluted before injection.

Official Title
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Prospective, Randomized, Observer-blind, Parallel-group, Multi-center Trial to Assess Efficacy and Safety of Two Different Dilutions of incobotulinumtoxinA (Xeomin) in Patients With Upper Limb Spasticity

Conditions
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Upper Limb Spasticity

Intervention / Treatment
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* Drug: incobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kD), free from complexing proteins)


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Female or male patients ≥ 18 years Stable upper limb spasticity of diverse etiology Focal spasticity with equal or more than 2 points on the Ashworth scale in the wrist flexors Disability Assessment Scale (DAS) ≥ 2 points for primary therapeutic target at both screening and baseline visits Main Exclusion Criteria: Fixed contracture Bilateral upper limb paresis/paralysis Previous treatment with BoNT of any serotype and for any body region within the 4 months prior to screening Previous or planned treatment with phenol- or alcohol-injection in the target limb Other muscle hypertonia (e.g. rigidity) Diagnosis of myasthenia gravis, Lambert-Eaton-Syndrome, amyotrophic lateral sclerosis, or any other significant neuromuscular disease which might interfere with the study Severe atrophy of the target limb muscles

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: incobotulinumtoxinA (Xeomin) High-volume Dilution 20 Units/mL<br>incobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kD), free from complexing proteins)(active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection; Mode of administration: intramuscular injection; The content of the vial was dissolved in 5.0 mL of sterile sodium chloride [NaCl] 0.9% solution without preservatives. Dilution with 5.0 mL resulted in a dose of 20 units per 1.0 mL. | Drug: incobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kD), free from complexing proteins)<br>* active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins; powder for solution for injection; Mode of administration: intramuscular injection; The content of the vial was dissolved in 2.0 or 5.0 mL of sterile sodium chloride [NaCl] 0.9% solution without preservatives. Dilution with 2.0 or 5.0 mL resulted in a dose of 50 or 20 units per 1.0 mL.<br>* Other names: Botulinum toxin type A (150 kD), free from complexing proteins;|
| Active Comparator: incobotulinumtoxinA (Xeomin) Low-volume Dilution 50 Units/mL<br>incobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kD), free from complexing proteins)(active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins) powder for solution for injection; Mode of administration: intramuscular injection; The content of the vial was dissolved in 2.0 mL sterile of NaCl 0.9% solution without preservatives. Dilution with 2.0 mL resulted in a dose of 50 units per 1.0 mL. | Drug: incobotulinumtoxinA (Xeomin, also known as NT 201 or Botulinum toxin type A (150 kD), free from complexing proteins)<br>* active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins; powder for solution for injection; Mode of administration: intramuscular injection; The content of the vial was dissolved in 2.0 or 5.0 mL of sterile sodium chloride [NaCl] 0.9% solution without preservatives. Dilution with 2.0 or 5.0 mL resulted in a dose of 50 or 20 units per 1.0 mL.<br>* Other names: Botulinum toxin type A (150 kD), free from complexing proteins;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder in Disability Assessment Scale (DAS) at Week 4 - Per Protocol Set | The primary efficacy endpoint is the number of responder at Week 4; response defined as an improvement (reduction) of at least one point in the DAS for the primary therapeutic target from baseline visit to Week 4. The DAS determines the functional impairment for the domains hygiene, dressing, limb position and pain according to the following scale: 0 = no disability; 1 = mild disability; 2 = moderate disability; 3 = severe disability. At Screening visit, the subject and investigator, selected together one of the four domains as the primary therapeutic target. | At week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Responder in DAS at Week 4 - Full Analysis Set | Response is defined as an improvement (reduction) of at least one point in the DAS for the primary therapeutic target from baseline visit. | week 4 | 
| Responder in DAS at Week 12 - Full Analysis Set | Response is defined as an improvement (reduction) of at least one point in the DAS for the primary therapeutic target from baseline visit. | week 12 | 
| Responder in DAS at Follow up - Full Analysis Set | Response is defined as an improvement (reduction) of at least one point in the DAS for the primary therapeutic target from baseline visit. | follow up visit, between week 12 and week 20 | 
| Responder in Frenchay Arm Test (FAT) at Week 4 - Full Analysis Set | Response is defined as an improvement (increase) of at least one point in the FAT from baseline visit. For the FAT the investigator assessed the extent of functionality of the upper limb according to five standardized tests. Each test is rated with 0 = failed or 1 = successfully passed. For the evaluation, the sum of all test scores was calculated resulting in a total score from 0 to 5. | Week 4 | 
| Responder in FAT at Week 12 - Full Analysis Set | Response is defined as an improvement (increase) of at least one point in the FAT from baseline visit. For the FAT the investigator assessed the extent of functionality of the upper limb according to five standardized tests. Each test is rated with 0 = failed or 1 = successfully passed. For the evaluation, the sum of all test scores was calculated resulting in a total score from 0 to 5. | Week 12 | 
| Responder in FAT at Follow up - Full Analysis Set | Response is defined as an improvement (increase) of at least one point in the FAT from baseline visit. For the FAT the investigator assessed the extent of functionality of the upper limb according to five standardized tests. Each test is rated with 0 = failed or 1 = successfully passed. For the evaluation, the sum of all test scores was calculated resulting in a total score from 0 to 5. | follow up visit, between week 12 and week 20 | 
| Responder in Ashworth Scale (Elbow Flexors) at Week 4 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. The Ashworth Scale is a 5-point-scale to rate to degree of spasticity: 0 = No increase in tone; 1 = Slight increase in tone giving a catch when the limb was moved in flexion or extension; 2 = More marked increase in tone, but limb easily flexed; 3 = Considerable increase in tone - passive movements difficult; 4 = Limb rigid in flexion or extension. | week 4 | 
| Responder in Ashworth Scale (Elbow Flexors) at Week 12 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 12 | 
| Responder in Ashworth Scale (Elbow Flexors) at Follow up - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | follow up visit, between week 12 and week 20 | 
| Responder in Ashworth Scale (Wrist Flexors) at Week 4 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 4 | 
| Responder in Ashworth Scale (Wrist Flexors) at Week 12 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 12 | 
| Responder in Ashworth Scale (Wrist Flexors) at Follow up - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | follow up visit, between week 12 and week 20 | 
| Responder in Ashworth Scale (Thumb Flexors) at Week 4 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 4 | 
| Responder in Ashworth Scale (Thumb Flexors) at Week 12 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 12 | 
| Responder in Ashworth Scale (Thumb Flexors) at Follow up - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | follow up visit, between week 12 and week 20 | 
| Responder in Ashworth Scale (Fingers Flexors) at Week 4 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 4 | 
| Responder in Ashworth Scale (Fingers Flexors) at Week 12 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 12 | 
| Responder in Ashworth Scale (Fingers Flexors) at Follow up - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | follow up visit, between week 12 and week 20 | 
| Responder in Ashworth Scale (Forearm Pronators) at Week 4 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 4 | 
| Responder in Ashworth Scale (Forearm Pronators) at Week 12 - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | week 12 | 
| Responder in Ashworth Scale (Forearm Pronators) at Follow up - Full Analysis Set | Response is defined as an improvement of at least one point in the Ashworth Scale for the treated muscle group from baseline visit. | follow up visit, between week 12 and week 20 | 
| Change From Baseline in Passive Range of Motion (PROM) - Wrist Extension | For the PROM all motions of wrist and elbow were measured from a defined neutral starting point position. The degrees of motion were added in the direction the wrist and elbow moved from the neutral starting position. The neutral starting position was the position of an upright standing/sitting person. The angle of the motion from the neutral starting position was measured in degrees using a goniometer. Angles were measured for the wrist with maximal dorsal extension, neutral position and maximal palmar flexion, and for the elbow with maximal extension, neutral position and maximal flexion. | baseline, week 4, week 12, follow up (between week 12 and week 20) | 
| Change From Baseline in Passive Range of Motion (PROM) - Elbow Extension | For the PROM all motions of wrist and elbow were measured from a defined neutral starting point position. The degrees of motion were added in the direction the wrist and elbow moved from the neutral starting position. The neutral starting position was the position of an upright standing/sitting person. The angle of the motion from the neutral starting position was measured in degrees using a goniometer. Angles were measured for the wrist with maximal dorsal extension, neutral position and maximal palmar flexion, and for the elbow with maximal extension, neutral position and maximal flexion. | baseline, week 4, week 12, follow up (between week 12 and week 20) | 
| Change From Baseline in Passive Range of Motion (PROM) - Wrist Maximum Flexion | For the PROM all motions of wrist and elbow were measured from a defined neutral starting point position. The degrees of motion were added in the direction the wrist and elbow moved from the neutral starting position. The neutral starting position was the position of an upright standing/sitting person. The angle of the motion from the neutral starting position was measured in degrees using a goniometer. Angles were measured for the wrist with maximal dorsal extension, neutral position and maximal palmar flexion, and for the elbow with maximal extension, neutral position and maximal flexion. | baseline, week 4, week 12, follow up (between week 12 and week 20) | 
| Change From Baseline in Passive Range of Motion (PROM) - Elbow Maximum Flexion | For the PROM all motions of wrist and elbow were measured from a defined neutral starting point position. The degrees of motion were added in the direction the wrist and elbow moved from the neutral starting position. The neutral starting position was the position of an upright standing/sitting person. The angle of the motion from the neutral starting position was measured in degrees using a goniometer. Angles were measured for the wrist with maximal dorsal extension, neutral position and maximal palmar flexion, and for the elbow with maximal extension, neutral position and maximal flexion. | baseline, week 4, week 12, follow up (between week 12 and week 20) | 
| Investigator's Global Assessment of Treatment Response (GATR) - Full Analysis Set | The investigator's global assessment of response to treatment were determined with the use of the Global Response Scale using the following scores: -4 = very marked worsening; -3 = marked worsening; -2 = moderate worsening; -1 = mild worsening; 0 = no change; +1 = mild improvement; +2 = moderate improvement; +3 = marked improvement; +4 = very marked improvement. | week 4 | 
| Patient's Global Assessment of Treatment Response (GATR) - Full Analysis Set | The patient's global assessment of response to treatment were determined with the use of the Global Response Scale using the following scores: -4 = very marked worsening; -3 = marked worsening; -2 = moderate worsening; -1 = mild worsening; 0 = no change; +1 = mild improvement; +2 = moderate improvement; +3 = marked improvement; +4 = very marked improvement. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 4 - Item Feeding | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 12 - Item Feeding | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 12 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Follow up - Item Feeding | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | follow up visit, between week 12 and week 20 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 4 - Item Grooming | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 12 - Item Grooming | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 12 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Follow up - Item Grooming | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | follow up visit, between week 12 and week 20 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 4 - Item Toilet Use | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 12 - Item Toilet Use | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 12 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Follow up - Item Toilet Use | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | follow up visit, between week 12 and week 20 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 4 - Item Bathing/Showering | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 12 - Item Bathing/Showering | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 12 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Follow up - Item Bathing/Showering | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | follow up visit, between week 12 and week 20 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 4 - Item Dressing | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 4 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Week 12 - Item Dressing | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | week 12 | 
| Response Rates in Activity of Daily Living (Barthel Index) at Follow up - Item Dressing | Response is defined as an improvement (increase) of at least one point in the Barthel Index from baseline visit. The Barthel Index was assessed for the items feeding, grooming, toilet use, bathing and dressing. Feeding: 0 = unable; 1 = needs help cutting, spreading butter etc.; 2 = independent; Grooming: 0 = needs help with personal care; 1 = independent face/hair/teeth/shaving; Toilet use: 1 = need some help, but could do something alone; 2 = independent; Bathing: 0 = dependent; 1 = independent; Dressing: 0 = dependent; 1 = needs help but could do about half unaided; 2 = independent. | follow up visit, between week 12 and week 20 |