A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Chinese Subjects With Post-stroke Upper Limb Spasticity

Study Overview
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Brief Summary
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This trial is a multicenter, double-blind, randomized, placebo-controlled study to compare GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox) with placebo on the efficacy and safety of treatment in poststroke subjects with focal wrist, finger and in some cases, thumb spasticity. Approximately 168 subjects will be enrolled. Subjects will receive a single treatment session of intramuscular GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox) '200U or 240U (if thumb spasticity is present)' or placebo in a randomization ratio of 1:1. The subjects will be observed until 12 weeks post injection. Outcome measures include changes from baseline at every post injection visit as measured on the Modified Ashworth Scale (MAS), Disability Assessment Scale (DAS) and Global Assessment Scale. The primary efficacy endpoint is the change from baseline at week 6 for wrist flexor muscle tone as measured on the Modified Ashworth Scale. Safety parameters will also be measured including adverse events, vital signs (pulse and blood pressure) and clinical laboratory tests (haematology, serum chemistry and urinanalysis).

Detailed Description
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The primary objective of this study is to confirm the superior efficacy of a single treatment session with GSK1358820 (Botulinum Toxin Type A, aslo known as OnabotulinumtoxinA or Botox) '200U or 240U (if thumb spasticity is present)' over placebo in subjects with post-stroke upper limb spasticity of both wrist and fingers flexors as measured on the Modified Ashworth Scale (MAS). This trial is a multicenter, double-blind, randomized, placebo-controlled, parallel group study comparing GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox) to placebo for the treatment of subjects with focal wrist, finger and in some cases, thumb spasticity post-stroke. Approximately 168 subjects will be enrolled. Subjects will receive a single treatment session with intramuscular injections of GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox) '200U or 240U (if thumb spasticity is present)' or placebo in a randomization ration of 1:1. The subjects will be observed until 12 weeks post injection. Each completed subject will attend 7 clinic visits. The maximum study duration is 13 weeks per subject. The study includes a 1 week pretreatment period, during which the screening visit (visit 1) is to take place. Only one upper limb (meeting inclusion/exclusion criteria) will be evaluated and treated in the study. Subjects will receive a single intramuscular treatment with either investigated drug or placebo at day 0 (visit 2). There will be five post-injection follow-up visits at weeks 1, 4, 6, 8 and 12 (visits 3 to 7). Week 6 (visit 5) is designated as the primary visit for determining efficacy. The primary endpoint is the change from baseline at week 6 for wrist flexor muscle tone as measured on the Modified Ashworth Scale (MAS). The secondary endpoints include The secondary endpoints include the area under curve (AUC) for the MAS wrist score change from baseline, change from baseline for wrist/finger/thumb flexor muscle tone as measured on MAS, Disability Assessment Scale and Global Assessment Scale. The safety measures include adverse events, clinical laboratory tests and pulse, blood pressure.

Official Title
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A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Chinese Subjects With Post-stroke Upper Limb Spasticity

Conditions
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Cerebrovascular Accident

Intervention / Treatment
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* Drug: GSK1358820(Botulinum toxin type A)
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects eligible for enrolment in the study must meet all of the following criteria: Subjects with upper limb spasticity who are at least 6 months post stroke and present with spasticity of both the wrist and fingers in the study limb. Wrist flexor muscle tone of 3 or greater and finger flexor muscle tone of 2 or greater as measured on MAS (0 to 4). At least one functional disability item (i.e., hygiene, dressing, pain, or cosmesis) with a rating of 2 or greater on DAS (0 to 3). If using oral anti-spasticity medications, must be stable for at least 1 month prior to study enrolment If using physical therapy, must be stable for at least 1 month prior to study enrolment. Male or female 18 to 75 years old at the time of informed consent. >=40kg in weight. QTc criteria: (either QTcb or QTcf, machine or manual overread, males or females); include the following details as appropriate: QTc<450 millisecond (msec) or <480msec for subjects with Bundle Branch Block-values based on either single electrocardiogram (ECG) values or triplicate ECG averaged QTc values obtained over a brief recording period. Liver function tests: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2xULN; alkaline phosphatase and bilirubin ≤1.5xULN (isolated bilirubin >1.5ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). In the opinion of the investigator, subject must clearly understand the intent of the study and be willing and able to comply with study instructions and complete the entire study. Informed consent has been obtained. Exclusion Criteria: Subjects meeting any of the following criteria must not be enrolled in the study: Presence of fixed contracture of the study limb (absence of passive range of motion). Profound atrophy of muscles to be injected (in the investigators opinion). Infection or dermatological condition at the injection sites. Significant inflammation in the study limb limiting joint movement. History of or planned treatment for spasticity with phenol or alcohol block in the study limb. History of or planned surgical intervention for spasticity of the study limb. History (within 3 months of qualification) of or planned (during study period) casting of the study limb. Participation in another clinical study currently, or within the 30 days immediately prior to enrolment. Previous or current botulinum toxin therapy of any serotype. Planned or anticipated initiation of new antispasticity medications during the clinical study. Any medical condition that may put the subject at increased risk with exposure to GSK1358820, including diagnosed myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or any other disorder that might have interfered with neuromuscular function. Concurrent use of aminoglycoside antibiotics or other agents that might interfere with neuromuscular function. A full list of prohibited medications that interfere with neuromuscular transmission is provided as Appendix 1. Current treatment for spasticity with an intrathecal baclofen. Females who are pregnant, nursing, or planning a pregnancy during the study period, or females of childbearing potential, not using a reliable means of contraception. Known allergy or sensitivity to study medication or its components. Bedridden subjects. Unstable liver disease (as defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Presence of clinically unstable severe cardiovascular, renal or respiratory disease. Investigator's opinion that the subject has a concurrent condition(s) that may put the subject at significant risk, may confound the study results, or may interfere significantly with the conduct of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: placebo<br>Sodium chloride | Drug: placebo<br>* placebo<br>|
| Experimental: GSK1358820(Botulinum Toxin Type A)<br>GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox) | Drug: GSK1358820(Botulinum toxin type A)<br>* GSK1358820 (Botulinum Toxin Type A, also known as OnabotulinumtoxinA or Botox)<br>* Other names: Botox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at Week 6 for Wrist Flexor Muscle Tone as Measured on the Modified Ashworth Scale (MAS) | The investigator, physiotherapist, or occupational therapist extended the participant's wrist as quickly as possible to grade flexor muscle tone. The MAS wrist score was calculated by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). Change from Baseline at Week 6 was calculated as the value at Week 6 minus the value at Baseline. | Baseline (Day 0) and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) for the Change From Baseline at Weeks 6 and 12 for MAS Wrist Score | The MAS wrist score was assessed by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). Mean change from Baseline for the MAS wrist score was calculated as the value at Week 6 and Week 12 minus the value at Baseline. In a graph plotting time points on the horizontal axis (HA) and changes from Baseline on the vertical axis, the area surrounded by the MAS wrist score change curve and the HA was calculated and used as a summary index (AUC) for assessment of the MAS wrist score. | Baseline (Day 0), Week 6, and Week 12 | 
| Change From Baseline at Weeks 1, 4, 8, and 12 for Wrist Flexor Muscle Tone as Measured on the MAS | The investigator, physiotherapist, or occupational therapist extended the participant's wrist as quickly as possible to grade flexor muscle tone. The MAS wrist score was calculated by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). Change from Baseline at the indicated time points was calculated as the value at the indicated time points minus the value at Baseline. | Baseline (Day 0) and Weeks 1, 4, 8, and 12 | 
| Number of Participants Classified as Wrist Treatment Responders at All Post-injection Visits | Wrist treatment responders were defined as participants with a decrease in wrist flexor muscle tone of at least one point on the MAS. The MAS wrist score was calculated by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). | Weeks 1, 4, 6, 8, and 12 | 
| Change From Baseline at Weeks 1, 4, 6, 8, and 12 for Finger Flexor Muscle Tone as Measured on the MAS | The investigator, physiotherapist, or occupational therapist extended the participant's finger as quickly as possible to grade the flexor muscle tone. The MAS finger score was calculated by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). Change from Baseline at the indicated time points was calculated as the value at Week 1, 4, 6, 8, and 12 minus the value at Baseline. | Baseline (Day 0) and Weeks 1, 4, 6, 8, and 12 | 
| Change From Baseline at Weeks 1, 4, 6, 8 and 12 for Thumb Flexor Muscle Tone as Measured on the MAS | The investigator, physotherapist, or occupational therapist extended the participant's thumb as quickly as possible to grade the flexor muscle tone. The MAS thumb score was calculated by using the 6-point MAS (0, 1, 1+ [regarded as 1.5], 2, 3, and 4; 0=no increase in muscle tone; 4=affected part[s] rigid in flexion/extension). Change from Baseline at the indicated time points was calculated as the value at Week 1, 4, 6, 8, and 12 minus the value at Baseline. | Baseline (Day 0) and Weeks 1, 4, 6, 8, and 12 | 
| Change From Baseline at Weeks 1, 4, 6, 8, and 12 for Principal Measure as Assessed on the Disability Assessment Scale (DAS) | The investigator assessed 4 areas of disability, hygiene, pain, dressing, and limb posture, using the 4-point DAS (0=No functional disability to 3=Severe disability). Prior to the first dose, the investigator, in consultation with the participant, selected 1functional disability item (which had to have a score of 2 or greater as measured on the DAS, indicating moderate to severe disability) from the 4 areas of disability and assessed it as a principal measure. Change from Baseline at the indicated time points was calculated as the value at Weeks 1, 4, 6, 8, and 12 minus the value at Baseline. | Baseline (Day 0) and Weeks 1, 4, 6, 8, and 12 | 
| Global Assessment Scale (GAS) Score as Evaluated by the Physician at the Indicated Time Points | The physician used the GAS to assess response to treatment at each visit after injection. The assessor was the same throughout the study period. GAS scores were assessed by using the 9-point GAS (-4, -3, -2, -1, -0, +1, +2, +3, +4; -4=very marked worsenig, -0=unchanged, +4=very marked improvement) at the indicated time points. | Weeks 1, 4, 6, 8, and 12 | 
| GAS Score as Evaluated by the Care Giver or the Participants at the Indicated Time Points | The care giver or participants used the GAS to assess response to treatment at each visit after injection. The assessor was the same throughout the study period. GAS scores were assessed by using the 9-point GAS (-4, -3, -2, -1, -0, +1, +2, +3, +4; -4=very marked worsening, -0=unchanged, +4=very marked improvement) at the indicated time point. | Weeks 1, 4, 6, 8, and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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efficacy, Spasticity, Post-Stroke, safety, Botulinum toxin type A, placebo, spasticity