Study Of GSK1358820 In Patients With Post-Stroke Upper Limb Spasticity

Study Overview
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Brief Summary
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This is a study to confirm the superior efficacy of a single treatment of GSK1358820 over placebo in patients with post-stroke upper limb spasticity of both the wrist and finger flexors using the Modified Ashworth Scale (MAS) wrist score.

Detailed Description
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This is a study to confirm the superior efficacy of a single treatment of GSK1358820 over placebo in patients with post-stroke upper limb spasticity of both the wrist and finger flexors using the Modified Ashworth Scale (MAS) wrist score.

Official Title
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A Multicenter Study to Evaluate the Efficacy and Safety in Patients With Post-Stroke Upper Limb Spasticity Receiving a Double-Blind, Placebo-Controlled GSK1358820 Treatment Followed by an Open-Label GSK1358820 Treatment

Conditions
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Post-Stroke Spasticity, Cerebrovascular Accident

Intervention / Treatment
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* Drug: GSK1358820
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects eligible for enrollment in the study must meet all of the following criteria: Patients with upper limb spasticity who are at least 6 months post stroke and present with spasticity of both the wrist and fingers at the start of double-blind phase (Visit 2). Wrist flexor muscle tone of ≥3 and finger flexor muscle tone of ≥2 on the MAS, and at least one functional disability item (i.e., hygiene, pain, dressing or limb posture) with a rating of ≥2 on the Disabilty Assessment Scale (DAS) at the start of double-blind phase (Visit 2). Male or female between 20 and 80 years of age at the time of informed consent. For males, only those who can practice contraception during the study period are eligible. ≥40kg in weight at the start of double-blind phase (Visit 2). Inpatient or outpatient; however, the hospitalization status must remain unchanged during the double-blind phase. Written informed consent from the subject him/herself. If the subject's signature is not legible, the attendance of a witness is required. Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: Bilateral hemiplegia or quadriplegia. Presence of fixed contractures of the wrist and/or fingers (absence of range of motion). Profound atrophy of the muscles to be injected. Previous surgical intervention, phenol block, ethanol block, or muscle afferent block (MAB) for wrist and/or finger spasticity. Casting of the study upper limb within 3 months prior to the start of double-blind phase (Visit 2). Current treatment with intrathecal baclofen. Use of peripheral muscle relaxants (dantrolene sodium, suxamethonium chloride, pancuronium bromide, vecuronium bromide, rocuronium bromide). Concurrent use of antibiotics that interfere with neuromuscular transmission, such as aminoglycoside antibiotics (e.g., streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulphate, spectinomycin hydrochloride), polypeptide antibiotics (e.g., polymixin B sulfate), lincomycin antibiotics (e.g., lincomycin hydrochloride, clindamycin), and enviomycin sulfate. Previous botulinum toxin therapy. Diagnosis of systemic neuromuscular disorders (e.g., myasthenia gravis, Lambert-Eaton syndrome, amyotrophic lateral sclerosis). Females who are pregnant, nursing, may be pregnant, or planning a pregnancy during the study period. Known allergy or hypersensitivity to any ingredient of study medication (e.g., human serum albumin). Presence of psychiatric disorder or impairment of intellectual function that may interfere with the subject's ability to give informed consent or the conduct of the study. Bedridden patients. Presence of clinically unstable severe cardiovascular disease. Presence of clinically significant severe renal, hepatic or respiratory disease. Infection or dermatological condition at the proposed injection sites. Previous or planned participation in another clinical study (including the lower limb spasticity study of GSK1358820) within 6 months prior to the start of double-blind phase (Visit 2). Others whom the investigator or sub investigator considers not eligible for the study. Clinically significant severe reduction of muscle strength. Angle closure glaucoma or its preposition (narrow angle).

Ages Eligible for Study
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Minimum Age: 20 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: High-Dose BTX<br> | Drug: GSK1358820<br>* botulinum toxin type A<br>|
| Placebo Comparator: High-Dose Placebo<br> | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: Low-Dose BTX<br> | Drug: GSK1358820<br>* botulinum toxin type A<br>|
| Active Comparator: Low-Dose Placebo<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) for the Change From Baseline in Modified Ashworth Scale (MAS) Wrist Score to the End of the DB Phase (Week 12) in the High-dose Groups | Change from baseline in MAS wrist score using a 6-point scale (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) to each time point in the DB phase was calculated. In the graph plotting time points on the horizontal axis and changes from baseline on the vertical axis, the area surrounded by the MAS wrist score change curve and the horizontal axis was calculated and used as a summary index (AUC) for assessment of the MAS wrist score. Negative changes from baseline indicate improvement, and the AUC has a negative sign. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) for the Change From Baseline in Modified Ashworth Scale (MAS) Wrist Score to the End of the DB Phase (Week 12) in the Low-dose Groups | Change from baseline in MAS wrist score using a 6-point scale (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) to each time point in the DB phase was calculated. In the 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. Negative changes from baseline indicate improvement, and the area under the AUC has a negative sign. | Baseline, Week 12 | 
| Mean Change From Baseline in MAS Wrist Score From Baseline to Week 12 of the Double-blind Phase | The investigator assessed MAS wrist score using a 6-point scale (0, 1, 1+, 2, 3, and 4; 0=No increase in muscle tone to 4=Affected part[s] rigid in flexion or extension) at each time point in the double-blind phase. The +1 (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder [less than half] of ROM [range of motion]) of MAS score is regarded as score 1.5. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in MAS Finger Score From Baseline to Week 12 of the Double-blind Phase | The investigator assessed MAS finger score using a 6-point scale (0, 1, 1+, 2, 3, and 4; 0=No increase in muscle tone to 4=Affected part[s] rigid in flexion or extension) at each time point in the double-blind phase. The +1 (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder [less than half] of ROM [range of motion]) of MAS score is regarded as score 1.5. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Disability Assessment Scale (DAS) Score of Principal Measure From Baseline to Week 12 of the Double-blind Phase | DAS scores of Hygiene, Pain, Dressing, and Limb posture were assessed using a 4-point scale (0=No functional disability to 3=Severe disability). Prior to the first injection, the investigator, in consultation with the participant, selected one functional disability item and assessed it as a principal measure at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Disability Assessment Scale (DAS) Score of Hygiene From Baseline to week12 of the Double-blind Phase | DAS score of Hygiene was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point in double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Disability Assessment Scale (DAS) Score of Pain From Baseline to Week 12 of the Double-blind Phase | DAS score of pain was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Disability Assessment Scale (DAS) Score of Dressing From Baseline to Week 12 of the Double-blind Phase | DAS score of Dressing was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Disability Assessment Scale (DAS) Score of Limb Posture From Baseline to Week 12 of the Double-blind Phase | DAS score of Limb Posture was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Investigator From Baseline to Week 12 of the Double-blind Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Participant From Baseline to Week 12 of the Double-blind Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Physiotherapist/Occupational Therapist From Baseline to Week 12 of the Double-blind Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the MAS Wrist Score at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The investigator assessed the MAS wrist score using a 6-point scale (0, 1, 1+, 2, 3, and 4; 0=no increase in muscle tone to 4=affected part[s] rigid in flexion or extension) at each time point from baseline (at the start of the double-blind phase) to week 48. The +1 (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder ([less than half] of ROM [range of motion]) of MAS score is regarded as score 1.5. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the MAS Finger Score From at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The investigator assessed the MAS finger score using a 6-point scale (0, 1, 1+, 2, 3, and 4; 0=No increase in muscle tone to 4=Affected part[s] rigid in flexion or extension) at each time point from baseline (at the start of the double-blind phase) to week 48. The +1 (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder [less than half] of ROM [range of motion]) of MAS score is regarded as score 1.5. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Disability Assessment Scale (DAS) Score of Principal Measure at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | DAS scores of Hygiene, Pain, Dressing, and Limb posture were assessed using a 4-point scale (0=No functional disability to 3=Severe disability). Prior to the first injection, the investigator, in consultation with the participant, selected one functional disability item and assessed it as a principal measure at each time point from baseline (at the start of the double-blind phase) to Week 48. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Disability Assessment Scale (DAS) Score of Hygiene at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The DAS score of Hygiene was assessed using a 4-point scale (0=No functional disability; 3=Severe disability) at each time point from baseline (at the start of the double-blind phase) to Week 48. BTX was injected in participants up to 3 times from Week 12 to Week 36 when participants met re-injection criteria. Measurements were taken at each point until Week 48 and summarized by the number of weeks after the re-injection in individuals (4, 8, and 12 weeks after each injection) in open-label phase; thus, measurements could have been taken up to Week 48 (12 weeks after the Week 36 injection). | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Disability Assessment Scale (DAS) Score of Pain at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The DAS score of Pain was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point from baseline (at the start of the double-blind phase) to Week 48. BTX was injected in participants up to 3 times from Week 12 to Week 36 when participants met re-injection criteria. Measurements were taken at each point until Week 48 and summarized by the number of weeks after the re-injection in individuals (4, 8, and 12 weeks after each injection) in open-label phase; thus, measurements could have been taken up to Week 48 (12 weeks after the Week 36 injection). | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Disability Assessment Scale (DAS) Score of Dressing at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The DAS score of Dressing was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point from baseline (at the start of the double-blind phase) to Week 48. BTX was injected in participants up to 3 times from Week 12 to Week 36 when participants met re-injection criteria. Measurements were taken at each point until Week 48 and summarized by the number of weeks after the re-injection in individuals (4, 8, and 12 weeks after each injection) in open-label phase; thus, measurements could have been taken up to Week 48 (12 weeks after the Week 36 injection). | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Disability Assessment Scale (DAS) Score of Limb Posture at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The DAS score of Limb Posture was assessed using a 4-point scale (0=No functional disability to 3=Severe disability) at each time point from baseline (at the start of the double-blind phase) to Week 48. BTX was injected in participants up to 3 times from Weeks 12 to 36 when participants met re-injection criteria. Measurements were taken at each point until Week 48 and summarized by the number of weeks after the re-injection in individuals (4, 8, and 12 weeks after each injection) in open-label phase; thus, measurements could have been taken up to Week 48 (12 weeks after the Week 36 injection). | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Investigator at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point from baseline (at the start of the double-blind phase) to Week 48. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the Double-blind Phase) in the Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Participant at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point from baseline (at the start of the double-blind phase) to Week 48. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 
| Mean Change From Baseline (at the Start of the DB Phase) in the Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Physiotherapist/Occupational Therapist at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The CGI score of functional disability was assessed at each visit using the 11-point Numeric Rating Scale (NRS) (-5=Worst Possible to 5=Best Possible) at each time point from baseline (at the start of the double-blind phase) to Week 48. | Baseline; Weeks 4, 8, and 12 after each injection (up to Week 48; injections given from Week 12 to Week 36) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spasticity, Post-Stroke, botulinum toxin type A, Upper Limb