Study of GSK1358820 In Patients With Post-Stroke Lower Limb Spasticity

Study Overview
=================
Brief Summary
-----------------
This is a study to confirm the superior efficacy of GSK1358820 over placebo in patients with equinus deformity associated with post-stroke lower limb spasticity using the Modified Ashworth Scale (MAS) ankle score.

Detailed Description
-----------------
This is a study to confirm the superior efficacy of GSK1358820 over placebo in patients with equinus deformity associated with post-stroke lower limb spasticity using the Modified Ashworth Scale (MAS) ankle score.

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

Conditions
-----------------
Post-Stroke Spasticity, Cerebrovascular Accident

Intervention / Treatment
-----------------
* Drug: GSK1358820
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects eligible for enrollment in the study must meet all of the following criteria: Patients with lower limb spasticity who are at least 6 months post-stroke and present with equinus deformity (plantar flexion of the ankle) at the start of double-blind phase (Visit 2). Patients with MAS ankle score of ≥3 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. ≥50kg 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. NOTE: Subjects may be hospitalized for ≤10 days after injection during the treatment period. 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 ankle (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 ankle spasticity. Casting of the study lower 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 or current botulinum toxin therapy of any serotype. 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 or hepatic disease. Infection or dermatological condition at the proposed injection sites. Previous or planned participation in another clinical study (including the upper 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
-----------------
Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve (AUC) for the Change From Baseline in Modified Ashworth Scale (MAS) Ankle Score to the End of the DB Phase (Week 12) | Change from baseline in MAS ankle 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 ankle score change curve and the horizontal axis was calculated and used as a summary index (AUC) for assessment of the MAS ankle 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 |
| --- | --- | --- |
| Mean Change From Baseline in the MAS Ankle Score From Baseline to Week 12 of the Double-blind Phase | The investigator assessed Modified Ashworth Scale (MAS) ankle 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 the Physician's Rating Score (PRS) From Baseline to Week 12 of the Double-blind Phase | The investigator assessed the PRS of gait pattern consisting of 3 parameters. Affected limb was scored on a scale of -1 (worst) to 9 (best) based on 3 parameters (initial foot contact, foot contact at midstance, gait assistive devices) at each time point in double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in the Time (Seconds) to Walk 10 Meters From Baseline to Week 12 of the Double-blind Phase | The time (seconds) required to walk 10 meters was measured at each time point in the double-blind phase. | Baseline; Weeks 1, 4, 6, 8, and 12 | 
| Mean Change From Baseline in the Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Investigator From Baseline to Week 12 of the Double-blind Phase | The CGI 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 the Clinical Global Impression (CGI) Score of Functional Disability Assessed by the Participant From Baseline to Week 12 of the Double-blind Phase | The CGI 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 the 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 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 Ankle Score at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The investigator assessed Modified Ashworth Scale (MAS) ankle 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 Physician's Rating Score (PRS) at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The investigator assessed the PRS of gait pattern consisting of 3 parameters. Affected limb was scored on a scale of -1 (worst) to 9 (best) based on 3 parameters (initial foot contact, foot contact at midstance, gait assistive devices) 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 Time (Seconds) to Walk 10 Meters at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The time (seconds) required to walk 10 meters was measured 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 Investigator at 4, 8, and 12 Weeks After Each Injection in the Open-label Phase | The CGI 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 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 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
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Post-Stroke, Lower Limb, botulinum toxin type A, Spasticity