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

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

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.

Study Overview

• Status: Completed
• Conditions: Cerebrovascular Accident; Post-Stroke Spasticity
• Intervention / Treatment: Drug: Placebo; Drug: GSK1358820

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 811-0213
    • GSK Investigational Site
  • Hiroshima, Japan, 720-0825
    • GSK Investigational Site
  • Hiroshima, Japan, 728-0001
    • GSK Investigational Site
  • Hokkaido, Japan, 005-0802
    • GSK Investigational Site
  • Hokkaido, Japan, 005-8555
    • GSK Investigational Site
  • Hokkaido, Japan, 006-0805
    • GSK Investigational Site
  • Hokkaido, Japan, 053-0803
    • GSK Investigational Site
  • Ibaraki, Japan, 302-0112
    • GSK Investigational Site
  • Kanagawa, Japan, 247-8533
    • GSK Investigational Site
  • Kanagawa, Japan, 227-8518
    • GSK Investigational Site
  • Kanagawa, Japan, 253-8558
    • GSK Investigational Site
  • Kanagawa, Japan, 257-0001
    • GSK Investigational Site
  • Kumamoto, Japan, 860-8518
    • GSK Investigational Site
  • Shizuoka, Japan, 410-1128
    • GSK Investigational Site
  • Shizuoka, Japan, 410-2507
    • GSK Investigational Site
  • Shizuoka, Japan, 410-3293
    • GSK Investigational Site
  • Tokyo, Japan, 142-8666
    • GSK Investigational Site
  • Tokyo, Japan, 105-8471
    • GSK Investigational Site
  • Tokyo, Japan, 140-0001
    • GSK Investigational Site
  • Yamaguchi, Japan, 740-0021
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo
Active Comparator: BTX	Drug: GSK1358820; botulinum toxin type A

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)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Kaji R, Osako Y, Suyama K, Maeda T, Uechi Y, Iwasaki M; GSK1358820 Spasticity Study Group. Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial. J Neurol. 2010 Aug;257(8):1330-7. doi: 10.1007/s00415-010-5526-3. Epub 2010 Apr 1. Erratum In: J Neurol. 2010 Aug;257(8):1416.

Study record dates

Study Major Dates

• Study Start: May 1, 2007
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: April 13, 2007
• First Submitted That Met QC Criteria: April 13, 2007
• First Posted (Estimate): April 16, 2007

Study Record Updates

• Last Update Posted (Estimate): September 8, 2010
• Last Update Submitted That Met QC Criteria: August 30, 2010
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Keywords: Spasticity; Lower Limb; botulinum toxin type A; Post-Stroke
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Stroke; Muscle Spasticity
• Other Study ID Numbers: BTX108512