A Phase III Study to Evaluate the Efficacy and Safety of GSK1358820 in Subjects With Post-stroke Upper Limb Spasticity

A Phase III Study (a Placebo Controlled, Randomized, Double-blind Comparative Study and an Open-label, Uncontrolled Study) to Evaluate the Efficacy and Safety of GSK1358820 in Patients With Post-stroke Upper Limb Spasticity

Botulinum toxin A (GSK1358820) is a sterile, purified type A botulinum neurotoxin complex. In Japan, 240 units of botulinum toxin A are approved as a maximum dose per administration for upper limb spasticity. This study is planned to evaluate the effectiveness and safety of 400 units of botulinum toxin A which can help to increase the maximum dose per administration to 400 units from 240 units as the treatment with 240 units is considered insufficient in subjects with post-stroke upper limb spasticity. Approximately 120 subjects will be randomized to receive either 400 or 240 units of botulinum toxin A in double blind phase followed by open-label phase in which 400 units of the study treatment will be injected in both the groups. The study period will be up to 52 weeks, consisting of a screening phase up to 4 weeks, minimum 12-week double blind phase (Part 1), maximum 36- week open-label phase (12 weeks per cycle with 3 treatment phases: Part 2, Part 3 and Part 4).

Inclusion Criteria:

• For screening phase (Day -28 to Day -1): Between 20 and 80 years of age at the time of informed consent (ICF).
• Subjects with at least a 3-month history of upper limb spasticity after the most recent stroke.
• Subjects who have spastic symptoms in the finger (including the thumb), wrist, and elbow flexors whom the investigator considers the injections of 400 units of the product is necessary for the upper limb based on the muscle spasms and the symptoms of the subject.
• Subjects who have a previous treatment history of 240 units of the product for the upper limb at least 16 weeks before screening.
• Subjects who meet following criteria on MAS at screening (Test position : sitting): at least 3 in for the elbow flexors and at least 2 in the finger or wrist flexors.
• Subjects who have severe upper limb spasticity, which deserves to be treated with 400 units of the product in the divided dose and was previously injected 240 units of the product.
• Subjects whom the investigator considers that enrolment in the study poses no problems based on the laboratory data results at screening.
• Subjects who are free from a history of acute decreased lung function (hospitalization with aggravated asthma/ chronic obstructive pulmonary disease (COPD), pneumonia, or signs of pneumonia, or abnormal reactive airway diseases suggested on X-rays) within the last 3 months at screening and have stable pulmonary function (oxygen saturation [SpO2]value is >=95%).
• Body weight >=40 kilograms (kg) at screening.
• Male or female subjects will be included. Male subjects must content to use highly effective contraceptive methods and sperm donation must be avoided. Female subjects who are not pregnant or lactating are considered eligible if at least one of the following criteria is met; non-childbearing potential, women of childbearing potential who content to follow the guidance about contraception during the study period and at least for 3 months after the last dose of the product, no plan of pregnancy during the study period.
• Subjects who have ability to sign their name on the ICF.
• For enrolment in the study (Day 1 [prior to injection]):Subjects who meet the following criteria on MAS score: (Test position : sitting): At least 3 in the elbow flexors and at least 2 in the finger or wrist flexors.
• If centrally acting muscle relaxants, tetracycline antibiotics, anticholinergics, benzodiazepines, or benzamides are given, the dose and regimen must be stable at least for the last 2 months before Day 1; Subjects who can maintain the same dosage and regimens at least in the blind phase after initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-label phase. However, second dose increase, resumption, and or new treatment will not be performed).
• If intrathecal baclofen is given, the dose and regimen must be stable at least for the last 1 month before Day 1; Subjects who can maintain the same dosage and regimens at least in the blind phase after initial injection (intravenous bolus is not acceptable, dose reductions and discontinuation of the drugs are acceptable. However, second dose increase, resumption, and or new treatment will not be performed).
• If antiepileptic agents are given, the dose and regimen must be stable at least for the 1 month before Day 1; Subjects who can maintain the same dose and regimens at least in the blind phase after initial injection (dose reductions and discontinuation of the drugs are acceptable in the open-label phase. However, second dose increase, resumption, and new treatment will not be performed).
• If a physical therapy, occupational therapy, or a static splint on the study involvement upper limbs is given, the frequency and treatment regimen must be stable at least for the last 3 weeks before Day 1; Subjects who can maintain the same dose and regimens at least in blind phase (In the open-label phase, the frequency and treatment regimen can be changed depending on the condition of spasticity).

Exclusion Criteria:

• For screening phase (Day -28 to Day -1): Subjects present with spasticity requiring treatment in the non-paralytic side of the upper limb.
• Subjects who have fixed contracture in the finger (upper limb), wrist, elbow or shoulder muscle, which will be involved in the study.
• Subjects who have medically significant capsulitis or subluxation in any one of the fingers (upper limb), wrist, elbow and shoulder, which will be involved in the study, or whom a investigator considers the complicated local signs of pain may affect the efficacy evaluation.
• Subjects's upper limb spasticity is attributed to other than stroke (traumatic brain injury, spinal cord injury, multiple sclerosis, or cerebral palsy).
• Subjects who have a 2-fold higher alanine aminotransferase (ALT) level than the upper limit of normal (ULN).
• Subjects who have a 1.5-fold higher bilirubin than the ULN (If a bilirubin fractionation shows direct bilirubin < 35%, a 1.5-fold higher free bilirubin than the ULN is acceptable).
• Subjects whom the investigator considers presence of a current medical history of unstable liver diseases or biliary tract diseases (the condition will be defined by development of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice or hepatic cirrhosis).
• Subjects with corrected QT interval (QTc) > 450 milliseconds (msec) or QTc > 480 msec in subjects with bundle branch block.
• Subjects who use peripherally acting muscle relaxants (dantrolene sodium, suxamethonium chloride, pancuronium bromide, vecuronium bromide, rocuronium bromide, etc.) within 1 week of screening.
• Subjects who use antibiotic agents with neuromuscular junction inhibitory effects: Aminoglycoside antibiotic agents (streptomycin sulfate, kanamycin sulfate, gentamicin sulfate, neomycin sulfate, spectinomycin hydrochloride, etc.), polypeptides (polymyxin B sulfate), lincomycins (lincomycin hydrochloride, clindamycin), and enviomycin sulfate within 1 week of screening.
• Subjects who was diagnosed as having a malignant tumor, or have a history of a malignant tumor within the last 5 years (except completely resected basal cell carcinoma or planocellular carcinoma at least 12 weeks before screening).
• Subjects who have participated in another study of an investigational product or other medical research (a clinical study of pharmacotherapy, non-pharmacotherapy, or interventional device) within 30 days before screening, or are currently participating in a study.
• Subjects who are concerned likely to have an increased risk for an underlying medical condition/neurological disease due to exposure of the product; subjects who have myasthenia gravis, Eaton-Lambert syndrome, amyotrophic lateral sclerosis, or a serious disease and use of a concomitant drug which may inhibit neuromuscular function.
• Subjects with antihuman immunodeficiency virus (HIV) antibody positive.
• Subjects who previously experienced allergic reactions or hypersensitivity due to botulinum toxin type A, an additive agent of sodium chloride, or human serum albumin.
• Subjects who were previously suspected to have neutralizing antibody production by a investigator during an injection of botulinum toxin type A.
• Subjects who have a skin disease such as infection at the site to be injected.
• Subjects who suffer from serious and unstable disease, which could pose problems for the safety of subjects and study procedure compliance.
• For enrolment in the study (Day 1 [prior to injection]): Subjects who have aspiration pneumonia, relapse of lower respiratory tract infection, uncontrollable asthma, uncontrollable COPD, and/or underlying or a history of serious respiratory dysfunction, which were clinically considered to be respiratory function impairment by a investigator within 12 months before Day 1 visit.
• Subjects who have a history of aspiration, or an underlying and/or a history of the symptoms that suggests high risks for aspiration by a investigator within 12 months before Day 1 (serious salivation requiring changing in a type of diet, chronic dysphagia that is difficult to swallow).
• Subjects who were treated with botulinum toxin for spasticity of upper limb less than 16 weeks before Day 1 visit.
• Subjects who underwent surgical interventions, phenol block, ethanol block or muscle afferent block (MAB) within 12 months before Day 1 visit, or these interventions are planned during the study period in any one of the finger (upper limb), wrist, elbow or shoulder muscles, which will be involved in the study.
• Subjects who placed a surgical cast or a dynamic splint within 3 months before Day 1 study visit, and/or these interventions are planned to be placed on the upper limb to be involved in the study.
• Subjects who were injected corticosteroid or an anesthetic agent into the finger (upper limb), wrist, or shoulder flexors, which will be involved in the study within 3 months before Day 1 visit, or these injections are planned during the study.
• Subjects who received constraint-induced movement therapy (CIMT) within 3 months before Day 1 visit or CIMT is planned during the blind phase.
• Subjects who underwent ultrasound therapy, transcutaneous electrical nerve stimulation (TENS) , electrical stimulation therapy, or acupuncture therapy in the upper arm, which will be involved in the study within 1 month before Day 1 visit, or these therapies are planned during the study.