A Phase III Study to Evaluate the Efficacy and Safety of GSK1358820 in Subjects With Post-stroke Upper Limb Spasticity
Condition: Spasticity, Post-Stroke
MeSH terms: Muscle Spasticity; Stroke
Intervention: Botulinum toxin A (GSK1358820); Placebo
Intervention description: GSK1358820 is sterile, purified type A botulinum neurotoxin complex. GSK1358820 injection will contain botulinum toxin A (100 units), sodium chloride (0.9 milligrams [mg]), and human serum albumin (0.5 mg). It will be available with doses of 400 units and 240 units.; Placebo injection will contain sodium chloride (0.9 mg).
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will receive either 400 units of botulinum toxin A injection or 240 units of botulinum toxin A injection plus placebo in double blind phase. Eligible subjects for open-label treatment period will receive 400 units of botulinum toxin A injection.
Masking: Double (Participant, Investigator)
Masking description: This study will contain a double blind treatment period (Part 1) followed by open-label treatment period (Part 2/Part3/Part4).
Enrollment: 124.0
Sex: All
Minimum age: 20 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Botulinum toxin A; Safety; post-stroke upper limb spasticity; Efficacy; GSK1358820; double blind

Summary:

      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).
    

Eligibility criteria:

        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.