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

NCT03261167 | Completed Phase 3 Results

• 1 other identifier: 207660
• Study Type: interventional
• Target: 124
• Locations: 1 country
• Sites: 38

Brief 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).

Conditions

Spasticity, Post-Stroke

Keywords

Botulinum toxin A; Safety; post-stroke upper limb spasticity; Efficacy; GSK1358820; double blind

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Who Had Modified Ashworth Scale (MAS) Score Reduced at Least 1 From Baseline in the Elbow Flexors at Week 6

  MAS was used to measure the level of spasticity. The test was performed in a sitting position throughout the study. The affected parts were extended as fast as possible to grade the flexor muscle tones. It was scored on a scale of 0 to 4 as: 0=No increase in muscle tone, 1=Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM) when the affected part(s) is moved in flexion or extension, 1+= Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half of ROM, 2 =More marked increase in muscle tone through most of the ROM, but affected part(s) easily moved, 3= Considerable increase in muscle tone, passive movement difficult and 4= Affected part(s) rigid in flexion or extension. Higher scores= Worst outcome while lower scores= Better outcome.

  Week 6

Secondary Outcomes (12)

• Percentage of Participants Who Had MAS Score Reduction in Elbow, Wrist, Finger and Thumb Flexors up to Week 12

  Week 2, Week 4, Week 6 and Week 12

• Change From Baseline in MAS Scores in Elbow, Wrist, Finger and Thumb Flexors up to Week 12 (Mixed Model Repeated Measures [MMRM])

  Baseline (Day 1), Week 2, Week 4, Week 6 and Week 12

• Change From Baseline in Principal Therapeutic Target of Disability Assessment Scale (DAS) - MMRM up to Week 12

  Baseline (Day 1), Week 2, Week 4, Week 6 and Week 12

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) After 84 Days of First Treatment

  Up to 84 days post first treatment

• Number of Participants With AEs and SAEs-Overall Study Period

  Up to Week 48

Study Arms (3)

Part 1: Subjects receiving 400 units of botulinum toxin A

EXPERIMENTAL

Subjects will receive a total dose of 400 units of botulinum toxin A of which 240 units will be injected into the muscles that act on finger (including thumb flexors) and wrist flexors, and a total of 160 units will be injected into the muscles that act on the elbow flexors.

Drug: Botulinum toxin A (GSK1358820)

Part 1: Subjects receiving 240 units of botulinum toxin A

ACTIVE COMPARATOR

Subjects will receive 240 units of botulinum toxin A injected into the muscles that act on the finger (including thumb flexors) and wrist flexors. Placebo will be injected into the muscles that act on the elbow flexors.

Drug: Botulinum toxin A (GSK1358820); Drug: Placebo

Part 2,3,4: Subjects receiving 400 units of botulinum toxin A

EXPERIMENTAL

Subjects will receive botulinum toxin A with a dose of 400 units injected in a divided doses.

Drug: Botulinum toxin A (GSK1358820)

Interventions

Botulinum toxin A (GSK1358820) DRUG

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.

Part 1: Subjects receiving 240 units of botulinum toxin A; Part 1: Subjects receiving 400 units of botulinum toxin A; Part 2,3,4: Subjects receiving 400 units of botulinum toxin A

Placebo DRUG

Placebo injection will contain sodium chloride (0.9 mg).

Part 1: Subjects receiving 240 units of botulinum toxin A

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (38)

GSK Investigational Site

Aichi, 465-8620, Japan

Location

GSK Investigational Site

Aichi, 490-1405, Japan

Location

GSK Investigational Site

Chiba, 277-8567, Japan

Location

GSK Investigational Site

Chiba, 279-0021, Japan

Location

GSK Investigational Site

Fukui, 910-0067, Japan

Location

GSK Investigational Site

Fukuoka, 819-8551, Japan

Location

GSK Investigational Site

Hiroshima, 720-0825, Japan

Location

GSK Investigational Site

Hiroshima, 734-8530, Japan

Location

GSK Investigational Site

Hokkaido, 005-0802, Japan

Location

GSK Investigational Site

Hyōgo, 651-2181, Japan

Location

GSK Investigational Site

Ibaraki, 300-0028, Japan

Location

GSK Investigational Site

Ibaraki, 312-0057, Japan

Location

GSK Investigational Site

Kagoshima, 890-0067, Japan

Location

GSK Investigational Site

Kanagawa, 227-8518, Japan

Location

GSK Investigational Site

Kanagawa, 232-0024, Japan

Location

GSK Investigational Site

Kanagawa, 245-8560, Japan

Location

GSK Investigational Site

Kanagawa, 259-1143, Japan

Location

GSK Investigational Site

Kochi, 780-0051, Japan

Location

GSK Investigational Site

Kumamoto, 862-0924, Japan

Location

GSK Investigational Site

Nagano, 399-6461, Japan

Location

GSK Investigational Site

Niigata, 945-8585, Japan

Location

GSK Investigational Site

Okayama, 703-8265, Japan

Location

GSK Investigational Site

Osaka, 538-0044, Japan

Location

GSK Investigational Site

Osaka, 570-8507, Japan

Location

GSK Investigational Site

Osaka, 580-0032, Japan

Location

GSK Investigational Site

Ōita, 870-0862, Japan

Location

GSK Investigational Site

Saga, 849-8501, Japan

Location

GSK Investigational Site

Shizuoka, 417-0801, Japan

Location

GSK Investigational Site

Shizuoka, 433-8511, Japan

Location

GSK Investigational Site

Tokushima, 770-8503, Japan

Location

GSK Investigational Site

Tokyo, 102-8798, Japan

Location

GSK Investigational Site

Tokyo, 105-8471, Japan

Location

GSK Investigational Site

Tokyo, 123-0853, Japan

Location

GSK Investigational Site

Tokyo, 165-8906, Japan

Location

GSK Investigational Site

Tokyo, 192-0032, Japan

Location

GSK Investigational Site

Tokyo, 201-8601, Japan

Location

GSK Investigational Site

Wakayama, 641-8509, Japan

Location

GSK Investigational Site

Yamagata, 992-0057, Japan

Location

Related Publications (1)

• Abo M, Shigematsu T, Hara H, Matsuda Y, Nimura A, Yamashita Y, Takahashi K. Efficacy and Safety of OnabotulinumtoxinA 400 Units in Patients with Post-Stroke Upper Limb Spasticity: Final Report of a Randomized, Double-Blind, Placebo-Controlled Trial with an Open-Label Extension Phase. Toxins (Basel). 2020 Feb 18;12(2):127. doi: 10.3390/toxins12020127.

  PMID: 32085529 BACKGROUND

MeSH Terms

Conditions

Muscle Spasticity

Interventions

Botulinum Toxins, Type A

Condition Hierarchy (Ancestors)

Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Botulinum Toxins; Metalloendopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Metalloproteases; Bacterial Proteins; Proteins; Amino Acids, Peptides, and Proteins; Bacterial Toxins; Toxins, Biological; Biological Factors

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: This study will contain a double blind treatment period (Part 1) followed by open-label treatment period (Part 2/Part3/Part4).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 23, 2017
• First Posted: August 24, 2017
• Study Start: August 2, 2017
• Primary Completion: March 20, 2018
• Study Completion: January 10, 2019
• Last Updated: June 2, 2020
• Results First Posted: October 18, 2019

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

JP (38)