Proof of Concept (POC) in Patients With Ischaemic Stroke

Terminated

Phase 2 Results

Trial Description

Study MAG104615, a Proof of Concept Study for GSK249320 versus placebo in Stroke Patients.

Detailed Description

Myelin-associated glycoprotein (MAG) is one of the key proteins known to inhibit neuronal regeneration when released from oligodendrocytes in conditions of neuronal injury, such as stroke. GSK249320 is a humanised monoclonal antibody (mAb) that binds with high specificity to MAG and antagonises or neutralises MAG-mediated inhibition and has been shown to improve functional recovery after stroke in pre-clinical models, possibly by promoting neuroregeneration and plasticity. The present study (MAG104615) is designed to establish Proof of Concept (PoC) for GSK249320 in ischemic stroke patients. MAG104615 will be a placebo-controlled, double-blind, multicenter, randomized, repeat dose, Bayesian design study. PoC will be achieved by demonstrating a clinically meaningful improvement in lower limb motor recovery, specifically by evaluating changes in gait velocity from baseline to Day 90/Month 3. Subjects will also be followed out to Day 180/Month 6 to further evaluate longer term motor recovery and safety. Additional secondary efficacy measures of motor recovery will be evaluated to further demonstrate and characterize the extent and duration of overall motor recovery after treatment with GSK249320. Changes in disability and neurological impairment will be characterized after treatment with GSK249320 and explored for how they relate to motor recovery. This PoC study will also further characterize the safety, PK, and immunogenicity of GSK249320 will explore pharmacodynamic (PD) markers, and will explore use of actigraphy to measure motor recovery. Subjects will be stratified by gait velocity at baseline for randomization (1:1 allocation) into one of two treatment groups: 15mg/kg GSK249320, or placebo. Each subject will receive 2 repeat IV doses of GSK249320 or placebo.

Trial Stopped: This study was terminated for futility.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Placebo is for intravenous (IV) use only.
    ARM 1: Kind: Experimental
    Label: Placebo
    Description: Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Both GSK249320 and placebo are for intravenous (IV) use only
  • GSK249320 100/mg Drug
    Intervention Desc: Clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial). GSK249320 is for IV use only.
    ARM 1: Kind: Experimental
    Label: GSK249320 100/mg
    Description: clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial)

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Investigator)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Change from baseline in gait velocity 6 months No
Secondary Change in proportion of subjects transitioning between gait velocity categories 6 months No
Secondary Change from baseline on box and blocks 6 months No
Secondary Number of falls 6 months No
Secondary Safety as measured by type and incidence of AEs 6 months Yes
Secondary Safety as measured by type and incidence of disease-related events 6 months Yes
Secondary Safety as measured by change from baseline in vital signs 6 months Yes
Secondary Safety as measured by incidence of abnormal ECG results 6 months Yes
Secondary Safety as measured by change from baseline in clinical safety labs 6 months Yes
Secondary Safety as measured by change from baseline in NIHSS 6 months Yes
Secondary Safety as measured by presence/absence of suicidality via CSSRS 6 months Yes
Secondary PK as measured by maximum observed plasma concentration (Cmax) 6 months No
Secondary PK as measured by time to reach maximum observed plasma concentration (Tmax) 6 months No
Secondary PK as measured by plasma decay half-life (t1/2) 6 months No
Secondary PK as measured by area under the curve from time zero to last quantifiable concentration [AUC (0-t)] 6 months No
Secondary PK as measured by area under the curve from time zero to extrapolated infinite time [AUC (0-∞)] 6 months No
Secondary Antibodies against GSK249320 6 months No
Primary Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity BL (Day 1) and Month 3/Day 90
Secondary Mean Change From BL to Month 6/ Day 180 in Gait Velocity BL (Day 1) and Month 6/Day 180
Secondary Number of Participants With Indicated Transition From One Gait Velocity Category to Another Category at the Indicated Time Points BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180.
Secondary Change From BL in Dexterity as Measured by Box and Blocks Test BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180
Secondary Number of Participants Experiencing Falls BL (Day 1) Day 90 and Day 180
Secondary Number of Falls Over Time BL (Day 1), Day 90 and Day 180
Secondary Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) Up to 14 months
Secondary Number of Participants With Events Common to Stroke From Day 1 until early withdrawal, death, Month 6/Day 180
Secondary Change From BL in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) BL (Day 1) , Day 6, Day 180 and early withdrawal (EW) visit
Secondary Change From BL in Vitals Signs-Heart Rate Day 1, Day 6, Day 180 and EW visit
Secondary Change From BL in ECG Parameter-Heart Rate BL (Day 1) Day 6, Day 30 and EW visit
Secondary Change From BL in ECG Parameters BL (Day 1), Day 6, Day 30 and EW visit
Secondary Change From BL in Clinical Chemistry- Albumin and Total Protein BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in Clinical Chemistry-urea/Blood Urea Nitrogen (BUN), Sodium (Na), Potassium (K), Glucose (Gluc), Chloride (Cl), Calcium (Ca) BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in Eosinophils (EOS), Lymphocytes (LYM), Total Absolute Neutrophil Count (ANC), Platelet (PLT) Count, White Blood Cell (WBC) Count BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in Hematology- Hemoglobin BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From Baseline in Hematology- Hematocrit BL (Day 1), Day 6, Day 30, Day 90 and Day 180
Secondary Change From BL in NIHSS Total Score BL (Day 1), Day 30, Day 90 and Day 180
Secondary Number of Participants With Suicidal Ideation Via Columbia Suicide Severity Rating Scale (CSSRS) Da y 1, Da y 6, Day 30, Day 60, Day 90 and Day 180
Secondary Maximum Observed Plasma Concentration (Cmax) for GSK249320 Pre-dose and post-dose up to Day 180
Secondary Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320 Pre-dose and post-dose up to Day 180
Secondary PK as Measured by Plasma Decay Half-life (t1/2) GSK249320 Up to Day 180
Secondary Area Under the Concentration-time Curve From 0 to 5 Days [AUC(0-5d)] and Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] for GSK249320 Pre-dose and post-dose up to Day 180
Secondary Clearance (CL) for GSK249320 Up to Day 180
Secondary Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320 Up to Day 180
Secondary Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay Day 1, Day 30, Day 180, EW visit and Follow-up visit

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