Safety Escalating Repeat IV, in Stroke Patients "MAG111539"

Completed

Phase 2 Results

Trial Description

The purpose of this study is to is to test increasing repeat doses of GSK249320 compared to placebo in patients with stroke.

Detailed Description

GSK249320 is a humanised monoclonal antibody (mAb) that binds with high specificity to myelin-associated glycoprotein (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 is the first in patients with stroke. The main aim of this study is to select tolerated doses of GSK249320 that can be used in future trials to evaluate its efficacy in improving clinical function in patients recovering from stroke. This clinical trial is designed as a placebo-controlled, single-blind, multicenter study to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of escalating repeat IV doses of GSK249320. Three sequential dose escalation cohorts (1, 5 and 15 mg/kg) are planned, with 8 patients on placebo and 8 on active in cohort 1 and 4 patients on placebo and 8 on active in cohorts 2 and 3. Each patient will receive 2 repeat IV doses 9 ± 1 days apart and assessments will extend to at least 16 weeks.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Placebo
    ARM 1: Kind: Experimental
    Label: PLACEBO
  • GSK249320 Drug
    Intervention Desc: I.V. infusion
    ARM 1: Kind: Experimental
    Label: ACTIVE

Trial Design

  • Allocation: Randomized
  • Masking: Single Blind (Subject)
  • Endpoint: Safety Study
  • Intervention: Parallel Assignment

Patient Involvement

Each patient will be randomized to receive 2 IV doses of either GSK249320 or placebo, given 9 days apart. Dose 1will be given 24-72 hr after stroke onset, and Dose 2 will be given 9+/- 1 days after Dose 1. There will be three dose escalation cohorts (1, 5 and 15 mg/kg per dose), with 8 patients on placebo and 8 on active cohort 1 and 8 patients on active and 4 on placebo in cohorts 2 and 3. Doses will be given in a blinded fashion; however study site staff preparing infusions will be unblinded to patient treatment assignment.

Outcomes

Type Measure Time Frame Safety Issue
Primary Adverse events (AEs), vital signs, physical examination (incl. full neurological exam.), 12-lead ECGs, nerve conduction tests (NCTs), magnetic resonance imaging (MRI) and clinical laboratory tests.
Secondary Presence of antibodies to GSK249320 will be assessed in serum samples using immunoelectro-chemiluminescent (ECL) assay; PK parameters: AUC(0-), Cmax, Tmax, T1/2 after second dose, clearance, volume of distribution; Gait velocity, Berg Balance, Fugl-Meyer Motor Assessment, Box and Blocks, grip strength (dynamometer), modified Rankin, Barthel, NIHSS, Transcranial Magnetic Stimulation (TMS), and MRI; Exploratory biomarker levels, such as S100?; & To explore linear or non-linear relationships between exposure parameters and one or a combination of PD endpoints. Possible extension to a disease progression model, if feasible.
Primary Adverse events (AEs), vital signs, physical examination (incl. full neurological exam.), 12-lead ECGs, nerve conduction tests (NCTs), magnetic resonance imaging (MRI) and clinical laboratory tests 16 weeks No
Secondary Presence of antibodies to GSK249320 will be assessed in serum samples using immunoelectro-chemiluminescent (ECL) assay At least 16 weeks No
Secondary PK parameters: AUC(0-), Cmax, Tmax, T1/2 after second dose, clearance, volume of distribution At least 16 weeks No
Secondary Gait velocity, Berg Balance, Fugl-Meyer Motor Assessment, Box and Blocks, grip strength (dynamometer), modified Rankin, Barthel, NIHSS, Transcranial Magnetic Stimulation (TMS), and MRI At least 16 weeks No
Secondary To explore linear or non-linear relationships between exposure parameters and one or a combination of PD endpoints. Possible extension to a disease progression model, if feasible At least 16 weeks No
Secondary Exploratory biomarker levels, such as S100β At least 16 weeks No
Primary Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) Up to 112 days
Primary Number of Participants With Vital Signs Changes of Potential Clinical Importance Up to 112 days
Primary Number of Participants With Electrocardiogram (ECG) Values Outside Range of Potential Clinical Importance Up to 112 days
Primary Number of Participants With Nerve Conduction Testing (NCT) Values Day 5 and 30 and at early withdrawal
Primary Number of Participants With White Matter Changes and Demyelination Assessed by Magnetic Resonance Imaging (MRI) Up to Day 60
Primary Number of Participants With Abnormal Clinical Chemistry Parameters Up to Day 112
Primary Number of Participants With Abnormal Hematological Parameters Up to Day 112
Secondary Number of Participants With Positive Antibodies to GSK249320 Day 1, 5, 10, 30, 60, 90 and 112
Secondary Mean Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC 0-inf) and Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t) Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Maximum Observed Concentration (Cmax) and Last Observed Quantifiable Concentration (Ct) Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Time of Occurrence of Cmax (Tmax) and Time of Last Observed Quantifiable Concentration (Tlast) Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Terminal Phase Half-life (t1/2) Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Terminal Phase Rate Constant ( Lambda-Z) Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Clearance of GSK249320 Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
Secondary Mean Change in Mean Gait Velocity Baseline (Day 5), Day 30, 60, 90, 112
Secondary Mean Change in Berg Balance Scale (BBS) Total Score Baseline (Day 5), Day 30, 60, 90 and 112
Secondary Mean Change in Total Fugl-Meyer Motor (FM) Assessment Baseline (Day 5), Day 30 and 112
Secondary Mean Change in Total Box and Blocks Transferred on Affected Side Baseline (Day 1), Day 30, 60, 90 and 112
Secondary Mean Change in Grip Strength on Affected Side Baseline (Day 1), Day 30, 60, 90 and 112
Secondary Number of Participants With Modified Rankin Scale (mRS) Day 30 and 90
Secondary Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) Baseline (Day 1), Day 10, 30 and 90
Secondary Mean Barthel Total Score Day 30 and 90
Secondary Mean Total Montreal Cognitive Assessment (MoCA) Score Day 5 and 90
Secondary Mean Geriatric Depression Scale (GDS) Day 5 and 90
Secondary Mean Change in Transcranial Magnetic Stimulations (TMS) Evaluated by Peak to Peak MEP by % Stimulation Level Baseline (Day 1), Day 30 and 112
Secondary Serum Levels of the S100β Protein Day 1 (Pre-dose, Post dose 1, 6, 24 hour), Day 5

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