Safety Escalating Repeat IV, in Stroke Patients

GlaxoSmithKline42 enrolled

Overview

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

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

OTHER

Masking

SINGLE

Enrollment

Conditions

Ischaemic Attack, Transient

Interventions

GSK249320DRUG

I.V. infusion

PLACEBODRUG

Placebo

Eligibility

Sex: ALLMin age: 18 YearsMax age: 90 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Have a confirmed diagnosis of stroke * Stroke onset must be within the last 24-72 hours. * Have a stroke that is either: * radiologically confirmed to be ischaemic and supratentorial. The diameter of the ischemic lesion is \>15mm in any singlle direction or the volume is \>4cc. OR * radiologically confirmed to be an intracerebral hemorrhage that is supratentorial, deep (i.e., blood must not directly contact cerebral cortex) and with minimal or no intraventricular extension. The Intracerebral Hemorrahage (CH) score must be 0-2 and is calculated based on age, Galsgow coma Scale score ad the initial CT or MRI findings for the index stroke. See the SOM for the full calculation procedure. * Have a total NIHSS score of 3-21. * Have an upper and/or lower limb deficit defined as: * Score of 1-3 on the NIHSS Motor Arm question, and palpable and observable voluntary extension or flexion of the fingers. AND/OR b. Score of 1-3 on the NIHSS Motor Leg question * Aged 18-90, inclusive. * Male subjects and females of non-child-bearing potential are allowed to participate in this study. * Females of child-bearing potential are also allowed to participate in this study provided they are using a contraceptive method with a failure rate of \<1%. Exclusion Criteria: * History of a previous symptomatic stroke within 3 months prior to study entry. * Presence of significant disability prior to the current stroke. Significant disability is defined as having a pre-stroke Rankin score of \>2. * Presence of depression that is active and not adequately controlled such that it interferred with major activities of daily living immediately prior to the current stroke. * Subjects who are not alert or are unresponsive as defined by a score of 2 or 3 on the NIHSS Level of Consciousness question (question #1a). * Presence of significant aphasia as likely to confound or interfere with completion of the study assessments. * Presence of peripheral neuropathy, including diabetic neuropathy, which is clinically active and symptomatic at time of screening. * Presence of neurological or psychiatric disease, such as dementia or mild cognitive impairment, prior to study entry that is likely to confound clinical evaluations. * Presence of a demyelinating disease, such as multiple sclerosis. * Evidence of other chronic co-morbid conditions or unstable acute systemic illnesses which, in the opinion of the investigator, could shorten the subject's survival or limit his/her ability to complete the study. * History of sensitivity to heparin or heparin-induced thrombocytopenia. * Presence of QTcB \> 500 msec; or uncorrected QT \>600msec (machine or manual over-read) on baseline ECG. * Contraindication to TMS, such as: * have metal present, such as hardware or plate on the scalp in the area to which TMS will be applied, implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials * occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan. * concomitant use of drugs that substantially lower seizure threshold (e.g., tricyclic antidepressants and neuroleptics) * known history of seizures or epilepsy * brain tumor, recent brain injury (within 5 years) associated with definite loss of consciousness, or any history of brain surgery * Contraindication to MRI, such as: * have metal present, such as implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials, permanent tattooed metallic eye-liner * occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan. * claustrophobia * Participation in any investigational rehabilitation paradigm targeting stroke recovery during the duration of this study. * The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Pregnant or lactating females. * Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol.

Locations (15)

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

Orange, California, United States

GSK Investigational Site

Outcomes

Primary Outcomes

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Time frame: Up to 112 days

Number of Participants With Vital Signs Changes of Potential Clinical Importance

The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (SBP) (\<85 and \>200 millimeter of mercury \[mmHg\]), diastolic blood pressure (DBP) (\<45 and \>110 mmHg) and heart rate (HR) (\<40 and \>110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.

Time frame: Up to 112 days

Number of Participants With Electrocardiogram (ECG) Values Outside Range of Potential Clinical Importance

Single 12-lead ECGs was obtained. The standard ECG criteria of potential clinical importance were uncorrected QT interval \<300 and \>600 milliseconds (msec), absolute QTc interval \>500 msec, increase from Baseline QTc \>60 msec, RR Interval \<90 and \>2000 msec, PR Interval \<110 and \>220 msec, QRS Interval \<75 and \>110 msec. The number of participants with potentially clinically significant ECG abnormality were reported.

Time frame: Up to 112 days

Number of Participants With Nerve Conduction Testing (NCT) Values

Data from ClinicalTrials.gov

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Secondary Outcomes

Number of Participants With Positive Antibodies to GSK249320

Presence of antibodies to GSK249320 were assessed in serum samples of participants using immunoelectro-chemiluminescent assay. Number of participants with positive antibodies to GSK249320 were reported. Only visits where the true positive antibody detection was observed were reported.

Time frame: Day 1, 5, 10, 30, 60, 90 and 112

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)

The pharmacokinetic parameters were calculated by standard non-compartmental analysis using Win Nonlin Pro 4.1. All calculations of non-compartmental parameters were based on actual sampling times. AUC0-t was determined using the linear trapezoidal rule for increasing concentrations and the logarithmic trapezoidal rule for decreasing concentrations. AUC(0-inf) were calculated, where data permit, as the sum of area under the concentration-time curve over the dosing interval from 0 to Day 10 ±1 day (AUC0-10d) and C10d/z, where C10d is the observed plasma concentration at day 10 and z is the terminal phase rate constant calculated after the second dose.