Safety Escalating Repeat IV, in Stroke Patients
Safety Escalating Repeat IV, in Stroke Patients
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.
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.