Safety Escalating Repeat IV, in Stroke Patients

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.