Safety Escalating Repeat IV, in Stroke Patients

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

Detailed Description
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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.

Official Title
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A Single-Blind Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Stroke

Conditions
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Ischaemic Attack, Transient

Intervention / Treatment
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* Drug: GSK249320
* Drug: PLACEBO


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: PLACEBO<br> | Drug: PLACEBO<br>* Placebo<br>|
| Experimental: ACTIVE<br> | Drug: GSK249320<br>* I.V. infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Up to 112 days | 
| Number of Participants With Nerve Conduction Testing (NCT) Values | NCT (electrode placement technique) of sensory and motor function was performed on the unaffected side (i.e., side that is not affected by the stroke) by appropriately qualified personnel at specified visits (Day 5 and 30 and at early withdrawal). Qualified technician performed the testing; however the same neurologist interpreted the NCT data within a single participant. Both upper and lower extremity nerves were tested and the data was recorded. Number of participants with normal and abnormal NCT data were reported. | Day 5 and 30 and at early withdrawal | 
| Number of Participants With White Matter Changes and Demyelination Assessed by Magnetic Resonance Imaging (MRI) | Whole brain MRI scans were performed by appropriately qualified personnel at those specified visits (Day 1, 10 and 60 or at early withdrawal [if participant withdrew from study before Day 60 MRI]). Required pulse sequences of diffusion weighted imaging (DWI), T1, and T2 FLAIR was performed to measure lesion volume and to look for the presence of any new acute inflammatory lesions. The investigator or other medically qualified study team member evaluated the Day 10 and 60 scans for any new abnormalities or clinically significant worsening. Digital data for each MRI was sent to a central MRI laboratory for an over-read of the MRI scan and calculation of the lesion volume. Number of participants with change in white matter and demyelination on Day 10 compared to Day 1, Day 60 compared to Day 1 and Day 60 compared to Day 10 were reported. | Up to Day 60 | 
| Number of Participants With Abnormal Clinical Chemistry Parameters | The clinical chemistry parameters analyzed were albumin, calcium, creatinine, glucose, potassium, sodium, total CO2, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. Only those parameters for which at least one abnormal value was reported are summarized. The number of participants with abnormal clinical chemistry findings at specified visit were reported. | Up to Day 112 | 
| Number of Participants With Abnormal Hematological Parameters | The clinical chemistry parameters analyzed were white blood cell count, neutrophil count, hemoglobin, platelet count, lymphocytes. Only those parameters for which at least one abnormal value was reported are summarized. The number of participants with abnormal hematology findings at specified visit were reported. | Up to Day 112 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Maximum Observed Concentration (Cmax) and Last Observed Quantifiable Concentration (Ct) | 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. Cmax and Ct were determined directly from the raw concentration-time data. | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Time of Occurrence of Cmax (Tmax) and Time of Last Observed Quantifiable Concentration (Tlast) | 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. Tmax and tlast were determined directly from the raw concentration-time data. | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Terminal Phase Half-life (t1/2) | 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. The apparent t1/2 obtained as the ratio of natural log (ln)^2/ lambda-Z, where lambda-Z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Terminal Phase Rate Constant ( Lambda-Z) | 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. Lambda-Z is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Clearance of GSK249320 | 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. The clearance was calculated as Dose/ AUC(0-inf). | Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour) | 
| Mean Change in Mean Gait Velocity | Gait velocity is an objective, quantitative, reliable, valid and sensitive measure of lower extremity motor recovery in the stroke population. Changes in gait velocity correlates with physical functioning and quality of life. Gait velocity was assessed over a level, indoor 10 meter distance. The time (in seconds) it takes the participant to travel the 10 meter distance was recorded. Participants was asked to walk at their usual or normal pace and may use their normal assistive devices. Baseline assessments were recorded at Day 5 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 5), Day 30, 60, 90, 112 | 
| Mean Change in Berg Balance Scale (BBS) Total Score | BBS is a performance based measure of balance. It is reliable, valid and responsive to change in the stroke population. BBS is a staff-assessed measure that requires the participant to perform 14 activities that evaluate ability to maintain balance. The BBS typically takes 10-15minute to complete. Participants were not allowed to use assistive devices while performing the activities. Each activity was evaluated by direct observation of the participant's performance and was scored on a 5-point ordinal scale (0-4) where a score of 0 represents inability to perform the activity and a score of 4 represents independence in the activity. The minimum total score on the BBS was 0 and maximum was 56. Baseline assessments were recorded at Day 5 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 5), Day 30, 60, 90 and 112 | 
| Mean Change in Total Fugl-Meyer Motor (FM) Assessment | The FM assessment is a staff-assessed, disease specific, quantitative measure of impairment that is used to assess recovery of sensorimotor function post stroke. The FM is designed to assess the domains of motor function, balance, sensation and joint function. For this study, only the motor function domain was assessed. The motor domain scale takes approximately 30 minutes to complete and evaluates both the upper and lower extremities by direct observation of the participant's performance of 50 items that measure movement, coordination, and reflex action. Each item was scored from 0-2 for a minimum total score of 0 (hemiplegia) and a maximum total score of 100 (normal motor performance). Baseline assessments were recorded at Day 5 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 5), Day 30 and 112 | 
| Mean Change in Total Box and Blocks Transferred on Affected Side | The Box and Blocks test is an objective, gross manual dexterity test that is reliable and valid in individuals with upper limb impairments. Box and Blocks was a staff-assessed, participant completed test that required the participant to move small wooden blocks from one side of a partitioned box to the other. The score was determined by the number of blocks transferred within a 60 second time period. More number of blocks transferred as compared to Baseline indicated improvement. Both the impaired and normal limbs were tested, starting with the normal limb. The number of blocks transferred were recorded. Baseline assessments were recorded at Day 1 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 1), Day 30, 60, 90 and 112 | 
| Mean Change in Grip Strength on Affected Side | Grip strength is an objective measure of arm motor recovery in stroke participants and correlate with functional status and predict recovery. Grip strength was evaluated by a hand grip dynamometer. Three replicate trials was collected for both the impaired and normal hand, starting with the normal hand. Each trial was separated by a resting period of approximately 15-30 seconds. Participants was instructed to squeeze as hard as possible while using a standardized position of grip and the resulting dynamometer reading (in kg) was recorded. The grip strength measures was conducted within approximately 5 minutes. Baseline assessments were recorded at Day 1 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 1), Day 30, 60, 90 and 112 | 
| Number of Participants With Modified Rankin Scale (mRS) | The mRS was a 6 point scale that measured participant handicap by evaluating limitations in activity and changes in lifestyle. The mRS was staff-assessed and scored from 0=no symptoms at all, 1=no significant disability, 2=slight disability, 3=moderate disability, 4=moderate severe disability, 5=severe disability (severe disability, bedridden, incontinent and requiring constant nursing care and attention). The structured interview was used to administer the mRS. The mRS took approximately 15 minutes to complete when using the structured interview. Number of participants with mRS were reported as per the category of the score. | Day 30 and 90 | 
| Change From Baseline of National Institutes of Health Stroke Scale (NIHSS) | The NIHSS is a staff-assessed, 15 item, standardized, disease-specific, deficit scale which measures neurological impairment and is used to quantify participant status by measuring the severity of the stroke. The total NIHSS score ranged from 0 (No impairment) to 42 (severe impairment). Approximately 15 minutes were needed to complete the NIHSS. The NIHSS will be collected as part of the eligibility requirements to exclude participants who have a deficit that is either too mild or too severe. Only NIHSS certified study personnel recorded the NIHSS. Baseline assessments were recorded at Day 1 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 1), Day 10, 30 and 90 | 
| Mean Barthel Total Score | The Barthel was a staff-assessed, 10 item activities of daily living index that evaluated feeding, grooming, dressing, excretion (bowels, bladder and toilet skills), bathing, and mobility (transfers, walking, stairs). The total Barthel score ranged from either 0-20 or 0-100 depending on which scoring algorithm was used where 0= unable or dependent and 20 or 100= independent to perform daily activities. For this study, the 100 point scoring algorithm was used. The Barthel takes approximately 5-10 minutes to complete with the participant. | Day 30 and 90 | 
| Mean Total Montreal Cognitive Assessment (MoCA) Score | MoCA was an examiner-administered, screening instrument with good validity, reliability, sensitivity and specificity for mild cognitive dysfunction. The MoCA had been studied in stroke participants and was recommended as a tool to monitor and measure cognitive changes post stroke as part of the 2006 National Institute of Neurological Disorders and Stroke - Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards. The MoCA assesses eight cognitive domains of visuospatial skills, executive function, language, attention, concentration, working memory, memory, and orientation. Participants were asked to complete 14 activities which the examiner scored according to the standardized scoring instructions. While there was no set time limit imposed on a participant. The total MoCA score ranges from 0-30, where 0= worsening and 30 reflects normal cognitive function. | Day 5 and 90 | 
| Mean Geriatric Depression Scale (GDS) | The short form GDS is a measure of depression developed specifically for use in elderly population and is sensitive and valid in the stroke population. The GDS was a participant-completed, 15 item questionnaire where each question referenced how the participant felt over the past week. Each question was answered with either a 'yes' or 'no' response. Of the 15 questions, 10 of them indicate depression when answered 'yes' (questions 2-4, 6, 8-10, 12, 14-15) and 5 indicate depression when answered 'no' (questions 1, 5, 7, 11, 13). Each question received a score of 1 point when the response was indicative of depression. Total score ranged from 0 to 15. the total score ranged from 0-15, where 0 implies no symptoms and higher score implies more severity of symptoms. | Day 5 and 90 | 
| Mean Change in Transcranial Magnetic Stimulations (TMS) Evaluated by Peak to Peak MEP by % Stimulation Level | TMS is an electrophysiological technique that was used to measure neurologic changes associated with recovery from stroke via alterations in the excitability of the motor system. Motor threshold measures reflect global excitability of the corticospinal pathway, including large pyramidal cells, excitatory/inhibitory interneurons, and spinal motorneurons. Motor threshold was recorded as the lowest stimulus intensity (in percent) eliciting motor evoked potentials (MEPs). Baseline assessments were recorded at Day 1 of the study. The change from Baseline was calculated by subtracting the Baseline values from the individual post -randomization values. If either the Baseline or post-randomization value was missing, the change from Baseline was set to missing as well. | Baseline (Day 1), Day 30 and 112 | 
| Serum Levels of the S100β Protein | The serum sample for S100β collected on Day 1 (predose, 1, 6, 12 and 24 hour) and Day 5 and was analyzed for levels. Serum levels of S100β protein were recorded as log transformed values therefore the negative values are reported. | Day 1 (Pre-dose, Post dose 1, 6, 24 hour), Day 5 |