Proof of Concept (POC) in Patients With Ischaemic Stroke

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Terminated

CT.gov ID

NCT01808261

Collaborator

(none)

134

Enrollment

Locations

Arms

14.3

Actual Duration (Months)

3.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Study MAG104615, a Proof of Concept Study for GSK249320 versus placebo in Stroke Patients.

Condition or Disease	Intervention/Treatment	Phase
Cerebrovascular Accident	Drug: GSK249320 100/mg Drug: Placebo	Phase 2

Detailed Description

Myelin-associated glycoprotein (MAG) is one of the key proteins known to inhibit neuronal regeneration when released from oligodendrocytes in conditions of neuronal injury, such as stroke. GSK249320 is a humanised monoclonal antibody (mAb) that binds with high specificity to 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 (MAG104615) is designed to establish Proof of Concept (PoC) for GSK249320 in ischemic stroke patients. MAG104615 will be a placebo-controlled, double-blind, multicenter, randomized, repeat dose, Bayesian design study. PoC will be achieved by demonstrating a clinically meaningful improvement in lower limb motor recovery, specifically by evaluating changes in gait velocity from baseline to Day 90/Month 3. Subjects will also be followed out to Day 180/Month 6 to further evaluate longer term motor recovery and safety. Additional secondary efficacy measures of motor recovery will be evaluated to further demonstrate and characterize the extent and duration of overall motor recovery after treatment with GSK249320. Changes in disability and neurological impairment will be characterized after treatment with GSK249320 and explored for how they relate to motor recovery. This PoC study will also further characterize the safety, PK, and immunogenicity of GSK249320 will explore pharmacodynamic (PD) markers, and will explore use of actigraphy to measure motor recovery. Subjects will be stratified by gait velocity at baseline for randomization (1:1 allocation) into one of two treatment groups: 15mg/kg GSK249320, or placebo. Each subject will receive 2 repeat IV doses of GSK249320 or placebo.

Study Design

Study Type:

Interventional

Actual Enrollment :

134 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Study MAG104615, a Proof of Concept Study for GSK249320 Versus Placebo in Stroke Patients

Actual Study Start Date :

May 18, 2013

Actual Primary Completion Date :

Jul 28, 2014

Actual Study Completion Date :

Jul 28, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Placebo is for intravenous (IV) use only.	Drug: Placebo Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Placebo is for intravenous (IV) use only.
Active Comparator: GSK249320 100/mg Clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial). GSK249320 is for IV use only.	Drug: GSK249320 100/mg Clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial). GSK249320 is for IV use only.

Arm

Intervention/Treatment

Placebo Comparator: Placebo

Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Placebo is for intravenous (IV) use only.

Drug: Placebo

Placebo is a clear, colorless solution (50mM acetate buffer, pH 5.5 containing 0.02% (w/v) polysorbate-80 and made isotonic with 111.2 mM sodium chloride). Placebo is for intravenous (IV) use only.

Active Comparator: GSK249320 100/mg

Clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial). GSK249320 is for IV use only.

Drug: GSK249320 100/mg

Clear to opalescent, colorless to pale yellow or pale brown, and is supplied as a sterile, concentrated solution (1000mg/vial). GSK249320 is for IV use only.

Outcome Measures

Primary Outcome Measures

Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity [BL (Day 1) and Month 3/Day 90]
Gait is the way or manner in which a person walks. Gait velocity (walking speed) is an objective, quantitative measure of lower extremity motor recovery in individuals who have had a stroke. Participants were asked to walk at their usual pace over a level, indoor 10 meter (m) distance and were allowed to use their normal assistive devices. The time (seconds[s]) taken by the participants to travel the 10 m distance was recorded. Gait velocity (m/s) as assessed by study personnel was derived as: 10 divided by time to walk 10 m. Two trials of gait velocity were conducted at each time point. Change from BL was calculated as the mean Month 3/Day 90 value minus the mean BL value. BL was defined as Day 1. The measure type displayed are posterior means.

Secondary Outcome Measures

Mean Change From BL to Month 6/ Day 180 in Gait Velocity [BL (Day 1) and Month 6/Day 180]
Gait is the way or manner in which a person walks. Gait velocity (walking speed) is an objective, quantitative measure of lower extremity motor recovery in individuals who have had a stroke. Participants were asked to walk at their usual pace over a level, indoor 10 m distance and were allowed to use their normal assistive devices. The time (s) taken by the participants to travel the 10 m distance was recorded. Gait velocity (m/s) as assessed by study personnel was derived as: 10 divided by time to walk 10 m. Two trials of gait velocity were conducted at each time point. Change from BL was calculated as the mean Month 3/Day 90 value minus the mean BL value. BL was defined as Day 1. The measure type displayed are posterior means.
Number of Participants With Indicated Transition From One Gait Velocity Category to Another Category at the Indicated Time Points [BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180.]
Participants were categorized at each visit into the following gait velocity categories: 0 m/s, >0 to <0.4 m/s, >=0.4 m/s to 0.8 m/s and >0.8m/s. A distinction was made between participants who are too incapacitated to walk (i.e., gait velocity = 0m/s) and participants for whom the gait velocity assessment was not performed due to another reason (i.e., truly missing data). Participants were asked to walk at their usual or normal pace and using their normal assistive devices. Two trials of gait velocity were conducted at each time point. The number of participants transitioning from one gait velocity category to another category was assessed at each post-Baseline visit and was presented in terms of the following transition categories: worsened, no change, improved 1 level, improved 2 levels and improved 3 levels. By-visit sample sizes vary due to missing data or early termination of the study, missing data was not imputed.
Change From BL in Dexterity as Measured by Box and Blocks Test [BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180]
Dexterity is ability of person to use hands skillfully in performing a task. Box and Blocks test is an objective, gross manual dexterity test in individuals with upper limb impairments. Participants were asked to move small wooden blocks from one side of a partitioned box to other. The score was determined by number of blocks transferred within a 60 second time period. Both affected and unaffected arms were tested, starting with the unaffected arm. Change from BL was calculated as the individual post- BL value minus BL value. A higher number of displaced blocks indicated a better gross dexterity and a low number of displaced blocks indicated poor gross dexterity. It was analyzed using fixed effects for treatment, visit, treatment by visit interaction, sex, age, Baseline National Institute of Health stroke scale (NIHSS) total score, BL number of blocks transferred by the affected and unaffected arms, country and presence of concomitant medications that potentially impact recovery.
Number of Participants Experiencing Falls [BL (Day 1) Day 90 and Day 180]
The number of participants who experienced at least one fall between BL to Day 90 and BL to Day 180 is summarized.
Number of Falls Over Time [BL (Day 1), Day 90 and Day 180]
The number of participants who experienced 1, 2, 3 or >=4 falls between BL to Day 90 and BL to Day 180 is summarized. By-visit sample sizes vary due to missing data or early termination of the study. The participants who experienced atleast one-fall were reported
Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) [Up to 14 months]
An AE is 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. A SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or all events of possible drug-induced liver injury with hyperbilirubinaemia. Medical or scientific judgment is exercised in other situations.
Number of Participants With Events Common to Stroke [From Day 1 until early withdrawal, death, Month 6/Day 180]
Events common to stroke were those events that commonly occurred after a stroke and are generally associated with the underlying stroke or the progression of stroke. These included joint or soft tissue pain, bladder incontinence, depression/mood disorder, urinary tract infection, dysphagia, bowel incontinence, dysarthia, confusion, spasticity, limb edema, aspiration pneumonia, hemorrhagic transformation (symptomatic or asymptomatic), pressure ulcers, progression of stroke, malnutrition, deep vein thrombosis, brain herniation, pulmonary embolism, seizures, and falls.
Change From BL in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [BL (Day 1) , Day 6, Day 180 and early withdrawal (EW) visit]
Safety was measured by monitoring vital signs including blood pressure. The BL for DBP and SBP was the value of pre-dose assessment on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Vitals Signs-Heart Rate [Day 1, Day 6, Day 180 and EW visit]
Safety was measured by monitoring vital signs including heart rate. The BL for heart rate was the value of pre-dose assessment on Day 1. Change from BL was calculated as the individual post-BL value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study. BL was defined as Day 1.
Change From BL in ECG Parameter-Heart Rate [BL (Day 1) Day 6, Day 30 and EW visit]
A single 12-lead ECG was obtained at each time point that measured heart rate. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in ECG Parameters [BL (Day 1), Day 6, Day 30 and EW visit]
A single 12-lead ECG was obtained at each time point and the following ECG intervals were determined: PR, QRS, QT, RR and corrected QT (QTc), QT interval corrected by Bazett's formula (QTcB), QT interval corrected by Fridericia's formula (QTcF). BL for ECG parameters was the value of Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Clinical Chemistry- Albumin and Total Protein [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
ALB and TP were measured at BL, Day 6, Day 30, Day 90 and Day 180. Baseline was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Clinical Chemistry-urea/Blood Urea Nitrogen (BUN), Sodium (Na), Potassium (K), Glucose (Gluc), Chloride (Cl), Calcium (Ca) [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
Ca, Cl, Gluc, K, Na and BUN were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
ALP, ALT and AST were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
Direct bilirubin, total bilirubin and creatinine were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Eosinophils (EOS), Lymphocytes (LYM), Total Absolute Neutrophil Count (ANC), Platelet (PLT) Count, White Blood Cell (WBC) Count [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
EOS, LYM, Total ANC, PLT count and WBC count were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value.By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in Hematology- Hemoglobin [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
Hemoglobin was measured at BL Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. . By-visit sample sizes vary due to missing data or early termination of the study.
Change From Baseline in Hematology- Hematocrit [BL (Day 1), Day 6, Day 30, Day 90 and Day 180]
Hematocrit was measured at Baseline, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value.By-visit sample sizes vary due to missing data or early termination of the study.
Change From BL in NIHSS Total Score [BL (Day 1), Day 30, Day 90 and Day 180]
The NIHSS is a 15 item, standardized, disease-specific, deficit scale which measures neurological impairment (level of consciousness, eye movements, visual fields, facial symmetry, motor strength (arm and leg), coordination, sensation, language (aphasia and dysarthria), and neglect) and is used to quantify participant status by measuring the severity of the stroke as assessed by NIHSS certified study personnel. The total NIHSS score is calculated as the sum of responses to the 15 items. The total NIHSS score ranges from 0-42, with a higher score indicative of a more severe impairment. By-visit sample sizes vary due to missing data or early termination of the study. Change from BL was calculated as the individual post-Baseline value minus the BL value. BL was defined as the value at Day 1.
Number of Participants With Suicidal Ideation Via Columbia Suicide Severity Rating Scale (CSSRS) [Da y 1, Da y 6, Day 30, Day 60, Day 90 and Day 180]
C-SSRS is a clinician-rated scale that evaluates severity and change of suicidality by integrating both suicidality behavior and ideation. For Suicidal Ideation (SI), participants were scored non-suicidal:0, wish to be dead:1, non-specific active suicidal thoughts:2, active suicidal ideation with associated thoughts of methods without intent:3, active suicidal ideation with some intent to act on suicidal thoughts without clear plan:4, active suicidal ideation with plan and intent:5 (most severe). SI intensity total score was the sum of suicidal ideation severity rating scores for frequency, duration, controllability, deterrents, and reasons for ideation. For each item, each participant got an intensity score from 0(none) to 5(worst). Therefore, the suicidal ideation intensity total score range from 0 to 25, with a score of 0 given for no suicidal ideation.
Maximum Observed Plasma Concentration (Cmax) for GSK249320 [Pre-dose and post-dose up to Day 180]
Cmax is the maximum observed concentration of GSK249320 obtained at the end of infusion post dose on Day 6. Due to early termination of the study, this data was not collected.
Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320 [Pre-dose and post-dose up to Day 180]
Tmax is the time of the occurrence of Cmax. The Cmax is defined as the maximum observed concentration of GSK249320 obtained at the end of infusion post dose on day 6. Due to early termination of the study data for Tmax was not collected.
PK as Measured by Plasma Decay Half-life (t1/2) GSK249320 [Up to Day 180]
Blood samples were collected for determination of plasma concentrations of GSK249320. Terminal phase half-life was derived from the plasma concentration-time data. Only participants in the GSK249320 15 mg/kg group were analyzed.
Area Under the Concentration-time Curve From 0 to 5 Days [AUC(0-5d)] and Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] for GSK249320 [Pre-dose and post-dose up to Day 180]
Blood samples were collected for determination of plasma concentrations of GSK249320. AUC (0-5d) and AUC (0-inf) were derived from the plasma concentration-time data. AUC(0-5d) is the model predicted AUC over the planned TAU of 5 days. Only participants in the GSK249320 15 mg/kg group were analyzed.
Clearance (CL) for GSK249320 [Up to Day 180]
Blood samples were collected for determination of plasma concentrations of GSK249320. CL was derived from the plasma concentration-time data. Analysis was performed for PK Population that comprised of all participants in the Safety Population who had at least one PK sample with a concentration above the non-quantifiable limit. Only participants in the GSK249320 15 mg/kg group were analyzed.
Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320 [Up to Day 180]
Blood samples were collected for determination of plasma concentrations of GSK249320. V1, V2 and Vss were derived from the plasma concentration-time data. Analysis was performed for PK Population that comprised of all participants in the Safety Population who had at least one PK sample with a concentration above the non-quantifiable limit. Only participants in the GSK249320 15 mg/kg group were analyzed.
Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay [Day 1, Day 30, Day 180, EW visit and Follow-up visit]
Blood samples were collected and the presence of antibodies against GSK249320 was assessed using ECL assays. Positive result indicated presence of antibodies and negative result indicated absence of antibodies. Confirmed samples with presence of antibodies were further characterized for neutralizing activity as binding antibody (BAb) and neutralising antibody (NAb) by a neutralization assay.By-visit sample sizes vary due to missing data or early termination of the study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Have a confirmed diagnosis of stroke according to the World Health Organization definition which is, 'a rapid onset event of vascular origin reflecting a focal disturbance of cerebral function, excluding isolated impairments of higher function, and persisting longer than 24 hours [World Health Organization, 1989].
Stroke onset must be within the last 24-72 hours of the first infusion of Investigational Product. Time of stroke onset is defined at the time at which the patient/relative is first aware of the stroke deficit. For patients who awake with deficits, or who are found unconscious, the time of onset is defined as the time at which they were last known to be symptom free.
Have a stroke that is radiologically confirmed to be ischemic and supratentorial. The diameter of the ischemic lesion is >15mm in any single direction or the volume is

4cc. See the Study Procedures Manual (SPM) for guidance on how to calculate the lesion size.

Have a total NIHSS score of 3-21.
Have a lower limb deficit from the incident stroke which is defined as a score of 1-4 on the NIHSS Motor Leg question (question #6).
Aged 18-90, inclusive.
Expectation the subject will receive standard physical, occupational and speech rehabilitation therapy as indicated for the post stroke deficits.
Male subjects and female subjects of non-child-bearing and child-bearing potential are allowed to participate in this study. See Section 11, Appendix 1 for definitions. Females of child-bearing potential must have a negative pregnancy test prior to enrollment and must agree to use one of the contraceptive methods specified in Section 11, Appendix 1.

Exclusion Criteria:

Ability to walk >0.8m/s as measured by the Gait Velocity assessment.
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.
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 likely to confound or interfere with completion of the study assessments.
Presence of a significant pre-existing gait deficit prior to study entry that is likely to confound clinical evaluations
Presence of pre-existing neurologic or psychiatric disease which is active and not adequately controlled such that it interfered with major activities of daily living immediately prior to the current stroke and is likely to interfere with study participation/visits or confound clinical evaluations.
The subject poses a significant suicide risk, in the opinion of the investigator.
Current or chronic history of liver disease, known hepatic or biliary abnormalities (except Gilbert's syndrome or asymptomatic gallstones), or known history of hepatitis B or hepatitis C infection. A positive hepatitis B or hepatitis C result on the GSK labs drawn at baseline/Study Day 1 do not exclude a subject from continuing in the study unless there are associated clinical signs/symptoms of liver disease; however, the subject should be treated as clinically indicated and the GSK Medical Monitor should be contacted for further discussion.
Presence of either a central or peripheral demyelinating disease, such as multiple sclerosis or IgM monoclonal gammopathy of unknown significance (MGUS).
Expected death due to the incident stroke, or evidence of a chronic co-morbid condition or unstable acute systemic illness which, in the opinion of the investigator, could shorten the subject's survival such that it would limit his/her ability to complete the study.
Presence of the following ECG values on baseline ECG: QTc > 500 msec (using either Bazett's formula (QTcB) or Fridericia's formula (QTcF)); or uncorrected QT >600msec (machine or manual over-read). If the ECG indicates a prolonged QTc interval value outside these limits, two further ECGs should be performed during the same sitting and the average QTc value of these triplicate ECGs calculated. If the average value exceeds the stated limits, the subject is not eligible.
Participation in any investigational rehabilitation paradigm targeting stroke recovery during the duration of this study.
Have a contraindication to MRI as per local hospital practice/guidelines.
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).
Prior treatment with GSK249320.
History of sensitivity to Investigational Product excipients (acetate buffer, polysorbate 80 and sodium chloride) that, in the opinion of the investigator or GSK Medical Monitor, contraindicates the subject's participation.
Pregnant females as determined by positive urine hCG test prior to enrollment.
Lactating females.
Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Orange	California	United States	92868-4280
2	GSK Investigational Site	Jacksonville	Florida	United States	32209
3	GSK Investigational Site	Peoria	Illinois	United States	61637
4	GSK Investigational Site	Lexington	Kentucky	United States	40536
5	GSK Investigational Site	Portland	Oregon	United States	97239
6	GSK Investigational Site	Nashville	Tennessee	United States	37232
7	GSK Investigational Site	Edmonton	Alberta	Canada	T6G 2B7
8	GSK Investigational Site	Edmonton	Alberta	Canada	T6L 5X8
9	GSK Investigational Site	London	Ontario	Canada	N6A 5A5
10	GSK Investigational Site	Toronto	Ontario	Canada	M4N 3M5
11	GSK Investigational Site	Greenfield Park	Quebec	Canada	J4V 2H1
12	GSK Investigational Site	St-Jérôme	Quebec	Canada	J7Z 5T3
13	GSK Investigational Site	Freiburg	Baden-Wuerttemberg	Germany	79106
14	GSK Investigational Site	Friedrichshafen	Baden-Wuerttemberg	Germany	88048
15	GSK Investigational Site	Ulm	Baden-Wuerttemberg	Germany	89081
16	GSK Investigational Site	Erlangen	Bayern	Germany	91054
17	GSK Investigational Site	Celle	Niedersachsen	Germany	29223
18	GSK Investigational Site	Hannover	Niedersachsen	Germany	30625
19	GSK Investigational Site	Osnabrueck	Niedersachsen	Germany	49076
20	GSK Investigational Site	Essen	Nordrhein-Westfalen	Germany	45122
21	GSK Investigational Site	Muenster	Nordrhein-Westfalen	Germany	48149
22	GSK Investigational Site	Leipzig	Sachsen	Germany	04103
23	GSK Investigational Site	Bremen		Germany	28177
24	GSK Investigational Site	Hamburg		Germany	22417
25	GSK Investigational Site	Hamburg		Germany	22763
26	GSK Investigational Site	Cambridge		United Kingdom	CB2 0QQ
27	GSK Investigational Site	Exeter		United Kingdom	EX2 5DW
28	GSK Investigational Site	Glasgow		United Kingdom	G51 4TF
29	GSK Investigational Site	Harrow		United Kingdom	HA1 3UJ
30	GSK Investigational Site	Liverpool		United Kingdom	L7 8XP
31	GSK Investigational Site	London		United Kingdom	SE5 9RS
32	GSK Investigational Site	London		United Kingdom	SW17 0QT
33	GSK Investigational Site	Newcastle upon Tyne		United Kingdom	NE1 4LP
34	GSK Investigational Site	Romford		United Kingdom	RM7 0AG
35	GSK Investigational Site	Salford		United Kingdom	M6 8HD
36	GSK Investigational Site	Torquay		United Kingdom	TQ2 7AA

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Publications

None provided.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT01808261

Other Study ID Numbers:

104615

First Posted:

Mar 11, 2013

Last Update Posted:

Nov 17, 2017

Last Verified:

Sep 1, 2017

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

Ischemic Stroke

Additional relevant MeSH terms:

Stroke

Study Results

Participant Flow

Recruitment Details	A total of 134 participants with Stroke, were randomized to the study. The study was conducted from 18 May 2013 to 28 July 2014 at 30 centers; with 5 in United States, 5 in Canada, 8 in United Kingdom, and 12 in Germany. The ITT population consisted of total 120 participants and the Per Protocol consisted of 104 participants.
Pre-assignment Detail	Screening details: This study consisted of a 6 month Core study period and an Extended follow Up period, if required. The study was terminated early at the time of Interim Analysis for reasons of futility. At that time, a total of 134 participants were randomized, of which 133 participants had received at least one dose of study medication.

Arm/Group Title	Placebo	GSK249320 15 mg/kg
Arm/Group Description	Participants received placebo administered as two intravenous (IV) infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 milliliters (mL) IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 milligrams (mg)/kilogram (kg) administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Period Title: Overall Study
STARTED	68	65
COMPLETED	32	32
NOT COMPLETED	36	33

Baseline Characteristics

Arm/Group Title	Placebo	GSK249320 15 mg/kg	Total
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Total of all reporting groups
Overall Participants	68	65	133
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.1 (11.2)	68.2 (11.92)	67.6 (11.53)
Sex: Female, Male (Count of Participants)
Female	29 42.6%	31 47.7%	60 45.1%
Male	39 57.4%	34 52.3%	73 54.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.5%	0 0%	1 0.8%
Asian	1 1.5%	1 1.5%	2 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 5.9%	2 3.1%	6 4.5%
White	62 91.2%	62 95.4%	124 93.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity
Description	Gait is the way or manner in which a person walks. Gait velocity (walking speed) is an objective, quantitative measure of lower extremity motor recovery in individuals who have had a stroke. Participants were asked to walk at their usual pace over a level, indoor 10 meter (m) distance and were allowed to use their normal assistive devices. The time (seconds[s]) taken by the participants to travel the 10 m distance was recorded. Gait velocity (m/s) as assessed by study personnel was derived as: 10 divided by time to walk 10 m. Two trials of gait velocity were conducted at each time point. Change from BL was calculated as the mean Month 3/Day 90 value minus the mean BL value. BL was defined as Day 1. The measure type displayed are posterior means.
Time Frame	BL (Day 1) and Month 3/Day 90

Outcome Measure Data

Analysis Population Description
Intent-To-Treat (ITT) population comprised of participants who received at least 1 infusion of investigational product and had at least 1 post-Baseline efficacy assessment.

Arm/Group Title	Placebo	GSK249320 15 mg/kg
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Measure Participants	60	60
Mean (Standard Deviation) [m/s]	0.5417 (0.062)	0.5859 (0.0535)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Credible intervals are displayed as confidence intervals. Posterior means, standard deviations, and credible intervals are provided in the table.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.713
	Comments	P-value presented is the posterior probability that the treatment difference (GSK249320 15mg/kg - placebo) is greater than 0 m/s at Month 3/Day 90.
	Method	Bayesian method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0443
	Confidence Interval	() 95% -0.119 to 0.2
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.0809
	Estimation Comments

2. Secondary Outcome

Title	Mean Change From BL to Month 6/ Day 180 in Gait Velocity
Description	Gait is the way or manner in which a person walks. Gait velocity (walking speed) is an objective, quantitative measure of lower extremity motor recovery in individuals who have had a stroke. Participants were asked to walk at their usual pace over a level, indoor 10 m distance and were allowed to use their normal assistive devices. The time (s) taken by the participants to travel the 10 m distance was recorded. Gait velocity (m/s) as assessed by study personnel was derived as: 10 divided by time to walk 10 m. Two trials of gait velocity were conducted at each time point. Change from BL was calculated as the mean Month 3/Day 90 value minus the mean BL value. BL was defined as Day 1. The measure type displayed are posterior means.
Time Frame	BL (Day 1) and Month 6/Day 180

Outcome Measure Data

Analysis Population Description
ITT Population.

Arm/Group Title	Placebo	GSK249320 15 mg/kg
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Measure Participants	60	60
Mean (Standard Deviation) [m/s]	0.5442 (0.0665)	0.6236 (0.0556)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Credible intervals are displayed as confidence intervals. Posterior means, standard deviations, and credible intervals are provided in the table.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.828
	Comments	P-value presented is the posterior probability that the treatment difference (GSK249320 15mg/kg - placebo) is greater than 0 m/s at Month 6/Day 180.
	Method	Bayesian method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.0794
	Confidence Interval	(2-Sided) 95% -0.093 to 0.247
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.0857
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Indicated Transition From One Gait Velocity Category to Another Category at the Indicated Time Points
Description	Participants were categorized at each visit into the following gait velocity categories: 0 m/s, >0 to <0.4 m/s, >=0.4 m/s to 0.8 m/s and >0.8m/s. A distinction was made between participants who are too incapacitated to walk (i.e., gait velocity = 0m/s) and participants for whom the gait velocity assessment was not performed due to another reason (i.e., truly missing data). Participants were asked to walk at their usual or normal pace and using their normal assistive devices. Two trials of gait velocity were conducted at each time point. The number of participants transitioning from one gait velocity category to another category was assessed at each post-Baseline visit and was presented in terms of the following transition categories: worsened, no change, improved 1 level, improved 2 levels and improved 3 levels. By-visit sample sizes vary due to missing data or early termination of the study, missing data was not imputed.
Time Frame	BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180.

Outcome Measure Data

Analysis Population Description
PP Population consisted of all participants who were included in the ITT population and did not violate protocol with regards to inclusion/exclusion criteria, unblinding, investigational product administration and gait velocity assessments. Only participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - PP	GSK249320 15 mg/kg - PP
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). Placebo - Per Protocol (PP) Population consisted of all participants who were included in the ITT population and did not violate protocol with regards to inclusion/exclusion criteria, unblinding, investigational product administration and gait velocity assessments.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The GSK249320 15 mg/kg - PP Population consisted of all participants who were included in the ITT population and did not violate protocol with regards to inclusion/exclusion criteria, unblinding, investigational product administration and gait velocity assessments.
Measure Participants	52	52
Day 30, Worsened	1 1.5%	0 0%
Day 30, No Change	19 27.9%	18 27.7%
Day 30, Improved 1 Levels	11 16.2%	11 16.9%
Day 30, Improved 2 Levels	9 13.2%	9 13.8%
Day 30, Improved 3 Levels	8 11.8%	11 16.9%
Day 60, Worsened	0 0%	0 0%
Day 60, No Change	13 19.1%	14 21.5%
Day 60, Improved 1 Level	14 20.6%	11 16.9%
Day 60, Improved 2 Levels	6 8.8%	7 10.8%
Day 60, Improved 3 Levels	9 13.2%	10 15.4%
Day 90, Worsened	1 1.5%	0 0%
Day 90, No Change	9 13.2%	8 12.3%
Day 90, Improved 1 Level	12 17.6%	14 21.5%
Day 90, Improved 2 Levels	10 14.7%	7 10.8%
Day 90, Improved 3 Levels	10 14.7%	12 18.5%
Day 180, Worsened	1 1.5%	0 0%
Day 180, No Change	7 10.3%	6 9.2%
Day 180, Improved 1 Level	9 13.2%	14 21.5%
Day 180, Improved 2 Levels	11 16.2%	5 7.7%
Day 180, Improved 3 Levels	8 11.8%	14 21.5%

4. Secondary Outcome

Title	Change From BL in Dexterity as Measured by Box and Blocks Test
Description	Dexterity is ability of person to use hands skillfully in performing a task. Box and Blocks test is an objective, gross manual dexterity test in individuals with upper limb impairments. Participants were asked to move small wooden blocks from one side of a partitioned box to other. The score was determined by number of blocks transferred within a 60 second time period. Both affected and unaffected arms were tested, starting with the unaffected arm. Change from BL was calculated as the individual post- BL value minus BL value. A higher number of displaced blocks indicated a better gross dexterity and a low number of displaced blocks indicated poor gross dexterity. It was analyzed using fixed effects for treatment, visit, treatment by visit interaction, sex, age, Baseline National Institute of Health stroke scale (NIHSS) total score, BL number of blocks transferred by the affected and unaffected arms, country and presence of concomitant medications that potentially impact recovery.
Time Frame	BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180

Outcome Measure Data

Analysis Population Description
PP Population.

Arm/Group Title	Placebo - PP	GSK249320 15 mg/kg - PP
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). Placebo PP Population consisted of all participants who were included in the ITT population and did not violate protocol with regards to inclusion/exclusion criteria, unblinding, investigational product administration and gait velocity assessments.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The GSK249320 15 mg/kg - PP Population consisted of all participants who were included in the ITT population and did not violate protocol with regards to inclusion/exclusion criteria, unblinding, investigational product administration and gait velocity assessments.
Measure Participants	52	52
Day 30	10.130 (2.195)	12.538 (1.587)
Day 60	11.469 (2.345)	14.484 (1.6)
Day 90	15.196 (2.962)	17.631 (1.926)
Day 180	14.869 (2.839)	18.813 (2.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Statistical data for Day 30. The point estimate and confidence interval are for the adjusted mean difference based on least square estimates.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.408
	Confidence Interval	(2-Sided) 95% -3.067 to 7.883
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.7495
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Statistical data for Day 60. The point estimate and confidence interval are for the adjusted mean difference based on least square estimates.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.015
	Confidence Interval	(2-Sided) 95% -2.704 to 8.735
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.8732
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Statistical data for Day 90. The point estimate and confidence interval are for the adjusted mean difference based on least square estimates.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.435
	Confidence Interval	(2-Sided) 95% -4.668 to 9.538
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.5633
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, GSK249320 15 mg/kg
	Comments	Statistical data for Day 180. The point estimate and confidence interval are for the adjusted mean difference based on least square estimates.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	3.944
	Confidence Interval	(2-Sided) 95% -3.15 to 11.037
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.5635
	Estimation Comments

5. Secondary Outcome

Title	Number of Participants Experiencing Falls
Description	The number of participants who experienced at least one fall between BL to Day 90 and BL to Day 180 is summarized.
Time Frame	BL (Day 1) Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety population is defined as participants who had received at least one infusion of investigational product.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Baseline to Day 90	15 22.1%	12 18.5%
Baseline to Day 180	18 26.5%	16 24.6%

6. Secondary Outcome

Title	Number of Falls Over Time
Description	The number of participants who experienced 1, 2, 3 or >=4 falls between BL to Day 90 and BL to Day 180 is summarized. By-visit sample sizes vary due to missing data or early termination of the study. The participants who experienced atleast one-fall were reported
Time Frame	BL (Day 1), Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Baseline to Day 90, 1 Fall	8 11.8%	6 9.2%
Baseline to Day 90, 2 Falls	3 4.4%	3 4.6%
Baseline to Day 90, 3 Falls	0 0%	2 3.1%
Baseline to Day 90, >=4 Falls	4 5.9%	1 1.5%
Baseline to Day 180, 1 Fall	7 10.3%	9 13.8%
Baseline to Day 180, 2 Falls	6 8.8%	2 3.1%
Baseline to Day 180, 3 Falls	1 1.5%	2 3.1%
Baseline to Day 180, >=4 Falls	4 5.9%	3 4.6%

7. Secondary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)
Description	An AE is 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. A SAE is any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect or all events of possible drug-induced liver injury with hyperbilirubinaemia. Medical or scientific judgment is exercised in other situations.
Time Frame	Up to 14 months

Outcome Measure Data

Analysis Population Description
Safety population.

Arm/Group Title	Placebo	GSK249320 15/mg
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Measure Participants	68	65
Any AE	57 83.8%	49 75.4%
Any SAE	16 23.5%	9 13.8%

8. Secondary Outcome

Title	Number of Participants With Events Common to Stroke
Description	Events common to stroke were those events that commonly occurred after a stroke and are generally associated with the underlying stroke or the progression of stroke. These included joint or soft tissue pain, bladder incontinence, depression/mood disorder, urinary tract infection, dysphagia, bowel incontinence, dysarthia, confusion, spasticity, limb edema, aspiration pneumonia, hemorrhagic transformation (symptomatic or asymptomatic), pressure ulcers, progression of stroke, malnutrition, deep vein thrombosis, brain herniation, pulmonary embolism, seizures, and falls.
Time Frame	From Day 1 until early withdrawal, death, Month 6/Day 180

Outcome Measure Data

Analysis Population Description
Safety Population.

Arm/Group Title	Placebo	GSK249320 15/mg
Arm/Group Description	Participants were administered placebo as two IV infusions, the first on Study Day 1 which was 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Measure Participants	68	65
Joint or soft tissue pain	19 27.9%	22 33.8%
Bladder Incontinence	11 16.2%	23 35.4%
Depression/Mood Disorder	17 25%	16 24.6%
Urinary tract infection	17 25%	13 20%
Dysphagia	12 17.6%	12 18.5%
Bowel Incontinence	11 16.2%	12 18.5%
Dysarthia	11 16.2%	11 16.9%
Confusion	8 11.8%	13 20%
Spasticity	9 13.2%	9 13.8%
Limb edema	5 7.4%	12 18.5%
Aspiration Pneumonia	5 7.4%	3 4.6%
Hemorrhagic Transformation	4 5.9%	4 6.2%
Pressure Ulcers	3 4.4%	2 3.1%
Progression of Stroke	2 2.9%	2 3.1%
Malnutrition	1 1.5%	2 3.1%
Deep vein thrombosis	2 2.9%	0 0%
Brain Herniation	0 0%	1 1.5%
Pulmonary embolism	1 1.5%	0 0%
Seizures	0 0%	1 1.5%
Falls	18 26.5%	16 24.6%

9. Secondary Outcome

Title	Change From BL in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Description	Safety was measured by monitoring vital signs including blood pressure. The BL for DBP and SBP was the value of pre-dose assessment on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1) , Day 6, Day 180 and early withdrawal (EW) visit

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
DBP, Day 1 Post-dose	1.7 (10.58)	0.5 (10.14)
DBP, Day 6 Pre-dose	0.2 (16.52)	-1.1 (11.98)
DBP, Day 6 Post-dose	2.4 (15.06)	1.9 (16.36)
DBP, Day 180	8.1 (13.97)	5.0 (14.60)
DBP, EW visit	-5.0 (15.55)	1.8 (15.05)
SBP, Day 1 Post-dose	3.1 (16.15)	0.7 (11.81)
SBP, Day 6 Pre-dose	-3.5 (26.46)	-6.0 (20.13)
SBP, Day 6 Post-dose	-0.9 (24.59)	-2.0 (20.14)
SBP, Day 180	-6.4 (22.96)	-6.4 (27.79)
SBP, EW visit	-15.2 (29.08)	-0.0 (25.42)

10. Secondary Outcome

Title	Change From BL in Vitals Signs-Heart Rate
Description	Safety was measured by monitoring vital signs including heart rate. The BL for heart rate was the value of pre-dose assessment on Day 1. Change from BL was calculated as the individual post-BL value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study. BL was defined as Day 1.
Time Frame	Day 1, Day 6, Day 180 and EW visit

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 1 Post-dose	0.9 (8.68)	0.7 (7.98)
Day 6 Pre-dose	-1.8 (13.03)	-0.4 (17.47)
Day 6 Post-dose	-3.9 (12.09)	-3.1 (15.30)
Day 180	-0.3 (17.50)	-3.0 (15.48)
EW visit	3.3 (15.47)	-2.1 (15.40)

11. Secondary Outcome

Title	Change From BL in ECG Parameter-Heart Rate
Description	A single 12-lead ECG was obtained at each time point that measured heart rate. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1) Day 6, Day 30 and EW visit

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 6, n=60, 58	-3.4 (17.57)	-4.9 (15.37)
Day 30, n=46, 50	-3.4 (19.81)	0.9 (16)
EW Visit, n=16, 16	-5.4 (16.82)	-10.3 (29.58)

12. Secondary Outcome

Title	Change From BL in ECG Parameters
Description	A single 12-lead ECG was obtained at each time point and the following ECG intervals were determined: PR, QRS, QT, RR and corrected QT (QTc), QT interval corrected by Bazett's formula (QTcB), QT interval corrected by Fridericia's formula (QTcF). BL for ECG parameters was the value of Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30 and EW visit

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
PR, Day 6	-1.0 (30.47)	-0.8 (20.02)
PR, Day 30	-5.9 (36.05)	-3.5 (42.08)
PR, EW Visit	-0.4 (21.01)	3.1 (33.96)
QRS, Day 6	4.9 (15.75)	-4.0 (44.11)
QRS, Day 30	3.4 (10.97)	1.1 (17.74)
QRS, EW Visit	2.6 (27.47)	-23.7 (81.24)
RR, Day 6	61.1 (246.84)	12.9 (154.09)
RR, Day 30	80.5 (245.31)	-21.8 (181.99)
RR, EW Visit	-21.6 (164.19)	85.6 (349.82)
QT, Day 6	10.4 (40.86)	9.4 (36.46)
QT, Day 30	4.1 (43.59)	-12.1 (42.06)
QT, EW Visit	20.8 (37.16)	43.7 (93.85)
QTc, Day 6	2.9 (30.70)	6.8 (43.87)
QTc, Day 30	-1.3 (32.92)	-2.2 (39.49)
QTc, EW Visit	7.1 (27.75)	8.9 (69.58)
QTcB, Day 6	2.2 (124.73)	4.5 (46.49)
QTcB, Day 30	-31.9 (120.26)	-13.9 (79.33)
QTcB, EW Visit	28.2 (37.06)	6.9 (52.02)
QTcF, Day 6	4.3 (74.12)	5.7 (33.25)
QTcF, Day 30	-16.9 (75.41)	-12.0 (58.16)
QTcF, EW Visit	26.0 (31.85)	18.3 (62.78)

13. Secondary Outcome

Title	Change From BL in Clinical Chemistry- Albumin and Total Protein
Description	ALB and TP were measured at BL, Day 6, Day 30, Day 90 and Day 180. Baseline was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
ALB, Day 6	0.0 (3.02)	-0.2 (3.67)
ALB, Day 30	1.0 (3.44)	3.0 (5.50)
ALB, Day 90	2.3 (3.23)	4.4 (5.14)
ALB, Day 180	2.3 (3.80)	5.3 (3.86)
TP, Day 6	1.0 (4.64)	0.9 (5.90)
TP, Day 30	2.7 (5.13)	5.6 (8.11)
TP, Day 90	3.1 (4.92)	6.5 (7.34)
TP, Day 180	4.4 (5.07)	7.6 (5.89)

14. Secondary Outcome

Title	Change From BL in Clinical Chemistry-urea/Blood Urea Nitrogen (BUN), Sodium (Na), Potassium (K), Glucose (Gluc), Chloride (Cl), Calcium (Ca)
Description	Ca, Cl, Gluc, K, Na and BUN were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Ca, Day 6	0.042 (0.1163)	0.059 (0.1564)
Ca, Day 30	0.091 (0.1254)	0.158 (0.1985)
Ca, Day 90	0.093 (0.1092)	0.186 (0.1960)
Ca, Day 180	0.087 (0.1053)	0.182 (0.1315)
Cl, Day 6	-0.9 (3.13)	-1.4 (4.08)
Cl, Day 30	-1.6 (3.72)	-3.1 (5.01)
Cl, Day 90	-1.3 (3.02)	-2.7 (4.67)
Cl, Day 180	-1.4 (2.48)	-3.4 (3.93)
Gluc, Day 6	0.21 (3.123)	-0.35 (2.619)
Gluc, Day 30	-0.93 (2.611)	-0.45 (2.476)
Gluc, Day 90	-1.12 (2.075)	-0.38 (2.170)
Gluc, Day 180	-1.09 (3.045)	-1.02 (2.136)
K, Day 6	0.17 (0.384)	0.21 (0.452)
K, Day 30	0.37 (0.487)	0.30 (0.429)
K, Day 90	0.36 (0.477)	0.39 (0.404)
K, Day 180	0.33 (0.517)	0.54 (0.472)
Na, Day 6	0.1 (2.82)	0.0 (2.83)
Na, Day 30	-0.3 (2.64)	-0.8 (3.21)
Na, Day 90	0.4 (1.87)	-0.7 (2.91)
Na, Day 180	0.5 (2.04)	-1.2 (2.90)
Urea/BUN, Day 6	1.57 (2.392)	1.61 (2.541)
Urea/BUN, Day 30	1.09 (2.673)	2.19 (5.436)
Urea/BUN, Day 90	1.02 (2.310)	1.04 (2.655)
Urea/BUN, Day 180	0.51 (2.364)	1.04 (3.502)

15. Secondary Outcome

Title	Change From BL in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
Description	ALP, ALT and AST were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
ALP, Day 6	7.7 (20.05)	6.2 (16.4)
ALP, Day 30	11.7 (21.47)	19.5 (35.87)
ALP, Day 90	8.6 (27.18)	6.7 (18.01)
ALP, Day 180	8.9 (12.73)	4.0 (17.63)
ALT, Day 6	11.4 (25.92)	10.7 (16.22)
ALT, Day 30	7.9 (19.02)	10.6 (27.84)
ALT, Day 90	-0.8 (16.14)	3.2 (11.21)
ALT, Day 180	-2.0 (12.83)	1.4 (10.66)
AST, Day 6	7.9 (26.39)	2.5 (15.52)
AST, Day 30	0.2 (14.24)	-0.9 (13.18)
AST, Day 90	-6.1 (11.78)	-5.2 (13.33)
AST, Day 180	-3.2 (7.13)	-5.0 (9.70)

16. Secondary Outcome

Title	Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine
Description	Direct bilirubin, total bilirubin and creatinine were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
direct bilirubin, Day 6	0.3 (3.81)	-0.0 (1.58)
direct bilirubin, Day 30	-1.0 (1.93)	-0.4 (1.48)
direct bilirubin, Day 90	-1.5 (1.92)	-0.5 (1.62)
direct bilirubin, Day 180	-1.2 (1.59)	-0.1 (1.38)
total bilirubin, Day 6	-1.5 (3.76)	-1.8 (5.90)
total bilirubin, Day 30	-4.6 (4.90)	-3.0 (4.85)
total bilirubin, Day 90	-4.9 (4.75)	-3.5 (5.59)
total bilirubin, Day 180	-4.6 (4.83)	-3.8 (5.28)
creatinine, Day 6	2.35 (20.520)	3.48 (16.778)
creatinine, Day 30	4.94 (31.767)	9.79 (28.329)
creatinine, Day 90	6.69 (18.980)	3.09 (15.387)
creatinine, Day 180	5.07 (12.925)	0.24 (13.857)

17. Secondary Outcome

Title	Change From BL in Eosinophils (EOS), Lymphocytes (LYM), Total Absolute Neutrophil Count (ANC), Platelet (PLT) Count, White Blood Cell (WBC) Count
Description	EOS, LYM, Total ANC, PLT count and WBC count were measured at BL, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value.By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
EOS, Day 6	0.049 (0.1153)	0.082 (0.1692)
EOS, Day 30	0.058 (0.2207)	0.086 (0.1318)
EOS, Day 90	0.058 (0.1175)	0.058 (0.1149)
EOS, Day 180	0.045 (0.1314)	0.048 (0.1206)
LYM, Day 6	-0.046 (0.3904)	-0.030 (0.6750)
LYM, Day 30	0.026 (0.4666)	-0.002 (0.5728)
LYM, Day 90	0.066 (0.4110)	0.236 (0.5854)
LYM, Day 180	0.017 (0.5005)	0.075 (0.5919)
Total ANC, Day 6	-0.375 (2.2795)	-0.756 (2.5842)
Total ANC, Day 30	-1.486 (2.4578)	-0.581 (4.7282)
Total ANC, Day 90	-1.469 (2.1498)	-1.455 (2.3515)
Total ANC, Day 180	-2.202 (2.7396)	-0.579 (1.6956)
PLT Count, Day 6	17.4 (37.57)	32.4 (41.01)
PLT Count, Day 30	40.5 (62.89)	47.6 (44.23)
PLT Count, Day 90	33.2 (53.36)	60.4 (56.30)
PLT Count, Day 180	19.9 (35.91)	35.9 (39.15)
WBC Count,Day 6	-0.40 (2.294)	-0.78 (2.288)
WBC Count, Day 30	-1.46 (2.524)	-0.54 (4.819)
WBC Count, Day 90	-1.45 (2.017)	-1.28 (2.119)
WBC Count, Day 180	-2.15 (2.496)	-0.55 (1.943)

18. Secondary Outcome

Title	Change From BL in Hematology- Hemoglobin
Description	Hemoglobin was measured at BL Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value. . By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 6	-0.1 (9.55)	2.4 (10.21)
Day 30	-1.0 (13.19)	3.8 (14.84)
Day 90	-4.1 (16.61)	4.7 (15.91)
Day 180	-6.2 (17.70)	7.6 (13.45)

19. Secondary Outcome

Title	Change From Baseline in Hematology- Hematocrit
Description	Hematocrit was measured at Baseline, Day 6, Day 30, Day 90 and Day 180. BL was the value obtained on Day 1. Change from BL was calculated as the individual post-Baseline value minus the BL value.By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	BL (Day 1), Day 6, Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 6	0.00096 (0.032094)	0.00896 (0.032858)
Day 30	-0.00350 (0.040669)	0.01116 (0.046146)
Day 90	-0.01446 (0.053418)	0.01329 (0.049054)
Day 180	-0.02455 (0.056181)	0.01909 (0.043139)

20. Secondary Outcome

Title	Change From BL in NIHSS Total Score
Description	The NIHSS is a 15 item, standardized, disease-specific, deficit scale which measures neurological impairment (level of consciousness, eye movements, visual fields, facial symmetry, motor strength (arm and leg), coordination, sensation, language (aphasia and dysarthria), and neglect) and is used to quantify participant status by measuring the severity of the stroke as assessed by NIHSS certified study personnel. The total NIHSS score is calculated as the sum of responses to the 15 items. The total NIHSS score ranges from 0-42, with a higher score indicative of a more severe impairment. By-visit sample sizes vary due to missing data or early termination of the study. Change from BL was calculated as the individual post-Baseline value minus the BL value. BL was defined as the value at Day 1.
Time Frame	BL (Day 1), Day 30, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 1	10.0 (4.40)	9.8 (3.79)
Day 30	6.4 (4.40)	5.7 (4.66)
Day 90	5.0 (3.83)	4.8 (4.89)
Day 180	3.9 (3.22)	4.2 (3.87)

21. Secondary Outcome

Title	Number of Participants With Suicidal Ideation Via Columbia Suicide Severity Rating Scale (CSSRS)
Description	C-SSRS is a clinician-rated scale that evaluates severity and change of suicidality by integrating both suicidality behavior and ideation. For Suicidal Ideation (SI), participants were scored non-suicidal:0, wish to be dead:1, non-specific active suicidal thoughts:2, active suicidal ideation with associated thoughts of methods without intent:3, active suicidal ideation with some intent to act on suicidal thoughts without clear plan:4, active suicidal ideation with plan and intent:5 (most severe). SI intensity total score was the sum of suicidal ideation severity rating scores for frequency, duration, controllability, deterrents, and reasons for ideation. For each item, each participant got an intensity score from 0(none) to 5(worst). Therefore, the suicidal ideation intensity total score range from 0 to 25, with a score of 0 given for no suicidal ideation.
Time Frame	Da y 1, Da y 6, Day 30, Day 60, Day 90 and Day 180

Outcome Measure Data

Analysis Population Description
Safety Population. Number of participants with at least one on-treatment C-SSRS assessment were included.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	63	63
Count of Participants [Participants]	10 14.7%	3 4.6%

22. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) for GSK249320
Description	Cmax is the maximum observed concentration of GSK249320 obtained at the end of infusion post dose on Day 6. Due to early termination of the study, this data was not collected.
Time Frame	Pre-dose and post-dose up to Day 180

Outcome Measure Data

Analysis Population Description
The Pharmacokinetics (PK) population consisted of all participants in the Safety population who have at least one PK sample with a concentration above the non-quantifiable limit. Data not collected due to early termination of study.

Arm/Group Title

GSK249320 15 mg/kg - PK

Arm/Group Description

Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). PK population consisted of all participants in the Safety population who have at least one PK sample with a concentration above the non-quantifiable limit.

Measure Participants

23. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320
Description	Tmax is the time of the occurrence of Cmax. The Cmax is defined as the maximum observed concentration of GSK249320 obtained at the end of infusion post dose on day 6. Due to early termination of the study data for Tmax was not collected.
Time Frame	Pre-dose and post-dose up to Day 180

Outcome Measure Data

Analysis Population Description
PK population. Due to early termination of the study, data for Tmax was not collected

Arm/Group Title

GSK249320 15 mg/kg - PK

Arm/Group Description

Measure Participants

24. Secondary Outcome

Title	PK as Measured by Plasma Decay Half-life (t1/2) GSK249320
Description	Blood samples were collected for determination of plasma concentrations of GSK249320. Terminal phase half-life was derived from the plasma concentration-time data. Only participants in the GSK249320 15 mg/kg group were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description
PK Population.

Arm/Group Title	GSK249320 15 mg/kg - PK
Arm/Group Description	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
Measure Participants	62
Median (Full Range) [Days]	23.09

25. Secondary Outcome

Title	Area Under the Concentration-time Curve From 0 to 5 Days [AUC(0-5d)] and Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time [AUC(0-inf)] for GSK249320
Description	Blood samples were collected for determination of plasma concentrations of GSK249320. AUC (0-5d) and AUC (0-inf) were derived from the plasma concentration-time data. AUC(0-5d) is the model predicted AUC over the planned TAU of 5 days. Only participants in the GSK249320 15 mg/kg group were analyzed.
Time Frame	Pre-dose and post-dose up to Day 180

Outcome Measure Data

Analysis Population Description
PK Population.

Arm/Group Title	GSK249320 15 mg/kg - PK
Arm/Group Description	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). PK population consisted of all participants in the Safety population who have at least one PK sample with a concentration above the non-quantifiable limit.
Measure Participants	62
AUC(0-5 d)	28.2273 (10.9)
AUC(0-inf)	120.6895 (20.4)

26. Secondary Outcome

Title	Clearance (CL) for GSK249320
Description	Blood samples were collected for determination of plasma concentrations of GSK249320. CL was derived from the plasma concentration-time data. Analysis was performed for PK Population that comprised of all participants in the Safety Population who had at least one PK sample with a concentration above the non-quantifiable limit. Only participants in the GSK249320 15 mg/kg group were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description
PK Population.

Arm/Group Title	GSK249320 15 mg/kg - PK
Arm/Group Description	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). PK population consisted of all participants in the Safety population who have at least one PK sample with a concentration above the non-quantifiable limit.
Measure Participants	62
Geometric Mean (Geometric Coefficient of Variation) [Milligrams/kilograms/hour]	0.1243 (20.4)

27. Secondary Outcome

Title	Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320
Description	Blood samples were collected for determination of plasma concentrations of GSK249320. V1, V2 and Vss were derived from the plasma concentration-time data. Analysis was performed for PK Population that comprised of all participants in the Safety Population who had at least one PK sample with a concentration above the non-quantifiable limit. Only participants in the GSK249320 15 mg/kg group were analyzed.
Time Frame	Up to Day 180

Outcome Measure Data

Analysis Population Description
PK Population

Arm/Group Title	GSK249320 15 mg/kg - PK
Arm/Group Description	Participants received GSK249320 15 mg/kg, administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). PK population consisted of all participants in the Safety population who have at least one PK sample with a concentration above the non-quantifiable limit.
Measure Participants	62
V1	43.6992 (6.7)
V2	41.4193 (17.8)
Vss	85.2892 (11.5)

28. Secondary Outcome

Title	Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay
Description	Blood samples were collected and the presence of antibodies against GSK249320 was assessed using ECL assays. Positive result indicated presence of antibodies and negative result indicated absence of antibodies. Confirmed samples with presence of antibodies were further characterized for neutralizing activity as binding antibody (BAb) and neutralising antibody (NAb) by a neutralization assay.By-visit sample sizes vary due to missing data or early termination of the study.
Time Frame	Day 1, Day 30, Day 180, EW visit and Follow-up visit

Outcome Measure Data

Analysis Population Description
Safety Population. Only those participants with data available at the specified time points were analyzed.

Arm/Group Title	Placebo - Safety	GSK249320 15 mg/kg - Safety
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.	Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush). The Safety Population included all participants who received at least one infusion of investigational product.
Measure Participants	68	65
Day 1, BAb Positive	7 10.3%	5 7.7%
Day 1, BAb Negative	60 88.2%	59 90.8%
Day 1, NAb Negative	0 0%	2 3.1%
Day 30, BAb Positive	4 5.9%	4 6.2%
Day 30, BAb Negative	44 64.7%	46 70.8%
Day 30, NAb Negative	1 1.5%	1 1.5%
Day 180, BAb Positive	0 0%	5 7.7%
Day 180, BAb Negative	24 35.3%	19 29.2%
EW visit, BAb Positive	1 1.5%	4 6.2%
EW visit, BAb Negative	22 32.4%	18 27.7%
EW visit, NAb Negative	1 1.5%	4 6.2%
FU visit, BAb Positive	0 0%	1 1.5%
FU visit, NAb Negative	0 0%	1 1.5%

Adverse Events

	Placebo		GSK249320 15 mg/kg
Time Frame	Up to 14 months
Adverse Event Reporting Description	SAEs and non-serious AEs were reported for members of the Safety Population, comprised of all participants who were randomized and took at least one dose of study medication.

Arm/Group Title	Placebo		GSK249320 15 mg/kg
Arm/Group Description	Participants received placebo administered as two IV infusions, the first on Study Day 1 which is 24-72 hours post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL, IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).		Participants received GSK249320 15 mg/kg administered as two IV infusions, the first on Study Day 1 which is 24-72 post-stroke onset, and the second on Study Day 6 (+/- 2 days). Each 100 mL IV infusion was delivered over a period of 75 minutes (a 60 minute infusion followed by a 10 to 15 minute flush).
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/68 (7.4%)		2/65 (3.1%)
Serious Adverse Events
	Placebo		GSK249320 15 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/68 (23.5%)		9/65 (13.8%)
Cardiac disorders
Acute myocardial infarction	0/68 (0%)		1/65 (1.5%)
Atrial fibrillation	0/68 (0%)		1/65 (1.5%)
Atrial flutter	1/68 (1.5%)		0/65 (0%)
Atrioventricular block complete	1/68 (1.5%)		0/65 (0%)
Bradyarrhythmia	1/68 (1.5%)		0/65 (0%)
Cardiac arrest	1/68 (1.5%)		0/65 (0%)
Cardiac failure congestive	0/68 (0%)		1/65 (1.5%)
Cardio-respiratory arrest	0/68 (0%)		1/65 (1.5%)
Sick sinus syndrome	0/68 (0%)		1/65 (1.5%)
Gastrointestinal disorders
Anal ulcer	0/68 (0%)		1/65 (1.5%)
Diarrhoea	1/68 (1.5%)		0/65 (0%)
Gastrointestinal hemorrhage	1/68 (1.5%)		0/65 (0%)
Rectal hemorrhage	1/68 (1.5%)		0/65 (0%)
Upper gastrointestinal hemorrhage	1/68 (1.5%)		0/65 (0%)
Infections and infestations
Pneumonia	1/68 (1.5%)		0/65 (0%)
Sepsis	0/68 (0%)		1/65 (1.5%)
Injury, poisoning and procedural complications
Femoral neck fracture	1/68 (1.5%)		0/65 (0%)
Joint injury	1/68 (1.5%)		0/65 (0%)
Neck injury	1/68 (1.5%)		0/65 (0%)
Nervous system disorders
Brain edema	1/68 (1.5%)		0/65 (0%)
Cerebral hemorrhage	1/68 (1.5%)		0/65 (0%)
Cerebrovascular accident	1/68 (1.5%)		0/65 (0%)
Haemorrhagic transformation stroke	0/68 (0%)		1/65 (1.5%)
Ischemic cerebral infarction	0/68 (0%)		1/65 (1.5%)
Stroke in evolution	1/68 (1.5%)		0/65 (0%)
Renal and urinary disorders
Renal failure acute	1/68 (1.5%)		1/65 (1.5%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	2/68 (2.9%)		0/65 (0%)
Respiratory failure	0/68 (0%)		1/65 (1.5%)
Vascular disorders
Hypertensive emergency	1/68 (1.5%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		GSK249320 15 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/68 (36.8%)		32/65 (49.2%)
Cardiac disorders
Atrial fibrillation	0/68 (0%)		4/65 (6.2%)
Gastrointestinal disorders
Constipation	6/68 (8.8%)		13/65 (20%)
Nausea	3/68 (4.4%)		5/65 (7.7%)
Urinary tract infection	4/68 (5.9%)		0/65 (0%)
Nervous system disorders
Headache	7/68 (10.3%)		12/65 (18.5%)
Psychiatric disorders
Insomnia	4/68 (5.9%)		5/65 (7.7%)
Skin and subcutaneous tissue disorders
Rash	3/68 (4.4%)		4/65 (6.2%)
Vascular disorders
Hypertension	4/68 (5.9%)		3/65 (4.6%)
Hypotension	4/68 (5.9%)		2/65 (3.1%)

Limitations/Caveats

The study was terminated early, on 27 May 2014, at the planned interim analysis for futility.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT01808261

Other Study ID Numbers:

104615

First Posted:

Mar 11, 2013

Last Update Posted:

Nov 17, 2017

Last Verified:

Sep 1, 2017

Proof of Concept (POC) in Patients With Ischaemic Stroke

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