Proof of Concept (POC) in Patients With Ischaemic Stroke

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

Detailed Description
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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.

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

Conditions
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Cerebrovascular Accident

Intervention / Treatment
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* Drug: GSK249320 100/mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|
| Active Comparator: GSK249320 100/mg<br>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<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity | 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. | BL (Day 1) and Month 3/Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From BL to Month 6/ Day 180 in Gait Velocity | 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. | BL (Day 1) and Month 6/Day 180 | 
| Number of Participants With Indicated Transition From One Gait Velocity Category to Another Category at the Indicated Time Points | 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. | BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180. | 
| Change From BL in Dexterity as Measured by Box and Blocks Test | 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. | BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180 | 
| Number of Participants Experiencing Falls | The number of participants who experienced at least one fall between BL to Day 90 and BL to Day 180 is summarized. | BL (Day 1) Day 90 and Day 180 | 
| Number of Falls Over Time | 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 | BL (Day 1), Day 90 and Day 180 | 
| Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs) | 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. | Up to 14 months | 
| Number of Participants With Events Common to Stroke | 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. | From Day 1 until early withdrawal, death, Month 6/Day 180 | 
| Change From BL in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | 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. | BL (Day 1) , Day 6, Day 180 and early withdrawal (EW) visit | 
| Change From BL in Vitals Signs-Heart Rate | 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. | Day 1, Day 6, Day 180 and EW visit | 
| Change From BL in ECG Parameter-Heart Rate | 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. | BL (Day 1) Day 6, Day 30 and EW visit | 
| Change From BL in ECG Parameters | 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. | BL (Day 1), Day 6, Day 30 and EW visit | 
| Change From BL in Clinical Chemistry- Albumin and Total Protein | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in Clinical Chemistry-urea/Blood Urea Nitrogen (BUN), Sodium (Na), Potassium (K), Glucose (Gluc), Chloride (Cl), Calcium (Ca) | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in Eosinophils (EOS), Lymphocytes (LYM), Total Absolute Neutrophil Count (ANC), Platelet (PLT) Count, White Blood Cell (WBC) Count | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in Hematology- Hemoglobin | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From Baseline in Hematology- Hematocrit | 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. | BL (Day 1), Day 6, Day 30, Day 90 and Day 180 | 
| Change From BL in NIHSS Total Score | 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. | BL (Day 1), Day 30, Day 90 and Day 180 | 
| Number of Participants With Suicidal Ideation Via Columbia Suicide Severity Rating Scale (CSSRS) | 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. | Da y 1, Da y 6, Day 30, Day 60, Day 90 and Day 180 | 
| Maximum Observed Plasma Concentration (Cmax) for GSK249320 | 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. | Pre-dose and post-dose up to Day 180 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320 | 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. | Pre-dose and post-dose up to Day 180 | 
| PK as Measured by Plasma Decay Half-life (t1/2) GSK249320 | 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. | Up to Day 180 | 
| 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 | 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. | Pre-dose and post-dose up to Day 180 | 
| Clearance (CL) for GSK249320 | 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. | Up to Day 180 | 
| Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320 | 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. | Up to Day 180 | 
| Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay | 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. | Day 1, Day 30, Day 180, EW visit and Follow-up visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic Stroke