Study MAG104615, a Proof of Concept Study for GSK249320 Versus Placebo in Stroke Patients
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 134
- 试验地点
- 1
- 主要终点
- Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity
研究概览
简要总结
Study MAG104615, a Proof of Concept Study for GSK249320 versus placebo in Stroke Patients.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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-
- •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.
排除标准
- •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 >
- •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 GSK
- •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.
研究组 & 干预措施
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.
干预措施: Placebo (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.
干预措施: GSK249320 100/mg (Drug)
结局指标
主要结局
Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity
时间窗: 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.
次要结局
- 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)
- Change From BL in ECG Parameters(BL (Day 1), Day 6, Day 30 and EW visit)
- Change From BL in Hematology- Hemoglobin(BL (Day 1), Day 6, Day 30, Day 90 and Day 180)
- PK as Measured by Plasma Decay Half-life (t1/2) GSK249320(Up to Day 180)
- Mean Change From BL to Month 6/ Day 180 in Gait Velocity(BL (Day 1) and Month 6/Day 180)
- Number of Falls Over Time(BL (Day 1), Day 90 and Day 180)
- Change From BL in NIHSS Total Score(BL (Day 1), Day 30, Day 90 and Day 180)
- Maximum Observed Plasma Concentration (Cmax) for GSK249320(Pre-dose and post-dose up to Day 180)
- 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.)
- Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)(Up to 14 months)
- 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)
- 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)
- Change From Baseline in Hematology- Hematocrit(BL (Day 1), Day 6, Day 30, Day 90 and Day 180)
- 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)
- Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay(Day 1, Day 30, Day 180, EW visit and Follow-up visit)
- 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)
- Number of Participants Experiencing Falls(BL (Day 1) Day 90 and Day 180)
- Number of Participants With Events Common to Stroke(From Day 1 until early withdrawal, death, Month 6/Day 180)
- Change From BL in Vitals Signs-Heart Rate(Day 1, Day 6, Day 180 and EW visit)
- Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine(BL (Day 1), Day 6, Day 30, Day 90 and 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(Pre-dose and post-dose up to Day 180)
- Clearance (CL) for GSK249320(Up to Day 180)
- Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320(Up to Day 180)
- Change From BL in ECG Parameter-Heart Rate(BL (Day 1) Day 6, Day 30 and EW visit)
- Change From BL in Clinical Chemistry- Albumin and Total Protein(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(BL (Day 1), Day 6, Day 30, Day 90 and Day 180)
- Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320(Pre-dose and post-dose up to Day 180)