A Single-Blind Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Stroke
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 42
- 试验地点
- 1
- 主要终点
- Number of Participants With Vital Signs Changes of Potential Clinical Importance
研究概览
简要总结
The purpose of this study is to is to test increasing repeat doses of GSK249320 compared to placebo in patients with stroke.
详细描述
GSK249320 is a humanised monoclonal antibody (mAb) that binds with high specificity to myelin-associated glycoprotein (MAG) and antagonises or neutralises MAG-mediated inhibition and has been shown to improve functional recovery after stroke in pre-clinical models, possibly by promoting neuroregeneration and plasticity. The present study is the first in patients with stroke. The main aim of this study is to select tolerated doses of GSK249320 that can be used in future trials to evaluate its efficacy in improving clinical function in patients recovering from stroke. This clinical trial is designed as a placebo-controlled, single-blind, multicenter study to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of escalating repeat IV doses of GSK249320. Three sequential dose escalation cohorts (1, 5 and 15 mg/kg) are planned, with 8 patients on placebo and 8 on active in cohort 1 and 4 patients on placebo and 8 on active in cohorts 2 and 3. Each patient will receive 2 repeat IV doses 9 ± 1 days apart and assessments will extend to at least 16 weeks.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- Single (Participant)
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
- •Stroke onset must be within the last 24-72 hours.
- •Have a stroke that is either:
- •radiologically confirmed to be ischaemic and supratentorial. The diameter of the ischemic lesion is >15mm in any singlle direction or the volume is >4cc. OR
- •radiologically confirmed to be an intracerebral hemorrhage that is supratentorial, deep (i.e., blood must not directly contact cerebral cortex) and with minimal or no intraventricular extension. The Intracerebral Hemorrahage (CH) score must be 0-2 and is calculated based on age, Galsgow coma Scale score ad the initial CT or MRI findings for the index stroke. See the SOM for the full calculation procedure.
- •Have a total NIHSS score of 3-
- •Have an upper and/or lower limb deficit defined as:
- •Score of 1-3 on the NIHSS Motor Arm question, and palpable and observable voluntary extension or flexion of the fingers. AND/OR b. Score of 1-3 on the NIHSS Motor Leg question
- •Aged 18-90, inclusive.
- •Male subjects and females of non-child-bearing potential are allowed to participate in this study.
- •Females of child-bearing potential are also allowed to participate in this study provided they are using a contraceptive method with a failure rate of <1%.
排除标准
- •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 >
- •Presence of depression that is active and not adequately controlled such that it interferred with major activities of daily living immediately prior to the current stroke.
- •Subjects who are not alert or are unresponsive as defined by a score of 2 or 3 on the NIHSS Level of Consciousness question (question #1a).
- •Presence of significant aphasia as likely to confound or interfere with completion of the study assessments.
- •Presence of peripheral neuropathy, including diabetic neuropathy, which is clinically active and symptomatic at time of screening.
- •Presence of neurological or psychiatric disease, such as dementia or mild cognitive impairment, prior to study entry that is likely to confound clinical evaluations.
- •Presence of a demyelinating disease, such as multiple sclerosis.
- •Evidence of other chronic co-morbid conditions or unstable acute systemic illnesses which, in the opinion of the investigator, could shorten the subject's survival or limit his/her ability to complete the study.
- •History of sensitivity to heparin or heparin-induced thrombocytopenia.
- •Presence of QTcB > 500 msec; or uncorrected QT >600msec (machine or manual over-read) on baseline ECG.
- •Contraindication to TMS, such as:
- •have metal present, such as hardware or plate on the scalp in the area to which TMS will be applied, implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials
- •occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan.
- •concomitant use of drugs that substantially lower seizure threshold (e.g., tricyclic antidepressants and neuroleptics)
- •known history of seizures or epilepsy
- •brain tumor, recent brain injury (within 5 years) associated with definite loss of consciousness, or any history of brain surgery
- •Contraindication to MRI, such as:
- •have metal present, such as implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials, permanent tattooed metallic eye-liner
- •occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan.
- •claustrophobia
- •Participation in any investigational rehabilitation paradigm targeting stroke recovery during the duration of this study.
- •The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
- •Pregnant or lactating females.
- •Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol.
研究组 & 干预措施
PLACEBO
干预措施: PLACEBO (Drug)
ACTIVE
干预措施: GSK249320 (Drug)
结局指标
主要结局
Number of Participants With Vital Signs Changes of Potential Clinical Importance
时间窗: Up to 112 days
The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (SBP) (\<85 and \>200 millimeter of mercury \[mmHg\]), diastolic blood pressure (DBP) (\<45 and \>110 mmHg) and heart rate (HR) (\<40 and \>110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.
Number of Participants With Electrocardiogram (ECG) Values Outside Range of Potential Clinical Importance
时间窗: Up to 112 days
Single 12-lead ECGs was obtained. The standard ECG criteria of potential clinical importance were uncorrected QT interval \<300 and \>600 milliseconds (msec), absolute QTc interval \>500 msec, increase from Baseline QTc \>60 msec, RR Interval \<90 and \>2000 msec, PR Interval \<110 and \>220 msec, QRS Interval \<75 and \>110 msec. The number of participants with potentially clinically significant ECG abnormality were reported.
Number of Participants With Nerve Conduction Testing (NCT) Values
时间窗: Day 5 and 30 and at early withdrawal
NCT (electrode placement technique) of sensory and motor function was performed on the unaffected side (i.e., side that is not affected by the stroke) by appropriately qualified personnel at specified visits (Day 5 and 30 and at early withdrawal). Qualified technician performed the testing; however the same neurologist interpreted the NCT data within a single participant. Both upper and lower extremity nerves were tested and the data was recorded. Number of participants with normal and abnormal NCT data were reported.
Number of Participants With White Matter Changes and Demyelination Assessed by Magnetic Resonance Imaging (MRI)
时间窗: Up to Day 60
Whole brain MRI scans were performed by appropriately qualified personnel at those specified visits (Day 1, 10 and 60 or at early withdrawal \[if participant withdrew from study before Day 60 MRI\]). Required pulse sequences of diffusion weighted imaging (DWI), T1, and T2 FLAIR was performed to measure lesion volume and to look for the presence of any new acute inflammatory lesions. The investigator or other medically qualified study team member evaluated the Day 10 and 60 scans for any new abnormalities or clinically significant worsening. Digital data for each MRI was sent to a central MRI laboratory for an over-read of the MRI scan and calculation of the lesion volume. Number of participants with change in white matter and demyelination on Day 10 compared to Day 1, Day 60 compared to Day 1 and Day 60 compared to Day 10 were reported.
Number of Participants With Abnormal Clinical Chemistry Parameters
时间窗: Up to Day 112
The clinical chemistry parameters analyzed were albumin, calcium, creatinine, glucose, potassium, sodium, total CO2, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin. Only those parameters for which at least one abnormal value was reported are summarized. The number of participants with abnormal clinical chemistry findings at specified visit were reported.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
时间窗: Up to 112 days
AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Number of Participants With Abnormal Hematological Parameters
时间窗: Up to Day 112
The clinical chemistry parameters analyzed were white blood cell count, neutrophil count, hemoglobin, platelet count, lymphocytes. Only those parameters for which at least one abnormal value was reported are summarized. The number of participants with abnormal hematology findings at specified visit were reported.
次要结局
- Number of Participants With Positive Antibodies to GSK249320(Day 1, 5, 10, 30, 60, 90 and 112)
- Mean Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC 0-inf) and Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC0-t)(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Maximum Observed Concentration (Cmax) and Last Observed Quantifiable Concentration (Ct)(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Time of Occurrence of Cmax (Tmax) and Time of Last Observed Quantifiable Concentration (Tlast)(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Terminal Phase Half-life (t1/2)(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Terminal Phase Rate Constant ( Lambda-Z)(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Clearance of GSK249320(Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour))
- Mean Change in Mean Gait Velocity(Baseline (Day 5), Day 30, 60, 90, 112)
- Mean Change in Berg Balance Scale (BBS) Total Score(Baseline (Day 5), Day 30, 60, 90 and 112)
- Mean Change in Total Fugl-Meyer Motor (FM) Assessment(Baseline (Day 5), Day 30 and 112)
- Mean Change in Total Box and Blocks Transferred on Affected Side(Baseline (Day 1), Day 30, 60, 90 and 112)
- Mean Change in Grip Strength on Affected Side(Baseline (Day 1), Day 30, 60, 90 and 112)
- Number of Participants With Modified Rankin Scale (mRS)(Day 30 and 90)
- Change From Baseline of National Institutes of Health Stroke Scale (NIHSS)(Baseline (Day 1), Day 10, 30 and 90)
- Mean Barthel Total Score(Day 30 and 90)
- Mean Total Montreal Cognitive Assessment (MoCA) Score(Day 5 and 90)
- Mean Geriatric Depression Scale (GDS)(Day 5 and 90)
- Mean Change in Transcranial Magnetic Stimulations (TMS) Evaluated by Peak to Peak MEP by % Stimulation Level(Baseline (Day 1), Day 30 and 112)
- Serum Levels of the S100β Protein(Day 1 (Pre-dose, Post dose 1, 6, 24 hour), Day 5)