Clinical trial NCT00833989: Safety Escalating Repeat IV, in Stroke Patients
Official title: A Single-Blind Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Repeat Doses of GSK249320 in Patients With Stroke
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischaemic Attack, Transient
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-02-02
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Have a confirmed diagnosis of stroke
* Stroke onset must be within the last 24-72 hours.
* Have a stroke that is either:
* radiologically confirmed to be ischaemic and supratentorial. The diameter of the ischemic lesion is \>15mm in any singlle direction or the volume is \>4cc. OR
* radiologically confirmed to be an intracerebral hemorrhage that is supratentorial, deep (i.e., blood must not directly contact cerebral cortex) and with minimal or no intraventricular extension. The Intracerebral Hemorrahage (CH) score must be 0-2 and is calculated based on age, Galsgow coma Scale score ad the initial CT or MRI findings for the index stroke. See the SOM for the full calculation procedure.
* Have a total NIHSS score of 3-21.
* Have an upper and/or lower limb deficit defined as:
* Score of 1-3 on the NIHSS Motor Arm question, and palpable and observable voluntary extension or flexion of the fingers. AND/OR b. Score of 1-3 on the NIHSS Motor Leg question
* Aged 18-90, inclusive.
* Male subjects and females of non-child-bearing potential are allowed to participate in this study.
* Females of child-bearing potential are also allowed to participate in this study provided they are using a contraceptive method with a failure rate of \<1%.

Exclusion Criteria:

* History of a previous symptomatic stroke within 3 months prior to study entry.
* Presence of significant disability prior to the current stroke. Significant disability is defined as having a pre-stroke Rankin score of \>2.
* Presence of depression that is active and not adequately controlled such that it interferred with major activities of daily living immediately prior to the current stroke.
* Subjects who are not alert or are unresponsive as defined by a score of 2 or 3 on the NIHSS Level of Consciousness question (question #1a).
* Presence of significant aphasia as likely to confound or interfere with completion of the study assessments.
* Presence of peripheral neuropathy, including diabetic neuropathy, which is clinically active and symptomatic at time of screening.
* Presence of neurological or psychiatric disease, such as dementia or mild cognitive impairment, prior to study entry that is likely to confound clinical evaluations.
* Presence of a demyelinating disease, such as multiple sclerosis.
* Evidence of other chronic co-morbid conditions or unstable acute systemic illnesses which, in the opinion of the investigator, could shorten the subject's survival or limit his/her ability to complete the study.
* History of sensitivity to heparin or heparin-induced thrombocytopenia.
* Presence of QTcB \> 500 msec; or uncorrected QT \>600msec (machine or manual over-read) on baseline ECG.
* Contraindication to TMS, such as:
* have metal present, such as hardware or plate on the scalp in the area to which TMS will be applied, implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials
* occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan.
* concomitant use of drugs that substantially lower seizure threshold (e.g., tricyclic antidepressants and neuroleptics)
* known history of seizures or epilepsy
* brain tumor, recent brain injury (within 5 years) associated with definite loss of consciousness, or any history of brain surgery
* Contraindication to MRI, such as:
* have metal present, such as implanted cardiac pacemaker, implanted prosthetic heart valve, medication pump or line, metallic implant or clip in the head/neck, electrical, mechanical or magnetic implants, neuro-stimulation device, or orthodontic work involving ferromagnetic materials, permanent tattooed metallic eye-liner
* occupation or activity that may cause accidental lodging of ferromagnetic materials or embedded metal fragments in the head. Subjects can be cleared by a head computed tomography scan.
* claustrophobia
* Participation in any investigational rehabilitation paradigm targeting stroke recovery during the duration of this study.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

Pregnant or lactating females.

* Subjects considered unwilling or unable to comply with the procedures and study visit schedule outlined in the protocol.

Primary outcomes:
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 112 days
measure: Number of Participants With Vital Signs Changes of Potential Clinical Importance
timeFrame: Up to 112 days
measure: Number of Participants With Electrocardiogram (ECG) Values Outside Range of Potential Clinical Importance
timeFrame: Up to 112 days
measure: Number of Participants With Nerve Conduction Testing (NCT) Values
timeFrame: Day 5 and 30 and at early withdrawal
measure: Number of Participants With White Matter Changes and Demyelination Assessed by Magnetic Resonance Imaging (MRI)
timeFrame: Up to Day 60
measure: Number of Participants With Abnormal Clinical Chemistry Parameters
timeFrame: Up to Day 112
measure: Number of Participants With Abnormal Hematological Parameters
timeFrame: Up to Day 112
Secondary outcomes:
measure: Number of Participants With Positive Antibodies to GSK249320
timeFrame: Day 1, 5, 10, 30, 60, 90 and 112
measure: 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)
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Maximum Observed Concentration (Cmax) and Last Observed Quantifiable Concentration (Ct)
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Time of Occurrence of Cmax (Tmax) and Time of Last Observed Quantifiable Concentration (Tlast)
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Terminal Phase Half-life (t1/2)
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Terminal Phase Rate Constant ( Lambda-Z)
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Clearance of GSK249320
timeFrame: Day 1 (Pre-dose, 1, 3, 6, 12 and 24 hour) and Day 10 (Pre-dose, 1, 3 hour)
measure: Mean Change in Mean Gait Velocity
timeFrame: Baseline (Day 5), Day 30, 60, 90, 112
measure: Mean Change in Berg Balance Scale (BBS) Total Score
timeFrame: Baseline (Day 5), Day 30, 60, 90 and 112
measure: Mean Change in Total Fugl-Meyer Motor (FM) Assessment
timeFrame: Baseline (Day 5), Day 30 and 112
measure: Mean Change in Total Box and Blocks Transferred on Affected Side
timeFrame: Baseline (Day 1), Day 30, 60, 90 and 112
measure: Mean Change in Grip Strength on Affected Side
timeFrame: Baseline (Day 1), Day 30, 60, 90 and 112
measure: Number of Participants With Modified Rankin Scale (mRS)
timeFrame: Day 30 and 90
measure: Change From Baseline of National Institutes of Health Stroke Scale (NIHSS)
timeFrame: Baseline (Day 1), Day 10, 30 and 90
measure: Mean Barthel Total Score
timeFrame: Day 30 and 90
measure: Mean Total Montreal Cognitive Assessment (MoCA) Score
timeFrame: Day 5 and 90
measure: Mean Geriatric Depression Scale (GDS)
timeFrame: Day 5 and 90
measure: Mean Change in Transcranial Magnetic Stimulations (TMS) Evaluated by Peak to Peak MEP by % Stimulation Level
timeFrame: Baseline (Day 1), Day 30 and 112
measure: Serum Levels of the S100β Protein
timeFrame: Day 1 (Pre-dose, Post dose 1, 6, 24 hour), Day 5
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: Orange
country: United States
facility: GSK Investigational Site
state: California
city: Fort Collins
country: United States
facility: GSK Investigational Site
state: Colorado
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Wiesbaden
country: Germany
facility: GSK Investigational Site
state: Hessen
city: Celle
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Koeln
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: GSK Investigational Site
state: Rheinland-Pfalz
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cramer SC, Abila B, Scott NE, Simeoni M, Enney LA; MAG111539 Study Investigators. Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke. Stroke. 2013 May;44(5):1337-42. doi: 10.1161/STROKEAHA.111.674366. Epub 2013 Mar 7.