Clinical trial NCT01808261: Proof of Concept (POC) in Patients With Ischaemic Stroke
Official title: Study MAG104615, a Proof of Concept Study for GSK249320 Versus Placebo in Stroke Patients
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Cerebrovascular Accident
Keywords: Ischemic Stroke
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-03-11
Enrollment: 134
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: TREATMENT

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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Change From Baseline (BL) to Month 3/ Day 90 in Gait Velocity
timeFrame: BL (Day 1) and Month 3/Day 90
Secondary outcomes:
measure: Mean Change From BL to Month 6/ Day 180 in Gait Velocity
timeFrame: BL (Day 1) and Month 6/Day 180
measure: Number of Participants With Indicated Transition From One Gait Velocity Category to Another Category at the Indicated Time Points
timeFrame: BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180.
measure: Change From BL in Dexterity as Measured by Box and Blocks Test
timeFrame: BL (Day 1), Month 1/Day 30, Month 2/Day 60, Month 3/Day 90 and Month 6/Day 180
measure: Number of Participants Experiencing Falls
timeFrame: BL (Day 1) Day 90 and Day 180
measure: Number of Falls Over Time
timeFrame: BL (Day 1), Day 90 and Day 180
measure: Number of Participants With Serious Adverse Events (SAEs) and Adverse Events (AEs)
timeFrame: Up to 14 months
measure: Number of Participants With Events Common to Stroke
timeFrame: From Day 1 until early withdrawal, death, Month 6/Day 180
measure: Change From BL in Vital Signs- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: BL (Day 1) , Day 6, Day 180 and early withdrawal (EW) visit
measure: Change From BL in Vitals Signs-Heart Rate
timeFrame: Day 1, Day 6, Day 180 and EW visit
measure: Change From BL in ECG Parameter-Heart Rate
timeFrame: BL (Day 1) Day 6, Day 30 and EW visit
measure: Change From BL in ECG Parameters
timeFrame: BL (Day 1), Day 6, Day 30 and EW visit
measure: Change From BL in Clinical Chemistry- Albumin and Total Protein
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in Clinical Chemistry-urea/Blood Urea Nitrogen (BUN), Sodium (Na), Potassium (K), Glucose (Gluc), Chloride (Cl), Calcium (Ca)
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in Alkaline Phosphatase (ALP), Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST)
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in Clinical Chemistry- Direct Bilirubin, Total Bilirubin, Creatinine
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in Eosinophils (EOS), Lymphocytes (LYM), Total Absolute Neutrophil Count (ANC), Platelet (PLT) Count, White Blood Cell (WBC) Count
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in Hematology- Hemoglobin
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From Baseline in Hematology- Hematocrit
timeFrame: BL (Day 1), Day 6, Day 30, Day 90 and Day 180
measure: Change From BL in NIHSS Total Score
timeFrame: BL (Day 1), Day 30, Day 90 and Day 180
measure: Number of Participants With Suicidal Ideation Via Columbia Suicide Severity Rating Scale (CSSRS)
timeFrame: Da y 1, Da y 6, Day 30, Day 60, Day 90 and Day 180
measure: Maximum Observed Plasma Concentration (Cmax) for GSK249320
timeFrame: Pre-dose and post-dose up to Day 180
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) GSK249320
timeFrame: Pre-dose and post-dose up to Day 180
measure: PK as Measured by Plasma Decay Half-life (t1/2) GSK249320
timeFrame: Up to Day 180
measure: 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
timeFrame: Pre-dose and post-dose up to Day 180
measure: Clearance (CL) for GSK249320
timeFrame: Up to Day 180
measure: Volume of Distribution (V1 and V2) and Volume at Steady State (Vss) for GSK249320
timeFrame: Up to Day 180
measure: Antibodies Against GSK249320, Assessed Using Electrochemi-luminescent Assay (ECL) Assay
timeFrame: Day 1, Day 30, Day 180, EW visit and Follow-up visit
Other outcomes:
Locations:
city: Orange
country: United States
facility: GSK Investigational Site
state: California
city: Jacksonville
country: United States
facility: GSK Investigational Site
state: Florida
city: Peoria
country: United States
facility: GSK Investigational Site
state: Illinois
city: Lexington
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Portland
country: United States
facility: GSK Investigational Site
state: Oregon
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Greenfield Park
country: Canada
facility: GSK Investigational Site
state: Quebec
city: St-Jérôme
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Friedrichshafen
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Celle
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Hannover
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Osnabrueck
country: Germany
facility: GSK Investigational Site
state: Niedersachsen
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Muenster
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Leipzig
country: Germany
facility: GSK Investigational Site
state: Sachsen
city: Bremen
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: Exeter
country: United Kingdom
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Harrow
country: United Kingdom
facility: GSK Investigational Site
city: Liverpool
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle upon Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Romford
country: United Kingdom
facility: GSK Investigational Site
city: Salford
country: United Kingdom
facility: GSK Investigational Site
city: Torquay
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Cramer SC, Enney LA, Russell CK, Simeoni M, Thompson TR. Proof-of-Concept Randomized Trial of the Monoclonal Antibody GSK249320 Versus Placebo in Stroke Patients. Stroke. 2017 Mar;48(3):692-698. doi: 10.1161/STROKEAHA.116.014517. Epub 2017 Feb 22.