This is a 3-part study where Parts A, B (single-blind - investigator and subject blind) will enrol healthy volunteers and Part C (open-label) will enrol RRMS patients. Parts A (single ascending dose) and B (repeat ascending dose) will assess safety, tolerability, PK and PD of GSK2618960. Part C (repeat doses) will assess safety, tolerability, PK, PD, immunogenicity, paraclinical (magnetic resonance imaging \[MRI\] lesion counts) disease activity and markers of Th1 and Th17 mechanisms. Part A: Each of the 24 healthy volunteers (divided in 5 groups), will take part in only 2 of the planned 8 dosing sessions (A-active, P-placebo). Subjects in each group of Part A will be randomized in a 2:1:1 ratio to one of the following sequences: AA, AP or PA such that in each dosing session they will receive study treatment in a 3:1 ratio of active: placebo respectively. Part B: Dosing levels and regimen are dependent upon safety tolerability and PK/receptor occupancy (RO) data from Part A. In Cohort 1, 12 subjects will be randomized in a 3:1 ratio to A or P. Each subject will receive the same study treatment for repeated doses. If the duration of full RO from highest dose in Part A is less than 4 weeks, a second cohort of 12 subjects in Part B may be recruited, based on Dose Escalation Committee (DEC) decision Part C: The 20 RRMS patients will be assigned to active treatments for 2 to 4 repeated doses. Safety/tolerability and PK data monitoring and the decision to proceed to the next dose level of GSK2618960, and the decisions to proceed to Part B and Part C of the study will be made by a dose escalation committee.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
16
100 mg/mL GSK2618960 solution for IV Infusion up to 1 hr except for the 1st dose (IV bolus) and 2nd dose (IV infusion over 5 min) of Part A
Matching placebo
100 mg/mL GSK2618960 solution for IV Infusion in repeat dose decided from Part A
Matching placebo
100 mg/mL GSK2618960 solution for IV Infusion in repeat dose decided from Part A and B
GSK Investigational Site
Cambridge, United Kingdom
Safety and tolerability of GSK2618960 as assessed by changes in: vital signs, ECG monitoring, haematology, clinical chemistry, urinalysis, and monitoring of AEs in healthy volunteers and MS patients
Safety and tolerability parameters will include recording of vital signs, electrocardiogram (ECG)s, safety labs, and adverse event (AE)s, in Part A/B/C of the study in healthy volunteers and Multiple Sclerosis (MS) patients.
Time frame: Upto Week 12 pending emerging data and DEC decisions.
Safety and tolerability of GSK2618960 as assessed by changes in MS relapses: Number, duration, severity in MS patients
Safety and tolerability parameters will include recording of the number/duration/severity of MS relapses in Part C of the study in MS patients
Time frame: Upto Week 12 pending emerging data and DEC decisions
Composite of PK parameters of GSK2618960
The following pharmacokinetic (PK) data will be calculated: maximum concentration (Cmax), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration \[AUC(0-tau)\] and AUC from zero to infinity \[AUC(0-inf)\], percentage of AUC(0-inf) obtained by extrapolation (%AUC(ex)), clearance (CL), volume of distribution (Vss), time from administration to Cmax (tmax) and elimination half life (t½) of GSK2618960.
Time frame: Day 1 predose 1,2,4, 8, 24 hour (hr)s post dose (Day 2), 36 hrs (Day 2), Day 3, Day 4, Day 8, Day 15, and post Day 15 every 2 weeks and dependent upon predictions.
Receptor occupancy by GSK2618960 - Blinding of fluorophore-conjugated competing and non-competing antibody of GSK2618960 following the single and repeat IV doses
The total receptor levels will be measured by counting the binding of fluorophore-conjugated competing antibody (PE-GSK2618960) to unoccupied GSK2618960 binding sites, normalized by baseline and maximum blocking controls, in addition to non-competing antibody binding.
Time frame: Day 1 predose 1, 4, 8 hrs dose, Day 2, Day 3, Day 4, Day 8, Day 15, and Day 29 onwards visits through final follow up, and dependent upon predictions.
Relationship between dose and duration of >95% RO of GSK2618960 following single and repeat IV doses in healthy volunteers
The PK/RO relationship of GSK2618960 following single and repeat IV doses in Part A and B of the study.
Time frame: Day 1 predose 1,2,4, 8, 24 hour (hr)s post dose (Day 2), 36 hrs (Day 2), Day 3, Day 4, Day 8, Day 15, and post Day 15 every 2 weeks and dependent upon predictions.
To characterize the effect of GSK2618960 on IL-7 downstream signalling - Phosphorylation level of stat5 protein upon ex vivo stimulation of IL-7 cytokine, normalized by baseline, maximum receptor blocking controls and unstimulated controls
Blood from 7 distinct healthy donors was incubated ex vivo with 0.003 to 100 microgram/mL GSK2618960 and then stimulated with 5ng/mL human IL-7 STAT5 phosphorylation as well as unbound GSK2618960 and total IL-7R levels were assayed by flow cytometry.
Time frame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, dependent upon predictions.
Presence of antibodies to GSK2618960
Presence of antibodies to GSK2618960 will be assessed in serum samples using validated ECL assays.
Time frame: Immunogenicity sampling will be performed at Day1 pre-dose, Day 15 and approximately 2 months after dosing for dosing sessions 1- 5, and performed every 3 months after final dosing for dosing sessions 6-8 and parts B & C.
Changes in numbers and relevant ratios of lymphocyte subsets
Lymphocyte subsets will include B cells, CD3+ T cells, NK cells, regulatory T cells, and recent thymic emigrants, and may include, CD4+T cell, CD8+ T cells, naïve CD4+ T cells, effect memory CD4+ T cells, and central memory CD4+ T cell, etc. For Part A, blood sampling for lymphocyte subset is not required for dosing sessions 1-3. For part A, after day 29, a maximum of 3 blood samples will be drawn, each separated by 2 weeks, at time points spanning the predicted end of full RO. For parts B and C, blood sampling is limited to Day -1, and 3 blood samples separated by 2 weeks.
Time frame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, will be dependent upon predictions.
Markers of serum inflammatory mediators in blood.
Serum inflammatory mediators, including some or all, but not limited to: IL-1β, IL-6, IL-8, MCP-1, TNF-α and IFN-γ blood sampling for serum inflammatory mediators will be performed for dose sessions 1, 2, 3, 6; optional for other dose sessions in part A, Part B and Part C pending emerging data
Time frame: Day 1 predose and 1 h and 4 h post dose, Day 2 and Day 3
Cumulative number of new brain lesions
Cumulative number of new brain lesions will be assessed in Part C of the study using magnetic resonance imaging (MRI). New lesion is defined as enhancing in the presence of Gadolinium contrast agent.
Time frame: 1st MRI baseline at -8weeks, 2nd MRI baseline at -4 weeks, 3rd MRI baseline on Day -1, and at Week 6, Week 10, Week 14 and Week 18 after first dose
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