Clinical Trial: A First Time in Human Study Exploring Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GSK2618960 in Healthy Volunteers and Patients With Relapsing Remitting Multiple Sclerosis (RRMS)

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: A First Time in Human Study Exploring Preliminary Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK2618960 in Healthy Volunteers and Patients With Relapsing Remi

Brief Summary:

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.

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

• 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 [ Time Frame: Upto Week 12 pending emerging data and DEC decisions. ]
  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.
• Safety and tolerability of GSK2618960 as assessed by changes in MS relapses: Number, duration, severity in MS patients [ Time Frame: Upto Week 12 pending emerging data and DEC decisions ]
  Safety and tolerability parameters will include recording of the number/duration/severity of MS relapses in Part C of the study in MS patients

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Composite of PK parameters 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. ]
  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.
• Receptor occupancy by GSK2618960 - Blinding of fluorophore-conjugated competing and non-competing antibody of GSK2618960 following the single and repeat IV doses [ 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. ]
  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.
• Relationship between dose and duration of >95% RO of GSK2618960 following single and repeat IV doses in healthy volunteers [ 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. ]
  The PK/RO relationship of GSK2618960 following single and repeat IV doses in Part A and B of the study.
• 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 [ Time Frame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, dependent upon predictions. ]
  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.
• Presence of antibodies to GSK2618960 [ 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. ]
  Presence of antibodies to GSK2618960 will be assessed in serum samples using validated ECL assays.
• Changes in numbers and relevant ratios of lymphocyte subsets [ Time Frame: Day -1, Day 8, Day 15 and Day 29 onwards through final follow up, will be dependent upon predictions. ]
  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.
• Markers of serum inflammatory mediators in blood. [ Time Frame: Day 1 predose and 1 h and 4 h post dose, Day 2 and Day 3 ]
  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
• Cumulative number of new brain lesions [ 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 ]
  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.

Original Secondary Outcome:

• Composite of PK parameters 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. ]
  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.
• Binding of fluorophore-conjugated competing and non-competing antibody of GSK2618960 following the single and repeat IV doses [ 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. ]
  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.
• Relationship between dose and duration of >95% RO of GSK2618960 following single and repeat IV doses in healthy volunteers [ 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. ]
  The PK/RO relationship of GSK2618960 following single and repeat IV doses in Part A and B of the study.
• Phosphorylation level of stat5 protein upon ex vivo stimulation of IL-7 cytokine, normalized by baseline, maximum receptor blocking controls and unstimulated controls [ Time Frame: Day 1 predose, 1h, 4h post dose, Day 2, Day 3, Day 4, Day 8, Day 15 and Day 29 onwards will be collected only if there is predicted quantifiable RO. ]
  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.
• Presence of antibodies to GSK2618960 [ Time Frame: Day 1, Day 15 and Day 29 onwards will be collected only if there is predicted quantifiable RO. ]
  Presence of antibodies to GSK2618960 will be assessed in serum samples using validated ECL assays.
• Changes in numbers and relevant ratios of lymphocyte subsets [ Time Frame: Day -1 predose, Day 8, Day 15 and Day 29 onwards will be collected only if there is predicted quantifiable RO. ]
  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.
• Markers of serum inflammatory mediators in blood. [ Time Frame: Day 1 predose and 1 h and 4 h post dose, Day 2 and Day 3 ]
  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
• Cumulative number of new brain lesions [ Time Frame: On Day -1 and at Week 6, Week 10, Week 14 and Week 18 after first dose ]
  Cumulative number of new brain lesions will be assessed in Part C of the study. New lesion is defined as enhancing in the presence of Gadolinium contrast agent

Dates:
Date Received: March 7, 2013
Date Started: March 2013
Date Completion:
Last Updated: January 27, 2017
Last Verified: January 2017