Clinical Trial: A Four Part Study to Investigate Relative Bioavailability, Safety and Tolerability of up to 5 Oral Formulation of GSK2251052 in Order to Identify a Formulation for Further Evaluation in a Future Later Phase Study

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

Official Title: A Study to Evaluate the Relative Bioavailability of Five Different Oral Formulations of GSK2251052 and the Multiple-dose, Safety, Tolerability, and Pharmacokinetics of GSK2251052 With and Without Food

Brief Summary: GSK2251052 is a member of a novel mechanistic and structural class of antibiotics that inhibits the bacterial enzyme leucyl tRNA synthetase (LeuRS) by forming a boron adduct with tRNA and is currently in development for the treatment of hospital acquired Gramnegative infections.

Detailed Summary: GSK2251052 is a member of a novel mechanistic and structural class of antibiotics that inhibits the bacterial enzyme leucyl tRNA synthetase (LeuRS) by forming a boron adduct with tRNA and is currently in development for the treatment of hospital acquired Gramnegative infections (including E. coli, K. pneumoniae, and Enterobacter spp.). This is a multi-part study. Part A is a randomized, open-label, single dose, three-period, incomplete block design to evaluate the relative bioavailability of five oral formulations of GSK2251052. Approximately 24 healthy subjects will be enrolled to receive treatment with GSK2251052 at a dose of 2000 mg and randomized to receive three of the following five formulations: 1) enteric-coated tablet (Treatment A), 2) modified release tablet (Treatment B), 3) enteric-coated powder for oral suspension (Treatment C), 4) immediate release tablet (Treatment D), and 5) oral solution (Treatment E). One or two formulations from Part A will be selected on the basis of acceptable safety and pharmacokinetic criteria for further dose evaluation in Part B. If no formulations are deemed to have the desired PK characteristics, Part B will not be conducted. Part B is a randomized, single-blind, placebo-controlled, dose-escalation evaluation of the selected formulation(s) from Part A. Approximately 8 subjects will be randomly assigned to receive GSK2251052 at the planned starting dose of 2000 mg or respective placebo in Period 1. In Period 2, the next dose level will be administered at an increment of 500 mg and/or based on the PK and safety of the preceding period. Additional periods may be conducted with the selected formulation pending acceptable safety in order to achieve target pharmacokinetic concentrations. Part C is a randomized, single-blind, placebo-controlled, two-cohort, two period, crossover study of the selected formulation of GSK2251052 in Part B to evaluate its multiple-dose safety and pharmacokinetics in both young and elderly, male and f
Sponsor: GlaxoSmithKline

Current Primary Outcome:

• Single dose relative bioavailability of five formulations [ Time Frame: 3 days ]
  Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.
• Pharamacokinetics of escalating single oral doses [ Time Frame: 4 days ]
  Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.
• To evaluate and compare the pharmacokinetics of multiple oral doses of GSK2251052 in young and elderly healthy adult subjects [ Time Frame: Days 1 to 4 and day 9 ]
  Plasma GSK2251052 Cmax, AUC(0-t), AUC(0-Tau), and AUC (0-∞), as applicable, for each formulation.

Original Primary Outcome: Same as current

Current Secondary Outcome:

• Safety and tolerability in Part A [ Time Frame: Days 1 to 4 and day 14 post-dose in periods 3 ]
  Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.
• Safety and tolerability in Part B [ Time Frame: Days 1 to4 and day 14 post dose in period 3 ]
  Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.
• Part C and Part D, to assess the safety and tolerability of GSK2251502 in healthy young and elderly volunteers following single and repeat dose administration with and without food [ Time Frame: Days 1 to 4 and day 9 and day 14 post last dose in period 2. ]
  Clinical safety data from all adverse event reporting, 12-lead ECGs, vital signs, concurrent medication, nursing/physician observation, and safety laboratory tests.

Original Secondary Outcome: Same as current

Information By: GlaxoSmithKline

Dates:
Date Received: September 20, 2012
Date Started: October 2011
Date Completion:
Last Updated: October 4, 2012
Last Verified: October 2012