This is a randomized, partially-blinded, placebo and moxifloxacin-controlled, single dose, 4-period, balanced crossover study. The primary objective of this study is to separately assess the effects of a therapeutic and supratherapeutic dose of GSK1322322 on the cardiac conduction (corrected QT interval \[QTc\]) compared with placebo in eligible healthy male and female subjects. Avelox (moxifloxacin hydrochloride) will be used as an open-label positive control in order to validate the sensitivity of the study in detecting QTc change. Approximately 56 healthy subjects will participate in the study for approximately 9 weeks i.e. 30 day Screening period, 4-week Treatment period, and a 7-10 day Follow-up period. There will be 4 treatment periods separated by at least 1 week. Subjects will be admitted to the clinical unit on Day -1 of each dosing period. Each subject will receive each of the four treatment sequences (GSK1322322 1200 milligram \[mg\] intravenous \[IV\] over 60 minutes x 1 dose, GSK1322322 3000 mg IV over 60 minutes x 1 dose, GSK1322322 Placebo IV over 60 minutes x 1 dose, moxifloxacin 400 mg administered orally x 1 dose) on Day 1 of each Treatment period in a randomized fashion. Twelve-lead electrocardiogram (ECG), continuous Holter monitoring, laboratory tests, vital sign measurements, and serial pharmacokinetic samples will be collected for up to 24 hours following each treatment. If no clinically significant abnormalities are noted, subjects will be discharged from the clinical research unit after the completion of all assessments on Day 2 in each period and return approximately one week later for the next dosing period. Each individual subject will follow the same dosing schedule at every period. A Follow-up visit will be conducted 7-10 days after administration of the last dose of study medication in treatment period 4.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
GSK1322322 will be supplied as white to slightly colored lyophilized powder 400 mg/vial for injection. Single dose of GSK1322322 1200 mg (3 vials) will be administered IV over 60 minutes
GSK1322322 will be supplied as white to slightly colored lyophilized powder 400 mg/vial for injection. Single dose of GSK1322322 3000 mg (8 vials) will be administered IV over 60 minutes
Placebo will be supplied as 0.9% sodium chloride solution. Single dose of placebo will be administered IV over 60 minutes
Moxifloxacin will be supplied as oblong, dull red film coated tablets of 400 mg strength. Single dose of moxifloxacin 400 mg will be administered orally
Change from baseline in QT duration corrected for heart rate by Fridericia's formula (QTcF) for GSK1322322 as compared with time-matched placebo
Triplicate 12-lead Holter ECG measurements for each subject at each time point will be averaged
Time frame: Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period
Change from baseline in QT duration corrected for heart rate by Bazett's formula (QTcB), Individual (linear) QT correction (QTci), QT, and heart rate (HR)
To estimate the effect of single dose IV GSK1322322 (1200 mg and 3000 mg) as compared with placebo. Triplicate 12-lead Holter ECG measurements for each subject at each time point will be averaged
Time frame: Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period
Change from baseline in QTcB, QTci, QT, and HR
To estimate the effect of single dose oral moxifloxacin (400 mg) as compared to placebo. Triplicate 12-lead Holter ECG measurements for each subject at each time point will be averaged
Time frame: Day 1: -1.5, -1.0 and -0.5 hours pre-dose (average as baseline) and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period
Plasma concentrations and selected pharmacokinetic (PK) parameters of moxifloxacin
PK parameters will include: maximum observed plasma concentration (Cmax); time to Cmax (tmax); area under the plasma concentration-time curve (AUC): from time zero (pre-dose) to last time of quantifiable concentration \[AUC (0-t)\], from time zero (pre-dose) to 24 hours \[AUC (0-24)\], and from time zero (pre-dose) extrapolated to infinite time \[AUC (0-∞)\]; apparent terminal phase half-life (t1/2); Systemic clearance of parent drug (CL); and volume of distribution at steady state (Vss), as data permit
Time frame: Day 1: 15 minutes pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period
Plasma concentrations and selected PK parameters of GSK1322322/moxifloxacin
To characterize the PK/pharmacodynamics (PD) relationship between GSK1322322/moxifloxacin plasma concentrations (and other PK parameters, if appropriate) and QTcF, QTcF changes relative to placebo (ddQTcF) , QTcB, and QTci
Time frame: Day 1: 15 minutes pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose (Day 2) of each treatment period
Safety and tolerability of GSK1322322 as assessed by change from baseline in 12-lead ECGs
Single 12-lead ECGs will be obtained
Time frame: Screening, Day 1 (pre-dose (x3) [mean value as baseline] and 0.5, 1, 1.5, 4, 8, 12 hours post-dose) of each treatment period, and Week 9
Safety and tolerability of GSK1322322 as assessed by change from baseline in vital signs
Vital sign measurements will include systolic and diastolic blood pressure, temperature and HR
Time frame: Screening, Day 1 (pre-dose (x3) [mean value as baseline] and 0.5, 1, 1.5, 4, 8, 12 hours post-dose) of each treatment period, and Week 9
Safety and tolerability of GSK1322322 as assessed by number of subjects with adverse events
Time frame: Through 9 weeks
Safety and tolerability of GSK1322322 as assessed by change from baseline in toxicity grading of clinical laboratory tests
Clinical laboratory tests will include clinical Chemistry, hematology and urinalysis assessments
Time frame: Through 9 weeks
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