This is a Phase I, single-center, double-blinded, randomized, placebo-controlled, five-period cross-over clinical study of PA-824 to evaluate the effect of PA-824 and of PA-824 plus moxifloxacin on cardiac repolarization (QT/QTc interval duration) in a total of 75 healthy male and female participants, aged 18 to 45 years. Moxifloxacin will be used as an active control. Participants will be blinded to the treatments they will receive. The study consists of a screening period up to 26 days; enrollment, 1 day; five in-patient treatment periods consisting of an admission day (except in the first treatment period, when the pre-dose day is the baseline), dosing day and two post-dosing days; an out-patient period of at least three days and not more than 10 days between treatment periods; and a final visit 7 - 14 days after discharge from the last treatment period.
This is a Phase I, single-center, double-blinded, randomized, placebo-controlled, five-period cross-over clinical study of PA-824 to evaluate the effect of PA-824 and of PA-824 plus moxifloxacin on cardiac repolarization (QT/QTc interval duration) in healthy male and female participants. Moxifloxacin will be used as an active control. Participants will be blinded to the treatments they will receive. The study consists of a screening period up to 26 days; enrollment, 1 day; five in-patient treatment periods consisting of an admission day (except in the first treatment period, when the pre-dose day is the baseline), dosing day and two post-dosing days; an out-patient period of at least three days and not more than 10 days between treatment periods; and a final visit 7 - 14 days after discharge from the last treatment period. During the study, the subjects will receive each one of the following five treatments: Treatment A: PA-824 placebo and moxifloxacin placebo; Treatment B: PA-824 400 mg plus moxifloxacin placebo; Treatment C: PA-824 1000 mg plus moxifloxacin placebo; Treatment D: PA-824 placebo plus moxifloxacin 400 mg; Treatment E: PA-824 400 mg plus moxifloxacin 400 mg. The primary objective is to evaluate the effect of single-dose administration of PA-824 400 mg and 1000 mg versus placebo on the QTcI interval. A total of 75 randomized (in order to have at least 60 evaluable) healthy male and female volunteers, aged 18 to 45 years will be enrolled.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
74
Moxifloxacin will be given orally to the following treatment groups, in combination with either PA-824 or PA-824 placebo: Treatment D: 400 mg + PA-824 placebo; Treatment E: 400 mg + PA-824 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.
PA-824 will be given orally to the following treatment groups, together with either moxifloxacin or moxifloxacin placebo: Treatment B: 400 mg + moxifloxacin placebo; Treatment C: 1000 mg + moxifloxacin placebo; Treatment E: 400 mg + moxifloxacin 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.
Placebo tablets to match Moxifloxacin or PA-824 will be given orally, in combination with either moxifloxacin or PA-824: Treatment A: PA-824 placebo + moxifloxacin placebo; Treatment B: PA-824 400 mg + moxifloxacin placebo; Treatment C: PA-824 1000 mg + moxifloxacin placebo Treatment D: PA-824 placebo + moxafloxacin 400 mg. Subjects will cross-over to the next Treatment Group after a 6-day washout period.
Quintiles Phase I Services - Overland Park
Overland Park, Kansas, United States
Effect of PA-824 on cardiac ventricular repolarization (CVR) as measured by QT interval corrected for heart rate using individual-specific formula (QTcI) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.
Time frame: 24 hours after dosing of PA-824
Effect of PA-824 on CVR measured by QT interval corrected for heart rate by group-specific formula (QTcN), Fridericia (QTcF) and Bazett (QTcB) formulae during the first 24 hours following dosing in healthy volunteers compared to placebo.
Time frame: 24 hours after dosing of PA-824
Effect of PA-824 plus moxifloxacin on CVR as measured by QT and QT corrected for heart rate (QTcI, QTcN, QTcF, and QTcB) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.
Time frame: 24 hours after dosing of PA-824
The effect of Moxifloxacin on CVR as measured by QTcI, QTcN, QTcF, and QTcB, HR and non-QTc ECG intervals (HR, and PR, QRS, and RR intervals) during the first 24 hours following dosing of PA-824 in healthy volunteers as compared to placebo.
Time frame: 24 hours after dosing of PA-824
Safety and tolerability evaluated by ophthalmology exam.
Time frame: Screening , Day -2 and Day 45
Analysis of the QTcI, QTcN, QTcF, QTcB, PR, QRS, and RR intervals and heart rate matched to PK sampling times to allow determination of any PK / pharmacodynamic effect of PA-824 alone and in combination with moxifloxacin.
Time frame: Day 1 of each treatment period at 0 h (pre-dose) and 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72(±4) and 96(±4) hrs (post-dose).
Safety and tolerability evaluated by standard 12-lead ECGs obtained pre-dose and 2, 4, 7 and 10 hrs post-dose on treatment days.
Time frame: ECGs: pre-dose, 2, 4, 7 & 10 hrs post dose.
Safety and tolerability evaluated by continuous AE monitoring throughout the study; physical exams, and laboratory evaluations
Time frame: Day 0 to Day 45
Serum pharmacokinetics (PK) of 400 mg and 1000 mg of PA-824 and of 400 mg of PA-824 plus 400 mg of moxifloxacin for up to 5 days following dosing.
Time frame: Day 1 of each treatment period at 0 h (pre-dose) and 0.25, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 48, 72(±4) and 96(±4) hrs (post-dose).
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