This is a 3-arm, parallel-group, active- and placebo-controlled, double-blind, randomized study, to compare treatment with intravenous custirsen at 640 mg (highest intended therapeutic dose) with placebo. The purpose of this study is to assess the effect of custirsen treatment on cardiac conduction and repolarization (electrical activity of the heart) in healthy subjects. The positive control employed to demonstrate assay sensitivity consists of a group receiving a single oral dose of 400 mg moxifloxacin on day 7. The moxifloxacin arm is un-blinded but the ECG readings are blinded.
The effects of custirsen will be evaluated following administration of a single dose following dose-titration period combined with dexamethasone pretreatment. On days -1 and 7, subjects will undergo a full ECG assessment for 24 hours. On day 1, randomization and assignment to the treatment groups will be performed prior to drug administration. Subjects will remain in the study center throughout the treatment period. All subjects will be discharged at the end of day 8 procedures, 24 hours after the last dose of custirsen has been administered. Subjects in groups 1 and 2 will return for an additional visit on day 9, 10 and 14 (±2 days) (approximately 7 days after the last study drug administration). Subjects in group 3 will not return for a follow-up visits.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
155
Custirsen will be administered iv using an infusion pump over a 2-hour period.
Placebo (commercially available normal saline) will be administered iv using an infusion pump over a 2-hour period.
Moxifloxacin (400 mg) will be administered orally with 240 mL of room temperature still water.
Teva Investigational Site 10565
Lenexa, Kansas, United States
Individually-corrected QT interval (QTcI)
The primary ECG variable and endpoint for this study is the time-matched change from baseline in QTcI method on day 7 at each time point. Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.
Time frame: Up to 23.5 hours after the start of study drug infusion on Day 7
Fridericia-corrected QT interval (QTcF)
QTcF time-matched change from baseline on day 7 at the following time points: 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours
Time frame: Up to 23.5 hours after study drug infusion on Day 7
Heart rate, PR interval, QRS interval and uncorrected QT interval
Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.
Time frame: Up to 23.5 hours after study drug infusion on Day 7
ECG morphological patterns
Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.
Time frame: Up to 23.5 hours after study drug infusion on Day 7
QTc (QTcI and QTcF) Intervals
The relationship between the placebo-corrected QTc (QTcI and QTcF) change from baseline and plasma concentrations of custirsen (pharmacokinetic/pharmacodynamic analysis). Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.
Time frame: Up to 23.5 hours after study drug infusion on Day 7
Assay sensitivity
A comparison between the active control, moxifloxacin (400 mg), and placebo will also be performed to demonstrate assay sensitivity as required by current regulatory guidance. Holter ECGs will be performed at baseline (day -1) and prior to the start of infusion on day 7 and 1, 2 (end of infusion), 2.5, 3, 4, 5, 6, 8, 12, 16, 20, and 23.5 hours after the start of infusion.
Time frame: Up to 23.5 hours after study drug infusion on Day 7
Maximum observed plasma concentration (Cmax)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Time to maximum observed plasma concentration (Tmax)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Area under the plasma concentration-time curve (AUC0-t)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Area under the curve from time 0 to infinity (AUC0-∞)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Percentage of AUC0-∞ due to extrapolation from the time of last measurable concentration to infinity
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Area under the curve from time 0 to 24 hours (AUC0-24)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Terminal elimination rate constant (kel)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Apparent terminal half life (t½)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Apparent volume of distribution (Vz)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Apparent total body clearance (CL)
Time frame: From Day 1 through the Follow-up Visit (approximately Day 17)
Occurrence of Adverse Events
Time frame: From signing of the informed consent through the Follow-up Visit (approximately 17 days)
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