Cardiac Conduction and Repolarization
Conditions
Keywords
Custirsen sodium, TV1011, OGX-011, Thorough QT study, cancer
Brief summary
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.
Detailed description
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.
Interventions
DRUGCustirsen
Custirsen will be administered iv using an infusion pump over a 2-hour period.
DRUGPlacebo
Placebo (commercially available normal saline) will be administered iv using an infusion pump over a 2-hour period.
DRUGMoxifloxacin
Moxifloxacin (400 mg) will be administered orally with 240 mL of room temperature still water.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Achieve Life Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. The subject is a man aged 18 through 45 years of age with a body mass index (BMI) of 18 through 30 kg/m2 at screening. 2. The subject is in good health as determined by medical history, ECG, vital signs measurements, physical examination, and clinical laboratory tests. 3. The subject must be able to understand and comply with the requirements of the study (eg, all medication, dietary, exercise, tobacco, and alcohol restrictions). 4. The subject must provide written informed consent to participate in the study after reading the information and consent form, and after having an opportunity to discuss the study with the investigator or delegate. 5. Other inclusion criteria apply.
Exclusion criteria
1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Individually-corrected QT interval (QTcI) | Up to 23.5 hours after the start of study drug infusion on Day 7 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Heart rate, PR interval, QRS interval and uncorrected QT interval | Up to 23.5 hours after study drug infusion on Day 7 | 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. |
| ECG morphological patterns | Up to 23.5 hours after study drug infusion on Day 7 | 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. |
| QTc (QTcI and QTcF) Intervals | Up to 23.5 hours after study drug infusion on Day 7 | 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. |
| Assay sensitivity | Up to 23.5 hours after study drug infusion on Day 7 | 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. |
| Maximum observed plasma concentration (Cmax) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Time to maximum observed plasma concentration (Tmax) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Area under the plasma concentration-time curve (AUC0-t) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Fridericia-corrected QT interval (QTcF) | Up to 23.5 hours after study drug infusion on Day 7 | 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 |
| Percentage of AUC0-∞ due to extrapolation from the time of last measurable concentration to infinity | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Area under the curve from time 0 to 24 hours (AUC0-24) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Terminal elimination rate constant (kel) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Apparent terminal half life (t½) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Apparent volume of distribution (Vz) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Apparent total body clearance (CL) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
| Occurrence of Adverse Events | From signing of the informed consent through the Follow-up Visit (approximately 17 days) | — |
| Area under the curve from time 0 to infinity (AUC0-∞) | From Day 1 through the Follow-up Visit (approximately Day 17) | — |
Countries
United States
Outcome results
None listed