Part 1: This is a Phase 1b, randomized, double-blind, crossover, dose escalation, placebo-controlled study to evaluate the effect of oral LQT-1213 on dofetilide-induced QTc prolongation in healthy adult subjects. This is a 2-treatment, 2-period crossover study with approximately up to 28 healthy subjects, with screening procedures within 28 days of enrolment. Part 2: This is a Phase 2a, single-blind, placebo run-in, multiple-dose safety study to evaluate the safety, tolerability, and PK of LQT-1213 in patients diagnosed with LQT2 or LQT3. Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be recruited.
Part 1: This is a 2-treatment, 2-period crossover study. Approximately 28 healthy subjects, with the attempt to balance for sexes, will be enrolled to complete approximately up to 20 subjects in the study. In both treatment periods, all subjects will receive dofetilide on Days 1 and 2 of each period. Randomization will take place before Day 3 of Period 1. Subjects will be randomly assigned to 1 of 2 treatment sequences (AB or BA). Part 2: Up to 12 participants with LQT2 and up to 12 participants with LQT3 will be enrolled. After initial screening, which may be conducted remotely by the CRU, individual participants with LQT2 or LQT3 will undergo a 1-day, single-blind placebo run-in period followed by 3 dosing days of LQT-1213 administered TID (the last dosing day will have a single dose). Participants will be discharged from the CRU on Day 5. Approximately 7 days after discharge from the CRU, the Follow-up Visit will be conducted remotely via telephone call.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
42
Spaulding Clinical Research, LLC
West Bend, Wisconsin, United States
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.0 hours after administration of study treatment on Day 4.
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.5 hours after administration of study treatment on Day 4
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.0 hours after administration of study treatment on Day 4
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.5 hours after administration of study treatment on Day 4
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 4.0 hours after administration of study treatment on Day 4
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.0 hours after administration of study treatment on Day 6
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.5 hours after administration of study treatment on Day 6
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.0 hours after administration of study treatment on Day 6
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.5 hours after administration of study treatment on Day 6
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 4.0 hours after administration of study treatment on Day 6
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.0 hours after administration of study treatment on Day 8
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 2.5 hours after administration of study treatment on Day 8
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.0 hours after administration of study treatment on Day 8
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 3.5 hours after administration of study treatment on Day 8
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
The primary outcome is time-based comparison in the change from baseline (baseline defined as Day 1 of Period 1 and Day 1 of Period 2 mean predose QTc) ΔΔQTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.
Time frame: 4.0 hours after administration of study treatment on Day 8
Part 2: Safety and Tolerability of Oral LQT-1213 in Participants With LQT-2 or LQT-3
The primary outcome is to measure the incidence of treatment emergent adverse events (TEAEs).
Time frame: up to day 12
Part 1: Pharmacokinetic LQT-1213 AUC0-t
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration
Time frame: 0 to 24 hours post-dose on Day 8
Part 1: Pharmacokinetic Dofetilide AUC0-t
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration
Time frame: 0 to 24 hours post-dose on Day 8
Part 1: Pharmacokinetic LQT-1213 AUCtau
AUCtau = Area under the curve from time 0 to 8.0 hours
Time frame: Day 4,6, 8
Part 1: Pharmacokinetic Dofetilide AUCtau
AUCtau = Area under the curve from time 0 to 12 hours
Time frame: Day 4,6,8
Part 1: Pharmacokinetic LQT-1213 Cmax
Maximum observed plasma drug concentration
Time frame: Day 4,6,8
Part 1: Pharmacokinetic Dofetilide Cmax
Maximum observed plasma drug concentration
Time frame: Day 4,6, 8
Part 1: Pharmacokinetic LQT-1213 Tmax
Time to the maximum observed plasma concentration
Time frame: Day 4,6,8
Part 1: Pharmacokinetic Dofetilide Tmax
Time to the maximum observed plasma concentration
Time frame: Day 4,6,8
Part 1: Pharmacokinetic LQT-1213 t1/2
Terminal half-life
Time frame: Day 8
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Part 1: Pharmacokinetic Dofetilide t1/2
Terminal half-life
Time frame: Day 8
Part 1: Number of Treatment Emerging Adverse Events (TEAEs)
Part 1: Number of Treatment Emerging Adverse Events (TEAEs) that occurred following administration of dofetilide Day1 up to Day 10 period 1 and in period 2 from Day 1 to up to the follow-up visit at Day 17.
Time frame: Period 1 from Day 1 to Day 10 and Period 2 from Day 1 up to Day 17.
Part 2: Pharmacokinetic LQT-1213 AUC0-t
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration
Time frame: Day 4 Pre-dose up to 29 hours post-dose administration
Part 2: Pharmacokinetic LQT-1213 AUCtau
Pharmacokinetic LQT-1213 AUCtau (time 0 to 8 hours)
Time frame: day 2 and day 4
Part 2: Pharmacokinetic LQT-1213 Cmax
Maximum observed plasma drug concentration
Time frame: day 2 and day 4
Part 2: Pharmacokinetic LQT-1213 Tmax
Time to the maximum observed plasma concentration
Time frame: Day 2 and Day 4
Part 2: Pharmacokinetic LQT-1213 t1/2
Part 2: Pharmacokinetic LQT-1213 terminal half-life t1/2
Time frame: Day 4