A Phase 1b/2a, 2-Part Study; Part 1: Randomized, Double-Blind, Crossover, Dose-Escalation, Placebo-Controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SGK-1 Kinase Inhibition by LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects. Part 2: Single-Blind, Multiple-Dose, Safety Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of LQT-1213 in Patients Diagnosed With Type 2 or 3 Long QT Syndrome
Overview
- Phase
- Phase 1
- Intervention
- Placebo
- Conditions
- Long QT Syndrome
- Sponsor
- Thryv Therapeutics, Inc.
- Enrollment
- 42
- Locations
- 1
- Primary Endpoint
- Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
- Status
- Terminated
- Last Updated
- 9 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male and female subjects between 18 and 60 years of age (inclusive) at Screening.
- •Not previously enrolled in a clinical study with LQT-
- •Normal general health.
- •Body mass index within 18.0 to 32.0 kg/m2, inclusively at Screening.
- •Female subjects of nonchildbearing potential must be either surgically sterile (hysterectomy, bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with follicle-stimulating hormone in the postmenopausal range at Screening, based on the central laboratory's ranges.
- •Female subjects of childbearing potential (ie, ovulating, premenopausal, and not surgically sterile) must use a highly effective contraceptive regimen during their participation in the study and for 30 days after the last administration of study drug. Highly effective contraceptive methods are defined as those with \<1% failure rate per year. Acceptable methods of contraception for female subjects enrolled in the study include the following:
- •Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal
- •Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable
- •Intrauterine device
- •Intrauterine hormone-releasing system
Exclusion Criteria
- •On Day 1 at 3 hours postdose in Period 1 only, of the first cycle of dofetilide, the QTcF on the triplicate ECGs will be manually confirmed by cardiologist experienced in ECG interval measurements. The ECG measurements at baseline and at the 3-hour time points will be performed by the same technician and cardiologist. If the mean QTcF increase from baseline is \<25 ms on triplicate safety ECGs compared to the mean from baseline (all ECG QTcF measurements averaged), the subject will be disqualified from further study participation.
- •Clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease or any other condition, which, in the opinion of the investigator, would jeopardize the safety of the subject or impact the validity of the study results. No history of myocardial infarction or angina or ischemic heart disease, nonsustained or sustained ventricular tachycardia, atrial fibrillation, stroke, transient ischemic attack, syncope, congestive heart failure, family history of LQTS, Torsades de Pointes, or sudden cardiac death.
- •Female subjects must not be pregnant, lactating, or breastfeeding, and must not be planning to become pregnant.
- •Female subjects of childbearing potential must have a negative result for the serum pregnancy test at Screening and Check-in.
- •Clinically significant abnormal findings on the physical examination or medical history during Screening as deemed by the investigator.
- •Participated in a previous clinical study in the previous 3 months before dosing.
- •Donation of blood volume greater than 300 mL within 30 days before Screening and agree to avoid donation from Screening and throughout the study.
- •At Screening and on Day -2, if the 12-lead ECG demonstrates any of the following: PR \>240 ms; QRS \>110 ms, or QTcF \<400 ms and \>440 ms; second- or third-degree atrioventricular block; bundle branch block, significant ST-T wave abnormalities or flat T waves that could interfere with QT analysis. If HR \<50 or \>85 bpm, then 2 more ECGs will be recorded, and the mean values will be used.
- •Known sensitivity to kinase inhibitors.
- •Abnormal renal function with an estimated glomerular filtration rate (eGFR) of \<70 mL/min/1.73 m2, with eGFR calculated by the Chronic Kidney Disease Epidemiology Collaboration \[CKD-EPI\] formula at Screening. One retest of the exclusionary eGFR value is allowed at the discretion of the investigator.
Arms & Interventions
Part 2: TID dosing of LQT-1213 16 mg (48 mg Daily)
LQT-1213 16 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.
Intervention: Placebo
Part 1: Arm A: Dofetilide with dose-escalating LQT-1213 TID followed by Dofetilide with placebo
Sequence A :Dofetilide 500 μg BID (Days 1-8) and LQT-1213 TID 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. After adequate washout, Dofetilide 500 μg BID (Days 1-8) and placebo (Days 3-8).
Intervention: LQT-1213
Part 1: Arm A: Dofetilide with dose-escalating LQT-1213 TID followed by Dofetilide with placebo
Sequence A :Dofetilide 500 μg BID (Days 1-8) and LQT-1213 TID 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. After adequate washout, Dofetilide 500 μg BID (Days 1-8) and placebo (Days 3-8).
Intervention: Placebo
Part 1: Arm A: Dofetilide with dose-escalating LQT-1213 TID followed by Dofetilide with placebo
Sequence A :Dofetilide 500 μg BID (Days 1-8) and LQT-1213 TID 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8. After adequate washout, Dofetilide 500 μg BID (Days 1-8) and placebo (Days 3-8).
Intervention: Dofetilide 250 μg Cap
Part 1: Arm B: Dofetilide with placebo followed by Dofetilide with LQT-1213 TID
Sequence B : Dofetilide 500 μg BID, orally (Days 1-8) and placebo TID (Days 3-8). After adequate washout, Dofetilide 500 μg BID, orally (Days 1-8) and LQT-1213 3 times a day (TID) 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8.
Intervention: LQT-1213
Part 1: Arm B: Dofetilide with placebo followed by Dofetilide with LQT-1213 TID
Sequence B : Dofetilide 500 μg BID, orally (Days 1-8) and placebo TID (Days 3-8). After adequate washout, Dofetilide 500 μg BID, orally (Days 1-8) and LQT-1213 3 times a day (TID) 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8.
Intervention: Placebo
Part 1: Arm B: Dofetilide with placebo followed by Dofetilide with LQT-1213 TID
Sequence B : Dofetilide 500 μg BID, orally (Days 1-8) and placebo TID (Days 3-8). After adequate washout, Dofetilide 500 μg BID, orally (Days 1-8) and LQT-1213 3 times a day (TID) 0.25 mg/kg (Days 3 and 4), 0.50 mg/kg (Days 5 and 6), and 0.70 mg/kg on Days 7 and 8.
Intervention: Dofetilide 250 μg Cap
Part 2: TID dosing of LQT-1213 16 mg (48 mg Daily)
LQT-1213 16 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.
Intervention: LQT-1213
Part 2: TID dosing of LQT-1213 7mg (21 mg Daily)
LQT-1213 7 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.
Intervention: LQT-1213
Part 2: TID dosing of LQT-1213 7mg (21 mg Daily)
LQT-1213 7 mg TID (at time 0, 8 and 16 hours) on Days 2-4, with a final single morning dose on Day 4. Day 1 was placebo.
Intervention: Placebo
Outcomes
Primary Outcomes
Part 1: Pharmacodynamics: By-time Point Analysis for QTc on LQT-1213 Versus Placebo
Time Frame: 4.0 hours after administration of study treatment on Day 8
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.
Part 2: Safety and Tolerability of Oral LQT-1213 in Participants With LQT-2 or LQT-3
Time Frame: up to day 12
The primary outcome is to measure the incidence of treatment emergent adverse events (TEAEs).
Secondary Outcomes
- Part 1: Pharmacokinetic LQT-1213 AUC0-t(0 to 24 hours post-dose on Day 8)
- Part 1: Pharmacokinetic Dofetilide AUC0-t(0 to 24 hours post-dose on Day 8)
- Part 1: Pharmacokinetic LQT-1213 AUCtau(Day 4,6, 8)
- Part 1: Pharmacokinetic Dofetilide AUCtau(Day 4,6,8)
- Part 1: Pharmacokinetic LQT-1213 Cmax(Day 4,6,8)
- Part 1: Pharmacokinetic Dofetilide Cmax(Day 4,6, 8)
- Part 1: Pharmacokinetic LQT-1213 Tmax(Day 4,6,8)
- Part 1: Pharmacokinetic Dofetilide Tmax(Day 4,6,8)
- Part 1: Pharmacokinetic LQT-1213 t1/2(Day 8)
- Part 1: Pharmacokinetic Dofetilide t1/2(Day 8)
- Part 1: Number of Treatment Emerging Adverse Events (TEAEs)(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(Day 4 Pre-dose up to 29 hours post-dose administration)
- Part 2: Pharmacokinetic LQT-1213 AUCtau(day 2 and day 4)
- Part 2: Pharmacokinetic LQT-1213 Cmax(day 2 and day 4)
- Part 2: Pharmacokinetic LQT-1213 Tmax(Day 2 and Day 4)
- Part 2: Pharmacokinetic LQT-1213 t1/2(Day 4)