Study of LQT-1213 on Dofetilide-Induced QTc Prolongation in Healthy Adult Subjects and Patients Diagnosed With Type 2 or 3 Long QT Syndrome

Sponsor

Thryv Therapeutics, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT05906732

Collaborator

(none)

Enrollment

Location

Arms

8.9

Anticipated Duration (Months)

3.2

Patients Per Site Per Month

Study Details

Study Description

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 patients diagnosed with LQT-2 and LQT-3 will undergo a one day, single blind run-in period followed by repeat doses of LQT-1213.

Condition or Disease	Intervention/Treatment	Phase
Long QT Syndrome	Drug: LQT-1213 Drug: Placebo Drug: Dofetilide 250 μg Cap	Phase 1/Phase 2

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).

Study Design

Study Type:

Interventional

Anticipated Enrollment :

28 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 8, 2023

Anticipated Primary Completion Date :

Dec 3, 2023

Anticipated Study Completion Date :

Dec 3, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: 500 μg of Dofetilide BID in combination with dose-escalating LQT-1213 TID, both orally Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and LQT-1213 3 times a day (TID) low dose (Days 3 and 4), mid dose (Days 5 and 6), and high dose (not to exceed 0.747 mg/kg TID, daily dose 2.24 mg/kg/day) on Days 7 and 8. The specific doses will be determined before administration of the first dose of LQT-1213, but the high dose will not exceed 0.747 mg/kg TID or 2.24 mg/kg/day. Only 1 dose of dofetilide and LQT-1213 will be administered on Day 8.	Drug: LQT-1213 LQT-1213 is a serum glucocorticoid regulated kinase 1 (SGK-1) inhibitor Drug: Dofetilide 250 μg Cap Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker
Placebo Comparator: Arm B: 500 μg of Dofetilide BID in combination with placebo Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and placebo matched to LQT-1213 TID (Days 3-8). Only 1 dose of dofetilide and placebo matched to LQT-1213 will be administered on Day 8.	Drug: Placebo Matching Placebo Drug: Dofetilide 250 μg Cap Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker

Arm

Intervention/Treatment

Experimental: Arm A: 500 μg of Dofetilide BID in combination with dose-escalating LQT-1213 TID, both orally

Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and LQT-1213 3 times a day (TID) low dose (Days 3 and 4), mid dose (Days 5 and 6), and high dose (not to exceed 0.747 mg/kg TID, daily dose 2.24 mg/kg/day) on Days 7 and 8. The specific doses will be determined before administration of the first dose of LQT-1213, but the high dose will not exceed 0.747 mg/kg TID or 2.24 mg/kg/day. Only 1 dose of dofetilide and LQT-1213 will be administered on Day 8.

Drug: LQT-1213

LQT-1213 is a serum glucocorticoid regulated kinase 1 (SGK-1) inhibitor

Drug: Dofetilide 250 μg Cap

Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker

Placebo Comparator: Arm B: 500 μg of Dofetilide BID in combination with placebo

Dofetilide 500 μg BID (2 × 250 μg capsules), orally (Days 1-8) and placebo matched to LQT-1213 TID (Days 3-8). Only 1 dose of dofetilide and placebo matched to LQT-1213 will be administered on Day 8.

Drug: Placebo

Matching Placebo

Drug: Dofetilide 250 μg Cap

Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker

Outcome Measures

Primary Outcome Measures

Part 1: Pharmacodynamics: by-time point analysis for QTc on LQT-1213 versus placebo [2, 2.5, 3, 3.5, and 4 hours after administration of study treatment.]
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) QTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment.

Secondary Outcome Measures

Part 1: Pharmacokinetic LQT-1213 AUC0-t [Day 8]
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration
Part 1: Pharmacokinetic Dofetilide AUC0-t [Day 8]
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable concentration
Part 1b: Pharmacokinetic LQT-1213 AUCtau [Day 8]
AUC from time 0 to 7.5 hours
Part 1: Pharmacokinetic Dofetilide AUCtau [Day 8]
AUC from time 0 to 12 hours
Part 1: Pharmacokinetic LQT-1213 Cmax [Day 8]
Maximum observed plasma drug concentration
Part 1: Pharmacokinetic Dofetilide Cmax [Day 8]
Maximum observed plasma drug concentration
Part 1: Pharmacokinetic LQT-1213 Tmax [Day 8]
Time to the maximum observed plasma concentration
Part 1: Pharmacokinetic Dofetilide Tmax [Day 8]
Time to the maximum observed plasma concentration
Part 1: Pharmacokinetic LQT-1213 t1/2 [Day 8]
Terminal half-life
Part 1: Pharmacokinetic Dofetilide t1/2 [Day 8]
Terminal half-life
Part 1: Safety incidence of adverse events (AEs) [up to day 17 of period 2]
Monitoring, including clinically significant ECG abnormalities

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Male and female subjects between 19 and 60 years of age (inclusive) at Screening
Not previously enrolled in a clinical study with LQT-1213
Normal general health
Body mass index within 18 to 32 kg/m 2 , inclusively at Screening
Female subjects of non-childbearing 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 notsurgically 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
Bilateral tubal occlusion
Vasectomized partner
Heterosexual abstinence

Male subjects and their partners must use highly effective methods of contraception (ie, condom and spermicide) for the entire duration of the study. Male subjects must continue to use contraception and refrain from fathering a child and sperm donation for 90 days after the last administration of study drug. Acceptable methods of contraception for male subjects enrolled in the study include the following:

Condoms and spermicide
Surgical sterilization (vasectomy) of the subject at least 26 weeks before Screening
Heterosexual abstinence (subject must agree to use condom and spermicide if they become sexually active)

Understand the requirements of the study and voluntarily consent to participate in the study.

Exclusion Criteria:

On Day 1 of the first cycle of dofetilide at 3 hours post dose, the QTcF on the triplicate ECGs will be measured semiautomatically and 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 the 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, non-sustained 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.
From Screening through pre-dose on Day 1, any 12-lead ECG demonstrating any of the following: PR >220 ms; QRS >110 ms, or QTcF <390 ms and >440 ms; second- or third-degree atrioventricular block; branch bundle block, significant ST-Twave abnormalities or flat T waves that could interfere with QT analysis. Heart rate<50 or

85 bpm.

Known sensitivity to kinase inhibitors.
Abnormal renal function with an estimated glomerular filtration rate (eGFR) of<70 mL/min/1.73 m 2 *eGFR calculated by the Chronic Kidney DiseaseEpidemiology Collaboration [CKD-EPI] formula at Screening. One retest of the exclusionary eGFR value is allowed at the discretion of the investigator.
Subject has abnormal liver function tests (transaminases or total bilirubin) greater than 2.5 × the upper limit of normal at Screening or baseline. One retest of exclusionary abnormal liver function tests is allowed at the discretion of the investigator.
Subject has a positive serology test for HIV antibodies, hepatitis B surface antigen, or hepatitis C virus antibody at Screening.
Subject has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, magnesium<1.9 mg/dL, or calcium <8.5 mg/dL at Screening or baseline. One retest of exclusionary hemoglobin, potassium, magnesium, and calcium is allowed at the discretion of the investigator.
Subject has a history of hypersensitivity to drugs with a clinically significant reactionor any clinically significant hypersensitivities.
Subject has an allergy to band aids, adhesive dressing, or medical tape.
Subject has a history within the past 2 months of strenuous exercise (e.g., marathon running) and is unwilling to refrain from strenuous exercise from 7 days beforeCheck-in and until the end of the study. Subject has abnormal creatine phosphokinase test greater than 3 × the upper limit of normal at Screening and baseline. One retest of exclusionary abnormal creatine phosphokinase tests is allowed at the discretion of the investigator.
Subject is unable to refrain from or anticipates the use of any drug, including prescription and nonprescription medications (with the exception of hormonal contraception), herbal remedies, or vitamin supplements beginning 14 days before the first dose and until the end of the study. After dosing, acetaminophen (up to 2 g per 24 hours) may be administered at the discretion of the investigator or designee.
Hepatic or renal clearance altering agents within 30 days before the first dose and until the end of the study.
Avoid vaccinations from Screening until the end of the study.
Has consumed cruciferous vegetables (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, and mustard greens) or charbroiled meats within 7 days before Day -2 through the Follow-up Visit.
Use of any drugs known to be significant strong inducers of cytochrome P450(CYP) 3A enzymes, including St. John's Wort, for 28 days before Day -1or 5 half-lives (whichever is longer) and through the Follow-up Visit.
Has consumed Seville oranges, grapefruit and/or grapefruit juice within 14 days before Check-in and is unwilling to abstain from consuming these items until the end of the study.
Subject is considering or scheduled to undergo any surgical procedure during the study.
Subject has experienced an acute illness that has resolved in less than 14 days before the first study drug dose or has had a major illness or hospitalization within 1 month before the first study drug dose.
Subject is unwilling to abstain from ingestion of caffeine- or xanthine-containing products (eg, tea, coffee, chocolate, cola, etc.) beginning 96 hours before Check-in until the final PK sample of each study period has been collected.
Subject is unwilling to abstain from alcohol beginning 48 hours before Check-in and until the final PK sample of each study period has been collected.
Subject has a history of high alcohol consumption within 9 months before Screening, defined as an average weekly intake of >14 units for males or >10 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 mL) of beer, 1 glass(125 mL) of wine, or 1 measure (25 mL) of spirits.
Subject has a history of drug abuse in the 3 years before Screening or positive screen for drugs of abuse or alcohol at Screening or baseline. Subjects may undergo a repeat urine drug screen at the discretion of the investigator.
Subject uses or has used tobacco-or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 6 months before Screening and is unwilling to abstain from tobacco-containing products until the end of the study, based on subject self-reporting.
Subject, who, for any reason, is deemed by the investigator to be inappropriate for this study or has any condition which would confound or interfere with the evaluation of the safety, tolerability, or PK of the investigational drug or prevent compliance with the study protocol.