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

• Status: Active, not recruiting
• Trial end date: 2023-12-03
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Thryv Therapeutics, Inc.
• Treatments: Dofetilide

Criteria

Inclusion Criteria:

1. Male and female subjects between 19 and 60 years of age (inclusive) at Screening

2. Not previously enrolled in a clinical study with LQT-1213

3. Normal general health

4. Body mass index within 18 to 32 kg/m 2 , inclusively at Screening

5. 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.

6. 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

7. 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)

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

Exclusion Criteria:

1. 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.

2. 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.

3. Female subjects must not be pregnant, lactating, or breastfeeding, and must not be planning to become pregnant.

4. Female subjects of childbearing potential must have a negative result for the serum pregnancy test at Screening and Check-in.

5. Clinically significant abnormal findings on the physical examination or medical history during Screening as deemed by the investigator.

6. Participated in a previous clinical study in the previous 3 months before dosing.

7. Donation of blood volume greater than 300 mL within 30 days before Screening and agree to avoid donation from Screening and throughout the study.

8. 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.

9. Known sensitivity to kinase inhibitors.

10. 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.

11. 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.

12. Subject has a positive serology test for HIV antibodies, hepatitis B surface antigen, or hepatitis C virus antibody at Screening.

13. 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.

14. Subject has a history of hypersensitivity to drugs with a clinically significant reactionor any clinically significant hypersensitivities.

15. Subject has an allergy to band aids, adhesive dressing, or medical tape.

16. 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.

17. 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.

1. Hepatic or renal clearance altering agents within 30 days before the first dose and until the end of the study.

2. Avoid vaccinations from Screening until the end of the study.

3. 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.

4. 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.

5. 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.

18. Subject is considering or scheduled to undergo any surgical procedure during the study.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.