Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).

Study Overview
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Brief Summary
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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
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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 BID (the last dosing day will have a single dose). LQT-1213 will be administered BID on Days 2-4. 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.

Official Title
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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

Conditions
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Long QT Syndrome

Intervention / Treatment
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* Drug: LQT-1213
* Drug: Placebo
* Drug: Dofetilide 250 μg Cap


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part1: 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. Part 2: Male and female participants between 18 and 60 years of age (inclusive) at Screening. Not previously enrolled in a clinical study with LQT-1213. Body weight of at least 45 kg with body mass index within 18.0 and 35.0 kg/m 2 , inclusively at Screening. Female participants 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 (>40 mlU/mL) at Screening, based on the central laboratory's ranges. Female participants 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 participants 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 participants and their partners must use highly effective methods of contraception (ie, condom and spermicide) for the entire duration of the study. Male participants 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 participants enrolled in the study include the following: Condoms and spermicide Surgical sterilization (vasectomy) of the participant at least 26 weeks before Screening Heterosexual abstinence (participant must agree to use condom and spermicide if they become sexually active) LQT2 or LQT3 mutation: LQTS 2: Participants with potassium voltage-gated channel subfamily H member 2 (KCNH2) mutations that are dominant negative and considered to be pathologic or likely pathologic by the screening laboratory can be included after approval from the sponsor. Participants with haploinsufficiency will not be eligible for this study. LQTS 3: Participants with a sodium voltage-gated channel alpha subunit 5 (SCN5A) gene chromosome 3 mutations that are mutations and considered to be pathologic or likely pathologic by the screening laboratory can be included after approval from the sponsor. Participants with mutations not associated with Brugada syndrome or overlap syndromes or where mutations affect the window current or the persistent 'late' Na current to exert a primary or major role in the phenotype, will be eligible for this study. QTcF interval >480 and <560 ms. The first 2 participants with LQT2 require having an implantable cardioverter defibrillator (ICD) before further participants with LQT2 are enrolled and the first 2 participants with LQT3 require having an implantable cardioverter defibrillator (ICD) before further participants with LQT3 are enrolled. The ICD implantation must have been at least 2 months before Screening. Note: Subsequent participants may or may not have had an ICD. The results of the ICD interrogation within the last 6 months should be available for review unless waived by the investigator and sponsor. Understand the requirements of the study and voluntarily consent to participate in the study. Exclusion Criteria: Part 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. 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. Part 2: Clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or significant structural cardiovascular disease or any other condition beyond LQT2 or LQT3, which, in the opinion of the investigator or sponsor, would jeopardize the safety of the participant or impact the validity of the study results. History of myocardial infarction or ongoing angina or active ischemic heart disease, atrial fibrillation, stroke, or transient ischemic attack within the past 12 months, greater than New York Heart Association Class II congestive heart failure, bundle branch block, hemodynamically significant ventricular tachycardia not due to Torsades de Pointes, or Brugada syndrome. Participant has a history of an aborted cardiac arrest, ICD implantation, syncopal episode due to a ventricular arrhythmia or where confidence in the etiology cannot be established, or appropriate ICD therapy for ventricular tachycardia/ventricular fibrillation within 2 months before Screening. Participants with LQT2 or LQT3 can be enrolled after the 2-month time period has lapsed. Female participants must not be pregnant, lactating, or breastfeeding, and must not be planning to become pregnant. Female participants 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 at Check-in or medical history during Screening as deemed by the investigator. Currently participating in another interventional clinical study. Donation of blood volume greater than 300 mL within 30 days before Screening and unwilling to avoid donation from Screening and throughout the study. Screening diastolic blood pressure <45 or >95 mm Hg, systolic blood pressure <90 or >150 mm Hg, or with sponsor and investigator approval. At Screening and on Day -1, if the 12-lead ECG demonstrates any of the following: PR >250 ms; QRS >110 ms, or QTcF >560 ms and <480 ms; bundle branch block or significant ST-T wave abnormalities or flat T waves that could interfere with QT analysis. Heart rate <50 bpm, unless receiving a beta-blocker in which case <40 bpm, or HR >90 bpm. If any of these exclusionary criteria are met, then 2 more ECGs may be acquired, and the mean values may be used. Atrial pacing rate set to ≥80 bpm in those with atrial pacing. Participant has a pacemaker or ICD that is actively used for ventricular pacing. Known sensitivity to kinase inhibitors. Abnormal renal function with an eGFR of <60 mL/min/1.73 m2 , with eGFR calculated by the CKD-EPI formula at Screening. One retest of the exclusionary eGFR value is allowed at Screening and Check-in at the discretion of the investigator. Participant has abnormal liver function tests (transaminases greater than 2 × ULN or total bilirubin > 1.5 × the upper limit of normal at Screening or baseline). Participant has a positive serology test for HIV antibodies, hepatitis B surface antigen, or hepatitis C virus antibody at Screening. Participant has a hemoglobin <11.0 g/dL, potassium <3.8 mg/dL, magnesium <1.8 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. Participant has a history of hypersensitivity to drugs with a clinically significant reaction or any clinically significant hypersensitivities. Participant has clinically significant drug allergies to any of the components of LQT-1213. Participant has a clinically significant allergy to band aids, adhesive dressing, or medical tape. Participant has abnormal creatine phosphokinase test greater than 3 × the upper limit of normal at Screening or baseline. One retest of exclusionary abnormal creatine phosphokinase tests is allowed at the discretion of the investigator. Participant is currently taking, within the last 7 days before Spaulding admission or 5 half-lives (whichever is longer), or anticipates the use of any antiarrhythmic medications (including mexilitene), other than beta-blockers or drugs known to affect the QT interval (including ranolazine; refer to the drug lists for Drugs with known, possible, or conditional risk of TdP that are known to prolong the QT interval at https://crediblemeds.org)), and antacids, proton pump inhibitors, or histamine H2 receptor antagonists, unless approved by the sponsor and principal investigator. Participant is not permitted to use/consume the following: Cruciferous vegetables (eg, kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, and mustard greens) or charbroiled meats within 7 days before Check-in until the end of the study. Any drugs known to be significant strong inducers of CYP 3A enzymes, including St. John's Wort, for 28 days before Day -1 or 5 half-lives (whichever is longer) and through the Follow-up Visit. 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. Participant is considering or scheduled to undergo any surgical procedure during the study. Participant 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. Participant 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 the study has been collected. Participant is unwilling to abstain from alcohol beginning 48 hours before Check-in and until the final PK sample of the study has been collected. Participant has a history of high alcohol consumption or substance abuse that would pose a risk for the participant's safety and compliance with the study protocol. Participant must not have positive screen for drugs of abuse at Screening or baseline and alcohol at baseline, except with sponsor permission. Participants may undergo a repeat urine drug screen at the discretion of the investigator. Participant uses or has used tobacco-or nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, etc.) within 2 months before Screening and is unwilling to abstain from tobacco-containing products until the end of the study, based on participant self-reporting. Participant, 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.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Arm A: 500 μg of Dofetilide BID in combination with dose-escalating LQT-1213 TID, orally<br>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<br>* LQT-1213 is a serum glucocorticoid regulated kinase 1 (SGK-1) inhibitor<br>Drug: Dofetilide 250 μg Cap<br>* Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker<br>|
| Placebo Comparator: Part 1: Arm B: 500 μg of Dofetilide BID in combination with placebo<br>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<br>* Matching Placebo<br>Drug: Dofetilide 250 μg Cap<br>* Dofetilide is a potent, pure inward-rectifier potassium channels (IKr) blocker<br>|
| Experimental: Part 2: BID dosing of LQT-1213<br>LQT-1213 2.24 mg/kg/day BID (at time 0 and 11.5 hours) on Days 2-4, with a final single morning dose on Day 4 at time 0, though these time points may be adjusted based upon emerging data. | Drug: LQT-1213<br>* LQT-1213 is a serum glucocorticoid regulated kinase 1 (SGK-1) inhibitor<br>|
| Other: Part 2: BID dosing of Placebo<br>Placebo matched to LQT-1213 (Day 1) BID | Drug: Placebo<br>* Matching Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) QTc by Fridericia's formula (QTcF) during peak dofetilide exposure between dofetilide and placebo treatment, and the dofetilide and LQT-1213 treatment. | 2, 2.5, 3, 3.5, and 4 hours after administration of study treatment. | 
| Part 2: Safety and tolerability of oral LQT-1213 in participants with LQT-2 or LQT-3 | The primary outcome is to measure the safety incidence of adverse events (AEs) during exposure to the LQT-1213 treatment. | up to day 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | Day 8 | 
| Part 1b: Pharmacokinetic LQT-1213 AUCtau | AUC from time 0 to 7.5 hours | Day 8 | 
| Part 1: Pharmacokinetic Dofetilide AUCtau | AUC from time 0 to 12 hours | Day 8 | 
| Part 1: Pharmacokinetic LQT-1213 Cmax | Maximum observed plasma drug concentration | Day 8 | 
| Part 1: Pharmacokinetic Dofetilide Cmax | Maximum observed plasma drug concentration | Day 8 | 
| Part 1: Pharmacokinetic LQT-1213 Tmax | Time to the maximum observed plasma concentration | Day 8 | 
| Part 1: Pharmacokinetic Dofetilide Tmax | Time to the maximum observed plasma concentration | Day 8 | 
| Part 1: Pharmacokinetic LQT-1213 t1/2 | Terminal half-life | Day 8 | 
| Part 1: Pharmacokinetic Dofetilide t1/2 | Terminal half-life | Day 8 | 
| Part 1: Safety incidence of adverse events (AEs) | Monitoring, including clinically significant ECG abnormalities | up to day 17 of period 2 | 
| 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 | up to day 4 | 
| Part 2: Pharmacokinetic LQT-1213 AUCtau | AUC from time 0 to 12 hours | up to day 4 | 
| Part 2: Pharmacokinetic LQT-1213 Cmax | Maximum observed plasma drug concentration | up to day 4 | 
| Part 2: Pharmacokinetic LQT-1213 Tmax | Time to the maximum observed plasma concentration | up to day 4 | 
| Part 2: Pharmacokinetic LQT-1213 t1/2 | Terminal half-life | up to day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LQTS, LQT-1213, Congenital Long QT Syndrome, Serum glucocorticoid regulated kinase-1, SGK-1 inhibitor