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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.
Full 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.
Enrollment
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Volunteers
Inclusion criteria
Part1:
Male and female subjects between 18 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 18.0 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:
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:
Understand the requirements of the study and voluntarily consent to participate in the study.
Part 2:
Male and female participants 18 years of age or older at Screening.
Body weight of at least 45 kg 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:
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:
LQT2 or LQT3 mutation:
QTcF interval ≥480 and ≤560 ms determined at Screening and on Day -1 triplicate ECGs as assessed by a physician trained in complex ECG interpretation.
The first 2 participants with LQT2 require having an ICD before further participants with LQT2 are enrolled and the first 2 participants with LQT3 require having an ICD before further participants with LQT3 are enrolled. This stipulation may be altered based on agreement between the principal investigator and Sponsor based on emerging data. 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 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.
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. Electrolyte supplementation is allowed at any time as long as it is >4 hours before dosing.
Subject has a history of hypersensitivity to drugs with a clinically significant reaction or 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 (eg, marathon running) and is unwilling to refrain from strenuous exercise from 7 days before Check-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 preparations, 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.
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 the study has been collected.
Subject is unwilling to abstain from alcohol beginning 48 hours before Check-in and until the final PK sample of the study 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 principal investigator.
Currently participating in another interventional clinical study.
Donation of blood volume greater than 300 mL within 30 days before dosing 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 triplicate 12-lead ECG demonstrates any of the following: mean PR >250ms; 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 <45 bpm, unless receiving a beta-blocker in which case <40 bpm, or HR >95 bpm. If any of these exclusionary criteria are met, then a second set of triplicate ECGs may be acquired, and the mean values may be used. For participants on beta blockade, the PR interval may be higher than 250 ms with sponsor and investigator approval.
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 or clinically significant drug allergies to any of the components of LQT-1213.
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 × the upper limit of normal [ULN] or total bilirubin > 1.5 × ULN. If the participant has documented Gilbert's Syndrome, participation is at the combined principal investigator and Sponsor's discretion after review of historical liver and bilirubin tests.
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 a clinically significant allergy to band aids, adhesive dressing, ECG electrodes, or medical tape.
Participant has abnormal creatine phosphokinase test greater than 3 × the ULN 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 except beta-blockers which are allowed,) or drugs known to affect the QT interval (including ranolazine; refer to drug lists for "Drugs with known, possible, or conditional risk of TdP" that are known to prolong the QT interval at https://crediblemeds.org), unless approved by the sponsor and principal investigator.
Participant is not permitted to use/consume the following:
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, 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.
Primary purpose
Allocation
Interventional model
Masking
42 participants in 4 patient groups
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Central trial contact
Doug Wight
Data sourced from clinicaltrials.gov
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