Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block

Five Period Crossover Study of the Ability of Late Sodium or Calcium Current Block (Mexiletine, Lidocaine, or Diltiazem) to Balance the Electrocardiographic Effects of hERG Potassium Current Block (Dofetilide or Moxifloxacin)

The primary objective of this research study is to test the hypothesis that late sodium current blocking drugs (mexiletine or lidocaine) can attenuate the effect of hERG potassium channel blocking drugs (dofetilide) on ventricular repolarization (QTc) by shortening early repolarization (J-Tpeakc). The secondary object is to assess the ability of calcium channel block (diltiazem) to reduce the QTc prolongation associated with hERG block (moxifloxacin).

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Pharmacodynamics; Drug-induced QT Prolongation
• Intervention / Treatment: Drug: Dofetilide; Drug: Mexiletine; Drug: Lidocaine; Drug: Moxifloxacin; Drug: Diltiazem; Drug: Placebo

Detailed Description

This is a randomized, double-blind, 5-period crossover study in healthy male and female subjects, 18 to 35 years of age, to compare the electrophysiological response of hERG potassium channel blocking drugs with and without the addition of late sodium or calcium channel blocking drugs. The 5 treatment periods are 1) dofetilide alone, 2) mexiletine with and without dofetilide, 3) lidocaine with and without dofetilide, 4) moxifloxacin with and without diltiazem and 5) placebo. During each treatment period, 12 blood samples for pharmacokinetic measurements are obtained with matched 12-lead ECG recordings.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 33 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at least 50 kg (110 pounds), no more than 85 kg (197 pounds) and has a body mass index of 18 to 27 kg/m2, inclusive, at Screening.
2. Subject has normal medical history findings, clinical laboratory results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening or, if abnormal, the abnormality is not considered clinically significant (as determined and documented by the investigator or designee).
3. Male or female subjects must agree to practice 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique) from Screening until 30 days after the last dose of study drug.

Exclusion Criteria:

• 1. Subject has a 12 lead safety ECG result at Screening or Check in of Period 1 with evidence of any of the following abnormalities:

  • QT corrected interval (QTc) using Fridericia correction (QTcF) >430 milliseconds (ms)
  • PR interval >220 ms or <120 ms
  • QRS duration >110 ms
  • Second- or third-degree atrioventricular block
  • Complete left or right bundle branch block or incomplete right bundle branch block
  • Heart rate <50 or >90 beats per minute
  • Pathological Q-waves (defined as Q wave >40 ms)

  • Ventricular pre-excitation

    2. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.

    3. Subject has a history of unexplained syncope, structural heart disease, long QT syndrome, heart failure, myocardial infarction, angina, unexplained cardiac arrhythmia, torsades de pointes, ventricular tachycardia, or placement of a pacemaker or implantable defibrillator. Subjects will also be excluded if there is a family history of long QT syndrome (genetically proven or suggested by sudden death of a close relative due to cardiac causes at a young age) or Brugada syndrome.

    4. Subject has a history or current evidence of any clinically significant (as determined by the investigator) cardiovascular, dermatologic, endocrine, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurologic, psychiatric, pulmonary, renal, urologic, and/or other major disease or malignancy (excluding nonmelanoma skin cancer). The investigator may allow exceptions to these criteria (e.g., stable mild joint disease [that will not interfere with or influence the activities required by the protocol, in the opinion of the investigator], cholecystectomy, childhood asthma) following discussion with the medical monitor.

    5. Subject has a history of thoracic surgery.

    6. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).

    7. Subject has a skin condition likely to compromise ECG electrode placement.

    8. Subject is a female with breast implants.

    9. Subject's laboratory test results at Screening or Check in of Period 1 are outside the reference ranges provided by the clinical laboratory and considered clinically significant (as determined and documented by the investigator or designee).

    10. Subject's laboratory test results at Screening or Check in of Period 1 indicate hypokalemia, hypocalcemia, or hypomagnesemia according to lower limits of the reference ranges provided by the clinical laboratory.

    11. Subject's laboratory test results at Screening or Check in of Period 1 are >2 × the upper limit of normal (ULN) for alanine aminotransferase or aspartate aminotransferase, >1.5 × ULN for bilirubin, or >1.5 × ULN for creatinine.

    12. Subject has a positive test result at Screening for human immunodeficiency virus, hepatitis C antibodies, or hepatitis B surface antigen.

    13. Subject has a mean systolic blood pressure <90 or >140 mmHg or a mean diastolic blood pressure <50 or >90 mmHg at either Screening or Check in of Period 1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dofetilide; Dofetilide alone arm	Drug: Dofetilide; 8 am: Placebo; 12 pm (noon): 250 µg; 5:30 pm: 250 µg; Other Names: Tikosyn
Active Comparator: Dofetilide + Mexiletine; Dofetilide combined with mexiletine	Drug: Dofetilide; 8 am: Placebo; 12 pm (noon): 250 µg; 5:30 pm: 250 µg; Other Names: Tikosyn; Drug: Mexiletine; 8 am: weight x 4 mg/kg; 12 pm (noon): Same as at 8 am; 5:30 pm: Same as at 8 am; Other Names: Mexitil
Active Comparator: Dofetilide + Lidocaine; Dofetilide combined with lidocaine	Drug: Dofetilide; 8 am: Placebo; 12 pm (noon): 250 µg; 5:30 pm: 250 µg; Other Names: Tikosyn; Drug: Lidocaine; 9 am : 30 µg/min per kg (loading) for 60 minutes and 10 µg/min per kg (maintenance) for 30 minutes; 2 pm: 55 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes; 7:30 pm: 52 µg/min per kg (loading) for 60 minutes and 20 µg/min per kg (maintenance) for 30 minutes; Other Names: Lidocaine hydrochloride
Active Comparator: Moxifloxacin + Diltiazem; Moxifloxacin with and without diltiazem.	Drug: Moxifloxacin; 9 am: 5.63 mg/h per kg (loading) for 1 hour and 0.26 mg/h per kg (maintenance for 30 minutes); 2 pm: 6.14 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes); 7:30 pm: 2.23 mg/h per kg (loading) for 1 hour and 0.49 mg/h per kg (maintenance for 30 minutes); Other Names: Avelox; Drug: Diltiazem; • 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes; Other Names: Diltiazem hydrochloride
Placebo Comparator: Placebo; Placebo (#2 gelcap and intravenous saline)	Drug: Placebo; Placebo (#2 Gelcap or IV saline); Other Names: #2 Gelcaps or IV saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Placebo Corrected Change From Baseline QTc and J-Tpeakc Intervals on the ECG Measured in Milliseconds When Dofetilide is Administered With Mexiletine or Lidocaine Compared to When Dofetilide is Administered Alone at Evening Dose on Treatment Day	After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.	5 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Placebo Corrected Change From Baseline QTc Interval on the ECG Measured in Milliseconds When Moxifloxacin is Administered With Diltiazem at the Evening Dose Compared to When Moxifloxacin is Administered Alone at Afternoon Dose on Treatment Day.	Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).	5 weeks

Collaborators and Investigators

• Sponsor: Food and Drug Administration (FDA)
• Collaborators: Spaulding Clinical Research LLC
• Investigators: Principal Investigator: Carlos Sanabria, MD, Spaulding Clinical

Publications and helpful links

General Publications

• Vicente J, Johannesen L, Hosseini M, Mason JW, Sager PT, Pueyo E, Strauss DG. Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block. PLoS One. 2016 Dec 30;11(12):e0163619. doi: 10.1371/journal.pone.0163619. eCollection 2016. Erratum In: PLoS One. 2018 May 21;13(5):e0197952.
• Johannesen L, Vicente J, Hosseini M, Strauss DG. Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk. PLoS One. 2016 Dec 30;11(12):e0166925. doi: 10.1371/journal.pone.0166925. eCollection 2016.
• Johannesen L, Vicente J, Mason JW, Erato C, Sanabria C, Waite-Labott K, Hong M, Lin J, Guo P, Mutlib A, Wang J, Crumb WJ, Blinova K, Chan D, Stohlman J, Florian J, Ugander M, Stockbridge N, Strauss DG. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin Pharmacol Ther. 2016 Feb;99(2):214-23. doi: 10.1002/cpt.205. Epub 2015 Nov 28.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: November 6, 2014
• First Submitted That Met QC Criteria: December 1, 2014
• First Posted (Estimate): December 4, 2014

Study Record Updates

• Last Update Posted (Estimate): June 8, 2016
• Last Update Submitted That Met QC Criteria: June 6, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Long QT Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Potassium Channel Blockers; Lidocaine; Moxifloxacin; Mexiletine; Diltiazem; Dofetilide
• Other Study ID Numbers: 14-022D; SCR-003 (Other Identifier: Spaulding Clinical Research)