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

Phase 1

Completed

• Conditions: Pharmacokinetics; Pharmacodynamics; Drug-induced QT Prolongation
• Interventions: Drug: Dofetilide; Drug: Placebo; Drug: Moxifloxacin; Drug: Mexiletine; Drug: Lidocaine; Drug: Diltiazem

• Registration Number: NCT02308748
• Lead Sponsor: Food and Drug Administration (FDA)

Brief Summary

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).

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 Timeline

• Study Start: 2014-05
• Primary Completion: 2014-06
• Study Completion: 2014-06
• Study First Submitted: 2014-11-06
• Study First Submitted QC: 2014-12-01
• Study First Posted: 2014-12-04
• Results First Submitted: 2016-01-13
• Status Verified: 2016-06
• Results First Submitted QC: 2016-06-06
• Last Update Submitted: 2016-06-06
• Results First Posted: 2016-06-08
• Last Update Posted: 2016-06-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 22

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Dofetilide	Dofetilide	Dofetilide alone arm
Dofetilide + Mexiletine	Dofetilide	Dofetilide combined with mexiletine
Dofetilide + Mexiletine	Mexiletine	Dofetilide combined with mexiletine
Dofetilide + Lidocaine	Dofetilide	Dofetilide combined with lidocaine
Placebo	Placebo	Placebo (#2 gelcap and intravenous saline)
Dofetilide + Lidocaine	Lidocaine	Dofetilide combined with lidocaine
Moxifloxacin + Diltiazem	Moxifloxacin	Moxifloxacin with and without diltiazem.
Moxifloxacin + Diltiazem	Diltiazem	Moxifloxacin with and without diltiazem.

Primary Outcome Measures

Name	Time	Method
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	5 weeks	After 3rd dose of mexiletine or lidocaine (evening dose) on treatment day when combined with dofetilide to evening dose on dofetilide alone day.

Secondary Outcome Measures

Name	Time	Method
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.	5 weeks	Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).