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

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE1

Total Enrollment

22 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-05-31

Study Completion Date

2014-06-30

Brief Summary

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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).

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Detailed Description

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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.

Conditions

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Drug-induced QT Prolongation Pharmacokinetics Pharmacodynamics

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Dofetilide

Dofetilide alone arm

Group Type ACTIVE_COMPARATOR

Dofetilide

Intervention Type DRUG

* 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg

Dofetilide + Mexiletine

Dofetilide combined with mexiletine

Group Type ACTIVE_COMPARATOR

Dofetilide

Intervention Type DRUG

* 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg

Mexiletine

Intervention Type DRUG

* 8 am: weight x 4 mg/kg
* 12 pm (noon): Same as at 8 am
* 5:30 pm: Same as at 8 am

Dofetilide + Lidocaine

Dofetilide combined with lidocaine

Group Type ACTIVE_COMPARATOR

Dofetilide

Intervention Type DRUG

* 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg

Lidocaine

Intervention Type DRUG

* 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

Moxifloxacin + Diltiazem

Moxifloxacin with and without diltiazem.

Group Type ACTIVE_COMPARATOR

Moxifloxacin

Intervention Type DRUG

* 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)

Diltiazem

Intervention Type DRUG

• 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes

Placebo

Placebo (#2 gelcap and intravenous saline)

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo (#2 Gelcap or IV saline)

Interventions

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Dofetilide

* 8 am: Placebo
* 12 pm (noon): 250 µg
* 5:30 pm: 250 µg

Intervention Type 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

Intervention Type 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

Intervention Type 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)

Intervention Type DRUG

Diltiazem

• 7:30 pm: 330 µg/h per kg (loading) for 60 minutes and 61 µg/h per kg (maintenance) for 30 minutes

Intervention Type DRUG

Placebo

Placebo (#2 Gelcap or IV saline)

Intervention Type DRUG

Other Intervention Names

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Tikosyn Mexitil Lidocaine hydrochloride Avelox Diltiazem hydrochloride #2 Gelcaps or IV saline

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Maximum Eligible Age

35 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes