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

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ClinicalTrials.gov Identifier: NCT02308748
Recruitment Status : Completed
First Posted : December 4, 2014
Results First Posted : June 8, 2016
Last Update Posted : June 8, 2016
Sponsor:
Collaborator:
Spaulding Clinical Research LLC
Information provided by (Responsible Party):
Food and Drug Administration (FDA)

Tracking Information
First Submitted Date  ICMJE November 6, 2014
First Posted Date  ICMJE December 4, 2014
Results First Submitted Date  ICMJE January 13, 2016
Results First Posted Date  ICMJE June 8, 2016
Last Update Posted Date June 8, 2016
Study Start Date  ICMJE May 2014
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 1, 2014)
Change in 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. [ Time Frame: 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
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. [ Time Frame: 5 weeks ]
Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 1, 2014)
Change in QTc and J-Tpeakc intervals on the ECG measured in milliseconds when moxifloxacin is administered with diltiazem compared to when moxifloxacin is administered alone. [ Time Frame: 5 weeks ]
Evening dose (moxifloxacin+diltiazem) versus afternoon dose (diltiazem alone).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ability of Late Sodium or Calcium Current Block to Balance the ECG Effects of Potassium Current Block
Official Title  ICMJE 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)
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Drug-induced QT Prolongation
  • Pharmacokinetics
  • Pharmacodynamics
Intervention  ICMJE
  • Drug: Dofetilide
    • 8 am: Placebo
    • 12 pm (noon): 250 µg
    • 5:30 pm: 250 µg
    Other Name: 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 Name: Mexitil
  • 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 Name: Lidocaine hydrochloride
  • 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 Name: 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 Name: Diltiazem hydrochloride
  • Drug: Placebo
    Placebo (#2 Gelcap or IV saline)
    Other Name: #2 Gelcaps or IV saline
Study Arms  ICMJE
  • Active Comparator: Dofetilide
    Dofetilide alone arm
    Intervention: Drug: Dofetilide
  • Active Comparator: Dofetilide + Mexiletine
    Dofetilide combined with mexiletine
    Interventions:
    • Drug: Dofetilide
    • Drug: Mexiletine
  • Active Comparator: Dofetilide + Lidocaine
    Dofetilide combined with lidocaine
    Interventions:
    • Drug: Dofetilide
    • Drug: Lidocaine
  • Active Comparator: Moxifloxacin + Diltiazem
    Moxifloxacin with and without diltiazem.
    Interventions:
    • Drug: Moxifloxacin
    • Drug: Diltiazem
  • Placebo Comparator: Placebo
    Placebo (#2 gelcap and intravenous saline)
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 6, 2016)
22
Original Actual Enrollment  ICMJE
 (submitted: December 1, 2014)
27
Actual Study Completion Date  ICMJE June 2014
Actual Primary Completion Date June 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 35 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02308748
Other Study ID Numbers  ICMJE 14-022D
SCR-003 ( Other Identifier: Spaulding Clinical Research )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Food and Drug Administration (FDA)
Study Sponsor  ICMJE Food and Drug Administration (FDA)
Collaborators  ICMJE Spaulding Clinical Research LLC
Investigators  ICMJE
Principal Investigator: Carlos Sanabria, MD Spaulding Clinical
PRS Account Food and Drug Administration (FDA)
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP