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

NCT02308748 | Completed Phase 1 Results

• 2 other identifiers: 14-022DSCR-003
• Study Type: interventional
• Target: 22
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Drug-induced QT Prolongation; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• 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

Study Arms (5)

Dofetilide

ACTIVE COMPARATOR

Dofetilide alone arm

Drug: Dofetilide

Dofetilide + Mexiletine

ACTIVE COMPARATOR

Dofetilide combined with mexiletine

Drug: Dofetilide; Drug: Mexiletine

Dofetilide + Lidocaine

ACTIVE COMPARATOR

Dofetilide combined with lidocaine

Drug: Dofetilide; Drug: Lidocaine

Moxifloxacin + Diltiazem

ACTIVE COMPARATOR

Moxifloxacin with and without diltiazem.

Drug: Moxifloxacin; Drug: Diltiazem

Placebo

PLACEBO COMPARATOR

Placebo (#2 gelcap and intravenous saline)

Drug: Placebo

Interventions

Dofetilide DRUG

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

Also known as: Tikosyn

Dofetilide; Dofetilide + Lidocaine; Dofetilide + Mexiletine

Mexiletine DRUG

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

Also known as: Mexitil

Dofetilide + Mexiletine

Lidocaine 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

Also known as: Lidocaine hydrochloride

Dofetilide + Lidocaine

Moxifloxacin 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)

Also known as: Avelox

Moxifloxacin + Diltiazem

Diltiazem DRUG

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

Also known as: Diltiazem hydrochloride

Moxifloxacin + Diltiazem

Placebo DRUG

Placebo (#2 Gelcap or IV saline)

Also known as: #2 Gelcaps or IV saline

Placebo

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.
• 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).
• 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.

You may not qualify if:

• \. 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
• \. Subject has more than 12 ectopic beats during the 3 hour Holter ECG at Screening.
• \. 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.
• \. 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.
• \. Subject has a history of thoracic surgery.
• \. Subject has any condition possibly affecting study drug absorption (e.g., gastrectomy, Crohn's disease, irritable bowel syndrome).
• \. Subject has a skin condition likely to compromise ECG electrode placement.

Sponsors & Collaborators

• Food and Drug Administration (FDA): lead
• Spaulding Clinical Research LLC: collaborator

Related Publications (3)

• 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.

  PMID: 26259627 RESULT

• 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.

  PMID: 28036334 DERIVED

• 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.

  PMID: 28036330 DERIVED

MeSH Terms

Interventions

dofetilide; Mexiletine; Lidocaine; Moxifloxacin; Diltiazem; Sodium Chloride

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Phenyl Ethers; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Acetanilides; Anilides; Amides; Aniline Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Benzazepines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Results Point of Contact

• Title: David G Strauss, MD, PhD
• Organization: U.S. Food and Drug Administration

david.strauss@fda.hhs.gov

301-796-6323

Study Officials

• Carlos Sanabria, MD

  Spaulding Clinical

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2014
• First Posted: December 4, 2014
• Study Start: May 1, 2014
• Primary Completion: June 1, 2014
• Study Completion: June 1, 2014
• Last Updated: June 8, 2016
• Results First Posted: June 8, 2016

Record last verified: 2016-06