Study of the Electrocardiographic Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects

NCT01873950 | Completed Phase 1 Results DMC

• 2 other identifiers: 13-011DSCR-002
• Study Type: interventional
• Target: 22
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study seeks to compare 4 known QT prolonging drugs versus placebo to determine their effects on electrophysiological and other clinical parameters. The underlying purpose is to determine if depolarization and repolarization effects caused by drugs with differing ionic channel mechanisms can be distinguished from one another, and to gauge the sensitivity and specificity of novel signal analyses for detection of depolarization and repolarization changes. Secondarily, to evaluate the exposure response relationship and drug induced effects on the heart rate biomarker relationship.

Conditions

Drug-induced Surface ECG Changes

Outcome Measures

Primary Outcomes (3)

• Placebo, and Baseline-adjusted Changes in PR, QRS, J-Tpeak, Tpeak-Tend and QTc

  Compute maximum mean placebo, and baseline-adjusted change for: PR (ms), QRS (ms), J-Tpeak (ms), Tpeak-Tend (ms) and QTc (ms)

  24 hours

• Placebo, and Baseline-adjusted Changes in Spatial QRS-T Angle

  Compute maximum mean placebo, and baseline-adjusted change for: spatial QRS-T angle (degrees)

  24 hours

• Placebo, and Baseline-adjusted Changes in Ventricular Gradient

  Compute maximum mean placebo, and baseline-adjusted change for: ventricular gradient (mV\*ms).

  24 hours

Secondary Outcomes (7)

• Change in Relationship (Ratio) Between Heart Rate and QT

  24 hours

• Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Dofetilide and Verapamil Arms)

  24 hours

• Change in PR, QRS, J-Tpeak, Tpeak-Tend and QTc Using Exposure/Response (Ranolazine and Quinidine Arms)

  24 hours

• Change in Spatial QRS-T Angle Using Exposure/Response (Dofetilide and Verapamil Arms)

  24 hours

• Change in Spatial QRS-T Angle Using Exposure/Response (Ranolazine and Quinidine Arms)

  24 hours

Study Arms (5)

Ranolazine 1500mg

EXPERIMENTAL

Ranolazine

Drug: Ranolazine

Dofetilide 500mcg

EXPERIMENTAL

Dofetilide

Drug: Dofetilide

Verapamil HCl 120 mg

EXPERIMENTAL

Verapamil

Drug: Verapamil

Quinidine sulfate 400mg

EXPERIMENTAL

Quinidine sulfate

Drug: Quinidine sulfate

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Ranolazine DRUG

Ranolazine 1500mg

Dofetilide DRUG

Dofetilide 500mcg

Verapamil DRUG

Verapamil HCl 120 mg

Quinidine sulfate DRUG

Quinidine sulfate 400mg

Placebo DRUG

Placebo

Eligibility Criteria

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

You may qualify if:

• Subject signs an IRB approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act \[HIPAA\] authorization for sites in the United States) before any study related procedures are performed.
• Subject is a healthy man or woman, 18 to 35 years of age, inclusive, who weighs at least 50 kg (110 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 electrocardiogram (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).
• Female subjects must be at least 2 years postmenopausal, surgically sterile or practicing 2 highly effective methods of birth control (as determined by the investigator or designee; one of the methods must be a barrier technique), and not pregnant or lactating before enrollment in the study.
• 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.
• Subject is highly likely (as determined by the investigator) to comply with the protocol defined procedures and to complete the study.

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:
• QTc using Fridericia correction (QTcF) \>450 milliseconds (ms) for men and \>470 ms for women
• PR interval \>220 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 \<40 or \>90 beats per minute
• Pathological Q-waves (defined as Q wave \>40 ms)
• Ventricular pre-excitation
• Subject has more than 12 to 20 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 \[that will not interfere with or influence the leg raises/exercises required by the protocol, in the opinion of the investigator\], 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 (6)

• Johannesen L, Vicente J, Mason JW, Sanabria C, Waite-Labott K, Hong M, Guo P, Lin J, Sorensen JS, Galeotti L, Florian J, Ugander M, Stockbridge N, Strauss DG. Differentiating drug-induced multichannel block on the electrocardiogram: randomized study of dofetilide, quinidine, ranolazine, and verapamil. Clin Pharmacol Ther. 2014 Nov;96(5):549-58. doi: 10.1038/clpt.2014.155. Epub 2014 Jul 23.

  PMID: 25054430 RESULT

• Vicente J, Johannesen L, Mason JW, Crumb WJ, Pueyo E, Stockbridge N, Strauss DG. Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil. J Am Heart Assoc. 2015 Apr 13;4(4):e001615. doi: 10.1161/JAHA.114.001615.

  PMID: 25870186 RESULT

• Vicente J, Johannesen L, Mason JW, Pueyo E, Stockbridge N, Strauss DG. Sex differences in drug-induced changes in ventricular repolarization. J Electrocardiol. 2015 Nov-Dec;48(6):1081-7. doi: 10.1016/j.jelectrocard.2015.08.004. Epub 2015 Aug 4.

  PMID: 26324176 RESULT

• Strauss DG, Vicente J, Johannesen L, Blinova K, Mason JW, Weeke P, Behr ER, Roden DM, Woosley R, Kosova G, Rosenberg MA, Newton-Cheh C. Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study. Circulation. 2017 Apr 4;135(14):1300-1310. doi: 10.1161/CIRCULATIONAHA.116.023980. Epub 2017 Feb 17.

  PMID: 28213480 DERIVED

• 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

Ranolazine; dofetilide; Verapamil; Quinidine

Intervention Hierarchy (Ancestors)

Acetanilides; Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenethylamines; Ethylamines; Cinchona Alkaloids; Alkaloids; Quinuclidines; Heterocyclic Compounds, Bridged-Ring; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

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 Research LLC

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2013
• First Posted: June 10, 2013
• Study Start: May 1, 2013
• Primary Completion: July 1, 2013
• Study Completion: December 1, 2014
• Last Updated: March 8, 2018
• Results First Posted: May 21, 2015

Record last verified: 2018-02