Study to Reduce Symptoms of Premature Beats With Ranolazine

Overview

Investigate whether ranolazine, a novel anti-anginal agent with antiarrhythmic properties, has a role in the management of symptomatic ventricular premature beats.

Full Title of Study: “Reduction of Symptomatic Ventricular Premature Beats With Ranolazine”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Care Provider, Investigator)
  • Study Primary Completion Date: June 2016

Detailed Description

The main objective is to compare the effect of ranolazine versus placebo on premature ventricular beats (using 24-hour ambulatory electrocardiographic monitoring) for subjects with symptomatic palpitations. Subject population will consist of seventy-two adult subjects of both sexes who have greater than 1,000 premature ventricular beats during initial monitoring.

Interventions

  • Drug: Ranolazine
    • After the initial 6 days of treatment with ranolazine, 500 mg twice daily or matched placebo, subjects will undergo repeat 24 hour electrocardiographic monitoring. If tolerated, the subjects will then have their study medication increased (Ranolazine 1,000 mg twice daily) with the plan to then undergo a repeat 24 hour ambulatory electrocardiographic monitoring in 6 days.

Arms, Groups and Cohorts

  • Experimental: Ranolazine
    • Subjects will be consented by the study investigator and then randomly assigned in an allocation-concealed fashion to double blinded treatment with either titrated doses of ranolazine or matched placebo. After the initial 6 days of treatment with ranolazine, 500 mg twice daily or matched placebo, subjects will undergo repeat 24 hour electrocardiographic monitoring. If tolerated, the subjects will then have their study medication increased (Ranolazine 1,000 mg twice daily or matching placebo) with the plan to then undergo a repeat 24 hour ambulatory electrocardiographic monitoring in 6 days. When the subject returns the monitor, subjects will enter the washout period (cessation of the study medication) for 6 days and have electrocardiographic monitoring prior to return to the subject’s referring provider for care.
  • Placebo Comparator: Placebo
    • Subjects will be consented by the study investigator and then randomly assigned in an allocation-concealed fashion to double-blinded treatment with either titrated doses of ranolazine or matched placebo. After the initial 6 days of treatment with ranolazine, 500 mg twice daily or matched placebo, subjects will undergo repeat 24 hour electrocardiographic monitoring. If tolerated, the subjects will then have their study medication increased (Ranolazine 1,000 mg twice daily or matching placebo) with the plan to then undergo a repeat 24-hour ambulatory electrocardiographic monitoring in 6 days. When the subject returns the monitor, subjects will enter the washout period (cessation of the study medication) for 6 days and have electrocardiographic monitoring prior to return to the subject’s referring provider for care.

Clinical Trial Outcome Measures

Primary Measures

  • Reduction in Premature Ventricular Beats
    • Time Frame: 24-hour Holter Monitor after 14 days of therapy
    • The primary endpoint will be a 50% reduction in premature ventricular beats during 24-hour Holter monitoring after randomization to active treatment or placebo for 14 days of therapy.

Secondary Measures

  • Changes in transthoracic echocardiographic parameters
    • Time Frame: 14 days of therapy
    • Measure changes in transthoracic echocardiographic parameters including diastolic parameters, mitral inflow velocities and deceleration time and mitral annular velocities using tissue doppler imaging.
  • Frequency of palpitations
    • Time Frame: 14 days of therapy
    • Patient perceived change in frequency of palpitations from baseline to follow-up visit.
  • Reduction of Premature Atrial Beats
    • Time Frame: 24-hour Holter Monitor after 14 days of therapy
    • Reduction of premature atrial beats during 24-hour holter monitoring after randomization to active treatment or placebo following 14 days of therapy.
  • Measure Temperature Rebound Rate (TRR)
    • Time Frame: 14 days of therapy
    • Measure serial change in endothelial function as measured using the Vendys® DTM device as measured by fingertip Temperature Rebound (TR) in degrees Celsius. Temperature rebound is measured as the absolute difference between low fingertip temperature during cuff occlusion and maximal temperature rebound following cuff release. In addition, rate of change (slope) in temperature rebound will be calculated, measured as the TR divided by the time from temperature nadir to temperature peak. This will be termed: temperature rebound rate (TRR).

Participating in This Clinical Trial

Inclusion Criteria

  • Subjects male and female 18 years and older
  • Symptoms of palpitations
  • Greater than or equal to 1,000 Ventricular Premature Beats during 24-hour electrocardiographic monitoring
  • Completion of a consent form prior to pre-randomization Holter monitor

Exclusion Criteria

  • Moderate to severe symptomatic heart failure, New York Heart Association Class III/IV
  • Moderate to severe symptomatic angina, Canadian Cardiovascular Classification III/IV
  • Moderate to severe structural heart disease in the absence of an implantable cardiac defibrillator in a subject who would otherwise be eligible for a defibrillator (e.g. history of myocardial infarction and a left ventricular ejection fraction less than 30%)
  • Clinically significant hepatic disease (cirrhosis or chronic hepatitis) or abnormal liver associated enzymes greater than three times the upper limits of normal
  • A baseline corrected QT interval greater than or equal to 500msec or history of congenital channelopathy (long QT syndrome, Brugada syndrome) or torsades de pointes.
  • Treatment with agents known to prolong the QTc interval
  • Treatment with agents that are potent or moderately potent inhibitors of CYP3A, to include, but is not limited to the following: ketoconazole, HIV protease inhibitors (i.e. ritonavir), macrolide antibiotics (i.e. clarithromycin), diltiazem and verapamil
  • Females who are pregnant, planning to get pregnant, or breast feeding ( females under the age of 55 years who have not previously undergone surgical sterilization procedures will have serum qualitative pregnancy testing)
  • Thyroid stimulating hormone less than 0.27 IU/mL
  • Serum magnesium less than 1.5mg/dL
  • Serum potassium less than 3.5 mEq/dL or greater than 5.0 mEq/dL
  • Estimated GFR less than 30 mL/min

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Walter Reed National Military Medical Center
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Michael S Cahill, MD, Principal Investigator, Walter Reed National Military Medical Center
  • Overall Contact(s)
    • Michael S Cahill, MD, 301-295-0394, michael.s.cahill.mil@health.mil

References

Nanda S, Levin V, Martinez MW, Freudenberger R. Ranolazine–treatment of ventricular tachycardia and symptomatic ventricular premature beats in ischemic cardiomyopathy. Pacing Clin Electrophysiol. 2010 Dec;33(12):e119-20. doi: 10.1111/j.1540-8159.2010.02733.x.

Deshmukh SH, Patel SR, Pinassi E, Mindrescu C, Hermance EV, Infantino MN, Coppola JT, Staniloae CS. Ranolazine improves endothelial function in patients with stable coronary artery disease. Coron Artery Dis. 2009 Aug;20(5):343-7. doi: 10.1097/MCA.0b013e32832a198b.

Sossalla S, Wagner S, Rasenack EC, Ruff H, Weber SL, Schöndube FA, Tirilomis T, Tenderich G, Hasenfuss G, Belardinelli L, Maier LS. Ranolazine improves diastolic dysfunction in isolated myocardium from failing human hearts–role of late sodium current and intracellular ion accumulation. J Mol Cell Cardiol. 2008 Jul;45(1):32-43. doi: 10.1016/j.yjmcc.2008.03.006. Epub 2008 Mar 14.

Gul KM, Ahmadi N, Wang Z, Jamieson C, Nasir K, Metcalfe R, Hecht HS, Hartley CJ, Naghavi M. Digital thermal monitoring of vascular function: a novel tool to improve cardiovascular risk assessment. Vasc Med. 2009 May;14(2):143-8. doi: 10.1177/1358863X08098850.

Kumar K, Nearing BD, Bartoli CR, Kwaku KF, Belardinelli L, Verrier RL. Effect of ranolazine on ventricular vulnerability and defibrillation threshold in the intact porcine heart. J Cardiovasc Electrophysiol. 2008 Oct;19(10):1073-9. doi: 10.1111/j.1540-8167.2008.01204.x. Epub 2008 May 9.

Sicouri S, Glass A, Belardinelli L, Antzelevitch C. Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations. Heart Rhythm. 2008 Jul;5(7):1019-26. doi: 10.1016/j.hrthm.2008.03.018. Epub 2008 Mar 21.

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