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Ranolazine Mediated PVC Reduction in Ischemic Heart Disease

Sponsor
Kent Hospital, Rhode Island (Other)
Overall Status
Completed
CT.gov ID
NCT02360397
Collaborator
Gilead Sciences (Industry)
6
Enrollment
1
Location
1
Arm
38.8
Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether ranolazine has beneficial effects on cardiac ischemia through reduction of premature ventricular contraction burden.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Ischemic heart disease is a heterogeneous condition with multiple etiologies that may contribute to an imbalance in myocardial oxygen supply and demand, resulting in depletion of myocardial cellular energy stores. Management of this disease state is aimed primarily at improving myocardial oxygen supply through revascularization of underlying obstructive atherosclerosis, in conjunction with interventions to reduce myocardial oxygen demand. Chronic treatment is directed at reducing recurrent ischemic symptoms. Despite advances in anti-thrombotic therapy, coronary revascularization, and other preventive therapies, the risk of recurrent events in this population remains substantial, in particular among those patients with indicators of higher risk (e.g. ST-segment depression, or arrhythmias).

Ranolazine is a piperazine derivative that exerts anti-ischemic actions without a clinically significant effect on heart rate or blood pressure. At clinically relevant concentrations, ranolazine is an inhibitor of the slowly inactivating component of the cardiac sodium current (late INa), which may reduce the deleterious effects associated with the intracellular sodium and calcium overload that accompany and may promote myocardial ischemia. Ranolazine is available as an anti-anginal agent for patients with chronic angina. The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes (MERLIN)-TIMI 36 trial demonstrated the safety of ranolazine in patients after ACS and also showed it's anti-arrhythmic properties. In addition to the safety properties of ranolazine, the study showed that ranolazine had a significant anti-ischemic effect and patient's on therapeutic dosing.

In an analysis of the 6560 patients in MERLIN-TIMI 36, using a digital continuous electrocardiographic Holter monitor for ischemia (Lifecard CF, Delmar Reynolds was applied to patients at the time of randomization and remained in place for 7 days, including after hospital discharge). Findings showed that patients treated with ranolazine had significantly lower incidences of arrhythmias. Specifically, fewer patients had an episode of ventricular tachycardia lasting ≥8 beats, supraventricular tachycardia or new-onset atrial fibrillation. In addition, pauses ≥3 seconds were less frequent with ranolazine. Based on this report, further studies of the antiarrhythmic effects of ranolazine were warranted.

Premature ventricular complexes (PVCs) are a frequent occurrence in the presence of ischemic heart disease. A very high PVC burden can be symptomatic or occasionally result in a cardiomyopathy. The mechanism by which PVCs cause cardiomyopathies or symptoms is not well understood, but may be related to an increase in myocardial strain or demand. Reduction in PVC burden has been associated with both improvement in ejection fraction and symptoms. Ranolazine has also been shown to reduce PVC burden in patients already on optimal medical therapy. The estimate of the minimal number of PVCs required to be associated with a cardiomyopathy is around 10%. In fact, subjects that had evidence for PVCs on baseline 12 lead electrocardiogram were found to have a significantly higher risk of cardiovascular events.

Current strategies for managing complex cardiomyopathies driven by arrhythmias have been complicated by intolerance to medical therapy as well as the requirement for frequent titration and the development of tolerance. Patients with ischemic heart disease have limited options for antiarrhythmic medical therapy. Prior trials of flecainide and eicainide in patients with ischemic heart disease for control of ventricular arrhythmias resulted in a significant and deleterious proarrhythmic effect current options for management line on amiodarone which has significant liver, thyroid, and lung toxicities or sotalol which can have significant bronchospastic effects as well as QT prolongation or tedious and which has to be carefully dose in the setting of renal insufficiency to avoid significant QT prolongation and the risk for proarrhythmia.

While ICD therapy has been appropriate for patients with reduced ejection fraction and evidence for unstable ventricular arrhythmias/sudden cardiac death, frequent or low level ventricular arrhythmias such as nonsustained VT or frequent PVCs would not be treated by ICD therapy. Escalation of traditional nodal therapies such as beta blockers or calcium channel blockers is his often limited by marginal systolic blood pressures and/or symptoms.

With the increasing prevalence of ischemic heart disease, it is critically important to identify therapies that have a neutral response to heart rate and blood pressure, good safety profile, and can reduce ischemia and the burden ventricular arrhythmias. Ultimately, the hope is that they will reduce strain induced ischemic heart changes. To that end, investigation of the effects of ranolazine in patients with ischemic heart disease and an elevated burden of PVCs is of great interest.

Study Design

Study Type:
Interventional
Actual Enrollment :
6 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Ranolazine Mediated Premature Ventricular Contraction Reduction in Ischemic Heart Disease
Study Start Date :
Dec 1, 2014
Actual Primary Completion Date :
Dec 31, 2017
Actual Study Completion Date :
Feb 23, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Ranolazine

Ranolazine 1000 mg tablet twice daily for 30 days

Drug: ranolazine
Ranolazine 1000 mg tablet twice daily for 30 days
Other Names:
  • ranexa

    		•

    Outcome Measures

    Primary Outcome Measures

    1. The Effect of Ranolazine on the PVC Burden Over 30 Days [Baseline (7 day) Holter compared to day 30 (7 day) Holter]

      The change in percentage of PVC burden after taking Ranolazine 1000mg twice daily for 30 days

    2. The Effect of Ranolazine on Cardiac Ischemia [Baseline and day 30]

      The effect of ranolazine on cardiac ischemia as measured by change in millimeters of ST segment deviation on ECG monitoring at Baseline and after 30 days of Ranolazine therapy (day 30).

    Secondary Outcome Measures

    1. Score on Seattle Angina Questionnaire at Baseline and at Day 30 [Baseline and day 30]

      The SAQ quantifies patients' physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life. Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life). Angina symptoms may be felt as: chest pain, a heaviness, tightness or squeezing sensation in the chest, aching across the chest, particularly behind the breastbone. The pain may radiate to the neck, jaw, arms, back or teeth.

    2. Number of Non-sustained Ventricular Tachycardia and Sustained Ventricular Arrhythmia Episodes on Holter Monitoring [Baseline and Day 30]

      Number of non-sustained ventricular tachycardia episodes (>8 beats) and sustained ventricular arrhythmia episodes on Holter monitoring at baseline and at 30 days

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Males and females aged 18 years and older

    • Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures

    • History of ischemic heart disease (prior bypass or coronary stenting, documentation on cardiac catheterization, nuclear SPECT imaging, cardiac MR, stress echocardiography, or exercise stress testing). Subjects are not required to have chronic angina to be enrolled in the study

    • Elevated PVC burden (1%) on prior Holter/event monitor in previous 12 months or evidence for PVC(s) on baseline ECG within prior 12 months.

    • Sexually active females of childbearing potential must agree to utilize effective methods of contraception during heterosexual intercourse throughout the treatment period and for 14 days following discontinuation of the study medication

    Exclusion Criteria:

    • Hospitalization for hyperthyroidism, pericarditis, myocarditis, or pulmonary embolism within 4 weeks prior to screening

    • Implantation of ICD or permanent pacemaker within 1 month of screening

    • New York Heart Association (NYHA) Class III and IV heart failure or NYHA Class II heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic within 4 weeks prior to Screening.

    • Myocardial infarction, unstable angina, or coronary artery bypass graft (CABG) surgery within three months prior to Screening or percutaneous coronary intervention (PCI) within 4 weeks prior to Screening

    • Clinically significant valvular disease in the opinion of the Investigator

    • Stroke within 1 months prior to Screening

    • History of serious ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation) within 4 weeks prior to Screening

    • Family history of long QT syndrome

    • QTc ≥ 500 msec (Bazett) at Screening ECG if in sinus rhythm (SR). If in AF, evidence of QTc ≥ 500 msec (Bazett) within 4 weeks prior to Screening

    • Prior heart transplant

    • Cardiac ablation within 3 months prior to Screening, or planned ablation during the course of the study

    • Need for concomitant treatment during the trial, with drugs or products that are strong inhibitors of CYP3A, or inducers of CYP3A. Such medications should be discontinued 5-half- lives prior to the Run-in period

    • Use of grapefruit juice or Seville orange juice during the study

    • Use of drugs that prolong the QT interval

    • Previous use of ranolazine within 2 months prior to screening

    • Prior use of ranolazine which was discontinued for safety or tolerability

    • Use of dabigatran during the study

    • Use of a greater than 1000 mg total daily dose of metformin during the study

    • Hypokalemia (serum potassium < 3.5 mEq/L) at Screening that cannot be corrected to a level of potassium ≥ 3.5 mEq/L prior to randomization

    • Moderate and severe hepatic impairment (ie, Child-Pugh Class B and C), abnormal liver function test defined as ALT, AST, or bilirubin > 2 x ULN at Screening

    • Severe renal impairment defined as creatinine clearance ≤ 30 mL/min at Screening

    • Females who are pregnant or are breastfeeding

    • Exclusion of patients with Contraindications to use of RANEXA, including patients on CYP3A4 inducers/potent inhibitors, and patients with liver cirrhosis

    • Exclusion of Patients with CrCl < 30 mL/min

    • Limit dose of RANEXA to 500mg BID in patients on concurrent diltiazem/verapamil

    • Limit concurrent simvastatin to 20 mg/day

    • In the judgment of the Investigator, any clinically-significant ongoing medical condition that might jeopardize the subject's safety or interfere with the study, including participation in another clinical trial within the previous 30 days using a therapeutic modality which could have potential residual effects that might confound the results of this study

    • Any technical issue (device related) which in the judgment of the investigator would disrupt adequate data collection or interpretation

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Kent Hospital Warwick Rhode Island United States 02886

    Sponsors and Collaborators

    • Kent Hospital, Rhode Island
    • Gilead Sciences

    Investigators

    • Principal Investigator: Chester M Hedgepeth, MD, PhD, Brigham and Women's Cardiovascular Associates at Care New England

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Chester Hedgepeth, MD, PhD, Chester Hedgepeth, MD, PhD, Kent Hospital, Rhode Island
    ClinicalTrials.gov Identifier:
    NCT02360397
    Other Study ID Numbers:
    • IN-US-259-1341
    First Posted:
    Feb 10, 2015
    Last Update Posted:
    Jan 29, 2020
    Last Verified:
    Jan 1, 2020
    Additional relevant MeSH terms:
    Premature Birth
    Heart Diseases
    Myocardial Ischemia
    Coronary Artery Disease
    Ventricular Premature Complexes
    Ischemia
    Ranolazine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days ranolazine: Ranolazine 1000 mg tablet twice daily for 30 days
    Period Title: Overall Study
    STARTED 6
    COMPLETED 2
    NOT COMPLETED 4

    Baseline Characteristics

    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days ranolazine: Ranolazine 1000 mg tablet twice daily for 30 days
    Overall Participants 6
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    0
    0%
    >=65 years
    6
    100%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    78
    Sex: Female, Male (Count of Participants)
    Female
    2
    33.3%
    Male
    4
    66.7%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    0
    0%
    White
    0
    0%
    More than one race
    0
    0%
    Unknown or Not Reported
    6
    100%
    Region of Enrollment (participants) [Number]
    United States
    6
    100%

    Outcome Measures

    1. Primary Outcome
    Title The Effect of Ranolazine on the PVC Burden Over 30 Days
    Description The change in percentage of PVC burden after taking Ranolazine 1000mg twice daily for 30 days
    Time Frame Baseline (7 day) Holter compared to day 30 (7 day) Holter

    Outcome Measure Data

    Analysis Population Description
    The percentage of PVC's on Holter monitor at baseline compared to day 30 were used to determine the statistical significance of the data.
    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days
    Measure Participants 2
    percentage of PVC burden at Baseline
    5.71
    percentage of PVC burden at Day 30
    5.495
    2. Primary Outcome
    Title The Effect of Ranolazine on Cardiac Ischemia
    Description The effect of ranolazine on cardiac ischemia as measured by change in millimeters of ST segment deviation on ECG monitoring at Baseline and after 30 days of Ranolazine therapy (day 30).
    Time Frame Baseline and day 30

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Effect of Ranolazine on Cardiac Ischemia
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days
    Measure Participants 2
    Mean (Full Range) [millimeters]
    0
    3. Secondary Outcome
    Title Score on Seattle Angina Questionnaire at Baseline and at Day 30
    Description The SAQ quantifies patients' physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life. Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life). Angina symptoms may be felt as: chest pain, a heaviness, tightness or squeezing sensation in the chest, aching across the chest, particularly behind the breastbone. The pain may radiate to the neck, jaw, arms, back or teeth.
    Time Frame Baseline and day 30

    Outcome Measure Data

    Analysis Population Description
    Score on Seattle Angina Questionnaire at Baseline and at day 30.
    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days
    Measure Participants 2
    Baseline SAQ score for Angina Frequency
    95
    Day 30 SAQ score for Angina Frequency
    95
    Baseline score for Angina Stability
    50
    Day 30 SAQ score for Angina Stability
    50
    Baseline SAQ score for Physical Limitation
    94.445
    Day 30 SAQ score for Physical Limitation
    94.445
    Baseline SAQ score for Day 30 SAQ score Quality of
    79.165
    Day 30 SAQ score for Quality of Life
    87.5
    4. Secondary Outcome
    Title Number of Non-sustained Ventricular Tachycardia and Sustained Ventricular Arrhythmia Episodes on Holter Monitoring
    Description Number of non-sustained ventricular tachycardia episodes (>8 beats) and sustained ventricular arrhythmia episodes on Holter monitoring at baseline and at 30 days
    Time Frame Baseline and Day 30

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days
    Measure Participants 2
    Baseline Holter
    0
    Day 30 Holter
    0

    Adverse Events

    Time Frame 30 days
    Adverse Event Reporting Description
    Arm/Group Title Ranolazine
    Arm/Group Description Ranolazine 1000 mg tablet twice daily for 30 days ranolazine: Ranolazine 1000 mg tablet twice daily for 30 days
    All Cause Mortality
    Ranolazine
    Affected / at Risk (%) # Events
    Total 0/6 (0%)
    Serious Adverse Events
    Ranolazine
    Affected / at Risk (%) # Events
    Total 1/6 (16.7%)
    Cardiac disorders
    Syncopy 1/6 (16.7%) 1
    Other (Not Including Serious) Adverse Events
    Ranolazine
    Affected / at Risk (%) # Events
    Total 0/6 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Chester M. Hedgepeth, MD, PhD
    Organization Brigham and Women's Cardiovascular Associates at Kent Hospital
    Phone (401) 737-7010 ext 32880
    Email chedgepeth@kentri.org
    Responsible Party:
    Chester Hedgepeth, MD, PhD, Chester Hedgepeth, MD, PhD, Kent Hospital, Rhode Island
    ClinicalTrials.gov Identifier:
    NCT02360397
    Other Study ID Numbers:
    • IN-US-259-1341
    First Posted:
    Feb 10, 2015
    Last Update Posted:
    Jan 29, 2020
    Last Verified:
    Jan 1, 2020