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Efficacy of Ranolazine in Patients With Chronic Total Occlusions of Coronary Arteries

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ClinicalTrials.gov Identifier: NCT02423265
Recruitment Status : Withdrawn (slow recruitment; local new isseus with CMR after study start)
First Posted : April 22, 2015
Last Update Posted : May 30, 2018
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Dr Ashesh N. Buch, East Carolina University

Study Description
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Brief Summary:

Anti-anginal drugs relieve ischemia and symptoms by reducing myocardial oxygen demand by reducing heart rate and or contractility (beta-blockers, phenylalkylamine and benzothiazepineate classes of calcium antagonists) or vasodilatation of the venous system (fall in pre-load) and coronary vessels.

Late sodium channels remain open for longer in the presence of myocardial ischaemia. Ranolazine, a novel anti-anginal agent, acts by inhibiting the inward late inward sodium current (INaL), reducing intracellular sodium accumulation and consequently intracellular calcium overload via the sodium/calcium exchanger. It is currently thought that this reduction in intracellular calcium reduces diastolic myocardial stiffness and therefore compression of the small coronary vessels. There is considerable animal data to support this theory.

There are good theoretical reasons to postulate that patients with chronically occluded vessels may derive less benefit from conventional anti-anginal agents, particularly vasodilators. The ischemic myocardium, subtended by the occluded vessel, will already be subject to significant concentrations of paracrine vasodilators such as adenosine. Ranolazine, therefore, may on the basis of its mechanism of action, provide greater relief of ischemia in such patients than conventional anti-anginal agents.


Condition or disease Intervention/treatment Phase
Myocardial Ischemia Coronary Artery Disease Arteriosclerosis Chronic Stable Angina Drug: Ranolazine Drug: Placebo Phase 4

Detailed Description:
To test this hypothesis, a randomized study comparing addition of ranolazine to addition of a minimum of 2 conventional anti-anginal agents in patients with chronic total occlusions would be required. To be sufficiently powered, this would require a significant number of patients recruited in a multi-center trial. This study is an initial pilot study with inactive placebo, not addition of a conventional anti-anginal agent, as the control using MRI imaging data as the primary end-point.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Effectiveness of Ranolazine in Reducing Cardiac Ischaemia Induced by Chronic Total Occlusions of Coronary Arteries
Study Start Date : June 2015
Estimated Primary Completion Date : December 2016
Estimated Study Completion Date : March 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Ranolazine

Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Ranolazine
500mg bd ranolazine for 1 week then uptitrated to 1000mg bd to continue for 8 weeks
 Drug: Ranolazine
Ranolazine: 500 mg twice day, up-titrated after 1 week to 1000 mg twice a day
Other Name: Renexa
Placebo Comparator: Placebo
Matching placebo, with up titration after 1 week as in active treatment arm
 Drug: Placebo
Matching placebo: up-titration after 1 week


Outcome Measures
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Primary Outcome Measures :
  1. Cardiac MRI (CMR) strain [ Time Frame: 8 weeks ]
    The extent of reversibly ischaemic LV myocardium will be assessed using CMR strain at rest and stress


Secondary Outcome Measures :
  1. Dobutamine wall motion scoring index (WMSI) [ Time Frame: 8 weeks ]
    CMR derived end point

  2. Quality of Life/burden of angina [ Time Frame: 8 weeks ]
    QoL questionnaire based assessment (Seattle Angina Quesstionnaire, SAQ; Duke Activity Status Index, DASI;Medical Outcomes Study-Short Form12 )

  3. Treadmill ECG exercise distance [ Time Frame: 8 weeks ]
    Functional capacity assessment

  4. Time to ECG changes (ST depression) on exercise ECG [ Time Frame: 8 weeks ]
    If baseline ECG permits, this will allow assessment of impact of treatment on ECG markers of ischemia


Eligibility Criteria
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Ages Eligible for Study:   21 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Angiographically proven coronary artery disease with chronic stable angina for at least 3 months.
  • Abnormal stress test (treadmill ECG, nuclear stress test, dobutamine stress echocardiogram or stress perfusion cardiac MRI)
  • ≥ 1 chronically occluded coronary artery of a dominant coronary vessel or the left anterior descending artery and/or ≥ 1 occluded vein graft to chronically occluded native coronary vessel
  • Subjects must be taking a minimum of 2 anti-anginal agents:

Exclusion Criteria:• Coronary revascularization in the preceding 2 months

  • LVEF < 40
  • Terminal illness such as cancer
  • Occluded recessive coronary vessel
  • Hepatic insufficiency,
  • Liver cirrhosis,
  • Prolonged QT interval on ECG,
  • Severe renal failure (see below), Excluding patients with CrCl < 30
  • Drugs that are strong inhibitors of CYP3A such as, ketoconazole, macrolide antibiotics and HIV protease inhibitors.
  • Limit Ranolazine to 500mg BID in patients on concurrent diltiazem/verapamil
  • Limit concurrent simvastatin to 20 mg/day
  • Limit concurrent metformin to 1700 mg/day
  • Inability to have an MRI scan/known claustrophobia
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02423265


Locations
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United States, North Carolina
East Carolina Heart Institute at Vidant Medical Center
Greenville, North Carolina, United States, 27834
Sponsors and Collaborators
East Carolina University
Gilead Sciences
Investigators
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Principal Investigator: Ashesh N Buch, MB.ChB, M.D. East Carolina University
More Information
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Responsible Party: Dr Ashesh N. Buch, Assistant Professor Cardiovascular Sciences (Interventional Cardiology), East Carolina University
ClinicalTrials.gov Identifier: NCT02423265    
Other Study ID Numbers: IN-US-259-0172 Buch ISR
UMCIRB 13-001574 ( Other Identifier: Institutional Review Board (IRB) )
First Posted: April 22, 2015    Key Record Dates
Last Update Posted: May 30, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Dr Ashesh N. Buch, East Carolina University:
Chronic total coronary occlusions
Ranolazine
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Angina, Stable
Arteriosclerosis
Ischemia
Coronary Disease
Heart Diseases
Cardiovascular Diseases
Arterial Occlusive Diseases
Vascular Diseases
 Pathologic Processes
Angina Pectoris
Chest Pain
Pain
Neurologic Manifestations
Ranolazine
Sodium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action