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

Sponsor

East Carolina University (Other)

Overall Status

Withdrawn

CT.gov ID

NCT02423265

Collaborator

Gilead Sciences (Industry)

Enrollment

Location

Arms

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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

Study Type:

Interventional

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 :

Jun 1, 2015

Anticipated Primary Completion Date :

Dec 1, 2016

Anticipated Study Completion Date :

Mar 1, 2017

Arms and Interventions

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 Names: 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

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 Names:

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

Primary Outcome Measures

Cardiac MRI (CMR) strain [8 weeks]
The extent of reversibly ischaemic LV myocardium will be assessed using CMR strain at rest and stress

Secondary Outcome Measures

Dobutamine wall motion scoring index (WMSI) [8 weeks]
CMR derived end point
Quality of Life/burden of angina [8 weeks]
QoL questionnaire based assessment (Seattle Angina Quesstionnaire, SAQ; Duke Activity Status Index, DASI;Medical Outcomes Study-Short Form12 )
Treadmill ECG exercise distance [8 weeks]
Functional capacity assessment
Time to ECG changes (ST depression) on exercise ECG [8 weeks]
If baseline ECG permits, this will allow assessment of impact of treatment on ECG markers of ischemia

Eligibility Criteria

Criteria

Ages Eligible for Study:

21 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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