Ranolazine in Diastolic Heart Failure

Study Overview
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Brief Summary
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Patients with CAD and clinical symptoms of heart failure or patients with suspected heart failure with preserved ejection fraction (HFpEF) will be enrolled. Study drug will be given as continuous IV infusion followed by oral treatment for 13 days. LV pressures and hemodynamic data will be measured prior to and after administration of study drug. In addition, Doppler ECHO, cardiopulmonary exercise testing (CPET), and NT-pro-BNP determination will be performed. Adverse events and safety labs will be collected and monitored.

Detailed Description
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This is a randomized, double-blind, placebo-controlled proof-of-concept study of ranolazine in patients with heart failure with preserved ejection fraction (HFpEF). Patients will be randomized to receive ranolazine or placebo in a 1.5:1 ratio (12 ranolazine: 8 placebo). Treatment will consist of intravenous infusion of study drug followed by oral treatment for a total of 14 days treatment period. Study contact will be made approximately 14 days after the treatment period to assess safety. Cardiac catheterization will be performed for LV pressures and hemodynamic measurements before and after drug administration. Doppler ECHO, CPET, and NT-pro-BNP determination will be performed at screening and at end of study. Adverse events and safety labs will be monitored and collected.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of Ranolazine in Patients With Heart Failure With Preserved Ejection Fraction

Conditions
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Diastolic Heart Failure

Intervention / Treatment
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* Drug: Ranolazine
* Other: Saline 0.9% and placebo tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged > 40 years Clinical symptoms of heart failure (NYHA class II-III) at time of screening (e.g., dyspnea, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema) Left ventricular ejection fraction (LVEF) > 45% at screening With: E/E' > 15 measured by Tissue Doppler echocardiography at screening NT-pro-BNP > 220pg/mL at screening Average resting LVEDP >18 mm Hg (refer to continued eligibility criteria), Average resting time constant of relaxation (tau) > 50 ms at time of cardiac catheterization (refer to continued eligibility criteria) Signed informed consent Exclusion Criteria: Acute cardiac decompensation requiring mechanical ventilation Hypotension with blood pressure < 90/50 mm Hg Primary hypertrophic or restrictive cardiomyopathy or systemic illness associated with infiltrative heart disease (e.g., cardiac amyloidosis) Pericardial constriction Hemodynamically significant uncorrected obstructive or regurgitant valvular disease Cor pulmonale or other causes of right heart failure not associated with left ventricular dysfunction Clinically significant pulmonary disease in the opinion of the Investigator or requiring home oxygen or oral steroid therapy History of serious cardiac dysrrhythmias including atrial fibrillation with resting heart rate of > 100 beats per minute Need for treatment with Class I or III antiarrhythmic medications Implantable pacemaker, cardioverter-defibrillator, or left ventricular assist device Clinically significant chronic hepatic impairment (Child-Pugh Class B [moderate] or Class C [severe]) Severe renal insufficiency defined as creatinine clearance ≤30 mL/min as calculated by Cockcroft-Gault formula or Modified Diet in Renal Disease (MDRD) equation. History of congenital or a family history of long QT syndrome, or known acquired QT interval prolongation Inability to exercise due to other co-morbidities that may affect performance of cardiopulmonary exercise test (CPET) (e.g., osteoarthritis, peripheral vascular disease) Current treatment with potent and moderate CYP3A inhibitors Current treatment with potent CYP3A inducers (e.g., rifampin/rifampicin, St. John's Wort, carbamazepin/carbamazepine) Prior treatment with ranolazine Other conditions that in the opinion of the investigator may increase the risk to the patient (e.g. pts with weight ≤60 kg), prevent compliance with study protocol or compromise the quality of the clinical trial Continued Eligibility Criteria: Patients must continue to meet eligibility criteria and have an average (of 3 measurements) resting LVEDP > 18 mm Hg and resting tau > 50 ms at time of cardiac catheterization to receive study drug.

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ranolazine<br> | Drug: Ranolazine<br>* Intravenous treatment followed oral treatment for 13 days.<br>* Other names: Ranexa;|
| Placebo Comparator: Saline 0.9%<br>Saline 0.9% and placebo tablet | Other: Saline 0.9% and placebo tablet<br>* Intravenous treatment followed by oral treatment for 13 days<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to 30 minutes in cardiac catheterization hemodynamic parameters at both resting and paced conditions | Change from baseline to 30 minutes from initiation of study drug bolus No.1 in cardiac catheterization hemodynamic parameters at both resting and paced conditions: Time-constant of relaxation (tau) Left ventricular end-diastolic pressure (LVEDP) dP/dtmin (minimal rate of LV pressure change) | Baseline to 30 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline to Day 14 in mitral E wave velocity/mitral annular velocity (E/E') ratio |  | Baseline to Day 14 | 
| Change from baseline to Day 14 in VO2 max |  | Baseline to Day 14 | 
| Change from baseline to Day 14 in N-terminal pro-brain B-type natriuretic peptide (NT-pro-BNP) |  | Baseline to Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure with Preserved Ejection Fraction (HFpEF), Coronary Artery Disease (CAD)