E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure with Preserved Ejection Fraction |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10069211 |
E.1.2 | Term | Diastolic heart failure |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to determine if ranolazine, compared to placebo, will be more effective in improving diastolic function in patients with HFpEF. |
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E.2.2 | Secondary objectives of the trial |
To collect further information about the safety and tolerability of ranolazine in this patient population through Day 28 safety follow-up. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males or females aged ≥ 40 years 2. Clinical symptoms of heart failure (NYHA class II-III) at time of screening (e.g., dyspnea, paroxysmal nocturnal dyspnea, orthopnea, bilateral lower extremity edema) 3. Left ventricular ejection fraction (LVEF) ≥ 45% at screening 4. With: a. E/E′ > 15 measured by Tissue Doppler echocardiography at screening OR b. NT-pro-BNP > 220pg/mL at screening AND c. Average resting LVEDP ≥ 18 mm Hg (refer to continued eligibility criteria), d. Average resting time constant of relaxation (tau) ≥ 50 ms at time of cardiac catheterization (refer to continued eligibility criteria) 5. For female patients only: be postmenopausal (no menses for last 24 months) or sterilized, or if of child-bearing potential, is not breastfeeding, has a negative pregnancy test at time of study, has no intention of becoming pregnant during the course of the study, and is using one or more of the following contraceptive measures: a. Stable regimen of hormonal contraception b. Intrauterine device c. Condoms with spermicide d. Diaphragm with spermicide e. Abstinence 6. Signed informed consent |
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E.4 | Principal exclusion criteria |
1. Acute cardiac decompensation requiring mechanical ventilation 2. Hypotension with blood pressure < 90/50 mm Hg 3. Primary hypertrophic or restrictive cardiomyopathy or systemic illness associated with infiltrative heart disease (e.g., cardiac amyloidosis) 4. Pericardial constriction 5. Hemodynamically significant uncorrected obstructive or regurgitant valvular disease 6. Cor pulmonale or other causes of right heart failure not associated with left ventricular dysfunction 7. Myocardial infarction, unstable angina, or coronary artery bypass graft (CABG) surgery within 90 days prior to screening, or percutaneous coronary intervention (PCI) within 30 days prior to screening 8. Stroke within 90 days prior to screening 9. Clinically significant pulmonary disease in the opinion of the Investigator or requiring home oxygen or oral steroid therapy 10. History of serious cardiac dysrrhythmias including atrial fibrillation with resting heart rate of > 100 beats per minute 11. Need for treatment with Class I or III antiarrhythmic medications 12. Implantable pacemaker, cardioverter-defibrillator, or left ventricular assist device 13. Clinically significant chronic hepatic impairment (Child-Pugh Class B [moderate] or Class C [severe]) 14. Severe renal insufficiency defined as creatinine clearance < 30 mL/min as calculated by Cockroft-Gault formula or Modified Diet in renal Disease (MDRD) equation. 15. History of congenital or a family history of long QT syndrome, or known acquired QT interval prolongation. 16. Inability to exercise due to other co-morbidities that may affect performance of cardiopulmonary exercise test, CPET (e.g., osteoarthritis, peripheral vascular disease) 17. Current treatment with potent and moderate CYP3A inhibitors 18. Current treatment with potent CYP3A inducers (e.g., rifampin/rifampicin, St. John’s Wort, carbamazepin/carbamazepine) 19. Prior treatment with ranolazine 20. Participation in another trial of an investigational drug or device within 30 days prior to screening 21. 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
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E.5 End points |
E.5.1 | Primary end point(s) |
The study will include the following exploratory endpoints; 1. Change from baseline to 30 minutes from initiation of study drug bolus No. 1 (T = 30 min) in cardiac catheterization hemodynamic parameters at both resting and paced conditions: a. time-constant of relaxation (tau) b. left ventricular end-diastolic pressure (LVEDP) c. dP/dtmin (minimal rate of LV pressure change) 2. Change from baseline to Day 14 in: a. mitral E wave velocity/mitral annular velocity (E/E′) ratio assessed by Tissue Doppler (TD) echocardiography b. VO2 max assessed by cardiopulmonary exercise test (CPET) c. N-terminal pro-brain B-type natriuretic peptide (NT-pro-BNP) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |