Heart failure patients with preserved ejection fraction (HFpEF) MedDRA version: 20.0 Level: HLGT Classification code 10019280 Term: Heart failures System Organ Class: 10007541 - Cardiac disorders
Conditions
Interventions
Pharmaceutical Form: Prolonged-release tablet
INN or Proposed INN: RANOLAZINE
CAS Number: 95635-55-5
Current Sponsor code: I 293
Concent
Sponsors
Menarini International Operations Luxembourg S.A., Avenue de la Gare, 1611 Luxembourg, Luxembourg
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female between the ages of 40 to 85 years, inclusive 2. Heart failure with preserved EF defined by the following: a. Signs or symptoms of HF (previous documented hospitalization for HF, decompensation in the last 12 months, or exertional dyspnea or fatigue, New York Heart Association [NYHA] Class II-IV with or without clinical signs of HF) b. LVEF > 45% measured by echocardiogram c. NT-ProBNP > 200 pg/ml or BNP > 80 pg/ml d. Evidence of LV diastolic dysfunction or increased LV filling pressure documented in the last month and defined by the following: • LV end diastolic pressure > 16 mmHg • or E/E’ > 15 (septal annular velocity) • or E/E’ between 8 and 15 and at least one of the following: – Plasma brain natriuretic peptide (BNP) > 150 pg/ ml or plasma N terminal pro b-type natriuretic peptide (NT proBNP) > 450 pg/ml – Ratio of early (E) to late (A) mitral valve flow velocity (E/A) 280 ms – LV atrial area > 25 cm² (apical 4 chamber) – LV posterior wall thickness > 12 mm e. Sinus rhythm 3. Written informed consent 4. 6MWT distance = 450 meters and = 100 meters at screening Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 120 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 60
Exclusion criteria
Exclusion criteria: 1. Unstable situation for acute acute coronary syndrome, or worsening angina in the last 3 months 2. Unstable situation for acute heart failure in the last month 3. Poor echogenicity 4. Significant chronic lung disease (e.g., chronic obstructive pulmonary disease, asthma), prior hospitalization for acute exacerbation, home oxygen use, chronic inhaled or systemic steroid therapy 5. Documented hypertrophic or restrictive cardiomyopathy 6. Body mass index (BMI) = 30 kg/m2 7. Tricuspid Rigurgitation Max Velocity > 4m/s 8. Previous Heart Failure hospitalization or decompensation, with documented LV Systolic Dysfunction (LVEF = 45%) 9. Sustained atrial fibrillation or flutter in the previous 3 months 10. Change in cardiovascular medication during the last 4 weeks 11. Change in diuretic medication during the last 2 weeks 12. Revascularization within the last 3 months 13. Second- or third-degree atrioventricular (AV) block 14. Severe and uncontrolled hypertension stage 3 (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg) 15. Significant valvular disease: moderate or severe mitral or aortic valve disease 16. Severe renal impairment (creatinine clearance 450 meters or 10% variability 22. Stroke within the last 3 months 23. Implantable pacemaker for chronotropic incompetence, cardioverter defibrillator, or LV assist device 24. Prior heart transplantation 25. Current treatment with potent inhibitors of CYP3A, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir 26. Current treatment with CYP3A inducers, such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John’s wort 27. Concomitant administration of Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol) antiarrhythmics other than amiodarone 28. Use of greater than 1000mg daily dose of metformin during the study 29. Prior treatment with ranolazine 30. Hypersensitivity to the active substance or to any of the excipients 31. Participation in another trial of an investigational drug or device within 30 days prior to screening 32. Pregnant or breast-feeding 33. Severe psychiatric disorders/neurological disorders 34. Abuse of alcohol, analgesics, or psychotropic drugs 35. Disabling or terminal illness 36. Inability or unwillingness, in the Investigator’s opinion, to follow study procedures
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective is to demonstrate that ranolazine treatment results in a placebo corrected improvement in the 6-minute walk test (6MWT) after 28 weeks of treatment; Secondary Objective: Mitral flow velocity to mitral annular velocity ratio (E/E’) from baseline to 6 months Mitral flow: maximum velocity during early diastole (VmaxE); maximal velocity during atrial contraction (VmaxA); deceleration time of E wave; isovolumetric relaxation time (IVRT) Tricuspidal regurgitation Vmax of septal and lateral E’ measured by Tissue Doppler Echocardiography (TDE) 2D strain evaluation: longitudinal systolic strain, LV twist, global diastolic longitudinal strain rate during isovolumic relaxation (IVR) and early diastole/untwisting rate Arterial elastance (LV end systolic pressure/stroke volume) and LV end systolic elastance (LV end systolic pressure/LV end systolic volume) Diastolic pressure/volume ratio measured as (E/E’)/end diastolic volume Myocardial Performance Index (MPI; included in ECHO protocol) N-terminal prohormone brain natriuretic peptide (NT-proBNP) change Quality of life (QoL) evaluation ;Primary end point(s): 6-minute walk test;Timepoint(s) of evaluation of this end point: after 16 and 28 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Central blinded Echolab evaluation NT-proBNP(13) Quality of Life scale (Minnesota Living with HF Questionnaire) Electrocardiogram Safety assessments ;Timepoint(s) of evaluation of this end point: after 16 and 28 weeks | — |
Countries
Italy, Spain, United Kingdom
Contacts
Public ContactDonatella Bemporad
A. Menarini Farmaceutica Internazionale S.R.L.
Outcome results
None listed