E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Heart failure patients with preserved ejection fraction (HFpEF) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10019280 |
E.1.2 | Term | Heart failures |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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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 is to demonstrate that ranolazine treatment results in a placebo corrected improvement in the 6-minute walk test (6MWT) after 28 weeks of treatment |
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E.2.2 | Secondary objectives of the trial |
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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) < 0.5 and mitral flow deceleration time (DT E) > 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
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E.4 | Principal 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 < 30 ml/min)
17. Moderate or severe hepatic impairment (Child-Pugh Class A or Class B)
18. Previous cardiac surgery
19. Inability to perform the 6MWT
20. 6MWT distance > 450 meters or < 100 meters at screening
21. Screening and baseline 6-minute walk distance (6MWD) with >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
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Central blinded Echolab evaluation
NT-proBNP(13)
Quality of Life scale (Minnesota Living with HF Questionnaire)
Electrocardiogram
Safety assessments |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 | No |
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 |