E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
chronic heart failure with preserved ejection fraction (LVEF equal or above 45%) |
|
E.1.1.1 | Medical condition in easily understood language |
chronic heart failure with preserved ejection fraction |
|
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 | 19.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008908 |
E.1.2 | Term | Chronic heart failure |
E.1.2 | System Organ Class | 100000004849 |
|
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 |
Find the optimal dose of neladenoson bialanate for the Phase III trial by detecting and characterizing a significant dose-response relationship in the primary efficacy endpoint, absolute change from baseline in 6-minute walking distance (6MWD) at 20 weeks, in patients with chronic heart failure with preserved ejection fraction (HFpEF), and by characterizing the safety, tolerability, pharmacokinetic and pharmacodynamic effects of the compound when given in addition to appropriate therapy for specific co-morbidities |
|
E.2.2 | Secondary objectives of the trial |
An exploratory objective is to further assess pharmacokinetic parameters and blood and urine biomarkers. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Men or women aged 45 years and older 2. Diagnosis of chronic heart failure (CHF), NYHA class II-IV (without evidence of a non-cardiac explanation for dyspnea), LVEF ≥ 45% assessed by any imaging modality (e.g. echocardiography, cardiac magnetic resonance, cine levocardiography) within the previous 6 months with no significant change in clinical status suggesting potential for deterioration in ejection fraction. 3. In the 6 months prior to run-in: a) Requirement of treatment with a diuretic AND b) Elevated natriuretic peptides, defined as one of: o BNP ≥ 75 pg/mL or NT-proBNP ≥ 300 pg/mL (sinus rhythm) o BNP ≥ 200 pg/mL or NT-proBNP ≥ 900 pg/mL (atrial fibrillation) AND c) At least one of the following: o LA enlargement (LA diameter ≥ 3.9 cm, LA volume ≥ 55 mL, LAVI ≥ 29 mL/m2, or LAA ≥ 20 cm2) (assessed by local imaging) o LV hypertrophy (septal or posterior wall thickness ≥ 1.1 cm) (local imaging) o Elevated filling pressures (invasive assessment) at rest (PAWP ≥ 20 mmHg or LVEDP ≥ 15 mmHg) or with exercise (PAWP ≥ 25 mmHg) (historical records) 4. 6MWD ≥ 100 m and ≤ 550 m at Visit 2 (baseline) 5. Written informed consent signed before any study-specific procedure
|
|
E.4 | Principal exclusion criteria |
1. Acute decompensated heart failure (defined as acute exacerbation of HF that may require IV therapy with diuretics, vasodilators or inotropic drugs and / or mechanical support) within the past 4 weeks 2. Initiation or dose modification of cardiovascular pharmacological therapy within the past 2 weeks (dose modification of pre-existing diuretic / anticoagulant medication is allowed based on patient-specific needs) 3. Inability to exercise: wheelchair / scooter / walker dependent; dependent on supplemental oxygen 4. HF is not the primary factor limiting activity as indicated by the patient affirming #1, #2 or #3 of the following questionnaire: My ability to be active is most limited by: #1 - Joint, foot, leg, hip or back pain #2 - Unsteadiness or dizziness impairing daily mobility #3 - Lifestyle, weather, or I just don’t like to be active 5. Previous diagnosis of HFrEF (LVEF < 40%) 6. Known clinically significant persistent coronary ischemia (based on medical history, a preexisting or a recent clinical stress test) 7. Occurrence of any of the following within 3 months: o Clinically evident myocardial infarction o Hospitalization for unstable angina o Stroke or transient ischemic attack o Coronary artery bypass graft (CABG) o Percutaneous coronary intervention (PCI) o Implantation of a cardiac resynchronization therapy device (CRTD) o Major surgery (that could interfere with patients’ ability to exercise) 8. PCI, CABG or implantation of a CRTD planned between randomization and end of study 9. Sustained systolic blood pressure ≤ 90 mmHg and / or signs and symptoms of hypotension prior to randomization 10. Sustained systolic blood pressure ≥ 160 mmHg prior to randomization 11. Sustained bradycardia with heart rate < 50 beats/minute or tachycardia with heart rate > 100 beats/minute prior to randomization 12. Known clinically relevant ventricular arrhythmias (sustained ventricular tachycardia, ventricular flutter or fibrillation) within 3 months prior to randomization based on either medical history or device generated data (if applicable) 13. Clinically relevant permanent or intermittent AV-block > grade II in patients without a permanent pacemaker or ICD / CRTD 14. Severe uncorrected valvular heart disease 15. Listing for heart transplantation and / or anticipated implantation of a ventricular assist device 16. Severe pulmonary disease with any of the following: o Requirement of continuous (home) oxygen or o History of chronic obstructive pulmonary disease ≥ GOLD III o Use of systemic corticosteroids 17. Asthma bronchiale with any of the following: o Symptoms not well-controlled within the past 6 months or o Ever intubated or in an intensive care unit for asthma 18. Anemia with hemoglobin < 10 g/dL within 3 months prior to randomization. If several values are available the latest result should be used. 19. Body mass index (BMI) > 45 kg/m2 at randomization 20. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 calculated by Modification of Diet in Renal Disease (MDRD) formula within 3 months prior to randomization (see Appendix 16.1). If several values are available the latest result should be used. 21. Hepatic insufficiency classified as Child-Pugh B or C (see Appendix 16.2), or any of the following: o Primary biliary cirrhosis (PBC) o Primary sclerosing cholangitis o PBC-autoimmune hepatitis overlap syndrome 22. Concomitant use of any of the following therapy that cannot be discontinued: o Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is a strong CYP3A4 inhibitor) o CYP3A4 inducers o Strong CYP2C8 inhibitors (Of note: clopidogrel is a strong CYP2C8 inhibitor) o Theophylline o Drugs having significant pre-systemic clearance via UGT1A1 in the intestine Respective substances must be stopped at least 7 days before randomization.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Absolute change from baseline in 6MWD after 20 weeks of treatment |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
at the end of the study, no formal interim analysis is planned |
|
E.5.2 | Secondary end point(s) |
• Activity (e.g. duration, intensity) reported values and absolute change from baseline at 20 weeks • NT-proBNP (pg/mL), measured values (log transformed) and absolute / relative change from baseline at 20 weeks to assess elevated filling pressures • High sensitivity troponin T (hs-TNT; ng/L), measured values (log transformed) and absolute / relative change from baseline at 20 weeks as a biomarker of myocardial injury • KCCQ, as described in protocol Section 9.4.6.1, measured values and absolute / relative change from baseline
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
at the end of the study, no formal interim analysis is planned |
|
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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | 6 |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Belgium |
Bulgaria |
Germany |
Greece |
Israel |
Italy |
Japan |
Poland |
Portugal |
Spain |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
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
|
The end of the study as a whole will be reached as soon as the last visit of the last patient has occurred in all centers in all participating countries (EU and non EU) |
|
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 | 25 |
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 | 25 |