| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chronic heart failure with reduced ejection fraction (LVEF equal or below 35%) |
|
| E.1.1.1 | Medical condition in easily understood language |
| chronic heart failure with reduced ejection fraction |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| 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 two primary efficacy endpoints, absolute change from baseline in LVEF and log-transformed NT-proBNP at 20 weeks, in patients with chronic heart failure with reduced ejection fraction (HFrEF), and by characterizing the safety, tolerability and pharmacodynamic effects of the compound when given in addition to standard therapy for HFrEF. |
|
| E.2.2 | Secondary objectives of the trial |
| An exploratory objective is to further investigate the drug and the pathomechanism of heart failure by evaluating 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 18 years and older
2. Diagnosis of chronic heart failure (CHF), NYHA class II-IV, LVEF ≤ 35% assessed by any imaging modality (e.g. echocardiography, cardiac magnetic resonance [CMR], cine levocardiography) within 6 months prior to run-in: if several values are available the last assessment of EF should be ≤ 35%.
3. One of the following (or both),
a) Worsening CHF requiring hospitalization or an unscheduled outpatient visit in the last 3 months, both requiring initiation or intensification of heart failure therapy and with either:
o BNP ≥ 100 pg/mL or NT-proBNP ≥400 pg/mL (sinus rhythm) or
o BNP ≥ 300 pg/mL or NT-proBNP ≥1200 pg/mL (atrial fibrillation)
AND/OR
b) at any time in the past 4 weeks one of:
o BNP ≥ 300 pg/mL or NT-proBNP ≥ 1200 pg/mL (sinus rhythm)
o BNP ≥ 600 pg/mL or NT-proBNP ≥ 2400 pg/mL (atrial fibrillation)
For patients on treatment with angiotensin receptor-neprilysin inhibitors (ARNIs), e.g. Entresto only NT-proBNP values can be used to assess eligibility.
4. Written informed consent before any study-specific procedure
|
|
| E.4 | Principal exclusion criteria |
1. Acute de-novo heart failure
2. Requirement of any of the following 48 hours prior to randomization:
IV vasodilating drugs (e.g. nitrates, nitroprusside)
- IV natriuretic peptides (e.g. nesiritide, carperitide) - IV positive
inotropic agents - IV diuretics - IV antibiotics - Mechanical support (e.g.
intra-aortic balloon pump, endotracheal intubation, mechanical
ventilation, or any ventricular assist device)
3. Any cause of chronic heart failure other than ischemic cardiomyopathy
and idiopathic dilated cardiomyopathy
4. Known clinically significant persistent coronary ischemia based on
medical history, preexisting or current exercise testing
5. Occurrence of any of the following within 3 months prior to
randomization:
o Myocardial infarction
o Hospitalization for unstable angina
o Stroke or TIA
o Coronary artery bypass graft (CABG)
o Percutaneous coronary intervention (PCI)
o Implantation of a cardiac resynchronization therapy device (CRTD)
o Carotid angioplasty
6. PCI, CABG or implantation of a CRTD planned between randomization
and end of study
7. Sustained* systolic blood pressure ≤ 90 mmHg and / or signs and
symptoms of hypotension prior to randomization
8. Sustained* systolic blood pressure ≥ 160 mmHg
9. Sustained* bradycardia with heart rate < 50 beats/minute or
tachycardia with heart rate > 100 beats/minute prior to randomization
10. Known clinically relevant ventricular arrhythmias (sustained
ventricular tachycardia, ventricular flutter or fibrillation) within 3
months prior to consent based on either medical history or ICD-testing
results (if applicable)
11. Clinically relevant permanent or intermittent AV-block > grade II in
patients without a permanent pacemaker or ICD / CRT device
12. Severe valvular disease with indicated or planned valve repair /
replacement
13. Listing for heart transplantation and / or anticipated implantation of
a ventricular assist device
14. Severe pulmonary disease with any of the following:
o Requirement of continuous (home) oxygen or
o History of COPD ≥ GOLD III or
o Use of systemic corticosteroids
15. 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
16. Anemia with hemoglobin < 10 g/dL within 3 months prior to
randomization. If several values are available the latest result should be
used.
17. Body Mass index (BMI) > 40 kg/m2 at randomization or a history of
poor quality LVEF measurement by echocardiography
18. 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. If several values are available
the latest result should be used.
19. Hepatic insufficiency classified as Child-Pugh B or C, or any of the following:
o Primary biliary cirrhosis (PBC)
o Primary sclerosing cholangitis
o PBC-autoimmune hepatitis overlap syndrome
20. Concomitant use of any of the following therapy that cannot be
discontinued:
o Moderate or strong CYP3A4 inhibitors (Of note: grapefruit is also 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.
21. Women of childbearing potential (women are considered of
childbearing potential if they are not surgically sterile or
postmenopausal, defined as amenorrhea for > 12 months)
22. Any condition or therapy, which would make the patient unsuitable
for the study, or life expectancy less than 12 months (e.g. active
malignancy)
23. Known current heavy alcohol consumption or the use of illicit drugs
that, in the opinion of the investigator, may interfere with the patient's
safety and / or compliance
24. Previous (within 30 days or 5 half-lives of the investigational drug,
whichever is longer) or concomitant participation in another clinical
study with investigational medicinal product(s) or device(s)
25. Previous assignment to treatment during this study
26. Close affiliation with the investigational site; e.g. a close relative of
the investigator, dependent person (e.g. employee or student of the
investigational site)
27. Known allergies, intolerance or hypersensitivities to the study
treatment (active substance or excipients), adhesives or hydrogel
* At two consecutive visits |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Absolute change from baseline in left ventricular ejection fraction (LVEF; %) after 20 weeks of treatment measured by echocardiography
• Absolute change from baseline in log-transformed NT-proBNP (pg/mL) after 20 weeks, i.e., log-transformed NT-proBNP at week 20 minus log-transformed NT-proBNP at baseline.
|
|
| 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) |
•Key echocardiographic parameters, measured values and absolute change from baseline at 20 weeks:
o Left ventricular end-systolic volume (LVESV; mL)
o Left ventricular end-diastolic volume (LVEDV; mL)
• 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
• CV mortality, HF hospitalization and urgent visits for HF as clinical outcome
|
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 56 |
| 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 |
| Belgium |
| Bulgaria |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Netherlands |
| Poland |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 19 |
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