| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | LLT |
| E.1.2 | Classification code | 10008908 |
| E.1.2 | Term | Chronic heart failure |
| E.1.2 | System Organ Class | 100000004849 |
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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 |
To assess the efficacy of 30 mg of BAY 1753011, with or without furosemide, versus furosemide alone in patients with HF and objective evidence of congestion
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| E.2.2 | Secondary objectives of the trial |
| To assess the safety and pharmacodynamics of 30 mg of BAY 1753011, with or without furosemide, versus furosemide alone in patients with HF and objective evidence of congestion |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent signed before any study-specific procedure.
2. Ability to understand and follow study-related instructions as a documented decision of the investigator
3. Men and women aged ≥ 18 years ≤ 85 years. Lower age limit may be higher if legally requested in the participating country.
4. Men must agree to use condoms during sexual intercourse.
5. Women can only be enrolled if of non-child bearing potential
6. History of CHF (HF with reduced, preserved or mid-range EF) on individually optimized treatment with HF medications unless contraindicated or not tolerated, for at least 12 weeks prior to index hospitalization and in accordance with international guidelines.
7. Patients admitted to the hospital with a primary diagnosis of decompensated HF including symptoms and signs of fluid overload requiring IV diuretic therapy in the ER or any time between day 1-3 of hospital admission
AND
8. At least one of the following 5 parameters any day between 3-7 of index hospitalization
Ai. Drop in BNP or NT-proBNP ≤ 30% from admission values (if measured during index hospitalization) or
Aii. BNP ≥ 500 pg/ml or NT-proBNP ≥ 1800 pg/ml at screening
B. BW loss <0.4 kg per 40 mg furosemide at day 4 of index hospitalization
C. CCS ≥ 2
D. Hypervolemic hyponatremia defined as serum sodium < 136 mmol/l
E. In hospital worsening renal function defined as increased serum creatinine ≥ 0.3 mg/dl compared to index hospitalization admission values
AND at least one the following
Ei. JVP ≥ 10 cm on physical examination
Eii. IVC diameter > 21 mm
Eiii. IVC collapse with sniff < 50%
Eiv. At least 2+ peripheral edema or pulmonary edema or pleural effusion on chest X-ray or clinical exam
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| E.4 | Principal exclusion criteria |
1. Body Mass Index (BMI) < 18.5 kg/m2 or > 35 kg/m
2. Known hypersensitivity to the study drugs
3. Participation in another interventional clinical study or treatment with investigational medicinal product 30 days or five half-lives of the investigational drug prior to screening
4. Any other condition or therapy that would make the subject unsuitable for this study and would not allow participation for the full planned study period in the judgment of the investigator (e.g. severe Chronic Obstructive Pulmonary Disease (COPD), Severe chronic infectious diseases [endocarditis, H.I.V, etc.])
5. Malignancy or other non-cardiac condition limiting life expectancy to < 1 year, per physician judgment
6. Known current alcohol and/or illicit drug abuse that may interfere with the subject’s safety and / or compliance at the discretion of the investigator
7. Close affiliation with the investigational site or the sponsor; e.g., a close relative of the investigator, or the sponsor or a dependent person (e.g., employee or student of the investigational site or the sponsor)
8. Subject is in custody by order of an authority or a court of law
9. Acute de-novo HF
10. Active or history of acute inflammatory heart disease, within 3 months prior to screening, e.g., acute myocarditis
11. Acute coronary syndrome, including unstable angina, NSTEMI or STEMI, or major CV surgery including CABG, PCI within 3 months prior to screening
12. Implantation of a CRT device within 3 months prior to screening
13. Stroke or carotid angioplasty within 3 months prior to screening
14. History of heart transplant or need for urgent heart transplantation, or presence of left ventricular assist device
15. Any primary cause of HF scheduled for surgery or interventional therapy (e.g., TAVI), e.g., valve disease such as severe aortic stenosis or mitral valve regurgitation
16. Hemodynamically significant ventricular arrhythmias or therapeutic defibrillator shock within 4 weeks prior to screening
17. Resting HR while awake of < 50 BPM or > 110 BPM (in case of AF > 120 BPM) at the time of screening or at randomization
18. Symptomatic hypotension with systolic BP < 95 mmHg during screening or at randomization
19. Any systolic BP < 85 mmHg during screening or at randomization
20. Complex congenital heart disease
21. Sepsis or ongoing systemic inflammation
22. Hypertrophic obstructive or restrictive cardiomyopathy
23. Requirement of mechanical support or ultrafiltration/hemodialysis
24. Use of IV vasodilators or IV inotropic support within 24 hours prior to randomization or tolvaptan at any time during index hospitalization
25. Estimated GFR of < 30 ml/min/1.73 m2 determined by the MDRD equation at screening
26. Serum potassium ≥ 5.5 mmol/L or ≤ 3.3 mmol/L at screening
27. Serum sodium ≥ 146 mmol/L or ≤ 130 mmol/L at screening
28. Clinically relevant hepatic dysfunction
indicated by either: Aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal (ULN) or Child-Pugh B or C in cirrhotic patients (see Section 10.6.8 for the criteria)
29. Syndrome of Inappropriate Antidiuretic Hormone Secretion
30. Diabetes insipidus
31. Thyroid disease requiring current treatment and/or (sub)clinical hyperthyroidism or hypothyroidism
32. Concomitant treatment with potassium-sparing diuretic (with the exception of MRA) that cannot be stopped prior to randomization and for the duration of the treatment period
33. Concomitant treatment with strong and moderate inducers or inhibitors of CYP3A4
34. Concomitant treatment with probenecid
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PART A: Change in body weight and serum creatinine (Day 1 vs. Day 30)
PART B: Change in body weight and BUN/creatinine ratio (Day 30 vs. Day 60)
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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) |
• Safety by TEAE reporting (including SAE)
• Pharmacodynamics by change in augmentation index
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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 | 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Biomarkers and Quality of Life |
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| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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 |
| Bulgaria |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Poland |
| Portugal |
| Spain |
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| 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
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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 | 2 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 2 |
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