A Trial to Study BAY1753011 in Patients With Congestive Heart Failure

A Multicenter, Randomized, Parallel Group, Double Blind, Active and Placebo Controlled Study of BAY1753011, a Dual V1a/V2 Vasopressin Receptor Antagonist, in Patients With Congestive Heart Failure: AVANTI Study

To assess the efficacy of 30 mg of BAY1753011, with or without furosemide, versus furosemide alone in patients with heart failure and objective evidence of congestion.

Inclusion Criteria:

• History of CHF 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.

• Subjects admitted to the hospital with a primary diagnosis of decompensated HF including symptoms and signs of fluid overload requiring IV diuretic therapy in the Emergency room (ER) or any time between day 1-3 of hospital admission (index hospitalization).

• Subjects on an average/usual total daily dose of loop diuretic ≥ 40 mg of furosemide or equivalent, within 4 weeks prior to index hospitalization.

• At least one of the following 5 parameters any day between 3-7 of index hospitalization (screening period)

  • Natriuretic peptides Brain natriuretic peptide/N-terminal prohormone of brain natriuretic peptide (BNP/NT-proBNP):

    • Drop in BNP or NT-proBNP ≤ 30% from admission values (if measured during index hospitalization) or
    • BNP ≥ 500 pg/ml or NT-proBNP ≥ 1800 pg/ml at screening (day 3 to 7 of index hospitalization)

  • Body weight (BW) loss <0.4 kg per 40 mg furosemide at day 4 of index hospitalization

  • Composite congestion score (CCS) ≥ 3

  • Hypervolemic hyponatremia defined as serum sodium < 136 mmol/l

  • 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

    • Jugular venous pressure (JVP) ≥ 10 cm on physical examination
    • Inferior vena cava (IVC) diameter > 21 mm
    • IVC collapse with sniff < 50%
    • At least 2+ peripheral edema or pulmonary edema or pleural effusion on chest X-ray or clinical exam

Exclusion Criteria

• Active or history of acute inflammatory heart disease, within 3 months prior to screening, e.g., acute myocarditis
• Acute coronary syndrome, including unstable angina, Non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), or major Cardiovascular (CV) surgery including coronary artery bypass graft (CABG), percutaneous coronary intervention (PCI) within 3 months prior to screening
• 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
• Requirement of mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) or ultrafiltration/hemodialysis
• Estimated glomerular filtration rate of < 30 ml/min/1.73 m*2 determined by the Modified Diet and Renal Disease equation at screening; reassessments allowed as clinically needed
• Serum potassium ≥ 5.5 mmol/L or ≤ 3.3 mmol/L at screening; reassessments allowed as clinically needed
• Serum sodium ≥ 146 mmol/L or ≤ 130 mmol/L at screening; reassessments allowed as clinically needed
• Concomitant treatment with potassium-sparing diuretic (with the exception of mineralocorticoid- receptor antagonist (MRA) that cannot be stopped prior to randomization and for the duration of the treatment period.