A Trial to Study BAY1753011 in Patients With Congestive Heart Failure

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Heart Failure (HF)

Intervention / Treatment
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* Drug: BAY 1753011
* Other: Placebo BAY 1753011
* Drug: Furosemide
* Other: Placebo Furosemide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>BAY1753011 30mg in addition to standard of care (SoC) for part A and part B | Drug: BAY 1753011<br>* Tablet; 30mg or 5mg unit; 30mg once daily in the morning; Oral<br>|
| Placebo Comparator: Arm 2<br>Placebo of BAY1753011 in addition to SoC for part A and part B | Other: Placebo BAY 1753011<br>* Tablet; Once daily in the morning; Oral<br>|
| Experimental: Arm 1-A<br>BAY1753011 30mg in addition to Placebo Furosemide 80mg for part B | Drug: BAY 1753011<br>* Tablet; 30mg or 5mg unit; 30mg once daily in the morning; Oral<br>Other: Placebo Furosemide<br>* Tablet; Once daily in the morning; Oral<br>|
| Active Comparator: Arm 1-B<br>Furosemide 80mg in addition to Placebo BAY1753011 30mg for part B | Other: Placebo BAY 1753011<br>* Tablet; Once daily in the morning; Oral<br>Drug: Furosemide<br>* Tablet; 40mg unit; 80mg once daily in the morning; Oral<br>|
| Experimental: Arm 2-A<br>BAY1753011 30mg in addition to Placebo Furosemide 80mg for part B | Drug: BAY 1753011<br>* Tablet; 30mg or 5mg unit; 30mg once daily in the morning; Oral<br>Other: Placebo Furosemide<br>* Tablet; Once daily in the morning; Oral<br>|
| Active Comparator: Arm 2-B<br>Furosemide 80mg in addition to Placebo BAY1753011 30mg for part B | Other: Placebo BAY 1753011<br>* Tablet; Once daily in the morning; Oral<br>Drug: Furosemide<br>* Tablet; 40mg unit; 80mg once daily in the morning; Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PART A: Change in body weight |  | Compare Day 30 (End of part A) with Day 1 (Start of part A) | 
| PART A: Change in serum creatinine |  | Compare Day 30 (End of part A) with Day 1 (Start of part A) | 
| PART B: Change in body weight |  | Compare Day 60 (End of part B) with Day 30 (Start of part B) | 
| PART B: Change in log transformed blood urea nitrogen (BUN)/creatinine ratio |  | Compare Day 60 (End of part B) with Day 30 (Start of part B) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-emergent adverse event (including Serious adverse event) |  | From the time of first study drug administration up to 7 days after the last dose of study drug (Day 60) | 
| Change in augmentation index |  | Up to 60 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic heart failure (CHF), Heart failure with reduced ejection fraction (HFrEF), Heart failure with preserved ejection fraction (HFpEF), Heart failure with mid-range ejection fraction (HFmrEF)