A Trial to Study BAY1753011 in Patients With Congestive Heart Failure (AVANTI)

Bayer

Status and phase: Completed; Phase 2

Conditions: Heart Failure (HF)

Treatments: Drug: Furosemide; Drug: BAY 1753011; Other: Placebo BAY 1753011; Other: Placebo Furosemide

Study type: Interventional

Funder types: Industry

Identifiers

NCT03901729

2018-004059-18 (EudraCT Number)

17909

Details and patient eligibility

About

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.

Enrollment: 482 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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482 participants in 6 patient groups, including a placebo group

Arm 1

Experimental group

Description:

BAY1753011 30mg in addition to standard of care (SoC) for part A and part B

Treatment:

Drug: BAY 1753011

Arm 2

Placebo Comparator group

Description:

Placebo of BAY1753011 in addition to SoC for part A and part B

Treatment:

Other: Placebo BAY 1753011

Arm 1-A

Experimental group

Description:

BAY1753011 30mg in addition to Placebo Furosemide 80mg for part B

Treatment:

Other: Placebo Furosemide

Drug: BAY 1753011

Arm 1-B

Active Comparator group

Description:

Furosemide 80mg in addition to Placebo BAY1753011 30mg for part B

Treatment:

Other: Placebo BAY 1753011

Drug: Furosemide

Arm 2-A

Experimental group

Description:

BAY1753011 30mg in addition to Placebo Furosemide 80mg for part B

Treatment:

Other: Placebo Furosemide

Drug: BAY 1753011

Arm 2-B

Active Comparator group

Description:

Furosemide 80mg in addition to Placebo BAY1753011 30mg for part B

Treatment:

Other: Placebo BAY 1753011

Drug: Furosemide