Single Dose Escalation Study in Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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This study is to demonstrate the safety and tolerability of a single oral dose of BAY60-4552 in a single dose escalation design. Furthermore, this study examines the changes in hemodynamics after application of the test substance.42 hospitalized stable patients with chronic heart failure will be included. Several measurements will be performed to test how good the drug works and wether there are any unwanted reactions to the drug (e.g. blood tests, ECG, heart rate, blood pressure, adverse events). After a observation period the patient will be discharged from the hospital.

Official Title
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Proof of Concept Study to Investigate Safety, Tolerability, Pharmacokinetics and the Impact on Pulmonary and Systemic Hemodynamics of a Single Oral Dose of BAY60-4552 in Patients With Biventricular Chronic Heart Failure and Pulmonary Hypertension in a Non-randomized, Non-blinded, Dose Escalation Design.

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: BAY60-4552


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic heart failure, undergoing routine invasive measurement of hemodynamic parameters Exclusion Criteria: Acute heart failure or acute decompensated heart failure, need for acute cardiologic intervention or surgery, severe renal or hepatic insufficiency, severe valvular disease

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAY60-4552, 1 mg<br>Subjects were planned to receive 1 mg of BAY60-4552 as solution | Drug: BAY60-4552<br>* Single dose escalation planned at dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg<br>|
| Experimental: BAY60-4552, 2.5 mg<br>Subjects were planned to receive 2.5 mg of BAY60-4552 as tablet | Drug: BAY60-4552<br>* Single dose escalation planned at dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg<br>|
| Experimental: BAY60-4552, 5 mg<br>Subjects were planned to receive 5.0 mg of BAY60-4552 as tablet | Drug: BAY60-4552<br>* Single dose escalation planned at dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg<br>|
| Experimental: BAY60-4552, 7.5 mg<br>Subjects were planned to receive 7.5 mg of BAY60-4552 as tablet | Drug: BAY60-4552<br>* Single dose escalation planned at dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg<br>|
| Experimental: BAY60-4552, 10 mg<br>Subjects were planned to receive 10 mg of BAY60-4552 as tablet | Drug: BAY60-4552<br>* Single dose escalation planned at dose of 1 mg, 2.5 mg, 5 mg, 7.5 mg, and 10 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pulmonary capillary wedge pressure |  | Pre-dose and up to 6 hr post-dose | 
| Change in mean pulmonary artery pressure |  | Pre-dose and up to 6 hr post-dose | 
| AUC | Area under the plasma concentration vs time curve from zero to infinity after single dose | Pre-dose and up to 72 hr post-dose | 
| AUC/D | AUC divided by dose (mg) | Pre-dose and up to 72 hr post-dose | 
| Cmax | Maximum drug concentration in plasma after single dose administration | Pre-dose and up to 72 hr post-dose | 
| Cmax/D | Cmax divided by dose (mg) | Pre-dose and up to 72 hr post-dose | 
| Number of participants with adverse events |  | Approximately 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean right atrial pressure |  | Pre-dose and up to 6 hr post-dose | 
| Systolic pulmonary artery pressure |  | Pre-dose and up to 6 hr post-dose | 
| Diastolic pulmonary artery pressure |  | Pre-dose and up to 6 hr post-dose | 
| Heart rate |  | At pre-study visit, pre-dose and up to 24 hr post-dose | 
| Cardiac output |  | Pre-dose and up to 6 hr post-dose | 
| Pulmonary vascular resistance |  | Pre-dose and up to 6 hr post-dose | 
| Pulmonary vascular resistance index |  | Pre-dose and up to 6 hr post-dose | 
| Systemic vascular resistance |  | Pre-dose and up to 6 hr post-dose | 
| Systemic vascular resistance index |  | Pre-dose and up to 6 hr post-dose | 
| Cardiac index |  | Pre-dose and up to 6 hr post-dose | 
| Mean arterial pressure |  | Pre-dose and up to 6 hr post-dose | 
| Systemic blood pressure |  | At pre-study visit, pre-dose and up to 24 hr post-dose | 
| Diastolic blood pressure |  | At pre-study visit, pre-dose and up to 24 hr post-dose | 
| Dyspnea Score | Subject is asked unpersuasively about his/her well-being in comparison to the baseline condition, measured on a 7-point Likert scale. | Pre-dose and up to 48 hr post-dose | 
| AUC(0-6) | AUC from time 0 to 6 h after study drug intake | Pre-dose and up to 6 hr post-dose | 
| AUCnorm | AUC divided by dose (mg) per kg body weight | Pre-dose and up to 72 hr post-dose | 
| AUC(0-tn) | AUC from time 0 to the last data point | Pre-dose and up to 72 hr post-dose | 
| AUC(0-tn)norm | AUC(0-tn) divided by dose (mg) per kg body weight | Pre-dose and up to 72 hr post-dose | 
| Cmax,norm | Cmax divided by dose (mg) per kg body weight | Pre-dose and up to 72 hr post-dose | 
| tmax | Time to reach maximum drug concentration in plasma after single dose | Pre-dose and up to 72 hr post-dose | 
| t½ | Half-life associated with the terminal slope | Pre-dose and up to 72 hr post-dose | 
| Mean residence time |  | Pre-dose and up to 72 hr post-dose | 
| Total body clearance of drug from plasma calculated after oral administration (apparent oral clearance) |  | Pre-dose and up to 72 hr post-dose | 
| Apparent volume of distribution associated with the terminal phase (after oral administration) |  | Pre-dose and up to 72 hr post-dose | 
| Amount of drug excreted via urine |  | Pre-dose and up to 6 hr post-dose | 
| Percent amount of drug excreted via urine |  | Pre-dose and up to 6 hr post-dose | 
| Renal clearance of drug |  | Pre-dose and up to 6 hr post-dose | 
| Renin activity |  | Pre-dose and up to 24 hr post-dose | 
| Change from baseline of noradrenaline after drug administration |  | Pre-dose and up to 24 hr post-dose | 
| N-terminal pro-atrial natriuretic peptide |  | Pre-dose and up to 24 hr post-dose | 
| NT-pro B-type natriuretic peptide |  | Pre-dose and up to 24 hr post-dose | 
| Big endothelin-1 |  | Pre-dose and up to 24 hr post-dose | 
| Cystatin C |  | Pre-dose and up to 24 hr post-dose | 
| Change from baseline of osteopontin after drug administration |  | Pre-dose and up to 24 hr post-dose | 
| Cyclic guanosine mono-phosphate |  | Pre-dose and up to 24 hr post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biventriular chronic heart failure, Pulmonary hypertension