E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Decompensated Chronic Congestive Heart Failure (ADHF) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064653 |
E.1.2 | Term | Acute decompensated heart failure |
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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 |
The primary objective of this study is to investigate the safety and efficacy of a fixed dose (10 µg/h or 25 µg/h) over at least 24 hours and up to 48 hours of intravenous BAY 58-2667 in subjects with acute decompensated chronic congestive heart failure needing parenteral pharmacotherapy and invasive hemodynamic monitoring (ie, indwelling pulmonary artery catheter [Swan-Ganz]) and pulmonary capillary wedge pressure (PCWP) ≥ 20 mmHg with CI ≤ 2.5. The primary endpoint will be to evaluate the PCWP reduction at eight hours.
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E.2.2 | Secondary objectives of the trial |
to evaluate the potential effects of three fixed doses of BAY 58-2667 (10 μg/h and 25 μg/h ) and placebo given intravenously on QT/QTc prolongation. An extended ECG/QT monitoring will be performed in this study. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Women without childbearing potential defined as postmenopausal women aged 55 years or older, women with bilateral tubal ligation, women with bilateral ovarectomy, and women with hysterectomy or Males and non-pregnant, non-lactating females, 18 years of age or older. For females of child-bearing potential, one of the following medically acceptable contraceptive methods must be used or they agree to abstain from heterosexual intercourse while participating in the study. One or more of these methods should be used during the study and continue for 30 days after completion of the study (i.e., the follow-up visit) : - Double-barrier methods of contraception (eg, condoms plus spermicidal foam) - Intrauterine contraceptive device - Approved pharmaceutical contraceptive product (eg, birth control pills or patches, long-term injectable or implantable hormonal contraceptive) • Subjects with ADHF, NYHA functional class III-IV, requiring hospitalization, and with clinical indication for parenteral pharmacotherapy and invasive hemodynamic monitoring (ie, in-dwelling pulmonary artery catheter [Swan-Ganz]) and PCWP ≥ 20 mmHg with CI ≤ 2.5 at run-in and baseline Note: PCWP and CI must be re-checked at baseline, immediately before starting study drug infusion, to ensure that this criterion is still met • Subjects must have the clinical diagnosis of CHF, either ischemic or non-ischemic, made at least three months prior to enrollment and a history of heart failure hospitalization or IV diuretic treatment required within the last 12 months • Subjects must experience worsening of both of the symptoms listed below leading to hospitalization at the time of hospital admission up to study run-in. Worsening of these symptoms does not need to be displayed at baseline. - Dyspnea Symptoms: > Dyspnea (labored or difficult breathing) at rest or > Dyspnea (labored or difficult breathing) on minimal exertion or > Orthopnea (difficult breathing except in the upright position) or > Nocturnal dyspnea (awaken from sleep due to respiratory distress) And - Clinical evidence of volume overload: > Peripheral edema or > Hepatic congestion with ascites or > Rales or pulmonary congestion or > Jugular venous distension • Left ventricular ejection fraction ≤40 % measured by any modality (echocardiography, nuclear testing, cardiac magnetic resonance imaging [MRI], ventricular angiography) in the patient’s medical history without intervening revascularization or cardiac surgery in the meantime • Systolic blood pressure ≥ 120 mm Hg and heart rate < 100 beats per minute [shock index (heart rate/systolic blood pressure) < 1] at run-in and baseline. Note: blood pressure and heart rate must be re-checked at baseline, immediately before starting study drug infusion, to ensure that this criterion is still met. • Ability to understand and willing to sign informed consent form
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E.4 | Principal exclusion criteria |
• Systolic blood pressure > 180 mm Hg at run-in or baseline. Note: blood pressure must be re-checked at baseline, immediately before starting study drug infusion, to ensure that this criterion is still met. • Acute de-novo heart failure • Acute myocardial infarction and/or myocardial infarction within the last 30 days • Valvular heart disease requiring surgical intervention during the course of the study • Heart failure due to or associated with uncorrected primary valvular disease, malfunctioning artificial heart valve, or uncorrected congenital heart disease • Primary hypertrophic cardiomyopathy • Acute inflammatory heart disease, eg; acute myocarditis • Unstable angina requiring angiography • Cardiogenic shock • Subjects requiring any of the following medication: any intravenous vasodilating drug (eg, nitrates, nitroprusside) or any intravenous natriuretic peptide (eg, nesiritide, carperitide) within the last 3 hours prior to dosing with study medication, or any catecholamine or levosimendan within the last 30 days prior to dosing with study medication • Need for endotracheal intubation and mechanical ventilation • Subjects with cardiac arrest or subjects with history of cardiac arrest within three months, unless precipitated by an event such as an acute myocardial infarction, induction by catheter placement, severe transient electrolyte abnormality, an electrophysiology procedure, or addressed by automatic implantable cardioverter defibrillator placement or pacemaker • Subjects with increased risk of cardiac arrest (eg, QTc > 450 msec in males and QTc > 470 msec in females, atrial ventricular block II or III) • Ventricular fibrillation within the last 30 days (duration > 15 seconds), unless precipitated by a transient event or addressed by an implantable cardioverter defibrillator (ICD) • Subjects showing during ECG monitoring sustained or unsustained ventricular tachycardia, either monomorphic or polymorphic (unless precipitated by an event such as catheter placement) • Uncontrolled atrial fibrillation or flutter or any supraventricular tachycardia with a ventricular rate more than 100 bpm for more than 30 minutes • Cardiac surgery within the last 30 days (such as cardiac revascularization surgery, valvular surgery, biventricular resynchronization procedure, ventricular reduction surgery or cardiac myoplasty, implantation of mechanical ventricular assist device) • Implantation of a device (such as hemodynamic transcutaneous device, pacemaker, cardiac resynchronization therapy, or implantable cardioverter defibrillator within 30 days prior to enrollment • Pulmonary embolism within the last 30 days prior to enrollment • PDE 3 or PDE-5 inhibitor use within the last 48 hours prior to onset of study drug infusion • Strong CYP2C8 inhibitors like gemfibrozil or montelukast (must have already been stopped at least 24 hours before study drug infusion) • Heart failure secondary to pulmonary disease and subjects with primary pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension • History of or clinically significant evidence of any severe disease other than heart failure that preclude participation • Clinical relevant hepatic dysfunction (eg, induced by acute clinical hepatitis, chronic active hepatitis, cirrhosis) indicated by one of the following : - bilirubin > 2 times upper limit normal and alanine aminotransferase (ALT) > 3 times upper limit normal OR - signs of severe hepatic insufficiency (eg, impaired albumin synthesis with albumin < 35g/l, hepatic encephalopathy > Stage 1 [according to West Haven Criteria of Altered Mental Status In Hepatic Encephalopathy) • Body mass index (BMI ) ≤ 20 kg/m2 • eGFR <30 mL/min using MDRD (Modification of Diet Renal Disease) • Ongoing drug or alcohol abuse • Concomitant participation in another trial or study • Therapy with another investigational product within 30 days prior start of study • Any other condition or therapy, which would make the subject unsuitable for this study and presumably, will not allow participation for the full planned study period
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E.5 End points |
E.5.1 | Primary end point(s) |
Change of pulmonary capillary wedge pressure (PCWP) from baseline to eight hours. |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | Information not present in EudraCT |
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 |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 15 |