A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY 58-2667 (50 µg/h, 100 µg/h, 150 µg/h) Given Intravenously to Subjects with Acute Decompensated Chronic Congestive Heart Failure (ADHF) within 12 hours after hospital admission (Pulmonary Artery Catheter eg, Swan-Ganz not required) - COMPOSE EARLY

• Register: EUCTR
• Last refreshed on: 14 August 2012
• Main ID: EUCTR2009-017082-39-DE
• Date of registration: 04/02/2010
• Prospective Registration: Yes
• Primary sponsor: Bayer Healthcare AG
• Public title: A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY 58-2667 (50 µg/h, 100 µg/h, 150 µg/h) Given Intravenously to Subjects with Acute Decompensated Chronic Congestive Heart Failure (ADHF) within 12 hours after hospital admission (Pulmonary Artery Catheter eg, Swan-Ganz not required) - COMPOSE EARLY
• Scientific title: A Placebo Controlled, Randomized, Double-Blind, Fixed-dose, Multicenter, Phase IIb Study to Investigate the Efficacy and Tolerability of BAY 58-2667 (50 µg/h, 100 µg/h, 150 µg/h) Given Intravenously to Subjects with Acute Decompensated Chronic Congestive Heart Failure (ADHF) within 12 hours after hospital admission (Pulmonary Artery Catheter eg, Swan-Ganz not required) - COMPOSE EARLY
• Date of first enrolment: 30/03/2010
• Target sample size: 160
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-017082-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Czech Republic, Finland, France, Germany, Hungary, Ireland, Italy, Spain, United Kingdom

Key inclusion & exclusion criteria

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 (ie, the follow-up visit):
a) Double-barrier methods of contraception (eg, condoms plus spermicidal foam)
b) Intrauterine contraceptive device
c) Approved pharmaceutical contraceptive product (eg, birth control pills or patches, long-term injectable or implantable hormonal contraceptive)
• Able to commence treatment within 12 hours of hospital admission (including emergency department)
• Subjects with ADHF, NYHA functional class III-IV requiring hospitalization
• 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
• Treatment with IV diuretic (after hospital admission)
• Subjects must experience worsening of both of the symptoms listed below leading to hospitalization admission up to study run-in. Worsening of these symptoms does not need to be displayed at baseline. o 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 o 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 (subject or legal representative)
• Subject is capable of self-assessing his/her well being by applied scales after Instruction
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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 and 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 insufficien

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Acute Decompensated Chronic Congestive Heart Failure (ADHF)
MedDRA version: 9.1 Level: LLT Classification code 10064653 Term: Acute decompensated heart failure

Intervention(s)

Product Name: BAY 58-2667
Product Code: BAY 58-2667
Pharmaceutical Form: Intravenous infusion
INN or Proposed INN: cinaciguat
CAS Number: 329773-35-5
Current Sponsor code: BAY 58-2667
Concentration unit: % (W/V) percent weight/volume
Concentration type: equal
Concentration number: 0.005-
Pharmaceutical form of the placebo: Intravenous infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Primary end point(s): Change from baseline (defined as the assessment within 60 minutes before start of study drug infusion) to 8 hours (or LOCF) on the Dyspnea VAS.

Secondary Objective: To evaluate the potential effects of the three fixed doses of BAY 58-2667 (50 µg/h, 100 µg/h, and 150 µg/h) and placebo given intravenously on QT/QTc prolongation.

Main Objective: To investigate the safety and efficacy of a fixed dose of intravenous BAY 58-2667 (50 µg/h, 100 µg/h, or 150 µg/h) over at least 24 hours and up to 48 hours in subjects with ADHF needing parenteral pharmacotherapy. The focus of the study will be to evaluate the subjects’ well-being based on the subjects’ symptoms and reported outcomes ie, Dyspnea VAS, Likert score, and EQ-5D at baseline, 8 hours, 24 hours, 48 hours, at discharge (or at Day 7), and at the follow-up visit, and the global clinical assessment by the physician at 8 hours, 24 hours and 48 hours. The primary efficacy endpoint will be the change from baseline to 8 hours (or Last Observation Carried Forward [LOCF]) on the Dyspnea VAS.

Secondary ID(s)

2009-017082-39-FI

Bay 58-2667 / 14836