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-HU
• Date of registration: 05/07/2010
• Prospective Registration: No
• 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: 30/04/2010
• 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:
• 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
• Dyspnea (labored or difficult breathing) on minimal exertion
• Orthopnea (difficult breathing except in the upright position)
• Nocturnal dyspnea (awaken from sleep due to respiratory
• distress)
And
o Clinical evidence of volume overload:
• Peripheral edema
• Hepatic congestion with ascites
• Rales or pulmonary congestion (confirmed by chest X-ray)
• Jugular venous distension
• Left ventricular ejection fraction < 40 % within the last 12 months
• Systolic blood pressure at inclusion of the study = 120 mmHg and = 180 mmHg
• Heart rate < 100 beats per minute
• 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
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:
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)

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:
• Acute de-novo heart failure
• Acute myocardial infarction and/or myocardial infarction within 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 vasodilating drug (eg,
nitrates, sodium nitroprusside), any intravenous positive inotropic drug (eg,
levosimendan, dobutamine), or any natriuretic petide (eg, nesiritide, carperitide)
within the last three hours 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
• Subjects with increased risk of cardiac arrest (eg, QTc > 450 msec, atrial
ventricular block II or III)
• Sustained ventricular tachycardia within 30 days (duration > 15 seconds)
• 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 110 bpm for more than 30 minutes
• Cardiac surgery within the last month (such as cardiac revascularization surgery,
valvular surgery, biventricular resynchronization procedure, ventricular reduction
surgery or cardiac myoplasty, implantation of mechanical ventricular assist device)
• Pulmonary embolism within the last 30 days prior to enrollment
• PDE 3 inhibitor use within the last 48 hours prior to onset of study drug infusion
• Strong CYP2C8 inhibitors like gemfibrozil (stop 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:
- bilirubin > 2 times upper limit normal
- and/or hepatic transaminases > 3 times upper limit normal
- and/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: Stage
0: Lack of detectable personality changes. No asterixis; Stage 1: Trivial
lack of awareness. Impaired attention span. Altered sleep, euphoria or
depression. Mild asterixis may be present; Stage 2: Lethargy or apathy.
Disorientation. Inappropriate behavior. Slurred speech. Asterixis; Stage 3:
Gross disorientation. Bizarre behavior. Semi-stupor. Asterixis absent; Stage
4: Coma)
• Calculated creatinine clearance < 30 mL/min. using MDRD (Modification of Diet
Renal Disease)
• Body mass index (BMI) < 20 kg/m2 (BMI equal to

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)

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.

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.

Secondary ID(s)

Bay 58-2667 / 14836

2009-017082-39-FI