A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Evaluate the Safety and Efficacy of IV Infusion Treatment With Omecamtiv Mecarbil in Subjects With Left Ventricular Systolic Dysfunction Hospitalized for Acute Heart Failure

Omecamtiv mecarbil (AMG 423, CK-1827452) is a novel small molecule that
increases cardiac contractility by selectively and directly activating the
enzymatic domain of cardiac myosin heavy chain, the force-generating motor
protein of the cardiac sarcomere.
An unmet need exists for more effective and safe strategies to treat acute
heart failure. Although available inotropes improve hemodynamics, their use
has been associated with clinical liabilities and increased mortality that
severely restrict their use. In contrast to currently available inotropes,
omecamtiv mecarbil does not raise intracellular calcium, which can increase
heart rate and myocardial oxygen consumption, and cause arrhythmias.
This study is conducted to gather information on the safety and efficacy of
three increasing dose levels of omecamtiv mecarbil. It is expected that at
least 1 dose level of omecamtiv mecarbil IV will be well tolerated and will
result in improvement of dyspnea in subjects with left ventricular systolic
dysfunction hospitalized for acute heart failure.

The primary objective of the study is to evaluate the effect of 48 hours of
intravenous (IV) omecamtiv mecarbil compared with placebo on dyspnea in
subjects with left ventricular systolic dysfunction hospitalized for acute
heart failure.

Secondary:
* To assess the safety and tolerability of 3 dose levels of IV omecamtiv
mecarbil compared with placebo in subjects with left ventricular systolic
dysfunction hospitalized for acute heart failure
* To evaluate the effects of 48 hours treatment with IV omecamtiv mecarbil on
additional measures of dyspnea, patient global assessment (PGA), change in
N-terminal pro brain-type natriuretic peptide (NT-proBNP) and short-term
clinical outcomes
* To characterize pharmacokinetics of omecamtiv mecarbil, including metabolites
M1 and M3, following IV infusion and to evaluate the relationship between
omecamtiv mecarbil plasma concentration and echocardiographic parameters in
subjects with acute heart failure

This is a multicenter, randomized, double-blind, placebo-controlled study with
3 dose cohorts enrolled sequentially in order of ascending dose strength of
omecamtiv mecarbil.
In each cohort, subjects are randomized 1:1 to omecamtiv mecarbil or placebo.
The safety risk to study subjects will be evaluated on an ongoing basis through
regular review of unblinded data by an independent Data Monitoring Committee
(DMC). Before proceeding to the next higher dose strength, the safety,
tolerability, and PK data of omecamtiv mecarbil at the lower dose(s) will be
evaluated by the DMC which will issue a recommendation whether to proceed or
whether to make any changes. Subjects will be enrolled within 24 hours after
their initial IV furosemide (or alternative IV loop diuretic) dose.
Randomization will be stratified by region and by planned participation in the
pharmacokinetic/pharmacodynamic (PK/PD) substudy (see below). Omecamtiv
mecarbil or placebo will be infused IV over 48 hours (4 hours loading infusion,
followed by 44 hours maintenance infusion). Subjects will remain hospitalized
for at least 24 hours after termination of the IV infusion. Evaluations are
scheduled at 2, 4, and 6 hours, once at 12 to 18 hours and then daily until
discharge or 7 days after initiation of investigational product (study day 8),
whichever is earlier, and on the day of discharge from inpatient treatment.
Active study participation of an enrolled subject concludes with an
end-of-study visit at day 30. For a mortality analysis, the investigator will
obtain the vital status of the subject at month 6 and, if deceased, will obtain
the date and reported cause of death. All subjects will be invited to
participate in a biomarker and pharmacogenetic substudy. At a number of sites,
subjects will be invited to participate in a PK/PD substudy with additional
blood sampling for PK analysis and with echocardiography imaging.

Treatment with IV omecamtiv mecarbil

Risk: Adverse effects of study medication and procedures
Burden: Maximum duration of 1 month follow up after 6 months. Up to 8 visits
(most of the procedures are performed while the patient is hospitalized for
acute heart failure).
1x 48 hours IV (dose depending on the patient's cohort, 384 ml in total).
Follow up 4 hours after infusion rate adjustments, after 24 hours infusion bag
replacement.
Physical examination 2x, vital signs 12x
8x blood, approximately 160 ml, plus 70 ml for PKPD substudy
Pregnancy test (if applicable) 2x
ECG 6x, plus 3x for PKPD substudy
Questionnaires 8x