Study With Omecamtiv Mecarbil (CK-1827452) to Treat Chronic Heart Failure With Severely Reduced Ejection Fraction

This study is designed to evaluate the efficacy and safety of omecamtiv mecarbil in reducing the risk of the primary composite endpoint of cardiovascular (CV) death, first heart failure (HF) event, left ventricular assist device (LVAD) implantation, cardiac transplantation, and stroke in patients with symptomatic heart failure with severely reduced ejection fraction (HFrEF).

Eligible patients will be randomized 1:1 to investigational product (IP) - omecamtiv mecarbil or placebo. The study is event-driven and will conclude when at least 850 participants experience a HF event or CV death, whichever comes first. An interim analysis for futility and efficacy based on the primary composite endpoint is planned when approximately 570 (67%) of the planned 850 first HF events or CV deaths are observed.

Estimated duration of participation: Up to 3 years.

Inclusion criteria

Adult patients who meet all the following criteria at screening may be included in the study:

• Are between ≥ 18 years and ≤ 85 years at the signing of informed consent
• Have a history of chronic HFrEF, defined as requiring treatment for HF for a minimum of 3 months prior to screening
• Are receiving oral loop diuretics on a regular schedule
• Patients without AFF on screening ECG:

• LVEF < 30% within 6 months of screening
• Elevated N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) ≥ 1000 pg/mL (BNP ≥ 300 pg/mL)
• Patients with AFF on screening ECG:

• LVEF < 25% within 6 months of screening
• Elevated N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) ≥ 3000 pg/mL (BNP ≥ 900 pg/mL)
• Not currently taking digoxin
• Meet one of the following criteria for a recent HF event:

• Are currently hospitalized with the primary reason of HF
• Had an HF event (as defined in the primary endpoint) within 12 months prior to screening. For the purposes of a qualifying HF event, subcutaneous furosemide will be treated as equivalent to intravenous furosemide Or
• Had outpatient escalation of oral diuretics due to worsening signs and symptoms of heart failure plus one of two additional criteria sustained for at least 1 week: (1) at least 50% or 1.5-fold increase in daily loop-diuretic-equivalent dose; (2) the addition of a new diuretic class to a loop diuretic.
• Are established on regional standard-of-care HF therapies for at least 30 days prior to screening
• Systolic blood pressure ≤ 140 mmHg

Exclusion criteria

Any of the following criteria will exclude potential patients from the study:

• Have AFF on the screening ECG and are currently taking digoxin
• Have had any event or procedure that may have resulted in a change in ejection fraction, including, but not limited to, acute coronary syndrome and/or any coronary revascularization, cardiac surgery, valve surgery, any coronary revascularization, and/or cardiac resynchronization, or cardiac contractility modulation therapy within 3 months of screening
• Are admitted to a long-term care facility or hospice
• Have a projected survival of < 12 months due to non-cardiovascular causes based on clinical judgment
• Are receiving intravenous inotropes or intravenous vasopressors ≤ 3 days prior to screening
• Are receiving mechanical hemodynamic support or mechanical ventilation ≤ 7 days prior to screening
• Are receiving intravenous diuretics, intravenous vasodilators, or supplemental oxygen therapy ≤ 12 hours prior to screening (except for nocturnal supplemental oxygen for sleep apnea or heart failure)
• Have an estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 or receiving dialysis at screening
• Have previously had a solid organ transplant
• Are receiving treatment in another investigational device or drug study or are within 30 days of ending such investigational treatment at screening
• Have received omecamtiv mecarbil in a previous clinical trial
• Are pregnant or planning pregnancy during the study period, or planning to breastfeed during treatment with IP or within 5 days after the end of treatment with IP
• Have primary infiltrative cardiomyopathy (e.g. cardiac amyloidosis) or severe stenotic valvular disease