GALACTIC-HF: A Double-blind, Randomized, Placebo-controlled, Multicenter Study to Assess the Efficacy and Safety of Omecamtiv Mecarbil on Mortality and Morbidity in Subjects With Chronic Heart Failure With Reduced Ejection Fraction

HF is a clinical syndrome marked by impaired cardiac contractility and is a final pathway for many diseases that affect the heart. HF affects over 26 million people worldwide, with more than 3.5 million people newly diagnosed every year. While several pharmacological and non-pharmacological intervention have been shown to reduce the rate of HF hospitalizations and improve mortality, including angiotensin-converting enzyme inhibitors (ACEis), beta-blockers, aldosterone antagonists, coronary revascularization, and biventricular pacing, mortality and morbidity still remain high.

Reduced LVEF is a central factor in HF, yet there are no safe medical therapies to directly improve cardiac function at the level of the cardiac sarcomere in HF patients. Attempts to improve cardiac contractility through chronic stimulation of the adrenergic receptor pathway (e.g. dobutamine or ibopamine) or phosphodiesterase inhibitors (i.e. milrinone) in chronic HF patients have not been successful.

Omecamtiv Mecarbil is a promising new oral therapeutic agent for HFrEF patients targeting myocardial contractility. Current recommended pharmacological therapies for chronic HF aim at blocking/controlling the physiological compensatory mechanism. Therapeutic options to directly improve myocardial contractility for these patients are lacking.

The study aims to evaluate the effect of treatment with Omecamtiv Mecarbil (OM) compared with placebo on time to cardiovascular (CV) death or first Heart Failure event in subjects with chronic HF with reduced ejection fraction (HFrEF) receiving standard of care (SoC) therapy.

Inclusion Criteria
101 Subject has provided informed consent
102 Male or female, ≥ 18 to ≤ 85 years of age at signing of informed consent
103 History of chronic HF (defined as requiring treatment for HF for a minimum of 30 days before randomization)
104 LVEF ≤ 35%, per subject’s most recent medical record, not in the setting of acute decompensation
105 NYHA class II to IV at most recent screening assessment
106 Managed with HF SoC therapies consistent with regional clinical practice guidelines according to investigator judgment of subject’s clinical status
Oral SoC therapies for chronic HF (eg, beta blockers, renin-angiotensin-aldosterone system inhibitors) should be present, if not contraindicated. Subjects enrolled during either HF hospitalization or early after
HF hospitalization discharge can be reinitiating or titrating oral SoC chronic HF therapies at the same time of randomization with the goal of achieving optimized therapy on study.
107 Current hospitalization with primary reason of HF or prior HF hospitalization, or urgent HF admission to emergency department (ED)within 1 year prior to
screening
108 B-type natriuretic peptide (BNP) level ≥ 125 pg/mL or an NT-proBNP level ≥ 400 pg/mL at most recent screening assessment (subjects receiving
angiotensin receptor-neprilysin inhibitor [ARNi] must use NT-proBNP assessment; for subjects with atrial fibrillation, the cut off levels are:
BNP ≥ 375 pg/mL or NT-proBNP ≥ 1200 pg/mL)

Exclusion Criteria
201 Currently receiving treatment in another investigational device or drug study, or < 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are
excluded.
202 Malignancy within 5 years prior to randomization with the following exceptions:
localized basal or squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, stage 1 prostate carcinoma, breast ductal carcinoma in situ.
203 Subject has known sensitivity to any of the products or components to be administered during dosing.
204 Subject not likely to be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator’s knowledge.
205 Inability to swallow study medication tablet (eg, swallowing disorders, feeding tubes)
206 Receiving mechanical hemodynamic support (eg, intra-aortic balloon pump counterpulsation), or mechanical ventilation (including non-invasive mechanical ventilation, ie, bilevel positive airway pressure [BiPAP] or continuous positive airway pressure [CPAP] devices) ≤ 7 days prior to randomization
207 Receiving IV inotropes (eg, dobutamine, milrinone, levosimendan) or IV vasopressors (eg, epinephrine, norepinephrine, dopamine, or vasopressin) ≤ 3 days prior to randomization
208 Receiving IV diuretics or IV vasodilators, or supplemental oxygen therapy ≤ 12 hours prior to randomization
209 Acute coronary syndrome (ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina), stroke, or transient ischemic attack, major cardiac surgery, percutaneous coronary intervention, or valvuloplasty within the 3 months prior to randomization
210 Implantable cardioverter defibrillator or initiation of cardiac resynchronization therapy (CRT) (with/without implantable cardioverter defibrillator) within 30 days prior to randomization
211 Severe uncorrected valvular heart disease, or hypertrophic obstructive cardiomyopathy, active myocarditis, constrictive pericarditis, or clinically
significant congenital heart disease
212 Untreated severe ventricular arrhythmia (eg, ventricular tachycardia or ventricular fibrillation)
213 Chronic antiarrhythmic therapy, with the exception of amiodarone. Note: for the purposes of this exclusion criterion, digoxin, calcium channel blocker, and beta-blocker therapy are not considered to be chronic antiarrhythmic therapies
214 Symptomatic bradycardia or second or third degree heart block without a pacemaker
215 Routinely scheduled outpatient intravenous infusions for HF (eg, inotropes, vasodilators [eg, nesiritide], diuretics) or routinely scheduled ultrafiltration
216 Systolic blood pressure > 140 mmHg or < 85 mmHg, or diastolic blood pressure > 90 mmHg, or heart rate > 110 beats per minute, or < 50 beats per minute at screening
217 Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73m2 or receiving dialysis at screening
218 Hepatic impairment defined by a total bilirubin (TBL) ≥ 2 times the upper limit of normal (ULN), or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times ULN at screening
219 Previously received OM
220 Severe, concomitant non-CV disease that is expected to reduce life expectancy to < 2 years
221 Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
222 Female subject of childbearing potential who is not willing to inform her partner of her participation in this clinical study and to use 2 acceptable methods of effective birth control or practice true sexual abstinence (the reliability of sexual abstinence must be evaluated by the investigator and be the preferred and usual lifestyle of the subject) during treatment with IP (OM or placebo) and for an additional 5 days after the last dose of IP. If the female subject or her sole male partner has had a surgical contraceptive method (bilateral tubal ligation/occlusion or vasectomy with medical assessment of surgical success), additional contraceptive methods are not required. Male subject with a female partner of childbearing potential and not willing to inform his partner of his participation in this clinical study.
- A female is considered of childbearing potential unless she has had a hysterectomy, bilateral oophorectomy, or bilateral salpingectomy or she is postmenopausal. Menopause is defined as ≥ 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old; or no spontaneous menses for at least 2 years in a female < 55 years old; or age < 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (eg, spontaneous or secondary to hysterectomy) and with follicle-stimulating hormone (FSH) levels > 40 IU/L, or postmenopausal estradiol levels (< 5 ng/dL), or according to the definition of “postmenopausal range” for the
laboratory involved.
- Two acceptable methods of effective birth control include the following 2 options:
− use of hormonal and barrier combination birth control methods (intrauterine device and barrier method with spermicide, intrauterine device and hormonal birth control method, hormonal birth control method and barrier method with spermicide),
− 2 barrier methods (each partner must use 1 barrier method except a female condom) with at least 1 of the barrier methods including spermicide (a male and female condom may not be used together due to the risk of tearing)
- Hormonal methods of birth control include oral, intravaginal, transdermal, injectable, or implantable. Barrier methods of birth control include diaphragm
with spermicide, cervical cap with spermicide, male or female condom with spermicide, and contraceptive sponge with spermicide. If spermicide is not commercially available in the local country/region a barrier method without spermicide is acceptable.
− Note: If additional medications are given during treatment which may alter the contraceptive requirements (these additional medications may
require an increase in the number of contraceptive methods and/or length of time that contraception is to be utilized after the last dose of protocol-required therapies) the investigator is to discuss these changes with the study subject.
223 Female subject is pregnant or breastfeeding or is planning to become pregnant or planning to breastfeed during treatment with IP (OM or placebo) or within 5 days after the end of treatment with IP.
224 Planned to be discharged from the hospital to long term care facility (eg, skilled nursing facility) or hospice.
225 History or evidence of any other clinically significant disorder (including cardiac arrhythmia), condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

Conditions:
• Cardiology