A Study of Ivabradine in African-American/ Black Subjects With Heart Failure and Left Ventricular Systolic Dysfunction.

The goal of this study is to determine the impact of adding ivabradine therapy to the
standard of care (SOC) in African-American/Black subjects with Heart Failure (HF) and reduced
ejection fraction (HFrEF) on changes in heart rate (HR) from baseline (SOC alone). Changes in
HR from baseline will be correlated with the genetic background of a subset of subjects with
available genetic data in the studied population, as well as with the changes from baseline
in activity level of the subjects, as measured by both a standard 6-minute walk distance and
an accelerometer device.

The primary hypothesis is that ivabradine effectively reduces HR between baseline and day 57
in African-American/Black subjects. Because mean reductions of approximately 5 beat per
minute (bpm) have been observed in the overall placebo-treated subjects in the SHIFT study as
well as in the placebo-treated subjects of the subgroup analysis of
non-African-American/Black subjects enrolled in the SHIFT study, we will test whether the
mean reduction with ivabradine exceeds 5 bpm, and estimate the degree to which the mean
reduction with ivabradine exceeds 5 bpm.

Inclusion Criteria:

- Subject has provided informed consent/assent prior to initiation of any study specific
activities/ procedures

- Male or female subject ≥ 18 years of age, describing self as African American/Black

- Must have a diagnosis of HF confirmed by medical records, be in stable condition, and
treated with stable optimal pharmacological therapy as per their personal physician's
care.

- LVEF ≤ 35% confirmed by investigator

- NYHA class II to IV assessed at the time of screening

- Electrocardiogram (ECG) documentation at the time of screening of sinus rhythm with
resting HR ≥ 70 bpm by local ECG reading

- Must be able to complete a 6MWT and wear an accelerometer

Exclusion Criteria:

- Recent myocardial infarction (≤ 2 months) or stroke (≤ 1 month) prior to enrollment

- If the subject received within 3 months before or is scheduled to receive within 42
days after enrollment any of the following: revascularization, ventricular assist
device, continuous or intermittent inotropic therapy, hospice care, major organ
transplant, or is receiving renal replacement therapy by dialysis

- If the subject received implantation of a cardioverter defibrillator or cardiac
resynchronization therapy within 42 days before or is scheduled to receive
implantation of a cardioverter defibrillator or cardiac resynchronization therapy
within 42 days after enrollment

- Severe primary valve disease or scheduled for surgery for valvular heart disease

- Pacemaker with atrial or ventricular pacing (except bi-ventricular pacing) >40% of the
time, or with a stimulation threshold at the atrial or ventricular level ≥ 60 bpm

- Permanent atrial fibrillation or flutter

- Sick sinus syndrome, sinoatrial block, or second and third degree atrio-ventricular
block

- History of symptomatic or sustained (≥ 30 sec) ventricular arrhythmia unless a
cardioverter defibrillator was implanted

- History of congenital QT syndrome

- Any cardioverter defibrillator shock experienced within 1 month of enrollment

- Hypertrophic obstructive cardiomyopathy, active myocarditis or constrictive
pericarditis, or clinically significant congenital heart disease

- Chronic antiarrhythmic therapy (except digitalis)

- Scheduled outpatient intravenous (IV) infusions for HF (eg, inotropes,vasodilators
[eg, nesiritide], diuretics) or routinely scheduled ultrafiltration

- Evidence of digitalis intoxication within 7 days prior to screening

- Systolic blood pressure > 180 mm Hg or < 90 mm Hg, or diastolic blood pressure > 110
mm Hg or < 50 mm Hg at any time during the screening phase

- Known untreated hypothyroidism or hyperthyroidism, adrenal insufficiency, active
vasculitis due to collagen vascular disease

- Have known acute or serious co-morbid condition (eg, major infection or hematologic,
renal, hepatic, metabolic, gastrointestinal or endocrine dysfunction) that may
interfere with the study, or severe concomitant non-cardiovascular disease that is
expected to reduce life expectancy to less than 1 year or malignancy within 5 years
prior to enrollment with the following exceptions: localized basal or squamous cell
carcinoma of the skin or cervical intraepithelial neoplasia

- Subjects taking QT prolonging medicinal products for cardiovascular (eg, but not
limited to, quinidine, disopyramide, bepridil, sotalol, ibutilide, amiodarone) or
non-cardiovascular disease (eg, but not limited to, pimozide, ziprasidone, sertindole,
mefloquine, halofantrine, pentamidine, cisapride, IV erythromycin).

- Subjects exposed to a strong CYP3A4 inhibitor (examples of strong CYP3A4 inhibitors
include; azole antifungals [eg, itraconazole], macrolide antibiotics [eg,
clarithromycin, telithromycin], human immunodeficiency virus (HIV) protease
inhibitors, [eg, nelfinavir], and nefazodone]) within 14 days prior to enrollment, or
to a strong CYP3A4 inducer (examples of CYP3A4 inducers include; St. John's wort,
rifampicin, barbiturates, and phenytoin) within 28 days prior to enrollment

- Subjects who received diltiazem or verapamil within 48 hours prior to enrollment.

- Previously received ivabradine prior to participation in this study

- Currently receiving treatment in another investigational device or drug study, or less
than 30 days since ending treatment on another investigational device or drug
study(ies). Other investigational procedures while participating in this study are
excluded.

- Female subject is pregnant or breastfeeding or planning to become pregnant or
breastfeed during treatment and for an additional 14 days after the last dose of
investigational product. Females of childbearing potential should only be included in
the study after a confirmed menstrual period and a negative highly sensitive urine
pregnancy test.

- Female subjects of childbearing potential unwilling to use 1 highly effective method
of contraception during treatment and for an additional 14 days after the last dose of
investigational product. Refer to Appendix 5 for additional contraceptive information.

- Subject has known sensitivity to any of the products or components to be administered
during dosing.

- Subject likely not 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.

- History or evidence of any other clinically significant disorder, 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.