A Randomized, Double-blind, Event-driven, Multicenter Study Comparing the Efficacy and Safety of Oral Rivaroxaban with Placebo for Reducing the Risk of Death, Myocardial Infarction or Stroke in Subjects with Chronic Heart Failure and Significant Coronary Artery Disease Following a Hospitalization for Exacerbation of Heart Failure

Heart Failure (HF) is a prothrombotic disease and thrombosis may be associated
with increased morbidity and mortality. For the last 15 to 20 years, more
research has centered around the hypercoagulable state that occurs in HF
patients. It has been observed in clinical studies that subjects with HF have
higher circulating levels of pro-coagulants. In addition, autopsy studies of
subjects with HF who died suddenly during a clinical trial had a high rate of
myocardial infarction (MI) or acute coronary events. Studies and guidelines
have reported that the prognosis after an index hospitalization for HF is poor
with a 50% readmission rate at 6 months and a 25% to 35% mortality rate at 12
months.
Although the results of previous studies with warfarin have demonstrated that
anticoagulation is associated with reduced rates of important clinical events
in patients with HF, results of these studies have not been conclusive. In a
recent Phase 3 study of rivaroxaban in acute coronary syndrome (ACS),
rivaroxaban was shown to reduce the incidence of the primary endpoint
(cardiovascular [CV] death, MI, or stroke) in a subset of subjects with a
history of HF (see Table 1 of the protocol). This supports the hypothesis that
rivaroxaban may help reduce thrombotic events in patients with HF that can lead
to death, MI or stroke. Thus, a large prospectively designed study with a novel
anticoagulant is warranted to adequately address whether or not rivaroxaban can
reduce the risk of death, MI, and stroke in patients with chronic HF and
significant coronary artery disease (CAD), following a hospitalization for
exacerbation of their HF. This study is designed to be a pivotal Phase 3 study,
with adequate power to determine if the use of the Factor Xa inhibitor
rivaroxaban in addition to standard HF therapy can reduce the risk of important
clinical outcome events (ie, all-cause mortality [ACM], MI, and stroke) in
patients with chronic HF and significant CAD. The addition of another
therapeutic approach to reduce the risk of morbidity and mortality in chronic
HF patients would fulfill a substantial unmet medical need.

The primary objective is to demonstrate that rivaroxaban is superior to placebo
in subjects with chronic HF and significant CAD, who are receiving standard
care, in reducing the risk of the composite of ACM, MI, or stroke following a
recent hospitalization for exacerbation of HF.
The secondary objectives are to compare rivaroxaban with placebo in addition to
standard care in subjects with chronic HF and significant CAD following a
recent hospitalization for exacerbation of HF in reducing the risk of the
following outcomes:
* Composite of CV mortality and re-hospitalization for worsening of HF
* CV mortality
* Re-hospitalization for worsening of HF
* Re-hospitalization for CV events
The exploratory objectives are to compare rivaroxaban with placebo in addition
to standard care in subjects with chronic HF and significant CAD following a
recent hospitalization for exacerbation of HF.
* Selected medical resource utilization (MRU) data on re-hospitalization for CV
events and for worsening of HF
* Symptomatic deep vein thrombosis (DVT)
* Symptomatic pulmonary embolism (PE)
* Benefit-risk balance
The safety objectives are to compare the occurrence of the following bleeding
events with rivaroxaban and placebo in addition to standard care in subjects
with chronic HF and significant CAD following a recent hospitalization for
exacerbation of HF:
* The composite of fatal bleeding or bleeding into a critical space
(intracranial, intraspinal, intraocular [vitreous or retinal], pericardial,
intra-articular, retroperitoneal, intramuscular with compartment syndrome) with
a potential for permanent disability
* Bleeding events requiring hospitalization
* Major bleeding events using the International Society on Thrombosis and
Haemostasis (ISTH) bleeding criteria
Overall safety will also be assessed.

This is a randomized, double-blind, placebo-controlled, parallel-group,
multicenter, event-driven, superiority study of rivaroxaban with clinical
outcome assessments in subjects with chronic symptomatic HF (3 months or
longer) and significant CAD. The subject population comprises men and women age
18 and over who have a diagnosis of previous MI or significant CAD with a left
ventricular (LV) dysfunction (left ventricular ejection fraction [LVEF]) *40%).
Only subjects hospitalized for decompensated HF (known as the index
hospitalization) will be eligible for enrollment at hospital discharge (and up
to 7 days after discharge) if they are in stable condition. The primary
efficacy outcome is the composite of ACM, MI, or stroke. The principal safety
outcome is the composite of fatal bleeding or bleeding into a critical space
(intracranial, intraspinal, intraocular, pericardial, intra-articular,
retroperitoneal, intramuscular with compartment syndrome) with a potential for
permanent disability. Additional bleeding outcomes are bleeding events
requiring hospitalization, and ISTH major bleeding events.
A total of 1200 primary efficacy outcome events are targeted to demonstrate the
superiority of rivaroxaban compared with placebo. A sample size of
approximately 5,000 subjects will be enrolled. Subjects who meet all of the
inclusion and none of the exclusion criteria will be randomly assigned to
receive either rivaroxaban or placebo. Randomization will be stratified by
country. After randomization, subjects will receive double-blind treatment
(oral rivaroxaban 2.5 mg or matching placebo b.i.d.). All subjects will also
receive standard care based on international clinical guidelines for HF and CAD
as prescribed by their managing physicians. Standard care is expected to
include a diuretic, renin angiotensin system (RAS) inhibitor/vasodilator
therapy (angiotensin-converting enzyme inhibitors, angiotensin receptor
blockers or hydralazine/nitrates), beta blocker therapy, aldosterone antagonist
if indicated, and aspirin/acetylsalicylic acid (ASA) (or other antiplatelet
agent as appropriate). The maximum dose of ASA will be 100 mg. Dual
antiplatelet therapy is allowed where indicated. The study consists of a
screening phase, a double-blind treatment phase, and a follow-up after the
sponsor-announced global treatment end date (GTED, defined as the date when
1200 primary efficacy outcome events are predicted to have occurred) which is
also the End of Study (EOS) visit. The screening phase will last up to 28 days
(up to 21 days during the index hospitalization and up to 7 days after
discharge from the index hospitalization), followed by an estimated 29 months
to 4.5 year double-blind treatment phase.
Subjects are expected to remain in the double-blind treatment phase until the
GTED. The date is based on site local time. The study sites will be notified of
the GTED at which time subjects will be instructed to discontinue study drug
(after taking both their AM and PM doses on GTED) and return to the study site
for the EOS visit (30±15 days, but no sooner than 15 days after the GTED).
Efficacy and safety outcome events will be collected at the EOS visit. Subjects
who permanently discontinue the study drug before the GTED will complete the
Early Permanent Study Drug Discontinuation visit as soon as possible after the
last dose of study drug. In addition, these subjects will be encouraged to
return for all scheduled visits, including the EOS visit. If these subjects
refuse office visits, the investigator is asked to strongly encourage the
subjects to allow regular contact until study end, according to the TIME AND
EVENTS SCHEDULE, either with them, or with a legally acceptable representative,
a close friend or relative, or their primary care physician to determine vital
status and if an efficacy or safety outcome event has occurred. A subject will
be considered as having completed the double-blind treatment phase, if the
subject continues taking double-blind study drug until either the announced
GTED or within 7 days before the death of the subject. If a subject experiences
an outcome event such as MI or stroke, study drug must be temporarily
discontinued and an appropriate treatment for the event must be administered.
This also applies to other efficacy outcome events such as DVT or PE. After the
appropriate treatment of the outcome event, the investigator may choose to
resume study medication for the subject. However, study medication must be
permanently discontinued for any intracranial hemorrhage. Vital status will be
collected for all subjects who permanently discontinue study drug early,
withdraw from study, or are lost to follow-up, either by telephone or in person
at the EOS visit, or if applicable, by a review of subject*s medical or public
records unless this contact is not allowed by local regulations.
A Steering Committee and an Independent Data Monitoring Committee (IDMC) will
be commissioned for this study. The IDMC will review unblinded safety data
periodically to ensure the safety of study subjects. If necessary or requested
by the IDMC, subject level unblinded data may be provided to the IDMC (see
Section 11.7 of the protocol for more details). In addition, the IDMC will
review results of the planned interim analysis and make a recommendation
whether the study should be terminated prematurely due to overwhelming benefit
or futility (see Section 11.8 of the protocol for more details). No independent
Clinical Event Committee will be used for adjudication of outcome events in
this study.

Subjects will be randomly assigned in a 1:1 ratio to receive oral rivaroxaban
2.5 mg or placebo bid (each in addition to standard of care for HF and CAD as
prescribed by their managing physician). Randomization will be stratified by
country.
All subjects will receive study drug (rivaroxaban or placebo) orally twice
daily; once in the morning and once in the evening, at approximately the same
times each day throughout the study. Once the GTED is reached, all subjects who
are receiving study drug should discontinue study drug and complete the
appropriate study visits.

For adverse events for Rivaroxaban, see informed consent form (regular risks
and bleeding risks).
Risks from having blood draws may include a temporary bruise or *black and blue
mark* . Very rarely, the vein may
become inflamed or infected. Fainting, and in rare cases infection, may occur.
The IDMC will review unblinded safety data periodically to ensure the safety of
study subjects. If necessary or requested by the IDMC, subject level unblinded
data may be provided to the IDMC. In addition, the IDMC will review results of
the planned interim analysis and make a recommendation whether the study should
be terminated prematurely due to overwhelming benefit or futility