A Phase 2, Placebo-Controlled, Randomized, Double-Blind, Parallel Arm, Dose Ranging Study to Evaluate Safety and Efficacy of Apixaban in Patients with a Recent Acute Coronary Syndrome

Cardiovascular disease remains a worldwide leading cause of morbidity and
mortality. This included also acute coronary syndrome (ACS). Thrombotic
processes or thromboembolic events appear to be directly involved in the
development of the disease or complicate its treatment and prognosis.
Antithrombotic therapy with parenteral and oral anticoagulants and antiplatelet
agents is the cornerstone of therapy for much of this cardiovascular disease.
Despite the availability of these agents, however, a significant number of
patients have recurrent thrombotic events and a higher rate of bleeding. One
mechanism for improving prophylaxis and treatment of thromoembolic diseases is
the inhibition of faxtor Xa and/or thrombin. Inhibition of factor Xa decreases
the conversion of prothrombin to active thrombin, thereby diminishing
thrombin-mediated activation of the coagulation process, including fibrin
formation and platelet activation. Apixaban is an oral faxtor Xa inhibitor. The
high affinity and selectivity of apixaban for factor Xa is expected to result
in potent antithrombotic activity with an improved safety and tolerability
profile compared to currently available treatments.

To evaluate the safety (bleeding) of 4 doses of apixaban as compared to placebo
over a 26 week treatment period in selected subjects with recent (<=7 days)
Acute Coronary Syndrome (ACS). To determine the optimal dose and regimen of
apixaban for use in a Phase 3 ACS trial.

Randomized, parallel-arm study assessing 4 double-blind dose arms of apixaban
vs. placebo, conducted in two phases, Phase A and Phase B. In Phase A, eligible
subjects will be randomized in equal numbers to apixaban 2.5 mg BID, and
apixaban 10mg QD or placebo. All subjects will receive ASA <= 165 mg/day and if
necessary with clopidogrel 75 mg/day. Randomization will be stratified by
clopidogrel use.
When approximately 360 subjects (approximately 120 subjects into each of the
arms) have been randomized and treated into Phase A, the DSMB will review
safety data and will make a recommendation about how to proceed with Phase B of
the study.
In Phase B, the DSMB may recommend either to expand randomization to include
higher apixaban dose levels, to maintain randomization to the original three
treatment arms, or to terminate the study. If randomization is expanded to
include the higher dose arms, eligible subjects will continue to be randomized
to apixaban 2.5 mg BID and apixaban 10 mg QD, as well as to apixaban 10 mg BID,
apixaban 20 mg QD or placebo. A total of 300 subjects will be randomized into
each apixaban arm, and 600 subjects will be randomized to placebo.

phase A:
1 group receives apixaban 2.5 mg BID
1 group receives apixaban 10 mg QD
1 group receives placebo

phase B: same as phase A or expanded to include the following higher dose arms:
1 group receives apixaban 10 mg BID
1 group receives apixaban 20 mg QD

In total 6 visits to the centre and 4 phone contacts
physical examination: at screening and week 26.
Interview: Medical history at screening; questions about safety and efficacy at
week 1, 3, 6, 9, 13, 18, 22, 26 and 30
Blood sampling: day 1, week 1, 3, 9, 18 en 26
ECG: screening, week 1, 9, en 26
vital signs (BP and RR): screening, day 1, week 1, 3, 9, 13, 18 en 26


Risks of apixaban:Clinically important bleeding may occur in critical organs of
the body or may be related to surgery or procedures. It may also occur as minor
bleeding, such as a nosebleed, bleeding gums, or bruising. In a small number of
patients, small amounts of blood have been seen in the urine, stool or as small
spots under the skin. Other possible side effects from the study medication
include low white blood count, loose stools, dizziness, headache, nausea,
increased liver function tests, heartburn, burning and tingling sensation, and
lightheadedness