Randomized, double-blind, triple-dummy trial to compare the efficacy of otamixaban with Unfractionated Heparin + eptifibatide, in patients with Unstable angina/Non ST segment Elevation Myocardial infarction scheduled to undergo an early invasive strategy

Acute coronary syndrome (ACS) remains a major cause of death and disability.
ACS is the result of a complex interaction of activation of coagulation and
platelet aggregation, superimposed on a disruptive atherosclerotic plaque. For
many years unfractionated heparin (UFH) has been the cornerstone of
antithrombotic therapy for ACS for patients presenting with a non STE elevation
acute coronary syndrome There are multiple disadvantages of this treatment,
heparin resistance and an unpredictable pharmacodynamic and pharmacokinetic
effects as a result of interactions are two examples. The optimal
anti-thrombotic regimen for ACS patients with unstable angina / non
ST-elevation myocardial infarction scheduled to undergo an early invasive
strategy remains, therefore, to be determined. A direct inhibitor of factor Xa
could be an effective therapy for these ACS patients, therefore otamixaban, a
direct factor Xa inhibitor could be an appropriate therapy.

Primary: To demonstrate the superior efficacy (composite of all-cause death +
Myocardial infarction) of otamixaban to unfractionated heparin (UFH) +
eptifibatide
Secondary:
• To demonstrate the superior efficacy ( composite of all-cause death +
Myocardial infarction + any stroke) of otamixaban as compared to UFH +
eptifibatide
• To document the effect of otamixaban on Rehospitalization or prolongation of
hospitalization due to a new episode of myocardial ischemia/myocardial
infarction as compared to UFH+ eptifibatide
• To document the effect on mortality (all cause mortality) of otamixaban as
compared to UFH + eptifibatide
• To document the safety of otamixaban as compared to UFH + eptifibatide
• To document the effect of otamixaban on Thrombotic procedural complications
during the index PCI as compared to UFH + eptifibatide
• To characterize otamixaban pharmacokinetics over the entire dosing interval
and to evaluate otamixaban exposure-response (safety and efficacy) in the
target population.
A single blood sample will be drawn if a subject participates in the
pharmacogenetic substudy. This sample may be used to determine a possible
genetic effect on response to treatment with otamixaban, efficacy, safety
and/or metabolism of otamixaban.

Randomized, double blind, triple-dummy study with two parallel groups; one
control arm of UFH + eptifibatide and one otamixaban arm. In two arms at
randomization patients will be assigned to receive blinded study medication A
(otamixaban /placebo), B (placebo/UFH) and in case of a PCI Drug C
(placebo/eptifibatide). In the otamixaban arms Drug A will be a bolus and an
infusion of active otamixaban, and Drug B and C will be a bolus and infusions
of placebo. In the UFH + eptifibatide arm Drug A will be a bolus and an
infusion of placebo, Drug B a bolus and a infusion of active UFH, and Drug C a
bolus and an infusion of active eptifibatide. Drug A (otamixaban or its
placebo) and drug B (UFH or placebo) will be administered from the time of
randomization until the end of the PCI or hospital discharge. Eptifibatide or
its placebo (drug C) will be initiated after the angiography, immediately prior
tot the PCI start andgiven up to 18-24 hour post PCI or until hospital
discharge.
During the initial hospitalization if a bailout use of GP IIb/IIIa is needed
(i.e. only as required because of a significant recurrent ischemia, procedural
complication or other clinical instability) patients will receive a blinded
bolus of Drug D followed by an infusion of open label eptifibatide in case they
already received Drug C. Then in the otamixaban arm the Drug D bolus will be a
bolus of active eptifibatide. In the UFH+eptifibatide the Drug D bolus will be
a placebo of eptifibatide. When the patient did not yet receive Drug C an
open-label bolus of eptifibatide will be given. In all arms the bolus will be
followed by an infusion of open label eptifibatide and the Drug C will be
stopped.
All patients will be treated with aspirin (75-325mg daily) as recommended in
the ACC/AHA and ESC guidelines. In addition to aspirin patients should be
treated from randomization by clopidogrel or prasugrel according to their
respective labelling. After discharge all patients will have a Day 30 follow up
visit and a visit or a telephone follow up at 3 Month and 6 Month.

Patients will be divided into two medication arms. Patients will receive
intravenous infusion of otamixaban and placebos or an intravenous infusion of
UFH (plus eptifibatide in case of a PCI) and placebo. Otamixaban or UFH and its
placebo will administered by one infusion system via a multifold.

Patients can experience otamixaban related side effects, of which bleedings was
the most frequent in previous studies. Pyrexia, headache, nausea and
hypotension were common side effects too.