An Open-label, Single-Sequence Study to Evaluate the Effects of Diltiazem, a Moderate CYP3A4/5 Inhibitor, on the Pharmacokinetics and Pharmacodynamics of E5555 and its Metabolites in Healthy Subjects

The study drug to be given is a new, investigational compound that may
eventually be used for the treatment of coronary artery disease and acute
coronary syndrome (for example heart attack or a restriction in blood flow to
the heart). In most cases, cardiovascular disease results from atherosclerosis
(formation of abnormal fatty deposit in the vessel of the artery) or the
formation of a clot (blockage) within the arteries of the heart.
Atherosclerosis can result in completely or partially blocking of the blood
flow to certain regions of the heart. Prevention or slowing down the formation
of abnormal fatty deposit would prevent these vascular problems caused by
exaggerated blood clotting. It is expected that the compound decreases the
initiation of clot formation. Thus the study drug may be beneficial in the
prevention or decrease of vascular problems caused by formation of potentially
dangerous blood clots.

In this study you will also receive diltiazem (Cardizem® LA). Diltiazem LA is a
registered drug, which belongs to a family of drugs known as *calcium channel
blockers*. It causes reduction in blood pressure, hence it is used in treating
patients with coronary artery disease, high blood pressure and abnormal heart
rhythms. Since administration of the study drug with diltiazem to patients with
cardiovascular disease is likely, our purpose in this study is to determine
whether, and if so, in what extent diltiazem affects the metabolism (the
breakdown and disposition) of the study drug in humans after administration.

Primary:
to evaluate the effects of a moderate CYP3A4/5 inhibitor, diltiazem on the
pharmacokinetics and pharmacodynamics (Thrombin and TRAP-induced platelet
aggregation) of the study drug and its known metabolites

secundary:
to evaluate the effects of co-administration of diltiazem and the study drug on
the pharmacokinetics of diltiazem and its metabolites.
to evaluate the effects of co-administration of diltiazem and the study drug on
QTcF interval compared to the study drug alone.
to assess the safety and tolerability of a single dose of the study drug when
given either alone or in combination with diltiazem

Design:
an open-label, randomized, two arm, single-sequence, crossover, drug-drug
interaction study in twenty-four healthy male and/or healthy female subjects
each receiving a single oral dose of the study drug in Period 1, and an oral
dose of diltiazem once daily on Days 1-14 and a single oral dose of the study
drug co-administered with diltiazem on Day 8 in Period 2; a washout of seven
days between dosing

Procedures and assessments;
clinical laboratory (including PT and aPTT), vital signs, physical examination,
weight, 12-lead ECG; at eligibility screening: medical history, urine drug
screen, HBsAg, anti HCV, anti-HIV 1/2 and serum pregnancy test (females only);
abbreviated physical examination, vital signs, 12-lead ECG, urine drug screen,
serum pregnancy test (females only) and clinical laboratory (including PT and
aPTT) to be repeated upon each admission; follow-up on Day 18 (Period 2)

Observation period:
Period 1: in clinic from -41 h up to 72 h after drug administration and
ambulatory visits on Days 5 and 6
Period 2: in clinic from -41 h before diltiazem administration on Day 1 up to
168 h after drug administration on Day 8

Blood sampling:
for pharmacokinetics of E5555: pre-dose and 1, 2, 4, 5, 6, 8, 12, 24, 48, 72,
96, 120 and 144 h post-dose (Period 1) and pre-dose and 1, 2, 4, 5, 6, 8, 12,
24, 48, 72, 96, 120, 144, 168 and 240 h post-dose on Day 8 (Period 2)

for pharmacokinetics of diltiazem: pre-diltiazem dose on Days 5 and 6,
pre-diltiazem dose and 2, 4, 5, 6, 8, 10, 12, 14 and 16 h post-diltiazem dose
on Day 7 and pre-diltiazem dose and 2, 4, 6, 8, 10, 12, 14, 16 and 24 h
post-diltiazem dose on Day 8 (Period 2)

for TRAP- and thrombin-induced platelet aggregation: -24 h pre-dose, pre-dose,
1, 2, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120 and 144 h post-dose (Period 1),
pre-dose and 1, 2, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, 144, 168 and 240 h
post-dose on Day 8 (Period 2)

for arachidonic acid-induced platelet aggregation: -48 h pre-dose (Period 1)

Safety
adverse events: throughout the study; vital signs: pre-dose and 2, 4, 5, 6, 8,
12 and 23 h post-dose on Days -1 and 1 and once on Days -2, 2 and 4 (Period 1)
and pre-dose and 4, 8, 12 h post-dose on Day 1 and pre-dose and 2, 4, 5, 6, 8,
12 and 23 h post-dose on Days 7 (relative to diltiazam dosing) and 8 and once
on Days -2, 4, 9, 10, 12 and 15 (Period 2); weight: once on Day -1 (Period 1);
12-lead ECG: once on Days -2 and 4 (period 1) and once on Days -2, 1, 6, 10 and
15 (Period 2); clinical laboratory: once on Day 2 (Period 1) and once on Day 8
(Period 2)

Bioanalysis
analysis of E5555 and diltiazem samples using validated methods by Sponsor
analysis of TRAP- and thrombin-induced platelet aggregation by PRA
analysis of arachidonic acid-induced platelet aggregation by PRA

Active substance: E5555

1 group with 2 dosing arms

arm 1
Period 1: single dose of 100 mg E5555
Period 2: single dose of 100 mg E5555 and a daily dose of 360 mg
diltiazemduring during 14 days

Arm 2
Period 1: single dose of 300 mg E5555
Period 2: single dose of 300 mg E5555 and a daily dose of 360 mg
diltiazemduring during 14 days

Procedures: pain, light bleeding, heamatoma, possibly an infection.