A Multi-center, Parallel-group, Double-blind, Placebo-controlled, Randomized, Ascending Dose Trial to Determine the Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Infusions of OPC-108459 Administered to Subjects with Paroxysmal and Persistent Atrial Fibrillation.

Atrial fibrillation (AF) is the most common type of arrhythmia and is a major
risk factor to form blood clots, making a person five to seven times more
likely to suffer a stroke. AF may be treated with anti-arrhythmia medication or
also with therapeutic interventions such as electric cardioversion or catheter
ablation procedure.

Otsuka Pharmaceutical Co., Ltd. discovered the new compound OPC-108459, being
developed as a therapeutic agent for the rapid conversion of paroxysmal and
persistent AF to sinus rhythm. OPC-108459 potently inhibits Kv1.5 and GIRK1/4
channel currents and is expected to show potent efficacy in the cardioversion
of AF to sinus rhythm in humans with little effect on ventricular functions.
Currently, other drugs (eg, ibutilide, amiodarone) used to treat AF also have
cross-reactivity to sodium and/or potassium channels in ventricular tissue,
producing delays in repolarization of ventricular tissue and increasing the
risk of Torsade de pointes.
As OPC-108459 is capable of being developed as an injection formulation, rapid
defibrillation of AF is anticipated, and therefore the compound is being
developed as an injection product for cardioversion of AF.

Objective(s): Part 1: To determine the safety, tolerability, pharmacokinetics
(PK), and efficacy of single ascending doses of OPC-108459 following one
10-minute constant rate infusion in adult
subjects diagnosed with paroxysmal or persistent AF. Part 2: To determine the
efficacy and safety of OPC-108459 following up to two 10-minute constant rate
infusions in adult subjects diagnosed with paroxysmal or persistent AF.

Study design:
The trial will consist of 2 parts. Each part will evaluate 2 populations of
subjects presenting for cardioversion in a hospital setting; one diagnosed with
paroxysmal AF (duration 3 hours to 7 days) and the second diagnosed with
persistent AF (duration > 7 and <= 30 days). Classification of AF is to be
current at the time of randomization.

Part 1: The safety, tolerability, PK, and efficacy of single ascending doses of
OPC-108459 will be studied following administration of a 10-minute constant
rate infusion in cohorts of 5 subjects. Subjects will be randomized 4:1,
OPC-108459:placebo- (vehicle-) control. Once the dose has been administered,
subjects will be followed for up to 30 days postdose. The initial follow-up
period will be 24 hours postdose to perform PK and safety evaluations. During
this initial 24-hour monitoring period, no further AF treatment is required per
protocol. However, rescue therapy, including
electrical cardioversion, may be initiated if: Symptoms/conditions of a trial
subject worsen; Rescue treatment is deemed necessary at the discretion of the
principal investigator.
Subjects will then return for a visit on Day 8 for safety evaluations. Subjects
will also receive a phone call on Day 31 as a final follow-up on their overall
health status. Cohorts of paroxysmal and persistent AF subjects may have their
dose increased independently. Each cohort will be evaluated separately for all
analysis parameters. The decision on whether or not to escalate the dose will
be made for a completed cohort using blinded safety data obtained through at
least 24-hours postdose.

The safety review team will consist of the Otsuka Pharmaceutical Development &
Commercialization, Inc. (OPDC) project leader, the Clinical Safety &
Pharmacovigilance representative, the trial medical
monitor, and an independent medical reviewer. If a subject has a serious
adverse event (SAE), or at least 2 of the 5 subjects were not considered to
have tolerated the dose, the independent reviewer will be unblinded to assess
the relationship of the events to the investigational medicinal product (IMP).
Should the nontolerated or SAE events be considered related to IMP, dose
escalation will be stopped. If the relationship to IMP is not clear, an
additional cohort at the same dose may be enrolled or the dose escalated.
Changes in vital signs should be confirmed with a repeat measurement. Values of
QT interval corrected for heart rate using the Fridericia formula (QTcF) > 500
msec or changes from baseline in QTcF of > 15 msec will receive further review
by the safety team. The OPDC clinical pharmacologist will analyze blinded
OPC-108459 concentrations for linearity and dose selection for the next
targeted maximum (peak) plasma concentration (Cmax) value; selection of the
next dose will be reviewed and agreed upon by the safety team. Analysis of
existing PK data arising from both the 269-11-215 trial and the 269-11-001
trial, a parallel trial being conducted in Japan, indicates that there is no
inter-regional variation. Therefore, at dose escalation meetings, decisions
regarding
selection of the next higher dose will be made using available safety and PK
data from both trials.

Part 2: Expanded cohorts of 21 adult male and female subjects with either
paroxysmal or persistent AF (42 total) will be evaluated for efficacy and
safety at a dose of OPC-108459 that has been selected based on the safety,
tolerability, and efficacy profile observed in Part 1. Subjects will be
randomized 2:1, OPC-108459:placebo- (vehicle-) control. Different doses may be
used for paroxysmal and persistent AF subjects. Subjects will be administered a
10-minute constant rate infusion of OPC-108459/placebo. If the subject fails to
convert to sinus rhythm within 10 minutes postinfusion, a
second 10-minute constant rate infusion of OPC-108459/placebo will be
administered; the dose will be determined by the safety and tolerability
profile observed in Part 1.

Investigational Medicinal Product, Dose, Formulation, Mode of Administration:
OPC-108459 powder, 50 mg, will be packaged in 50-mL sterile vials. OPC-108459
powder in 50-mL vials will be reconstituted with 25 mL sterile water for
injection to produce a 0.2% solution of OPC-108459/1% solution of Captisol®.
OPC-108459 placebo powder, 0 mg of active drug, will be packaged and prepared
similarly.
Part 1: OPC-108459 will be administered as a 10-minute constant rate
intravenous (IV) infusion. OPC-108459 doses will be based on achieving expected
target OPC-108459 Cmax values of 1.0, 1.6, 2.4, 3.6, 5.4, 7.0, 8.0, 9.0,
and 10.0 µg/mL. The concentrations correspond to estimated doses of 0.26,
0.4, 0.6, 0.9, 1.35, 1.75, 2.0, 2.25, and 2.5 mg/kg for those subjects
with ideal body weight; the estimates are based on a slope of 4,000 ng/mL per
mg/kg dose of OPC-108459 that was observed in the healthy subject trial
(269-09-201). Should the slope change, doses will be adjusted to produce the
target Cmax values. Exact dose selection will be communicated formally to the
sites should dose adjustment be necessary.
Part 2: OPC-108459 will be administered as a 10-minute constant rate IV
infusion. If the subject fails to convert to sinus rhythm within 10 minutes
postinfusion, a second 10-minute constant rate infusion of OPC-108459 will be
administered. The doses of the first and second infusions will
be determined based on the safety and tolerability profile observed in Part 1.

The length of time of participation in this study is approximately 31 days not
including the screening visit. This study requires 24 hours of monitoring,
after administering the study drug intravenously, while patient is admitted to
the hospital, followed by a 1 outpatient visit and 1 follow-up telephone call.
A screening visit is required within 7 days prior to the start of the study.

The following data is collected and following examinations are performed which
could burden the patient:
1) Screening:
- inclusion and exclusion criteria will be reviewed
- a comprehensive medical history will be assessed
- concomitant medications will be recorded within 30 days of dosing.
- demographic information will be collected (i.e. date of birth, age, gender,
race, ethnicity)
- patients will be measured for height and weight and IBW will be calculated
- vital signs (oral temperature, respiratory rate, blood pressure, and heart
rate)
- a complete physical exam will be performed
- a resting 12-lead ECG will be performed after the subject has been recumbent
and at rest for at least 10 minutes prior to the ECG
Burden/Risks associated with ECGs:
ECG patches may cause a skin reaction such as redness or itching. Patients may
also experience skin discomforts where the ECG patch was placed and/or hair
loss associated with the placement of ECG leads.

- blood samples will be collected for serum chemistry, hematology, and urine
sample for analysis
- blood sample will be collected for screening for hepatitis B and C
Burden/Risks associated with Blood Sampling:
Blood samples will be taken approximately 20 times throughout the course of the
study. Approximately 197 mL of blood, will be drawn throughout the study.
Additional blood samples may be required if any of the laboratory tests are
abnormal or if the study doctor considers it necessary for monitoring the
patient*s health.
During the collection of blood samples, one may experience pain and/or bruising
at the needle injection site. Although rare, clots may form and infections may
occur near the injection site. Lightheadedness and/or fainting may also occur
during or shortly after the blood draw.
Blood will be drawn through a small needle placed in the vein. An intravenous
catheter may be used for some blood draws. Study staff will remove the
catheter before the patient leaves the clinic.
- urine sampling will be done for alcohol and drug screening
- a urine pregnancy test will be performed. If a positive urine pregnancy test
is observed, a serum pregnancy test will be performed for confirmation.

Reproductive Risks:
There are unknown risks in taking most drugs during conception, pregnancy, or
while breast-feeding. Therefore female patients/ partners of male patients
should not get pregnant during this study or for 30 days after taking the study
drug. Female subjects should also not breast-feed or use breast milk during or
for one month after this trial.

2) Day 1 (Dosing):
Patient will be admitted to the hospital by his/her regular doctor, as part of
the treatment for his/her AF.
- vital signs (before and after administration study drug)
- abbreviated physical examination
- resting 12-lead ECGs will be performed locally after the subject has been
recumbent and at rest for at least 10 minutes prior to the ECG.
Electrocardiograms should be performed at predose (within 45 minutes of dosing)
and 5, 10, 30, and 40 minutes and 1, 4, 8, and 12 hours post-start-of-infusion.
- blood samples for Hematology, Serum Biochemistry and urine sample for analysis
- urine pregnancy test
- High resolution, 24-hour, 12-lead Holter monitoring will be initiated at
predose (within 45 minutes of dosing) and continue through 24 hours
post-start-of-infusion.
- cardiac telemetry monitoring from predose (within 45 minutes of dosing) to 24
hours post-start-of-infusion. If NSR is observed, a 12-ECG will be taken to
confirm NSR. Telemetry monitoring should be continuous. Any brief interruptions
in order to accommodate movement of the subjects should be documented.
- a neurological exam will be completed at predose
- administration study drug or placebo: in Part 1, a single 10-minute constant
rate IV infusion of OPC-108459 or placebo will be administered. In Part 2, if
sinus rhythm is not observed after the first infusion, a second infusion will
be administered after a 10-minute wait.

Risks associated with IV infusion of a study drug:
OPC-108459 will be given as a IV infusion. At the area where the needle is
inserted, you may experience mild pain, bruising and swelling. There is a
possibility that the area may become infected. Medications given itravenously
can sometimes cause pain, swelling and redness of the vein and surrounding
tissues, which may not go away quickly, even if the medication is stopped.

Risks and Discomforts associated with study drug:
This research study is the fourth time that the study drug is being tested in
humans. Therefore the exact side effects caused by the study drug are not yet
clear.
In 127 healthy subjects previously studied, the complaints that have been
reported after receiving OPC-108459 include major depression, headache, back
pain, joint pain, musculoskeletal pain, soreness in the mouth, fatigue (feeling
tired and weak), feeling hot, infusion site reactions (like pain and itching),
joint swelling, muscle tightness and pain, dry skin, upset stomach, nausea,
swelling in the feet and legs, syncope (fainting), decreased heart rate,
decreased diastolic blood pressure, unstable angina (chest pain) and increased
liver function test results in the urine (urobilinogen). These may or may not
be caused by OPC-108459.
In this study, the levels of the drug in the blood may approach but are not
expected to exceed the same level shown to produce seizures in animals. The
meaning of these findings for humans is not known, however there are study
procedures in place to make sure that you are monitored for any similar side
effects as seen in the animal studies, like seizures.

In addition to the risks listed above, there may be some unknown or infrequent
and unforeseeable risks associated with the use of this study drug, including
allergic reaction or interaction with another medication, including reactions
that may be life threatening.
Patients must report all problems and worries to a member of the study staff.
During this study patients will be observed closely for any bad or harmful
effects. The study doctor will decide if it is safe for the patient to
continue in the study.

- after dosing, a shorter neurological exam will be performed
- blood samples for PK analysis:
- blood samples for PK analysis of OPC-108459 and its designated metabolites
will be collected at predose (within 45 minutes of dosing) and 10 and 30
minutes (**1 minute) and 1, 2, 4, and 8 hours (**10 minutes)
post-start-of-infusion.
In Part 2, if the second infusion is given, an additional PK blood draw should
be taken 20 minutes (**1 minute) after the start of the first infusion (predose
of the second infusion).
- blood samples for PK analysis of Captisol**will be collected at predose
(within 45 minutes of dosing) and 10 and 30 minutes (**1 minute) and 1, 2, 4,
and 8 hours (**10 minutes) post-start-of-infusion. In Part 2, if the second
infusion is given, an additional PK blood draw should be taken 20 minutes (**1
minute) after the start of the first infusion (predose of the second infusion).
- in all cases, successful cardioversion will be followed by a minimum of 4
weeks
of anticoagulation in patients who can tolerate this.

Restrictions/Rescue therapy
Rescue therapy, including electrical cardioversion, may be performed as soon as
medically necessary at the discretion of the PI. Subjects that do not convert
after 1 hour of the end of the last infusion with IMP may receive rescue
therapy (e.g. cardioversion) and will be considered as treatment failures.
The use of other antiarrhythmic agents (e.g. procainamide, lidocaine,
flecainide, propafenone, amiodarone, bretylium, dofetilide, dronedarone
ibutilide, adenosine) is discouraged until 24 hours after the last infusion of
IMP (in order to determine the efficacy endpoints of
OPC-108459) unless rhythm should be restored earlier in the opinion of the PI.
Any subject requiring rescue therapy will continue to be monitored for safety.
Subjects will return for a visit on Day 8 for safety evaluation. Subjects will
also receive a phone call on Day 31 as a final follow-up on their overall
health status.

Meals:
Standardized meals and snacks will be served at regular times when patients are
in the hospital for the study, except when fasting is required or otherwise
noted.


3) Day 2 (Discharge):
- vital signs
- physical examination
- a resting 12-lead ECG will be performed after the subject has been recumbent
and at rest for at least 10 minutes prior to the ECG at 24 hours
post-start-of-infusion.
- blood samples for Hematology, Serum Biochemistry and urine sample for analysis
- 24 hour Holter monitoring will conclude at 24 hours post termination of the
last infusion of IMP.
- 24 hour cardiac telemetry monitoring will conclude at 24 hours post
termination of the last infusion of IMP.
- blood samples for PK analysis as described for Day 1

After completion of all study procedures, you may be discharged from the
hospital.

4) Day 8 (Follow-up visit with study staff):
- any changes in health since last study visit
- vital signs
- physical examination
- a resting 12-lead ECG will be performed after the subject has been recumbent
and at rest for at least 10 minutes prior to the ECG.
- blood samples for Hematology, Serum Biochemistry and urine sample for analysis
- blood sample for PK analysis not on Day 8 but at Early Termination, if Early
Termination is 24hours prior to post dose
- urine pregnancy test

5) Day 31 (Follow-up Telephone Call):
The patient will complete a follow-up telephone call with the study staff 30
days after the last dose of study medication to determine if he/she is having
any side effects and what medications he/she is taking. After completion of
the telephone call, the participation in the study will be complete.