A prospective, randomised, open-label, blinded endpoint evaluation (PROBE) parallel group study comparing edoxaban (DU-176b) with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion of nonvalvular atrial fibrillation

AF is a condition that becomes more common as people get older. Patients with
AF have a higher risk of having a stroke and other blood clot complications. A
stroke happens when a blood vessel begins to leak in the brain or gets a clot
in it.
At the present time, patients with AF undergoing a cardioversion procedure are
most commonly treated with a medicine called warfarin or sometimes other
blood-thinning drugs. Warfarin is a drug to be used in this study. Warfarin is
used for the prevention of stroke in patients with AF. People who take warfarin
have to have regular blood tests to make sure they are not taking too much or
too little medication. Too much warfarin can cause serious bleeding.
Warfarin can also cause interactions when taken along with other common
medications. People taking warfarin must avoid certain foods, alcohol, and
dietary supplements. Because of these problems Daiichi Sankyo is developing a
new drug that is taken in tablet form.
The purpose of this study is to compare this new drug with warfarin to see if
it is safe and effective in preventing thromboembolism (formation of a clot
(thrombus) in a blood vessel that breaks loose and is carried by the blood
stream to block another vessel) and strokes which results when a brain blood
vessel becomes blocked by a clot) in patients with AF who have undergone
electrical cardioversion.

The primary efficacy objective of this study is to:
* Compare the incidences of the composite endpoints of stroke, systemic embolic
event (SEE), myocardial infarction (MI) and cardiovascular (CV) mortality
between the edoxaban group and the enoxaparin/warfarin group from randomization
to end of follow up (FU).

The primary safety objective of this study is to:
* Compare the incidence of the composite endpoints of major and
clinically-relevant non-major (CRNM) bleeding between the edoxaban group and
the enoxaparin/warfarin group from the first administration of study drug to
end of treatment + 3 days.

The secondary objective of this study is to:
* Compare the incidences of the composite endpoints of stroke, SEE, MI, CV
mortality and major bleedings between the edoxaban group and the
enoxaparin/warfarin group from randomization to end of FU.

This is a prospective, randomized, open-label, blinded endpoint evaluation
(PROBE) parallel group study in subjects with confirmed ongoing AF of no longer
than 12 months and in whom electrical cardioversion is planned. This study is
designed to compare the incidence of the composite endpoints of stroke, SEE, MI
and CV death and to compare the incidence of major and CRNM bleedings after TEE
or non-TEE-guided electrical cardioversion in the edoxaban arm versus the
enoxaparin/warfarin arm. Composite endpoints of the key efficacy and safety
parameters are also going to be tested.

Stratification
The stratification in the study will be performed on the following levels:
* approach to cardioversion (TEE or non-TEE) as determined by the Investigator;
* subject*s experience in taking anticoagulants at the time of randomization
(anticoagulant-experienced or anticoagulant-naïve);

* selected edoxaban dose (full 60 mg or reduced 30 mg dose). A subject with one
or more factors (CrCL * 15mL/min and * 50 mL/min, low body weight [* 60 kg],
and concomitant use of p-pg inhibitors (excluding amiodarone) will be on the
reduced dose (30 mg) of edoxaban if the subject is randomized to the edoxaban
group.
Subjects will be randomized in a 1:1 ratio to two treatment groups within each
stratum. Enrollment will be managed to achieve the balance of treatment
assignment within each stratum. Recruitment will continue until at least 1000
subjects in each arm have undergone cardioversion (spontaneous or electric).

TEE-guided Stratum
Warfarin arm: On the day of randomization (Day -3), subjects assigned to this
arm will either be:
a) Naive to anticoagulation or have been taking VKA but have a sub-therapeutic
International Normalized Ration (INR) (<2.0) or have been taking anticoagulants
other than VKA (e.g. dabigatran, rivaroxaban or apixaban OR parenteral
anticoagulants);
b) Have been taking anticoagulants and have an INR *2 at the time of
randomization.
Subjects in category a) will start treatment with a minimum of 1 dose each of
enoxaparin and warfarin on the day of randomisation and these drugs will be
continued until INR *2 has been obtained. After a therapeutic range (TR) is
achieved, subjects will discontinue enoxaparin and continue warfarin until end
of treatment (Day 28 following the procedure).

Subjects in category b) will not require enoxaparin and will start treatment
with warfarin alone. If INR in the subject is >3 at randomisation, the dose of
warfarin in the study will be adjusted to achieve and maintain the therapeutic
INR level of 2.0-3.0. Please refer to section 16.8 for the detailed instruction
on the management of warfarin in the study.
In both categories within the first several days from the start of warfarin
treatment, INR measurements will be conducted with a frequency of once every
2-3 days until the value reaches the TR; thereafter subjects will attend
theplanned study visits but may have ad hoc INR checks as deemed necessary by
the Investigator.
Both TEE and cardioversion may be performed on the day of randomization
providing that the subject has either received at least 1 dose of enoxaparin or
for those patients not requiring enoxaparin at randomisation, that the patients
INR is in TR (2.0-3.0). In any case cardioversion has to be performed within a
maximum of 3 days from randomization.
If no thrombi are identified in the atria by TEE, electrical cardioversion will
be conducted and subjects will continue on enoxaparin (if started from
randomisation) and warfarin until their INR reaches the TR. In both categories
it will be important to aim at achieving the TR of warfarin within 8 days after
randomization and to maintain the TR during the study treatment period. Please
refer to section 16.8 for the detailed instruction on the management of
warfarin in the study. Enoxaparin given beyond 14 days of treatment will
trigger automatic notification of the Sponsor.

Edoxaban arm: On the day of randomization, subjects will start treatment with
edoxaban and continue treatment until day of TEE/cardioversion (Day 0). If the
subject transitions from a prior anticoagulant to edoxaban, this will be done
in accordance with the transition algorithm provided in Appendix 16.5.1 (that
is, either discontinue VKA and start edoxaban when INR is *2.5 or for novel
anticoagulants [NOAC], such as dabigatran, rivaroxaban or apixaban or
parenteral anticoagulants (e.g. low molecular weight heparins) start edoxaban
when the next dose of the NOAC is due (note that for unfractionated heparin
(UFH) start edoxaban 4 hours after the last dose of UFH)). Both TEE and
cardioversion may be performed on the same day but cardioversion has to be
performed within a maximum of 3 days from randomization.
The cardioversion procedure itself should be performed approximately no earlier
than 2 hours and no later than 12 hours after the dose of edoxaban on the day
of the procedure.
The next dose of edoxaban will be taken the day after cardioversion and then
continued on a 24-hours cycle.
If no thrombi are identified in the atria by TEE, electrical cardioversion will
be conducted and the subject will continue with edoxaban until Day 28 following
the procedure.

All subjects will be followed-up for safety for 30 days (Day 58) after
completing treatment with warfarin/edoxaban in both arms. If thrombi are
identified during the TEE procedure; the subject will not be eligible for
subsequent cardioversion and may be discontinued from treatment (but the
subject will continue to participate in the study including the follow-up
period). The Investigators will be encouraged to continue treatment with the
drug to which the subject was randomized and repeat the TEE on Day 28 to assess
progress of the thrombus. Note that this repeated TEE is not mandatory for
continuation in the study.
Subjects with unsuccessful cardioversion or relapse of AF may be cardioverted
again at the Investigator*s discretion; however, duration of treatment in the
study will be calculated based on the initial cardioversion date. These
subjects will be encouraged to remain in the study and continue the study
treatment as per the protocol.

All subjects with the CHA2DS2-VASc (or CHADS2)score *2 (refer to Appendix 16.2
for details on calculation) and subjects with CHA2DS2-VASc score =1 (when the
use of oral anticoagulants is preferred over aspirin) will require to be
transitioned at the end of the study treatment to a standard-of-care
anticoagulant which is in accordance with the current European and US
guidelines on the anticoagulant treatment of patients with AF22,26,39. These
subjects will be transitioned to the treatment chosen by the Investigator and
strictly in accordance with the transition algorithms provided in Appendix
16.5.2.

Non-TEE-guided Stratum
Warfarin arm: Subjects assigned to this arm will either:
a) Have taken VKA prior to randomization and have an INR *2 on the day of
randomization;
b) Have sub-therapeutic INR at randomization (<2), have taken an anticoagulant
other than VKA (e.g. dabigatran, rivaroxaban or apixaban OR parenteral
anticoagulants) or are anticoagulant-naïve.
The following algorithms will be implemented:
Subjects in category a) will not require enoxaparin and will start 21 days of
warfarin anticoagulation from the day of randomization (Day -21). If INR in the
subject is >3 at randomisation, the dose of warfarin in the study will be
adjusted to achieve and maintain the therapeutic INR level of 2.0-3.0. Please
refer to section 16.8 for the detailed instruction on the management of
warfarin in the study.
Patient*s management in this pre-procedural period will be conducted in
accordance with the instructions provided in Table 3-1 of the protocol, Section
3.1.1.
Subjects in category b) will receive enoxaparin and daily warfarin until the
INR is *2.0. At this time, enoxaparin will be discontinued and warfarin
continued for a total minimum of 21 days. Please refer to section 16.8 for the
detailed instruction on the management of warfarin in the study.



In both categories within the first several days from the start of warfarin
treatment, INR measurements will be conducted with a frequency of once every
2-3 days until the value reaches the TR; thereafter subjects will attend the
planned study visits but may have ad hoc INR checks as deemed necessary by the
Investigator.
For all subjects, cardioversion will be performed on Day 0, which will occur at
a minimum of 21 days following the start of treatment with the study drug or
within 3 days thereafter. Refer to Table 3-1 on the guidance of patient
management in accordance with the INR value before and on the day of
cardioversion.
In subjects who do not have a TR INR (2.0-3.0) on the day of randomization, it
will be important to aim at achieving the TR of warfarin within 8 days after
randomization and to maintain the TR during the study treatment period. Please
refer to section 16.8 for the detailed instruction on the management of
warfarin in the study.
Enoxaparin given beyond 14 days of treatment will trigger an automatic alert to
the Sponsor.

Edoxaban arm: After randomization into this study, subjects will receive
edoxaban for 21 days before cardioversion followed by cardioversion on Day 0
(or within 3 days thereafter) and an additional 28 days of edoxaban treatment
starting from the day of cardioversion. If the subject transitions from a prior
anticoagulant to edoxaban, this will be done in accordance with the transition
algorithm provided in section Appendix 16.5.1(that is, for VKA discontinue the
drug and startedoxaban when INR is *2.5; for novel anticoagulant [NOAC, e.g.
dabigatran, rivaroxaban, apixaban] start edoxaban when the next dose of the
NOAC is due or for parenteral anticoagulants start edoxaban when the next dose
of the anticoagulant is due with the exception of UFH where the first dose of
edoxaban will be 4 hours after the last dose of UFH). The count of 21 days will
start from the day of the first dose of edoxaban.


Both arms: All subjects will be followed-up for safety for 30 days (Day 58)
after completing treatment with warfarin/edoxaban in both arms.
Subjects with unsuccessful cardioversion or relapse of AF may be cardioverted
again at the Investigator*s discretion; however, duration of treatment in the
study will be calculated based on the initial cardioversion date. These
subjects will be encouraged to remain in the study and continue the study
treatment as per the protocol.
All subjects with the CHA2DS2-VASc (or CHADS2)score *2 (refer to Appendix 16.2
for details on calculation) and subjects with CHA2DS2-VASc score =1 (when the
use of oral anticoagulants is preferred over aspirin) will require to be
transitioned at the end of the study treatment to a standard-of-care
anticoagulant which is in accordance with the current European and US
guidelines on the anticoagulant treatment of patients with AF22,26,39. These
subjects will be transitioned to the treatment chosen by the Investigator and
strictly in accordance with the transitioning algorithms provided in Appendix
16.5.2.

Subjects with spontaneous cardioversion in the pre-procedural period (confirmed
by a recording of sinus rhythm) will still need to complete 28 days of
treatment from the day that spontaneous cardioversion was noted and 30 days of
follow-up (58 days in total).

o Warfarin tablets once per day (and with a dose based on your International
Normalized Ratio (INR) clotting test results. Some patients in this group may
also receive enoxaparin injected just under the skin (subcutaneously).
o Edoxaban once per day 60mg

Edoxaban * the investigational study drug

The Sponsor has recently conducted two very large world-wide phase 3 studies
using up to 60 mg of edoxaban. As of September 2013, more than 17,500 study
subjects had received edoxaban for 12-24 months.
The main known risk associated with taking edoxaban is bleeding. Bleeding
events, seen in clinical studies, can occur at any site and have been mostly
mild. However, severe bleeding and bleeding into the brain, resulting in stroke
or death, has been reported in both edoxaban and warfarin groups. Other side
effects seen with edoxaban (based on the concluded studies with edoxaban)
included anaemia, skin rash and increased liver enzymes. Edoxaban is an
investigational study drug and it may also have unknown side effects.

Warfarin

The main side-effect of warfarin is bleeding. The risk of severe bleeding is
small, occurring in approximately 1 or 2 out of 100 patients each year. Other
side effects include blackening and dying skin (necrosis) and other tissues,
allergic reaction, skin rashes, diarrhoea, hair loss, fever, yellow skin and
eyes, and liver problems although these complications are quite rare. Warfarin
can also cause interactions when taken along with other common medications.
People taking warfarin must avoid certain foods, alcohol, and dietary
supplements.

Enoxaparin:

Enoxaparin is in a class of medications called low molecular weight heparins.
It works by stopping the formation of substances that cause clots. Enoxaparin
is marketed under the trade names Lovenox, Xaparin and Clexane, among others.
Enoxaparin is an anticoagulant used to prevent and treat deep vein thrombosis
or pulmonary embolism, and is given as a subcutaneous injection. The most
common side effects include bleedings, mild reactions or irritation, pain,
bruising, and redness of the skin where you have the injection.

Pregnancy:
Edoxaban has not been tested in pregnant women. The effects of this drug on a
human foetus (developing baby still in the womb) or a nursing child are
unknown.