A multi-center, Randomized, double-blind, placebo-controlled study to Evaluate the Safety and efficacy of a single oral dose of vanoxerine for The conversion Of subjects with REcent onset atrial fibrillation or flutter to normal Sinus Rhythm

AF is the most common arrhythmia resulting in health care utilization, and by
way of example, in the USA alone AF currently afflicts more than 2.3 million.
It is estimated that there will be more than 12 million individuals with AF by
2050. Unfortunately, current antiarrhythmic drug options are limited due to
poor efficacy, and associated toxicity. Antiarrhythmic drugs such as ibutilide
and dofetilide are effective in terminating AF by blocking or inhibiting
various ion currents, and causing QT prolongation which expose patients to the
potential ventricular arrhythmia such as Torsades De Pointes (TdP) and the
risk of sudden cardiac death. Alternatively, the blockade of multiple ion
channels, such as is the case with amiodarone, is a more effective approach for
maintaining sinus rhythm. However Amiodarone has been associated with variety
of adverse events, of which is the most serious is amiodarone pulmonary
toxicity. Vanoxerine is a compound uniquely suited for the proposed indication
and may be of clinical benefit in several other important ways. Vanoxerine*s
unique properties include the inhibition or blocking of well described ion
channels that terminate AF. The principal antiarrhythmic effect of vanoxerine
on AF and AFL is thought to be its inhibition of multiple cardiac ion channels.
Nonclinical studies demonstrated a high degree of efficacy in terminating and
preventing induction of AF/AFL, while also demonstrating no evidence of
predisposition to ventricular proarrhythmia. Furthermore in the recently
conducted phase 2 study in AF/AFL, Vanoxerine resulted in a dose dependent
prolongation of QT but resulted in no cases of proarrhythmia. The unique set of
ion channel properties suggest the potential for efficacy in termination of
AF/AFL without proarrhythmia.

To evaluate the safety and efficacy of a single oral dose of vanoxerine for the
conversion of subjects with recent atrial fibrillation (AF) or atrial flutter
(AFL) to normal sinus rhythm.

Up to 625 subjects will be randomized in a 2:1 fashion so that at least 400
vanoxerine and 200 placebo subjects receive study drug. Vanoxerine HCl, 400 mg
(2 capsules of 200 mg vanoxerine HCl per capsule) or identical appearing
placebo capsules will be assigned randomly and administered orally in a single
dose in a double-blind fashion.
After informed consent is obtained, the screening process will be undertaken,
followed by randomization. Atrial fibrillation (AF) or atrial flutter (AFL)
must be reconfirmed electrocardiographically, e.g., bedside monitor, telemetry,
paper ECG, etc., immediately (within 5 minutes) prior to the time of study drug
administration. Subjects who spontaneously convert to sinus rhythm after
randomization but before study drug administration will not receive study drug.
The subject*s ECG will be continuously displayed for safety monitoring. In
addition, a Holter ECG will be recorded continuously to document safety
beginning 45 to 30 minutes prior to study drug administration and through a
minimum of 32 hours after study drug administration and until QTc criteria have
been met. Extractions by a central Holter ECG laboratory at specified time
points will be used to document rhythm and measure ECG intervals. All episodes
of termination of AF or AFL as well as predefined brady- and tachy- arrhythmias
will be adjudicated by a blinded clinical events committee (CEC). In addition,
12-lead ECGs (paper) will be performed at specified time points. During the
interval from administration of study drug through 24 hours, if and when the
investigator observes that AF/AFL has terminated, two 12-lead ECGs separated by
at least 1 minute will be recorded to document persistence of sinus rhythm.
Subjects will be hospitalized in a monitored bed for a minimum of 32 hours
after study drug administration.
Subjects may be discharged from observation at 32 hours after study drug
initiation; however, discharge is allowed only when the QTc is no greater than
460 msec for men or 480 msec for women. Also, any clinically important rhythm
disturbance identified during the observation period could, at the discretion
of the investigator, result in continued in-hospital observation.
If the subject requires continued monitoring because of a prolonged QTc (not
due to use of another antiarrhythmic known to prolong QT), the Holter monitor
as well as bedside monitoring should be continued until such time that the QTc
falls below the pre-specified threshold. Once QTc falls below the threshold, a
final 12-lead ECG should be recorded.
Subjects will return for a clinic visit on Day 8 (+1 day). The subjects* vital
status as of Day 30 will also be assessed.

Patients will be randomised in a 2:1 ratio to receive vanoxerine or placebo
400mg (2 capsules of 200mg to be taken orally) via a pre-determined
randomization scheme.

participation involves screening/baseline visit. Patient will be randomised and
stay hospitalised for a minimum of 32 hours. In addition to routine practise
patient will have additional blooddraws, 5 or 6 in total during the stay.
Patient will get a holter ECG for minimum of 32 hours. At 3 times during the
stay patient will be asked several questions regarding his symptoms.

At day 8 post randomisation the patient will visit the hospital. A blood draw,
physical exam, questions about sympoms will be asked and whether the patient
experienced any adverse events.

Patient will receive phonecall at day 30 to check vital status.

Patient may benefit from participation in having sinus rhythm restored.

Patient may suffer from side effects previously reported in studies with
vanoxerine. However, patient may also suffer adverse event not previously
reported.