A prospective, randomized, multicenter study of flecainide acetate oral inhalation solution in single and repeat dose regimens for acute conversion to sinus rhythm (SR) in subjects with recent onset of symptomatic paroxysmal atrial fibrillation (AF).

1) Subjects with recent-onset symptomatic AF at presentation.
2) With a duration at onset of symptoms from 1 hour to 48 hours,
3) And from one of the following categories:
a) First detected episode of paroxysmal AF
b) Recurrent episode of paroxysmal AF
c) Episode post-cardiac ablation for paroxysmal AF
4) Part C Self-Administration (Patient-Led) Cardioversion Study only:
Subjects whose AF converts to SR with inhaled flecainide and without serious
AE(s) or complications in Part A, Part B, or the Medically-Led Cardioversion
Study of Part C.

NOTE: Subjects who:
- are prescribed a pill-in-the-pocket regimen (flecainide or propafenone) for
paroxysmal AF, or
- are within 3 months of having undergone ablation of paroxysmal AF, or
- have experienced an episode of new AF but are not currently experiencing an
episode of recent-onset paroxysmal AF, or
- are known to have paroxysmal AF (or previously diagnosed with paroxysmal AF)
and
have one or more previous symptomatic episodes but are not currently
experiencing
an episode of recent-onset paroxysmal AF
may consent to pre-study screening prior to presenting with recent-onset
symptomatic AF. These subjects will be eligible to receive study drug only when
presenting with symptomatic paroxysmal AF of recent-onset (i.e., * 48 hours),
consenting to the full study, and after meeting all eligibility criteria.

General
1) Subject < 18 or > 85 years of age
2) Hemodynamic and/or cardiac instability, with systolic blood pressure < 100
mmHg or > 150 mmHg, and/or ventricular heart rate < 80 bpm or > 150 bpm. For
subjects to meet eligibility criteria, at least 2 of the 3 measurements of
vital signs during screening (45, 30, and/or 15 minutes prior to dosing) must
meet criteria.
3) Current AF episode has been treated with Class I or Class III antiarrhythmic
drugs or electrical cardioversion. Subjects whose current AF episode has been
treated with flecainide
are eligible if their total cumulative exposure to flecainide (including the
study drug to be
administered in this study) does not exceed 320 mg within a 24-hour period, per
site
standard of care.

Relevant structural heart disease
4) History of acute decompensated heart failure (HF)
5) History within 6 months prior to screening of, or present HF with abnormal
left ventricular ejection fraction (LVEF), and/or Class II or higher HF as
defined by the New York Heart Association (NYHA) (see details under Section
20.1), and/or medication history suggestive of HF, in the opinion of the
Investigator. If participating in the optional Handheld Echo Sub-Study, the
subject must have a LVEF * 45%, absent or mild left ventricular hypertrophy,
and absent or mild valvular disease (stenosis or regurgitation)
6) Evidence of current ongoing myocardial ischemia, such as signs (e.g.,
significant [e.g., > 2 mm] ST segment elevation or depression on ECG,
echocardiographic findings suggestive of acute myocardial infarction) and/or
symptoms (e.g., angina pectoris, atypical angina pectoris), and/or being
medicated with anti-anginal medication. In addition, subjects with signs of
prior myocardial infarction (such as pathological Q waves) who are also taking
concomitant medications for angina
pectoris should be evaluated for presence of ongoing ischemia.
7) History of myocardial infarction (MI) within 3 month of screening
8) Known uncorrected severe aortic or mitral valve stenosis
9) Known hypertrophic cardiomyopathy with outflow tract obstruction, Other
cardiac conditions
10) Current diagnosis of persistent AF
11) One or more episodes of atrial flutter within 6 months prior to screening
or atrial flutter at presentation
12) History of any of the following heart abnormalities:
a) Long QT syndrome
b) Conduction disease (e.g. second- or third-degree heart block, bundle branch
block)
c) Diagnosed with sinus node dysfunction (e.g., sick sinus syndrome) and/or one
of the following:
(i) history of unexplained or cardiovascular syncope,
(ii) known bradycardia suggestive of sinus node dysfunction, and/or
(iii) prior electrical or pharmacological cardioversion associated with
prolonged sinus pause (e.g., >3 seconds) and/or slow ventricular rhythm (e.g.,
<45 bpm) or ventricular pause (e.g., >3 seconds) at time of conversion
Note: Sinus node dysfunction in AF is more prevalent
d) Brugada Syndrome
e) Torsades de pointes (TdP)
13) Any of the following ECG-related features:
a) QTc interval >480 msec at screening (estimated by the Fridericia*s formula)
b) QRS duration * 120 ms or history of previous documented wide QRS tachycardia
c) Predominantly (> 30%) paced heart rhythm,
d) Ventricular tachycardia (VT, sustained or non-sustained), or excessive
premature ventricular complexes (PVCs, >20 multifocal PVCs per hour), prior to
dosing as per site telemetry. Site telemetry should be equipped with an alarm
system for VT and PVCs or be continously visually observed prior to dosing.
Concomitant conditions
14) Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
15) Known abnormal liver function prior to randomization/allocation (incl.
hepatic disease or biochemical evidence of significant liver derangement known
prior to randomization/allocation)
16) Uncorrected hypokalemia (defined as serum potassium < 3.6 mEq/L) at
screening. If potassium < 3.8 mEq/L at screening, therapeutic correction (e.g.,
potassium supplementation) is strongly encouraged, although reassessing the
serum potassium level is not required as long as a value >= 3.6 mEq/L is
documented at screening.
17) Subjects with established pulmonary disease in need of inhalation
medication. Subjects with
COPD are excluded. Subjects with mild to moderate asthma that are not
experiencing active
symptoms at screening and whose asthma is well controlled with steroids and/or
as-needed
administration of a bronchodilator are eligible for the study.
18) Known hypersensitivity to flecainide acetate or any of its active
metabolites
19) Concomitant therapy with systemic drugs that are strong inhibitors of CYP
2D6 (e.g. antidepressants, neuroleptics, propranolol, ritonavir, some
antihistamines) or CYP 2D6 inducers (e.g. phenytoin, phenobarbital,
carbamazepine).
20) Treatment with Class I or Class III antiarrhythmic drugs within the last
week. Subjects whose
current AF episode has been treated with flecainide are eligible if their total
cumulative
exposure to flecainide (including the study drug to be administered in this
study) does not
exceed 320 mg within a 24-hour period, per site standard of care.
21) Treatment with amiodarone within the last 12 weeks, Other
22) Subject is deemed unsuitable for the trial by the Investigator (including
but not limited to: patients who are considered at high risk for stroke based
on screening coagulation panel or medical history (e.g. CHA2DS2-VASc score);
patients with congenital heart disease; patients with history of AF refractory
to pharmacological or electrical cardioversion; patients whose AF is secondary
to electrolyte imbalance, thyroid disease, or other reversible or
non-cardiovascular cause; patients with episodes of syncope; patients with any
serious or life threatening medical condition; patients with any acute
infection). The subject may be deemed unsuitable for the trial by the
Investigator if the subject is not able or willing to inhale the study drug.
23) Known drug or alcohol dependence within the past 12 months as judged by the
Investigator
24) A body mass index >40 kg/m2
25) Legally incompetent to provide informed consent (IC)
26) Previous enrollment in this study (unless a subject is enrolled but not
dosed; this exclusion criterion does not apply to enrollment in the Patient-Led
Cardioversion Study in Part C) or previous treatment with any other
investigational drug within 30 days from screening or 5 half-lives of the drug,
whichever is longer
27) Female of childbearing potential
a) Who are not surgically sterile, or post-menopausal (defined as no menses for
2 years without an alternative cause), or
b) For whom a negative pregnancy test is unavailable before study entry, or
c) Who are pregnant or breast feeding at study entry
28) Previous administration of IV flecainide for an episode of paroxysmal AF or
new AF did not
result in conversion of AF to SR (i.e., subject is considered a non-responder
to flecainide)
29) Cardiac surgery for any of the exclusionary conditions (e.g., valvular
disease, hypertrophy, coronary artery disease [CAD], etc.) within the last 6
months prior to screening
30) Respiratory rate of > 22 breaths per minute