| Eligibility |
Inclusion Criteria:
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:
1. First detected episode of paroxysmal AF
2. Recurrent episode of paroxysmal AF
3. Episode post-cardiac ablation for paroxysmal AF
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.
Exclusion Criteria:
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 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.
4. History of acute decompensated heart failure (HF)
5. History within 6 months prior to screening of, or present HF with a left ventricular
ejection fraction (LVEF) < 45%, and/or Class II or higher HF as defined by the New
York Heart Association (NYHA), and/or medication history suggestive of HF, in the
opinion of the Investigator. An echocardiogram with LVEF within 6 months of screening
is required to demonstrate eligibility. If no echocardiogram is available, subject
must undergo a diagnostic echocardiogram using a portable handheld ultrasound device
(handheld echocardiogram; HHE) during screening to confirm eligibility.
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), 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 months of screening
8. Known uncorrected severe aortic or mitral stenosis
9. Hypertrophic cardiomyopathy with outflow tract obstruction
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:
1. Long QT syndrome
2. Conduction disease (e.g. second- or third- degree heart block, bundle brach
block)
3. 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 or ventricular pause (e.g., >3 seconds)
and/or slow ventricular rhythm (e.g., <45 bpm) at time of conversion Note: Sinus node
dysfunction in AF is more prevalent in subjects >75 years old. d) Brugada Syndrome e)
Torsades de pointes (TdP)
13. Any of the following ECG-related features:
1. QTc interval >480 msec at screening (estimated by the Fridericia's formula)
2. QRS duration = 120 ms or history of previous documented wide QRS tachycardia
3. Predominantly (i.e., >30%) paced heart rhythm
4. 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 continuously visually observed prior to dosing
14. Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
15. Known abnormal liver function prior to randomization/allocation (including 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 serum
potassium result is <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, 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
22. Subject is deemed unsustainable 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 randomization/allocation in this study or 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
1. Who are not surgically sterile, or post-menopausal (defined as no menses for 2
years without an alternative cause), or
2. For whom a negative pregnancy test is unavailable before study entry, or
3. Who are pregnant or breast feeding at study entry
28. Previous administration of 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
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