Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria:

Subjects with recent-onset symptomatic AF at presentation,
With a duration at onset of symptoms from 1 hour to 48 hours,

And from one of the following categories:

First detected episode of paroxysmal AF
Recurrent episode of paroxysmal AF
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:

Subject < 18 or > 85 years of age
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.
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.
History of acute decompensated heart failure (HF)
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.
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.
History of myocardial infarction (MI) within 3 months of screening
Known uncorrected severe aortic or mitral stenosis
Hypertrophic cardiomyopathy with outflow tract obstruction
Current diagnosis of persistent AF
One or more episodes of atrial flutter within 6 months prior to screening or atrial flutter at presentation

History of any of the following heart abnormalities:

Long QT syndrome
Conduction disease (e.g. second- or third- degree heart block, bundle brach block)
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)

Any of the following ECG-related features:

QTc interval >480 msec at screening (estimated by the Fridericia's formula)
QRS duration ≥ 120 ms or history of previous documented wide QRS tachycardia
Predominantly (i.e., >30%) paced heart rhythm
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
Severe renal impairment (eGFR < 30 mL/min/1.73 m2) or on dialysis
Known abnormal liver function prior to randomization/allocation (including hepatic disease or biochemical evidence of significant liver derangement known prior to randomization/allocation)
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.
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.
Known hypersensitivity to flecainide acetate or any of its active metabolites
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)
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.
Treatment with amiodarone within the last 12 weeks
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.
Known drug or alcohol dependence within the past 12 months as judged by the Investigator
A body mass index > 40 Kg/m2
Legally incompetent to provide informed consent (IC)
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

Female of childbearing potential

Who are not surgically sterile, or post-menopausal (defined as no menses for 2 years without an alternative cause), or
For whom a negative pregnancy test is unavailable before study entry, or
Who are pregnant or breast feeding at study entry
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)
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
Respiratory rate of > 22 breaths per minute