INhalation of Flecainide to Convert Recent Onset SympTomatic Atrial Fibrillation to siNus rhyThm (INSTANT)

A Prospective Randomized Multicenter Study of Flecainide Acetate Oral Inhalation Solution in Single and Repeat Dose Regimens for Acute Conversion to Sinus Rhythm in Subjects With Recent Onset of Symptomatic Paroxysmal Atrial Fibrillation

The study consisted of 3 parts (Part A, Part B and Part C). Part A was an open-label, randomized, multi center design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens. Part B was an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal inhaled flecainide dose determined from Part A. Part C was an open-label, multi center study with exploratory objectives to explore the feasibility of patient-led self administration of flecainide. Part C also included an exploratory sub-study to assess the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in an emergent setting.

Subjects eligible to participate in the study must provide written informed consent (IC) before randomization or any study- specific procedures.

The study consists of 3 parts (Part A, Part B and Part C) as described below:

Part A: was completed in March 2020 and was an open-label, randomized, multicenter design to evaluate the feasibility of administration of inhaled flecainide in two dosing regimens.

Subjects were randomized at a 1:1 ratio to a single (N = 10) or repeat (N = 10) dose regimen. Randomization, for the initial 20 patients in Part A was stratified by duration of the presenting AF episode (≥ 1 h up to ≤ 24 hours; > 24h up to ≤ 48h).

After completion of the 60 mg dose cohort and review of safety/tolerability and PK data, additional subjects were enrolled in an additional repeat dose regimen (90 mg estimated total lung dose (TLD), N= up to 30 subjects. An additional dose cohort of 120 mg was added to Part A which utilized a different concentration of flecainide (75 mg/mL) and formulation (FlecIH-103). The final dose of 120 mg was selected as the dose to continue evaluating in Part B.

Part B: was an open-label, multicenter design to confirm the safety (including tolerability) and efficacy of the optimal inhaled flecainide dose determined from Part A (120 mg, using the FlecIH-103 inhalation solution).

Part C: was an open-label, multi center design study with exploratory objectives to explore the feasibility of patient-led self administration of flecainide. Part C also included an exploratory sub-study to assess the feasibility of implementing a portable cardiac ultrasound (HHE) at screening in an emergent setting.

Upon return to the clinic with a recurrent episode of AF, eligibility was reconfirmed and the subjects self-administered the study treatment and inhalation regimen under medical supervision.

If at 90 minutes after initiation of dosing, no conversion to sinus rhythm (SR) was observed, the Investigator was allowed to offer the subject another appropriate therapy. Discharge was left up to the discretion of the treating physician but no less than 90 min after initiation of dosing. Heart rhythm was confirmed with an Event Recorder during follow up.

An independent Data and Safety Monitoring Board (DSMB) was responsible for monitoring safety during the study.

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