Flecainide Acetate Inhalation Solution for Cardioversion of Recent-Onset, Symptomatic Atrial Fibrillation

• Status: Not yet recruiting
• Trial end date: 2023-03-30
• Target enrollment: 0
• Participant gender: All

Summary

This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical study designed to evaluate the efficacy and safety of FlecIH-103 (flecainide acetate inhalation solution) compared with placebo in patients with recent-onset, symptomatic newly diagnosed or paroxysmal AF. Approximately 400 patients are expected to be enrolled in this study. Patients will be randomized 3:1 to receive FlecIH-103 at a total dose of up to 120 mg estimated total lung dose (eTLD) (n=300) or placebo inhalation solution (n=100). Randomization will be stratified by geographic region (US and ex-US) and duration of symptoms of the current AF episode (≥1 hour to ≤24 hours and >24 hours to ≤48 hours).

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: InCarda Therapeutics, Inc.

Criteria

Inclusion Criteria:

1. ≥18 and ≤85 years of age

2. Recent onset of symptomatic newly diagnosed or paroxysmal AF

1. Recent onset is defined as a symptom duration ≥1 and ≤48 hours at time of dosing

2. Newly diagnosed AF is AF that has not been diagnosed previously, independent of its duration

3. Paroxysmal AF is defined as recurrent AF in a patient whose previous AF episode(s) self-terminated (ie, without treatment) or terminated with intervention ≤7 days of onset.

4. A symptomatic recent-onset AF episode post cardiac ablation for paroxysmal AF would be considered eligible

Exclusion Criteria:

1. History of non self-terminating AF/AFL as defined by

1. One or more failed attempts to restore SR with pharmacological therapy

2. ECV procedure for an AF episode ≤1 year prior to screening. Exception: One (1) prior ECV is allowed if no option for pharmacological conversion was previously available

3. More than 3 ECV procedures in ≤5 years prior to screening

2. Current diagnosis of persistent AF

1. Persistent AF defined as AF that is continuously sustained >7 days, including episodes terminated by cardioversion (drugs or electrical cardioversion) after >7 days. Patients with persistent AF do not have self-terminating AF episodes

2. Patients who have undergone an ablation procedure for persistent AF are not eligible

3. One or more episodes of AFL ≤6 months prior to randomization

a. Exception: a patient who has received ablation for AFL ≤3 months prior to screening with no recurrence of AFL prior to randomization is considered eligible Vital signs

4. Hemodynamic or cardiac instability during AF, defined as any of the following:

1. Systolic blood pressure <100 or ≥160 mmHg

2. Diastolic blood pressure ≥95 mmHg

3. Ventricular heart rate <80 or >160 bpm

5. Respiratory rate >22 breaths per minute Relevant structural heart disease

6. History of decompensated heart failure (HF)

7. Evidence of significant HF defined as any of the following:

a. Hospitalization in the last 12 months for HF or suspected HF event b. Most recent assessment of left ventricular ejection fraction (LVEF) <45% i. For patients in the United States, a standard diagnostic echocardiogram assessed ≤180 days prior to screening is required to ascertain eligibility. If none is available, the patient must undergo a standard diagnostic echocardiogram or a diagnostic echocardiogram using a portable ultrasound device (handheld echocardiogram [HHE]) during screening to confirm eligibility c. New York Heart Association (NYHA) Class II-IV symptoms d. Medication history suggestive of HF per the Investigator's discretion

8. Signs or symptoms of ongoing myocardial ischemia, including any of the following:

1. Significant ST segment elevation or depression (ie, ≥2 mm) on a standard 12-lead ECG

2. Echocardiogram findings (eg, wall motion abnormalities) suggestive of acute myocardial infarction (MI)

3. Angina pectoris, atypical angina pectoris, or receiving antianginal medication for ischemia

9. History of MI ≤3 months of screening

10. History of uncorrected moderate or severe aortic or mitral valvular stenosis, in the opinion of the Investigator

a. If an echocardiogram is performed at screening, moderate or severe valve disease observed during the examination is considered exclusionary

11. History of LV hypertrophy with LV thickness >12 mm as observed in the most recent assessment, ie, an echocardiogram Other CV conditions

12. Stroke (including transient ischemic attack) ≤3 months prior to randomization

13. History of any of the following cardiac abnormalities:

1. Long QT syndrome

2. Conduction system disease (eg, PR interval >200 ms, second- or third degree heart block, bundle branch block)

3. Brugada syndrome

4. Torsade de pointes

5. Diagnosed with sinus node dysfunction (eg, sick sinus syndrome) or any of the following:

i. History of unexplained or cardiovascular syncope ii. Bradycardia suggestive of sinus node dysfunction iii. Prior electrical or pharmacological cardioversion associated with sinus or ventricular pause >3 seconds or ventricular heart rate <45 bpm at time of conversion

14. Any of the following ECG-related features at screening:

1. QT interval corrected for heart rate using the Fridericia formula (QTcF) >480 msec

2. Wide QRS complex (ie, duration ≥120 msec) or history of documented wide QRS complex tachycardia (ie, wide QRS complex with ventricular heart rate >100 bpm)

3. Presence of ventricular tachycardia (VT). Site telemetry should be equipped with an alarm system for VT and PVCs or be continuously visually observed prior to dosing

15. Presence of a pacemaker

16. Cardiac surgery for any of the exclusionary conditions (eg, valvular disease, hypertrophy, coronary artery disease) ≤6 months prior to randomization Prior and concomitant non-CV conditions

17. Known severe renal impairment or patient receiving dialysis

18. Known abnormal liver function, including hepatic disease or biochemical evidence of significant liver derangement

19. Uncorrected hypokalemia

1. Hypokalemia is defined as serum potassium below the normal range according to the local laboratory reference ranges at screening

2. If serum potassium is below the normal range at screening, therapeutic correction (eg, potassium supplementation) is required

20. Uncorrected hypomagnesemia

1. Hypomagnesemia is defined as serum magnesium below the normal range according to the local laboratory reference ranges at screening

2. If serum magnesium result is below the normal range at screening, therapeutic correction (eg, magnesium supplementation) is required

21. Chronic obstructive pulmonary disease or other established pulmonary disease in need of inhalation medication

a. Exception: patients with intermittent mild asthma who are not experiencing active symptoms at screening, and whose asthma is well controlled with as-needed administration of a bronchodilator ≤2 days/week, and who has not experienced ≥2 exacerbations requiring oral systemic corticosteroids ≤1 year prior to screening

22. History of bronchospasm (eg, hyperreactive airways to inhalants) or difficulty inhaling medications

23. Previous or current hospitalization for COVID-19, or any secondary cardiomyopathy from COVID-19 Prior and concomitant medications and procedures

24. Treatment with Class I or III AADs ≤7 days prior to randomization

25. Treatment with amiodarone ≤12 weeks prior to randomization

26. Known hypersensitivity to flecainide acetate or any of its active metabolites Other

27. Any condition or circumstance which in the opinion of the Investigator may make the patient unsuitable for the study, such as:

1. High risk for stroke based on the screening coagulation panel or medical history per Investigator's discretion (eg, CHA2DS2-VASc score)

2. Congenital heart disease

3. AF that is secondary to electrolyte imbalance, thyroid disease, or other reversible or non-cardiovascular cause

4. A serious or life-threatening medical condition

5. An acute infection

28. Known drug or alcohol dependence ≤12 months prior to screening as judged by the Investigator

29. A body mass index >40 kg/m2

30. Legally incompetent to provide informed consent

31. Previous treatment with any other investigational drug ≤30 days from screening or 5 half-lives of the drug, whichever is longer

32. Female of childbearing potential defined as any of the following:

1. Not surgically sterile or postmenopausal (Appendix 1)

2. A negative pregnancy test is unavailable at screening

3. Pregnant or breastfeeding at screening Males whose sexual partners are women of childbearing potential (WOCBP) must use at least one highly effective method of contraception during the study unless permenantly sterile by bilateral orchiectomy.