Dose Escalation Study to Assess Safety, Tolerability, and Efficacy of Budiodarone Treatment With Non-permanent Atrial Fibrillation

A Multicenter, Open-Label, Dose Escalation Study of the Safety, Tolerability, and Efficacy of Budiodarone for the Treatment of Subjects With Non-permanent Atrial Fibrillation

This multicenter, open-label study aims to assess the safety, tolerability and efficacy of budiodarone in treating participants with non-permanent AF, in particular paroxysmal atrial fibrillation (PAF). The trial will serve as a 6-month safety and a proof-of-concept study for a dose escalation strategy using AF monitoring, enrolling approximately 100 participants who will undergo 24 weeks of treatment. The study aims to evaluate the feasibility of dose escalation through AF monitoring of long episodes atrial fibrillation last 5 hours or longer.

The study will allow AF participants from three specific populations: 1) Participants with a pre-implanted Cardiac Implantable Electrical Device (CIED), which includes implantable pacemakers or implantable loop recorders (ILR) and who have a history of paroxysmal AF with LEAF lasting 5 hours or longer recorded in their pacemaker within the 3 months before screening; 2) Participants undergoing first-time elective electrical (direct current) cardioversion for persistent AF, or second-time elective electrical (direct current) cardioversion; and 3) Participants with paroxysmal AF who do not have a pacemaker or ILR and who have a history of frequent AF and LEAF, with a minimum CHA2DS2-VASc score of 1 or more for males and 2 or more for females.

AF monitoring will be conducted via a pre-implanted Cardiac Implantable Electrical Device (CIED), which includes implantable pacemakers or implantable loop recorders (ILR), for those who have one. Participants without a CIED will undergo AF monitoring using a cardiac patch and/or a wearable device on the wrist.

All participants who meet the study entry criteria will be started on 200 mg budiodarone BID. The participants will return to the study site every 4 weeks and dose adjustments will follow the following algorithm. If no AF episode lasting 5 hours or longer is recorded and no rolling 24-hour period shows a cumulative AF burden of 5 hours or longer, the participant is classified as a monthly responder, and the budiodarone dose remains unchanged. If at least one AF episode of 5 hours or longer is observed, or if any rolling 24-hour period indicates a cumulative AF burden of 5 hours or longer, the participant is designated as a monthly non-responder, and the budiodarone dose is increased by 200 mg BID up to a maximum of 800 mg BID.

Key Inclusion Criteria:

• Proven paroxysmal atrial fibrillation or undergoing first-time elective electrical (direct current) cardioversion for persistent atrial fibrillation, or second-time elective electrical (direct current) cardioversion.
• Baseline AF Criteria: To qualify for treatment, each participant must have during the 28-day baseline period an AFB greater than 5% and one of the following qualifying events: 1) 2 continuous AF episodes (LEAF) of 5 hours or longer; or 2) 2 rolling 24-hour periods in which cumulative AF duration is 5 hours or longer; or 3) 1 continuous AF episode (LEAF) of 5 hours or longer plus 1 rolling 24-hour period in which cumulative AF duration is 5 hours or longer
• Must have failed at least one prior therapy for AF
• Must have an AFSS greater than 3.
• CHA₂DS₂-VASc score of 1 or more for males and 2 or more for females and be on oral anticoagulant for at least 3 weeks prior to receiving the study medication.
• For participants with heart failure: NYHA Class I or II heart failure.

Key Exclusion Criteria:

• NYHA Class 3 or 4 heart failure.
• MI, ischemic stroke, or any clinically relevant venous thromboembolism within 3 months of screening.
• Unstable angina, percutaneous transluminal coronary angioplasty (PTCA), or CABG within 3 months of screening.
• Prolonged QTcF Interval with a normal QRS duration (>500 ms with QRS ≤120 ms).
• Persistent AF (≥7 consecutive days or episodes >23 hours). Those presenting with persistent AF at screening are eligible if they are scheduled to undergo first-time elective cardioversion, or second-time cardioversion
• Recent treatment with rhythm control medications (Class I or III Singh-Vaughan Williams) within five half-lives before screening (rate control drugs permitted) and amiodarone within 3 months prior to screening.
• Cardiac ablation procedures within 30 days of screening or participants who have scheduled an ablation procedure
• Severe end-organ disease