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

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