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

Prior treatment

• Prior history of sustained ventricular tachycardia without an AICD or Torsades de Pointes.
• Persistent AF (≥7 consecutive days of 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 and no antiarrhythmic concomitant drugs (or who wash out) and who are on stable DOAC for at least 3 weeks and who do not require a TEE to rule out thrombus. If a TEE is performed as a standard of care, the TEE must be negative for atrial thrombus.
• 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.
• Termination of previous amiodarone treatment for severe toxicity.
• Investigational Drug Use: Recent treatment with investigational drugs within 30 days or 5 half-lives, whichever is longer.

Other illness

• Advanced His-Purkinje system disease or bifascicular block associated with syncope or presyncope without a functioning pacemaker.
• Reversible causes of AF (e.g., hyperthyroidism, recent open- heart surgery, metabolic or electrolyte shift, or ongoing active ischemia).
• Cardiac ablation procedures within 30 days of screening or participants who have scheduled an ablation procedure
• Known allergy or hypersensitivity to amiodarone or iodine.
• Active/uncontrolled thyroid disease, unexplained thyroid function test abnormalities under investigation, history of thyroid malignancy/nodules, or conditions/medications affecting thyroid function, unless stable for ≥3 months with normal thyroid function tests (stable hypo/hyperthyroid patients on consistent therapy are eligible).
• Any illness or condition judged by the investigator to compromise the participant’s safety during study drug administration.
• 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.

Lab values

• Presence or history of congenital or primary cardiac channelopathies. This includes, but is not limited to: a. Congenital Long QT Syndrome (LQTS), including: i. Romano–Ward syndrome (autosomal dominant LQTS) ii. Jervell and Lange–Nielsen syndrome (autosomal recessive LQTS with sensorineural deafness) iii. Andersen–Tawil syndrome (LQT7; KCNJ2 mutation) iv. Timothy syndrome (LQT8; CACNA1C mutation) b. Brugada syndrome (SCN5A-related sodium channelopathy) c. Short QT syndrome d. Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT; RyR2 or CASQ2 mutations) e. Long–Ganong–Levine syndrome f. Wolff–Parkinson–White syndrome or any form of pre-excitation due to an accessory pathway
• Severe end-organ disease: a. Estimated glomerular filtration rate (eGFR) <30 mL/min at screening. b. Advanced hepatic disease. c. Advanced pulmonary disease. d. Severe psychiatric disorders, e.g., advanced dementia.
• Clinically significant (heavy) anemia [hemoglobin <8 g/deciliter (dL) at screening].
• Thrombocytopenia (platelet count <90,000/μL at screening).

Age

• Concomitant Risks: Participants with conditions or treatments that could: a. Interfere with the study's conduct. b. Pose an unacceptable risk to safety, or compromise study data interpretation, such as: i. Life expectancy less than 2 years. ii. Active/suspected malignancy (except history of malignancy treated ≥2 years ago without evidence of recurrence). iii. Substance abuse (alcohol/illicit drugs) in the last 12 months. iv. Any known or suspicion for relevant infectious diseases associated with clinical signs (e.g., TSE/Cruetzfield Jacobs disease, Viral Hepatitis, HIV/AIDS, Ebola, West Nile virus, Zika virus). v. The participant is receiving analgesia via a continuous pain pump.

Other

• Pregnancy/Contraception: Pregnant women, women intending to become pregnant, or women not practicing effective contraception (pharmacological or barrier methods).
• Third-degree Atrioventricular Block without a functioning pacemaker.
• Lactating Women: Breastfeeding women are excluded.
• Ongoing alcohol or substance abuse.
• Protocol Compliance: Subjects unable/unwilling to follow the study protocol.
• Prolonged QTcF Interval with a normal QES duration (>500 ms with QRS ≤120 ms).

• CIED (Pacemaker or implantable loop recorder) Population o Participants with a history of paroxysmal AF with LEAF lasting more than 5 hours recorded in their pacemaker within the 3 months before screening. o The CIED data will be used to assess baseline AF eligibility criteria
• Prior Therapy: Must have failed at least one prior therapy for AF including: • Prior AAD based upon physician judgement • Prior rate control drugs based upon physician judgement and continued symptoms • AF catheter ablation • Cardioversion
• AFSS: 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.
• No heart failure or NYHA Class I or II heart failure. However, those with NYHA Class II heart failure or a documented ejection fraction (EF) below 45% within the past two years must complete additional assessments
• Able to understand study requirements and willing to follow instructions, attend all required study visits, and undergo all planned tests.
• Elective Cardioversion Population (Persistent AF) o participants undergoing first-time elective electrical (direct current) cardioversion for persistent AF, or second-time elective electrical (direct current) cardioversion and no antiarrhythmic concomitant drugs (or who wash out) and who are on stable DOAC for at least 3 weeks and who do not require a TEE to rule out thrombus. If a TEE is performed as a standard of care, the TEE must be negative for atrial thrombus.
• PAF Population Without Pacemakers or ILR where AF is quantified with wearable bands / patches o 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 and are on oral anticoagulant for at least 3 weeks prior to receiving the study medication. o The patch data and/or the Corsano Cardiowatch data will be used to assess baseline AF eligibility criteria
• Age: Adults between 18 and 80 years old.
• Informed Consent: Must be capable and willing to provide written IC.
• Women: Either postmenopausal for at least one year or surgically sterile; if premenopausal, must agree to use an approved method of contraception
• Men: Must agree to use an approved method of contraception, such as condoms with spermicide, or have a sterile partner, throughout the 12-week treatment period
• Proven paroxysmal atrial fibrillation (ECG, Holter monitor, cardiac patch, wearable or pacemaker diagnosis obtained by the clinical site or patient’s prior medical record documenting clear evidence of a diagnosis of PAF) or undergoing first-time elective electrical (direct current) cardioversion for persistent atrial fibrillation, or second-time elective electrical (direct current) cardioversion and no antiarrhythmic concomitant drugs (or who wash out) and who are on stable DOAC for at least 3 weeks and who do not require a TEE to rule out thrombus. If a TEE is performed as a standard of care, the TEE must be negative for atrial thrombus.
• 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: • 2 continuous AF episodes (LEAF) of 5 hours or longer • 2 rolling 24-hour periods in which cumulative AF duration is 5 hours or longer • 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