Clinical Randomised Phase 2 Trial of AP31969 versus Placebo for Rhythm Control of Atrial Fibrillation.

The primary objective of this study is to assess the effect of AP31969 on atrial fibrillation burden. This endpoint is clinically relevant as AF burden represents a quantifiable measure of arrhythmia duration and frequency, which correlates with cardiovascular morbidity, stroke risk, and overall disease severity in patients with atrial fibrillation.

The secondary objectives include:

• To assess the effect of AP31969 on other measures of AF.
• To assess the effect of AP31969 on signs and symptoms of AF.
• To assess the effect of AP31969 on quality of life (QoL) and patient-reported outcomes (PRO).
• To evaluate the safety of AP31969.

This clinical trial enrolled a total of **20 participants** diagnosed with **atrial fibrillation**. The study population included both **male and female participants** aged **18 years and older**, encompassing **adults** and **elderly individuals**. Participants were required to have an **ECG-documented diagnosis of atrial fibrillation** with a history suggesting an expected AF burden between 1% and 90% at screening. The selection process involved assessment of AF burden using an **ECG patch device**, confirming a burden of at least 1% but not exceeding 90%. Participants currently experiencing an AF episode at screening were eligible only if the episode duration was less than 7 days. Key eligibility requirements included willingness to undergo **loop recorder implantation** and agreement to avoid non-trial rhythm control interventions throughout the study duration. **Female participants of childbearing potential** and male participants with female partners of childbearing potential were required to adhere to specific contraceptive measures from screening through follow-up. The trial included a **vulnerable population**.

This is a randomized, placebo-controlled Phase 2 clinical trial evaluating the efficacy and safety of **AP31969 sulfate** administered as **film-coated tablets** via the **oral route** in participants with **atrial fibrillation**. The trial employs a double-blind design in which participants are randomized to receive either AP31969 at various dose levels (200 mg, 400 mg, 700 mg, or 1000 mg daily) or matching **placebo** tablets that are visually identical to the active treatment. The maximum treatment period is 12 weeks. The primary objective is to assess the effect of AP31969 on atrial fibrillation burden, defined as the percentage of time spent in atrial fibrillation from week 2 to week 12. Secondary objectives include evaluation of the number and mean duration of atrial fibrillation episodes, time to first atrial fibrillation episode exceeding 5 hours in participants in **sinus rhythm** at randomization, changes in symptom scores using the Modified European Heart Rhythm Association (mEHRA) score, quality of life assessments through the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire and **EQ-5D-5L** score, Patient Global Assessment of Change (PGI-C) score, and safety parameters including **adverse events**, episodes of **ventricular tachycardia** exceeding 30 seconds, and changes in **QTcF interval**.

Eligible participants must be adults aged 18 years or older with electrocardiographically documented atrial fibrillation and an expected atrial fibrillation burden between 1% and 90% based on screening assessments. Participants currently in atrial fibrillation must have an episode duration of less than 7 days at screening. Confirmation of atrial fibrillation burden between 1% and 90% is required through assessment with an **ECG patch device**. All participants must be willing to have a **loop recorder** implanted for continuous cardiac rhythm monitoring throughout the trial and must agree to avoid non-trial related rhythm control interventions during the study period. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception from 4 weeks prior to first trial drug administration until the follow-up visit. Female participants must not be pregnant or breastfeeding at enrollment.

The trial is expected to commence recruitment in September 2025 and conclude in November 2026. Participant involvement spans approximately 12 weeks of active treatment followed by a follow-up visit. The screening visit includes assessment of eligibility criteria, documentation of atrial fibrillation history, and placement of monitoring devices. During the treatment period, participants undergo regular study visits for safety assessments, efficacy evaluations, and collection of patient-reported outcomes. Continuous cardiac rhythm monitoring via the implanted loop recorder provides data for assessment of atrial fibrillation burden and episode characteristics throughout the treatment period. The end-of-study visit includes final safety and efficacy assessments, evaluation of quality of life measures, and device data retrieval. Participants may be withdrawn from the trial early if they experience unacceptable adverse events, require prohibited concomitant medications or interventions, become pregnant, withdraw consent, or meet other protocol-defined discontinuation criteria as determined by the investigator or sponsor.

The experimental medication **AP31969** contains the active substance **AP31969 sulfate** and is formulated as a **film-coated tablet** for **oral use**. The investigational medicinal product is classified as an **antiarrhythmic drug** and is administered in multiple dosage strengths throughout the trial. Four different dosing regimens are evaluated: 200 mg, 400 mg, 700 mg, and 1000 mg as maximum daily doses. The corresponding maximum total doses over the treatment period are 16800 mg, 33600 mg, 58800 mg, and 84000 mg respectively. The **maximum treatment period** is 12 weeks for all dosing regimens. All tablet strengths are visually identical to ensure blinding integrity.

The **placebo** tablets are formulated to contain the same excipients as the active investigational medicinal product but without AP31969 sulfate. The placebo tablets are manufactured to be visually identical to all active tablet strengths to maintain blinding throughout the study. The placebo is administered via the oral route with the same dosing schedule as the active treatment arms.

Efficacy will be assessed through evaluation of atrial fibrillation burden as the primary endpoint, measured from week 2 to week 12. Secondary efficacy endpoints include the number of atrial fibrillation episodes from week 2 to week 12, mean duration of atrial fibrillation episodes from week 2 to week 12, and time to first atrial fibrillation episode exceeding 5 hours for participants in sinus rhythm at randomisation. Additional efficacy parameters comprise change from baseline in Modified European Heart Rhythm Association (mEHRA) score at week 12, change from baseline in Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire at week 12, change from baseline in EQ-5D-5L score at week 12, and Patient Global Assessment of Change (PGI-C) score at week 12. Safety assessments include monitoring of adverse events, number of ventricular tachycardia episodes exceeding 30 seconds duration from week 0 to week 12, and change from baseline in QTcF at week 12.