A Study Evaluating the Efficacy and Safety of AP30663 for Cardioversion in Participants With Atrial Fibrillation (AF)

The 12-lead Holter monitoring equipment was used to monitor heart rate and its rhythm. Electrocardiogram (ECG) was performed in a standardized manner after the participant had rested in the semi-supine position for at least 5 minutes. Conversion from AF to normal sinus rhythm within 90 minutes from start of infusion was determined by the investigator and documented with a rhythm strip confirming conversion. Percentages were based on number of participants converted from atrial fibrillation and absence of recurrence of AF within 1 minute of conversion divided by total number of participants \*100 in each treatment group. Analysis was performed based on Bayesian model.

Time frame: Within 90 minutes from the start of infusion (Day 1)

Population: Full Analysis Set included all randomized participants who were administered double-blind study treatment and had an evaluable AF conversion status within 90 minutes from the start of infusion.

AUC0-0.5 was defined as area under the concentration time curve from pre-dose concentration up to 30 minutes. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30 minutes post-infusion

Population: The PK Set included all participants in the safety set who had at least one evaluable post-baseline drug concentration value.

AUC0-inf was defined as area under the concentration time curve from pre-dose through concentration to infinity (extrapolated), calculated as AUC0-t + Ct/Kel, where Ct is the last observed non-zero concentration. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the safety set who had at least one evaluable post-baseline drug concentration value. Here, overall number of participants analyzed signifies those participants were evaluable for this outcome.

AUC0-t was defined as area under the concentration-time curve from time zero to time of last measurable concentration. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the safety set who had at least one evaluable post-baseline drug concentration value.

QTcF was assessed based on 12-lead Holter monitoring equipment. Triplicate ECGs were extracted at the same time points as PK sampling and were read in a semi-automated manner by a blinded cardiologist. The participant rested in the semi-supine position for at least 5 minutes at ECG extraction timepoints. Change from baseline was estimated based on a linear mixed-effects model: ΔQTcF = Time + Treatment + Time\*Treatment + Baseline QTcF.

Time frame: Baseline, 15 minutes, 45 minutes, 2 hours, 8 hours and 24 hours post-dose

Population: All randomized participants who were administered double-blind study treatment and with measurements at baseline as well as on-treatment with at least 1 post-dose time point with a valid ΔQTcF value. Participants were analyzed according to the treatment received. Here, number analyzed signifies those participants were evaluable at specific timepoints.

Kel represents the fraction of drug eliminated per unit of time. Elimination rate constant was calculated using linear regression on the terminal portion of the log-linear concentration versus time curve. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the safety set who had at least one evaluable post-baseline drug concentration value. Here, overall number of participants analyzed signifies those participants were evaluable for this outcome.

Cmax was defined as the maximum observed peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. Blood samples were collected at indicated timepoints. Pharmacokinetics (PK) was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the Safety Set who had at least one evaluable post-baseline drug concentration value.

An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. TEAEs are defined as any AE occurring or worsening on or after the first dose of study medication. A serious adverse event (SAE) is defined as any serious adverse event that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, significant medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed before. TEAEs include both serious and non-serious adverse events.

Time frame: From start of infusion (Day 1) up to follow-up (Day 35)

Population: Safety set included all randomized participants who were administered double-blind study treatment. Participants analyzed according to the treatment received.

The 12-lead Holter monitoring equipment was used to monitor heart rate and its rhythm. ECG was performed in a standardized manner after the participant had rested in the semi-supine position for at least 5 minutes. Participants with relapse of AF within 5 minutes following pharmacological or DC cardioversion was presented by treatment and analyzed using a logistic regression model. Percentages were based on number of participants with relapse of AF within 5 minutes after Pharmacological or DC cardioversion divided by total number of participants \*100 in each treatment group.

Time frame: Within 5 minutes after cardioversion (Day 1)

Population: Full Analysis Set included all randomized participants who were administered double-blind study treatment and had an evaluable AF conversion status within 90 minutes from the start of infusion.

The 12-lead Holter monitoring equipment was used to monitor heart rate and its rhythm. ECG was performed in a standardized manner that the participant had rested in the semi-supine position for at least 5 minutes. Percentage of participants in SR was assessed from Holter ECGs at 3 hours, 24 hours and Day 30 after start of infusion. Percentages were based on number of participants in SR at 3 hours, 24 hours and Day 30 after start of infusion divided by total number of participants \*100 in each treatment group.

Time frame: At 3 hours, 24 hours and Day 30 after start of Infusion (Day 1)

Population: Full Analysis Set included all randomized participants who were administered double-blind study treatment and had an evaluable AF conversion status within 90 minutes from the start of infusion. Here, overall number of participants analyzed signifies those participants were evaluable for this outcome and number analyzed signifies participants at specific timepoints.

T1/2 was calculated as loge (2) per elimination rate constant (kel), where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the Safety Set who had at least one evaluable post-baseline drug concentration value. Here, overall number of participants analyzed signifies those participants were evaluable for this outcome.

The 12-lead Holter monitoring equipment was used to monitor heart rate and its rhythm. ECG was performed in a standardized manner after the participant had rested in the semi-supine position for at least 5 minutes. Time to conversion (in minutes) was calculated by time of conversion or censoring minus time of start of infusion.

Time frame: From start of infusion (Day 1) up to Day 2

Population: Full Analysis Set included all randomized participants who were administered double-blind study treatment and had an evaluable AF conversion status within 90 minutes from the start of infusion. Here, overall number of participants analyzed signifies those participants were evaluable for this outcome measure. No participant had conversion from AF to normal rhythm in placebo arm.

Tmax was directly determined from concentration time data. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.

Time frame: Baseline (pre-infusion) and at 5, 15, 25, 30, 45 minutes, 1 hour, 1.5 hours, 4 hours, 8 hours and 24 hours post-infusion

Population: The PK Set included all participants in the Safety Set who had at least one evaluable post-baseline drug concentration value.