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

A Double-Blind, Randomised, Placebo-Controlled, Parallel-Group Study of AP30663 Given Intravenously for Cardioversion in Patients With Atrial Fibrillation

This study will evaluate the efficacy, safety, tolerability and pharmacokinetics (PK) of one or more doses of AP30663 for cardioversion in adult participants with AF.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: AP30663; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Aalborg, Denmark
    • Acesion Pharma Investigational Site 110
  • Copenhagen, Denmark
    • Acesion Pharma Investigational Site 106
  • Hellerup, Denmark
    • Acesion Pharma Investigational Site 108
  • Hillerød, Denmark
    • Acesion Pharma Investigational Site 113
  • Roskilde, Denmark
    • Acesion Pharma Investigational Site 105
• Hungary
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 202
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 203
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 207
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 212
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 213
  • Budapest, Hungary
    • Acesion Pharma Investigational Site 214
  • Pecs, Hungary
    • Acesion Pharma Investigational Site 211
  • Szekszárd, Hungary
    • Acesion Pharma Investigational Site 201
  • Szentes, Hungary
    • Acesion Pharma Investigational Site 210
  • Zalaegerszeg, Hungary
    • Acesion Pharma Investigational Site 204

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Clinical indication for cardioversion of AF
• Current episode of symptomatic AF lasting between 3-hour and 7 days (inclusive) at randomization
• Adequate anticoagulation according to international and/or national guidelines

Key Exclusion Criteria:

• Significant clinical illness or surgical procedure within 4 weeks preceding the screening visit
• History of significant mental, renal or hepatic disorder, chronic obstructive pulmonary disease, sinus nodal disease, or other significant disease, as judged by the investigator.
• Any cardioversion attempt of AF or atrial flutter within 4 weeks preceding randomization
• Use of any antiarrhythmic drug class I and/or III within 6 months before randomisation

Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: AP30663; Participants will receive single dose of AP30663.	Drug: AP30663; Administer by intravenous infusion.
Placebo Comparator: Part 1: Placebo; Participants will receive placebo matched to AP30663.	Drug: Placebo; Placebo matched to AP30663.
Experimental: Part 2: AP30663; Participants will receive a single dose of one of the multiple dose levels of AP30663.	Drug: AP30663; Administer by intravenous infusion.
Placebo Comparator: Part 2: Placebo; Participants will receive placebo matched to AP30663.	Drug: Placebo; Placebo matched to AP30663.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Converted From Atrial Fibrillation (AF) Within 90 Minutes From Start of Infusion and Subsequently Had no AF Recurrence Within 1 Minute of Conversion From 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.	Within 90 minutes from the start of infusion (Day 1)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Conversion From Atrial Fibrillation From 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 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.	From start of infusion (Day 1) up to Day 2
Percentage of Participants With Relapse of AF Within 5 Minutes (IRAF) After Pharmacological or Direct Current (DC) Cardioversion	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.	Within 5 minutes after cardioversion (Day 1)
Percentage of Participants With Sinus Rhythm (SR) at 3 Hours, 24 Hours and Day 30 After 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.	At 3 hours, 24 hours and Day 30 after start of Infusion (Day 1)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	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.	From start of infusion (Day 1) up to follow-up (Day 35)
Changes From Baseline in Fridericia's Correction of QT Interval (ΔQTcF) Interval Data Over Time	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.	Baseline, 15 minutes, 45 minutes, 2 hours, 8 hours and 24 hours post-dose
Maximum Observed Peak Plasma Concentration (Cmax) of AP30663	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.	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
Time to Reach Peak Plasma Concentration (Tmax) of AP30663	Tmax was directly determined from concentration time data. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.	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
Terminal Half Life of (T1/2) of AP30663	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.	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
Area Under the Concentration Time Curve From Pre-dose Concentration up to 30 Minutes (AUC0-0.5) of AP30663	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.	Baseline (pre-infusion) and at 5, 15, 25, 30 minutes post-infusion
Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUC0-t) of AP30663	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.	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
Area Under the Concentration-Time Curve From Pre-dose (Zero) Through Concentration to Infinity (AUC0-inf) of AP30663	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.	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
Elimination Rate Constant (Kel) of AP30663	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.	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

Collaborators and Investigators

• Sponsor: Acesion Pharma

Study record dates

Study Major Dates

• Study Start (Actual): September 9, 2019
• Primary Completion (Actual): December 13, 2022
• Study Completion (Actual): January 23, 2023

Study Registration Dates

• First Submitted: September 25, 2020
• First Submitted That Met QC Criteria: September 25, 2020
• First Posted (Actual): October 1, 2020

Study Record Updates

• Last Update Posted (Actual): May 6, 2024
• Last Update Submitted That Met QC Criteria: November 17, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: AP30663-2001; 2018-004445-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No