A Phase 2 interventional study of AP30663 and Placebo in Atrial Fibrillation, sponsored by Acesion Pharma. Completed at 15 sites in 2 countries. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2024-05-06.
Sponsored by Acesion Pharma · Phase 2, Interventional, and Treatment
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.
Key Inclusion Criteria:
Key Exclusion Criteria:
Other protocol defined Inclusion/Exclusion criteria may apply
Participants will receive single dose of AP30663.
Drug: AP30663
Participants will receive placebo matched to AP30663.
Drug: Placebo
Participants will receive a single dose of one of the multiple dose levels of AP30663.
Drug: AP30663
Participants will receive placebo matched to AP30663.
Drug: Placebo
Administer by intravenous infusion.
Placebo matched to AP30663.
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.
Time frame: Within 90 minutes from the start of infusion (Day 1)
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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
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.
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
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.
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
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.
Time frame: 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.
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
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.
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
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.
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
The study was conducted at 8 active sites in 2 countries (Denmark and Hungary) from 09 September 2019 to 23 January 2023.
| Milestone | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Started | 27 | 16 | 23 |
| Part 1 | 16 | 16 | 0 |
| Part 2 | 11 | 0 | 23 |
| Full analysis set (fas) | 25 | 12 | 22 |
| Safety set | 26 | 15 | 22 |
| Pharmacokinetic (pk) set | 0 | 15 | 22 |
| Treated | 26 | 15 | 22 |
| Completed | 26 | 15 | 22 |
| Not completed | 1 | 1 | 1 |
| Withdrew: Participant non-compliance | 1 | 0 | 0 |
| Withdrew: Converted to sinus rhythm (sr) before the infusion | 0 | 1 | 0 |
| Withdrew: Screen failure | 0 | 0 | 1 |
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.
| Percentage of participants | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| 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 | 0 | 41.7 | 54.5 |
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.
| Minutes | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Time to Conversion From Atrial Fibrillation From Start of Infusion | — | 42.0 (24 to 81) | 35.0 (19 to 89) |
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.
| Percentage of participants | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Percentage of Participants With Relapse of AF Within 5 Minutes (IRAF) After Pharmacological or Direct Current (DC) Cardioversion | 4.0 | 0 | 0 |
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.
| Percentage of participants | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Sinus Rhythm at 3 hours | 84.0 | 100.0 | 95.2 |
| Sinus Rhythm at 24 hours | 76.0 | 100.0 | 100.0 |
| Sinus Rhythm at Day 30 | 64.0 | 90.0 | 71.4 |
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.
| Participants | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Participants with TEAEs | 13 | 4 | 11 |
| Participants with Serious TEAEs | 4 | 0 | 0 |
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.
| Millisecond | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Change at 15 minutes post-dose | 1.9 ± 3.21 | 11.7 ± 4.26 | 21.2 ± 3.49 |
| Change at 45 minutes post-dose | 1.0 ± 3.21 | 19.4 ± 4.26 | 37.7 ± 3.53 |
| Change at 2 hours post-dose | 6.2 ± 3.93 | 23.0 ± 4.26 | — |
| Change at 8 hours post-dose | 11.5 ± 3.29 | 13.6 ± 4.34 | 17.2 ± 3.59 |
| Change at 24 hours post-dose | 10.3 ± 3.74 | 14.9 ± 4.67 | 13.1 ± 4.53 |
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.
| Micrograms per liter | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Maximum Observed Peak Plasma Concentration (Cmax) of AP30663 | 7606.065 ± 31.5 | 10281.754 ± 30.9 |
Tmax was directly determined from concentration time data. Blood samples were collected at indicated timepoints. Pharmacokinetics was conducted using standard noncompartmental method.
| Hours | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Time to Reach Peak Plasma Concentration (Tmax) of AP30663 | 0.4170 (0.250 to 0.500) | 0.4170 (0.250 to 1.000) |
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.
| Hours | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Terminal Half Life of (T1/2) of AP30663 | 5.363 (2.60 to 8.39) | 5.620 (4.35 to 8.74) |
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.
| Hours*micrograms per liter | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Area Under the Concentration Time Curve From Pre-dose Concentration up to 30 Minutes (AUC0-0.5) of AP30663 | 2568.175 ± 41.2 | 3446.078 ± 79.1 |
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.
| Hours*micrograms per liter | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Area Under the Concentration Time Curve up to the Last Measurable Concentration (AUC0-t) of AP30663 | 19328.384 ± 44.0 | 29587.109 ± 31.4 |
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.
| Hours*micrograms per liter | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Area Under the Concentration-Time Curve From Pre-dose (Zero) Through Concentration to Infinity (AUC0-inf) of AP30663 | 21623.095 ± 43.4 | 31448.932 ± 33.3 |
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.
| Per hour | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|
| Elimination Rate Constant (Kel) of AP30663 | 0.13092 ± 31.4 | 0.11817 ± 18.6 |
Collected over From start of infusion (Day 1) up to follow-up (Day 35). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Part 1 and 2: Pooled Placebo | 0/26 (0%) | 4/26 (15.4%) | 13/26 (50%) |
| Part 1: AP30663 3mg/kg | 0/15 (0%) | 0/15 (0%) | 4/15 (26.7%) |
| Part 2: AP30663 5mg/kg | 0/22 (0%) | 0/22 (0%) | 11/22 (50%) |
| Event | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Atrial fibrillationCardiac disorders | 4/26 | 0/15 | 0/22 |
| Event | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg |
|---|---|---|---|
| Atrial fibrillationCardiac disorders | 7/26 | 1/15 | 7/22 |
| Atrial flutterCardiac disorders | 1/26 | 0/15 | 3/22 |
| Atrioventricular block first degreeCardiac disorders | 1/26 | 2/15 | 0/22 |
| HaematuriaRenal and urinary disorders | 0/26 | 0/15 | 2/22 |
| PhlebitisVascular disorders | 2/26 | 0/15 | 0/22 |
| HypotensionVascular disorders | 0/26 | 1/15 | 1/22 |
| HypertensionVascular disorders | 0/26 | 1/15 | 0/22 |
| Electrocardiogram QT prolongedInvestigations | 0/26 | 1/15 | 0/22 |
| Bundle branch block leftCardiac disorders | 0/26 | 0/15 | 1/22 |
| Bundle branch block rightCardiac disorders | 0/26 | 0/15 | 1/22 |
Safety set included all randomized participants who were administered double-blind study treatment and had analyzed according to the treatment received.
| Age, Continuous(years) | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg | Total |
|---|---|---|---|---|
| Mean | 64.3 ± 9.23 | 65.4 ± 8.48 | 65.5 ± 10.38 | 65.0 ± 9.35 |
| Sex: Female, Male(Participants) | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg | Total |
|---|---|---|---|---|
| Female | 8 | 3 | 7 | 18 |
| Male | 18 | 12 | 15 | 45 |
| Ethnicity (NIH/OMB)(Participants) | Part 1 and 2: Pooled Placebo | Part 1: AP30663 3mg/kg | Part 2: AP30663 5mg/kg | Total |
|---|---|---|---|---|
| Hispanic or Latino | 0 | 0 | 0 | 0 |
| Not Hispanic or Latino | 26 | 15 | 22 | 63 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
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Acesion Pharma