Atrial Fibrillation, Paroxysmal Atrial Fibrillation, Persistent Atrial Fibrillation
Conditions
Keywords
Atrial fibrillation, Paroxysmal Atrial fibrillation, Persistent Atrial fibrillation, A-fib
Brief summary
The purpose of Part 1 of this study is to determine the maximally tolerated dose of OPC-108459 in patients with paroxysmal and persistent atrial fibrillation (AF). The purpose of Part 2 of this study is to determine potential efficacy of dose(s) of OPC-108459 for the treatment of paroxysmal and persistent atrial fibrillation.
Detailed description
This trial will test the pharmacokinetic and pharmacodynamic characteristics of ascending doses of OPC-108459 in separate populations of paroxysmal and persistent AF subjects. The trial will consist of two parts. Each part will evaluate two populations of subjects presenting for cardioversion in a hospital setting. Cohorts of paroxysmal and persistent subjects may have their dose increased independently.
Interventions
DRUGOPC-108459
Part 1: single dose OPC-108459, 10-minute constant rate IV infusion to achieve specified Cmax target Part 2: single dose OPC-108459, 10-minute constant rate IV infusion to achieve Cmax target concentration from Part 1; if failure to convert to sinus rhythm, second dose OPC-108459 administered, 10-minute constant rate IV infusion to achieve target concentration from Part 1
DRUGPlacebo
Placebo dose, 10-minute constant rate IV infusion
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with paroxysmal atrial fibrillation (AF) (recent or new onset) or subjects with persistent AF at the time of randomization * Subjects who are hemodynamically stable * Subjects with a low risk of thromboembolic potential * Subjects who are willing to comply with the reproductive precautions
Exclusion criteria
Subjects with: * History of long QT syndrome, Torsade de Pointes or an uncorrected QT interval of \> 450 ms * History of myocardial infarction within 6 months of screening * Acute coronary syndrome, angina or active myocardial ischemia diagnosed by ECG, or other imaging within 6 months of screening * History of ventricular tachycardia, fibrillation, or resuscitated cardiac arrest * History of clinically significant congenital heart disease * Presence of severe aortic or mitral stenosis, aortic or mitral regurgitation, atrial septal defect, or other conditions leading to AF * Diagnosis of heart failure NYHA Class II-IV or with an ejection fraction \<40% (Part 1 only) * Diagnosis of heart failure NYHA Class IV or NYHA I, II, or III with an ejection fraction \<35% (Part 2 only) * Concomitant treatment with class I or III anti-arrhythmics agents unless the medication was discontinued more than 5 half-lives before dosing * History of seizures * Diagnosis of atrial flutter * Diagnosis of stroke, TIA (transient ischemic attack), or any transient neurological deficit within 1 year of screening or known carotid artery stenosis of \>50% * Cardiac surgery within 3 months of screening * Bradycardia (\< 50 bpm) or sick sinus syndrome, unless controlled by a pacemaker * Current reversible cause of AF * Wolff-Parkinson-White syndrome * Any congenital abnormality, severe valve disease * Subjects who have taken another investigational product within 30 days of dosing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Percentage of Subjects With Normal Sinus Rhythm (NSR) | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2: QTcF | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2: Ventricular Rate | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2: Diastolic and Systolic Blood Pressure | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 24 hours | OPC-108459 was administered as a 10-minute constant rate IV infusion. Blood samples were collected pre-dose (within 45 minutes of dosing), at the end of infusion and 0.5, 1, 2, 4, 8 and 24 hours post start of infusion. |
| Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 24 hours | OPC-108459 was administered as a 10-minute constant rate IV infusion. Blood samples were collected pre-dose (within 45 minutes of dosing), at the end of infusion and 0.5, 1, 2, 4, 8 and 24 hours post infusion. |
| Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | 24 hours | 12-lead Holter monitors were placed on all participants within 45 minutes prior to dosing. Post dose measurements were made at 2, 4, 6, 8, 10, 20, 30, and 40 minutes and 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours post-dose. To achieve consistent recording, Holter sampling will be recorded with the participant recumbent and at rest for at least 10 minutes prior to collection. |
| Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | 24 hours | 12-lead Holter monitors were placed on all participants within 45 minutes prior to dosing. Post dose measurements were made at 2, 4, 6, 8, 10, 20, 30, and 40 minutes and 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours post-dose. To achieve consistent recording, Holter sampling will be recorded with the participant recumbent and at rest for at least 10 minutes prior to collection. |
| Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | 24 hours | Maximum change from baseline in diastolic and systolic blood pressure(BP) collected during vital sign measurements in the 24-hour postdose interval. Participants must be hemodynamically stable defined as a screening systolic blood pressure between 90 to 160 mmHg, diastolic \<100 mmHg. BP was measured after at least 3 minutes in the supine position. BP was measured at predose (within 45 minutes of dosing); 3 and 7 minutes and approximately 1, 4, 8, 12, and 24 hours. |
| Part 2/1 Infusion: Cmax | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2/2 Infusions: Cmax | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2/1 Infusion: AUCt | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2/2 Infusions: AUCt | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Time to NSR | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 2: Duration of NSR | 24 hours | The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document. |
| Part 1: Percentage of Participants With NSR | 30 minutes | Percent of participants with NSR, defined as NSR for at least 1 minute within 30 minutes of the end of OPC-108459 infusion. |
Countries
Germany, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
This trial was conducted in 40 participants at 10 trial sites in the following 3 countries: Germany, Spain, and the United States.
Pre-assignment details
The trial consists of two parts (Part 1 and Part 2). Each part evaluates two populations of participants for cardioversion in a hospital setting; one diagnosed with paroxysmal atrial fibrillation (AF) and the second diagnosed with persistent AF. However, Part 2 was not conducted and therefore is not included in this document.
Participants by arm
| Arm | Count |
|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg Participants had received a single dose of OPC-108459 0.26 mg/kg, 10-minute constant rate IV infusion to achieve specified Cmax target. | 4 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg Participants had received a single dose of OPC-108459 0.40 mg/kg,10-minute constant rate IV infusion to achieve specified Cmax target. | 1 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg Participants had received a single dose of OPC-108459 1.00 mg/kg,10-minute constant rate IV infusion to achieve specified Cmax target. | 5 |
| Paroxysmal AF - Placebo Participants had received placebo dose 10-minute constant rate IV infusion. | 3 |
| Persistent AF - OPC-108459 0.26 mg/kg Participants had received a single dose of OPC-108459 0.26 mg/kg,10-minute constant rate IV infusion to achieve specified Cmax target. | 4 |
| Persistent AF - OPC-108459 0.40 mg/kg Participants had received a single dose of OPC-108459 0.40 mg/kg,10-minute constant rate IV infusion to achieve specified Cmax target. | 4 |
| Persistent AF - OPC-108459 0.60 mg/kg Participants had received a single dose of OPC-108459 0.60 mg/kg, 10-minute constant rate IV infusion to achieve specified Cmax target. | 6 |
| Persistent AF - OPC-108459 1.35 mg/kg Participants had received a single dose of OPC-108459 1.35 mg/kg, 10-minute constant rate IV infusion to achieve specified Cmax target. | 4 |
| Persistent AF - OPC-108459 1.55 mg/kg Participants had received a single dose of OPC-108459 1.55 mg/kg, 10-minute constant rate IV infusion to achieve specified Cmax target. | 4 |
| Persistent AF - Placebo Participants had received a single dose of placebo, 10-minute constant rate IV infusion. | 5 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Paroxysmal AF - OPC-108459 0.26 mg/kg | Paroxysmal AF - OPC-108459 0.40 mg/kg | Paroxysmal AF - OPC-108459 1.00 mg/kg | Paroxysmal AF - Placebo | Persistent AF - OPC-108459 0.26 mg/kg | Persistent AF - OPC-108459 0.40 mg/kg | Persistent AF - OPC-108459 0.60 mg/kg | Persistent AF - OPC-108459 1.35 mg/kg | Persistent AF - OPC-108459 1.55 mg/kg | Persistent AF - Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.3 years STANDARD_DEVIATION 19 | 75.0 years STANDARD_DEVIATION 0 | 68.4 years STANDARD_DEVIATION 9.1 | 61.0 years STANDARD_DEVIATION 14.1 | 65.0 years STANDARD_DEVIATION 5.7 | 75.0 years STANDARD_DEVIATION 10.1 | 63.5 years STANDARD_DEVIATION 14.7 | 64.8 years STANDARD_DEVIATION 12.9 | 64.3 years STANDARD_DEVIATION 7.7 | 70.4 years STANDARD_DEVIATION 8.8 | 66.6 years STANDARD_DEVIATION 11.75 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 3 Participants | 5 Participants | 4 Participants | 3 Participants | 4 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 4 | 1 / 1 | 2 / 5 | 0 / 3 | 0 / 4 | 1 / 4 | 0 / 4 | 1 / 4 | 1 / 4 | 2 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 1 | 0 / 5 | 1 / 3 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 5 |
Outcome results
Primary
Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ)
OPC-108459 was administered as a 10-minute constant rate IV infusion. Blood samples were collected pre-dose (within 45 minutes of dosing), at the end of infusion and 0.5, 1, 2, 4, 8 and 24 hours post infusion.
Time frame: 24 hours
Population: PK analysis dataset included all participants who had concentration time profiles consistent with proper intravenous infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 1.94 μg∙h/mL | Standard Deviation 0.834 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 1.25 μg∙h/mL | — |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 2.10 μg∙h/mL | Standard Deviation 0.318 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 1.28 μg∙h/mL | Standard Deviation 0.388 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 1.68 μg∙h/mL | Standard Deviation 0.65 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 1.51 μg∙h/mL | Standard Deviation 0.651 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 2.79 μg∙h/mL | Standard Deviation 0.99 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ) | 4.38 μg∙h/mL | Standard Deviation 1.55 |
Primary
Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion
Maximum change from baseline in diastolic and systolic blood pressure(BP) collected during vital sign measurements in the 24-hour postdose interval. Participants must be hemodynamically stable defined as a screening systolic blood pressure between 90 to 160 mmHg, diastolic \<100 mmHg. BP was measured after at least 3 minutes in the supine position. BP was measured at predose (within 45 minutes of dosing); 3 and 7 minutes and approximately 1, 4, 8, 12, and 24 hours.
Time frame: 24 hours
Population: Safety dataset included all participants who had received at least one dose of the trial medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 14.3 mmHg | Standard Deviation 10.4 |
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -11.3 mmHg | Standard Deviation 6.4 |
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -13.8 mmHg | Standard Deviation 11.4 |
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 4.3 mmHg | Standard Deviation 2.5 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | NA mmHg | — |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | NA mmHg | — |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 42.0 mmHg | — |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 26.0 mmHg | — |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 18.6 mmHg | Standard Deviation 25.1 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 16.6 mmHg | Standard Deviation 11.9 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -13.4 mmHg | Standard Deviation 8.7 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -20.8 mmHg | Standard Deviation 14.1 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 14.3 mmHg | Standard Deviation 23.1 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -18.3 mmHg | Standard Deviation 18.6 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -25.7 mmHg | Standard Deviation 18.3 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 8.0 mmHg | Standard Deviation 11.3 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -7.8 mmHg | Standard Deviation 5.7 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -13.5 mmHg | Standard Deviation 15.3 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 7.5 mmHg | Standard Deviation 8.4 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 5.3 mmHg | Standard Deviation 5.1 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 11.3 mmHg | Standard Deviation 8.2 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 5.0 mmHg | Standard Deviation 2.6 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -5.0 mmHg | Standard Deviation 4.2 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -3.0 mmHg | Standard Deviation 1.4 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -14.5 mmHg | Standard Deviation 9.3 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 1.7 mmHg | Standard Deviation 0.6 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -9.0 mmHg | Standard Deviation 6.2 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 8.5 mmHg | Standard Deviation 7.5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 9.8 mmHg | Standard Deviation 7.9 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -18.7 mmHg | Standard Deviation 24.6 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 21.7 mmHg | Standard Deviation 6.4 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -17.3 mmHg | Standard Deviation 13.7 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -24.5 mmHg | Standard Deviation 10.5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -19.0 mmHg | Standard Deviation 6.2 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 21.0 mmHg | Standard Deviation 6.7 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 15.0 mmHg | Standard Deviation 6.4 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Decrease) | -10.8 mmHg | Standard Deviation 5.5 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Diastolic BP Supine (Increase) | 10.2 mmHg | Standard Deviation 6.7 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Decrease) | -23.0 mmHg | Standard Deviation 15.1 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion | Systolic BP Supine (Increase) | 12.1 mmHg | Standard Deviation 8.6 |
Primary
Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion
12-lead Holter monitors were placed on all participants within 45 minutes prior to dosing. Post dose measurements were made at 2, 4, 6, 8, 10, 20, 30, and 40 minutes and 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours post-dose. To achieve consistent recording, Holter sampling will be recorded with the participant recumbent and at rest for at least 10 minutes prior to collection.
Time frame: 24 hours
Population: Safety dataset included all participants who had received at least one dose of the trial medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 15.0 msec | Standard Deviation 8 |
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -30.8 msec | Standard Deviation 7.8 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | NA msec | — |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | NA msec | — |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 28.8 msec | Standard Deviation 12 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -18.2 msec | Standard Deviation 7.8 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 11.5 msec | Standard Deviation 10.6 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -37.0 msec | Standard Deviation 8.5 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -15.3 msec | Standard Deviation 9.6 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 24.5 msec | Standard Deviation 21.4 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -17.8 msec | Standard Deviation 14.1 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 24.0 msec | Standard Deviation 9.5 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -23.0 msec | Standard Deviation 6.5 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 23.3 msec | Standard Deviation 20.2 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 19.7 msec | Standard Deviation 6.5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -18.7 msec | Standard Deviation 16.5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 42.5 msec | Standard Deviation 29 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -13.3 msec | Standard Deviation 14 |
| Persistent AF - Placebo | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Increase | 27.4 msec | Standard Deviation 22.9 |
| Persistent AF - Placebo | Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion | Decrease | -25.8 msec | Standard Deviation 8.5 |
Primary
Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion
12-lead Holter monitors were placed on all participants within 45 minutes prior to dosing. Post dose measurements were made at 2, 4, 6, 8, 10, 20, 30, and 40 minutes and 1, 1.5, 2, 4, 6, 8, 12, 16, and 24 hours post-dose. To achieve consistent recording, Holter sampling will be recorded with the participant recumbent and at rest for at least 10 minutes prior to collection.
Time frame: 24 hours
Population: Safety dataset included all participants who had received at least one dose of the trial medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -14.3 beats/minute | Standard Deviation 6.6 |
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 22.3 beats/minute | Standard Deviation 18.5 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | NA beats/minute | — |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | NA beats/minute | — |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -29.8 beats/minute | Standard Deviation 26.6 |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 14.6 beats/minute | Standard Deviation 5 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 15.5 beats/minute | Standard Deviation 6.4 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -24.0 beats/minute | Standard Deviation 1.4 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -6.8 beats/minute | Standard Deviation 6.4 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 19.5 beats/minute | Standard Deviation 9.1 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 18.5 beats/minute | Standard Deviation 6.2 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -12.3 beats/minute | Standard Deviation 3.3 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -19.8 beats/minute | Standard Deviation 13.5 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 14.8 beats/minute | Standard Deviation 13.1 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 28.0 beats/minute | Standard Deviation 5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -11.5 beats/minute | Standard Deviation 3.5 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 31.5 beats/minute | Standard Deviation 15.6 |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -8.3 beats/minute | Standard Deviation 6.4 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Decrease | -12.4 beats/minute | Standard Deviation 6.4 |
| Persistent AF - Placebo | Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion | Increase | 26.0 beats/minute | Standard Deviation 13.2 |
Primary
Part 1: Maximum (Peak) Plasma Concentration (Cmax)
OPC-108459 was administered as a 10-minute constant rate IV infusion. Blood samples were collected pre-dose (within 45 minutes of dosing), at the end of infusion and 0.5, 1, 2, 4, 8 and 24 hours post start of infusion.
Time frame: 24 hours
Population: PK analysis dataset included all participants who had concentration time profiles consistent with proper intravenous infusion.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 1.11 μg/mL | Standard Deviation 0.358 |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 1.49 μg/mL | — |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 2.96 μg/mL | Standard Deviation 0.787 |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 1.45 μg/mL | Standard Deviation 1.43 |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 1.54 μg/mL | Standard Deviation 0.538 |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 1.62 μg/mL | Standard Deviation 1.07 |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | NA μg/mL | — |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Maximum (Peak) Plasma Concentration (Cmax) | 5.14 μg/mL | Standard Deviation 1.26 |
Primary
Part 2/1 Infusion: AUCt
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2/1 Infusion: Cmax
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2/2 Infusions: AUCt
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2/2 Infusions: Cmax
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2: Diastolic and Systolic Blood Pressure
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2: Percentage of Subjects With Normal Sinus Rhythm (NSR)
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2: QTcF
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Primary
Part 2: Ventricular Rate
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Secondary
Part 1: Percentage of Participants With NSR
Percent of participants with NSR, defined as NSR for at least 1 minute within 30 minutes of the end of OPC-108459 infusion.
Time frame: 30 minutes
Population: Safety dataset included all participants who had received at least one dose of the trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paroxysmal AF - OPC-108459 0.26 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Paroxysmal AF - OPC-108459 0.40 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Paroxysmal AF - OPC-108459 1.00 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 0.26 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 0.40 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 0.60 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 1.35 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - OPC-108459 1.55 mg/kg | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
| Persistent AF - Placebo | Part 1: Percentage of Participants With NSR | 0 percentage of participants |
Secondary
Part 2: Duration of NSR
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours
Secondary
Part 2: Duration of NSR
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 168 hours
Secondary
Part 2: Time to NSR
The trial was terminated after Part 1 enrollment completed. All analyses described in this document were performed on Part 1 data. However, Part 2 was not conducted and therefore is not included in this document.
Time frame: 24 hours