Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Multi-center, Parallel-group, Double-blind, Placebo-controlled, Randomized, Ascending Dose Trial to Determine the Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Infusions of OPC-108459 Administered to Subjects With Paroxysmal and Persistent Atrial Fibrillation

Conditions
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Atrial Fibrillation, Paroxysmal Atrial Fibrillation, Persistent Atrial Fibrillation

Intervention / Treatment
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* Drug: OPC-108459
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Persistent or Paroxysmal AF Part 1: OPC-108459<br>To safely meet each of the following Cmax targets: 1.0-10.0 µg/mL. There will be 9 cohorts in all: 1.0, 1.6, 2.4, 3.6, 5.4, 7.0, 8.0, 9.0, and 10.0. | Drug: OPC-108459<br>* 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<br>* Other names: 269-11-215;|
| Placebo Comparator: Persistent or Paroxysmal AF Part 1: Placebo<br> | Drug: Placebo<br>* Placebo dose, 10-minute constant rate IV infusion<br>|
| Experimental: Persistent or Paroxysmal AF Part 2: OPC-108459<br>Single dose to safely meet target concentration from Part 1, if subject fails to convert to sinus rhythm within 10 minutes, second dose will be administered to achieve 25% increase when compared to first infusion | Drug: OPC-108459<br>* 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<br>* Other names: 269-11-215;|
| Placebo Comparator: Placebo Part 2<br> | Drug: OPC-108459<br>* 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<br>* Other names: 269-11-215;Drug: Placebo<br>* Placebo dose, 10-minute constant rate IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 30 minutes | 
| 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. | 24 hours | 
| 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. | 24 hours | 
| 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. | 168 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Paroxysmal Atrial fibrillation, Persistent Atrial fibrillation, A-fib