A Trial to Determine the Safety, Pharmacokinetics, and Efficacy of OPC-108459 Administered as a Single Intravenous Dose to Patients With Paroxysmal or Persistent Atrial Fibrillation (AF)

Study Overview
=================
Brief Summary
-----------------
To investigate the safety, pharmacokinetics, and efficacy following 30-minute continuous intravenous administration of OPC-108459 at 0.4, 0.8, 1.6, or 2.4 mg/kg or placebo to patients with paroxysmal or persistent atrial fibrillation

Official Title
-----------------
A Multicenter, Parallel-group-comparison, Double-blind, Placebo-controlled, Randomized Trial to Determine the Safety, Pharmacokinetics, and Efficacy of OPC-108459 Administered as a Single Intravenous Dose to Patients With Paroxysmal or Persistent Atrial Fibrillation

Conditions
-----------------
Atrial Fibrillation

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Japanese Male or female age 20 to 85 years, inclusive (at the time of informed consent) Patients diagnosed with recent or new onset of paroxysmal AF (3 hours to 7 days since the onset) or persistent AF (8 to 30 days since the onset) at time of randomization (prior to Investigational Medicinal Product [IMP] administration). Review of the patient's medical records and the judgment of the investigator or sub-investigator must be documented in the source documents to establish the date and duration of the most recent onset of AF. Patients who are receiving treatment according to the Guidelines for Pharmacotherapy of Atrial Fibrillation (JCS 2008) at time of screening and predosing examinations or who have a low risk of thromboembolic potential specified as follows: AF lasting less than 48 hours, OR For AF lasting for 48 hours or longer: Patients receiving warfarin therapy for whom at least 3 weeks have elapsed since achieving an international normalized ratio (INR) of 2.0 to 3.0 (1.6 to 2.6 for patients age 70 years or older) or in whom no thrombus in the atrial main body or appendage is observed by transesophageal echocardiography (TEE) within 24 hours before IMP administration Patients in whom no thrombus in the atrial main body or appendage is observed by TEE within 24 hours before IMP administration if they have not undergone antithrombotic therapy or if they have undergone antithrombotic therapy (including a new oral antithrombotic drug) which does not meet the above criterion Patients with systolic blood pressure (sBP) of 90 mmHg or higher and lower than 160 mmHg and diastolic blood pressure (dBP) of lower than 100 mmHg at screening examinations Female patients who have been postmenopausal for at least 12 consecutive months, or male and female patients who agree, together with their partners, to practice birth control as specified until 3 months after the start of IMP administration or who are surgically sterile (ie, have undergone orchiectomy or hysterectomy, respectively) Exclusion Criteria: QRS interval of > 120 msec Patients with heart failure of New York Heart Association (NYHA) Class II to IV or with left ventricular ejection fraction (LVEF) of < 40% Patients who currently have or have a history of a long QT syndrome, torsade de pointes, or an uncorrected QT interval of > 450 msec History of ventricular tachycardia, ventricular fibrillation, or resuscitated cardiac arrest History of AF and failed electrical or pharmacological cardioversion Current diagnosis of atrial flutter Patients with bradycardia (< 50 beats per minute [bpm]) or sick sinus syndrome, unless controlled by a pacemaker, except for physiologically transient sinus bradycardia observed at rest or during sleep Patients with Wolff-Parkinson-White syndrome Patients with any congenital severe heart disease Patients with severe aortic or mitral stenosis (aortic-valve area, < 1 cm2), severe mitral regurgitation, aortic regurgitation, congenital atrial septal defect, moderate or severe pulmonary hypertension, or any other disease leading to AF confirmed by echocardiography within one year prior to screening examinations Patients diagnosed with congenital valvular anomaly or severe valve disease (eg, aortic or mitral stenosis, severe right or left ventricular systolic dysfunction, or severe pulmonary hypertension) and confirmed current presence of the condition by TEE at screening examinations Patients diagnosed with stroke or transient ischemic attack within one year prior to screening examinations or with carotid artery stenosis of 50% History of myocardial infarction within 6 months prior to screening examinations Findings of acute coronary syndrome, angina, or myocardial ischemia diagnosed by ECG or drug-induced or exercise stress testing within 6 months prior to screening examinations

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OPC-108459<br>OPC-108459 solution will be intravenously administered by 30-minute infusion in the forearm. | Drug: OPC-108459<br> <br> |
| Placebo Comparator: Placebo<br>placebo solution will be intravenously administered by 30-minute infusion in the forearm. | Drug: Placebo<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 24 subjects with paroxysmal AF, 6 subjects per cohort (5 for OPC-108459 and one for placebo), 4 dose steps; Step 1: 0.4 mg/kg, Step 2: 0.8 mg/kg, Step 3: 1.6 mg/kg, Step 4: 2.6 mg/kg The number of subjects achieving NSR within 90 minutes after the start of IMP administration and sustaining NSR for at least one minute. | 90 minutes | 
| Subjects Achieving NSR in Patients With Persistent AF | 24 subjects with persistent AF, 6 subjects per cohort (5 for OPC-108459 and one for placebo), 4 dose steps; Step 1: 0.4 mg/kg, Step 2: 0.8 mg/kg, Step 3: 1.6 mg/kg, Step 4: 2.6 mg/kg The number of subjects achieving NSR within 90 minutes after the start of IMP administration and sustaining NSR for at least one minute. No subjects achieved NSR within 90 minutes after the start of IMP administration in the persistent AF cohort. | 90 minutes | 
| Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | Of 20 subjects for whom plasma OPC-108459 concentrations were measured, 19 subjects were included in the PK analysis, and one subject was excluded. | 0, 30, 50 minute and 2, 4, 8, 24 hour | 
| Cmax of Plasma OPC-108459 in Patients With Persistent AF | Of 20 subjects for whom plasma OPC-108459 concentrations were measured, all subjects were included in the PK analysis. | 0, 30, 50 minute and 2, 4, 8, 24 hour |