Atrial Fibrillation
Conditions
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
Interventions
DRUGOPC-108459
DRUGPlacebo
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 85 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 90 minutes | 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. |
| Subjects Achieving NSR in Patients With Persistent AF | 90 minutes | 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. |
| Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | 0, 30, 50 minute and 2, 4, 8, 24 hour | Of 20 subjects for whom plasma OPC-108459 concentrations were measured, 19 subjects were included in the PK analysis, and one subject was excluded. |
| Cmax of Plasma OPC-108459 in Patients With Persistent AF | 0, 30, 50 minute and 2, 4, 8, 24 hour | Of 20 subjects for whom plasma OPC-108459 concentrations were measured, all subjects were included in the PK analysis. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OPC-108459（Paroxysmal） | 20 |
| Placebo（Paroxysmal） | 4 |
| OPC-108459（Persistent） | 20 |
| Placebo（Persistent） | 4 |
| Total | 48 |
Baseline characteristics
| Characteristic | Placebo（Paroxysmal） | OPC-108459（Persistent） | OPC-108459（Paroxysmal） | Placebo（Persistent） | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 11 Participants | 17 Participants | 1 Participants | 32 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 9 Participants | 3 Participants | 3 Participants | 16 Participants |
| Age, Continuous | 67.5 years STANDARD_DEVIATION 3.8 | 65.4 years STANDARD_DEVIATION 8.8 | 70.1 years STANDARD_DEVIATION 7.7 | 60.0 years STANDARD_DEVIATION 13.3 | 67.1 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment Japan | 4 Participants | 20 Participants | 20 Participants | 4 Participants | 48 Participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 7 Participants | 0 Participants | 16 Participants |
| Sex: Female, Male Male | 2 Participants | 13 Participants | 13 Participants | 4 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 20 | 12 / 20 | 2 / 4 | 3 / 4 |
| serious Total, serious adverse events | 1 / 20 | 0 / 20 | 0 / 4 | 0 / 4 |
Outcome results
Primary
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.
Time frame: 0, 30, 50 minute and 2, 4, 8, 24 hour
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-108459 Step 1 (0.4 mg/kg) | Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | 786.2 ng/mL | Standard Deviation 228.1 |
| OPC-108459 Step 2 （0.8 mg/kg） | Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | 1942.0 ng/mL | Standard Deviation 2428 |
| OPC-108459 Step 3 （1.6mg/kg） | Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | 3629.0 ng/mL | Standard Deviation 499.1 |
| OPC-108459 Step 4 （2.6 mg/kg） | Cmax of Plasma OPC-108459 in Patients With Paroxysmal AF | 5316.0 ng/mL | Standard Deviation 1230 |
Primary
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.
Time frame: 0, 30, 50 minute and 2, 4, 8, 24 hour
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-108459 Step 1 (0.4 mg/kg) | Cmax of Plasma OPC-108459 in Patients With Persistent AF | 1037.0 ng/mL | Standard Deviation 154.5 |
| OPC-108459 Step 2 （0.8 mg/kg） | Cmax of Plasma OPC-108459 in Patients With Persistent AF | 1593.0 ng/mL | Standard Deviation 382.1 |
| OPC-108459 Step 3 （1.6mg/kg） | Cmax of Plasma OPC-108459 in Patients With Persistent AF | 3676.0 ng/mL | Standard Deviation 826.8 |
| OPC-108459 Step 4 （2.6 mg/kg） | Cmax of Plasma OPC-108459 in Patients With Persistent AF | 6412.0 ng/mL | Standard Deviation 964.6 |
Primary
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.
Time frame: 90 minutes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OPC-108459 Step 1 (0.4 mg/kg) | Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 0 Participants |
| OPC-108459 Step 2 （0.8 mg/kg） | Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 2 Participants |
| OPC-108459 Step 3 （1.6mg/kg） | Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 0 Participants |
| OPC-108459 Step 4 （2.6 mg/kg） | Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 0 Participants |
| Placebo | Subjects Achieving Normal Sinus Rhythm (NSR) in Patients With Paroxysmal AF | 0 Participants |
Primary
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.
Time frame: 90 minutes
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OPC-108459 Step 1 (0.4 mg/kg) | Subjects Achieving NSR in Patients With Persistent AF | 0 Participants |
| OPC-108459 Step 2 （0.8 mg/kg） | Subjects Achieving NSR in Patients With Persistent AF | 0 Participants |
| OPC-108459 Step 3 （1.6mg/kg） | Subjects Achieving NSR in Patients With Persistent AF | 0 Participants |
| OPC-108459 Step 4 （2.6 mg/kg） | Subjects Achieving NSR in Patients With Persistent AF | 0 Participants |
| Placebo | Subjects Achieving NSR in Patients With Persistent AF | 0 Participants |