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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Part 2/1 Infusion: AUCt
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Persistent or Paroxysmal AF Part 1: OPC-108459
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.
干预措施: OPC-108459 (Drug)
Persistent or Paroxysmal AF Part 1: Placebo
干预措施: Placebo (Drug)
Persistent or Paroxysmal AF Part 2: OPC-108459
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
干预措施: OPC-108459 (Drug)
Placebo Part 2
干预措施: OPC-108459 (Drug)
Placebo Part 2
干预措施: Placebo (Drug)
结局指标
主要结局
Part 2/1 Infusion: AUCt
时间窗: 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)
时间窗: 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)
时间窗: 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
时间窗: 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
时间窗: 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 2/2 Infusions: Cmax
时间窗: 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: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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: Percentage of Subjects With Normal Sinus Rhythm (NSR)
时间窗: 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.
次要结局
- Part 1: Percentage of Participants With NSR(30 minutes)
- Part 2: Time to NSR(24 hours)
- Part 2: Duration of NSR(168 hours)