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

Phase 1

Terminated

Conditions: Atrial Fibrillation
Paroxysmal Atrial Fibrillation
Persistent Atrial Fibrillation

Interventions: Drug: OPC-108459
Drug: Placebo

Registration Number: NCT01483183

Lead Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Persistent or Paroxysmal AF Part 1: OPC-108459	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.
Persistent or Paroxysmal AF Part 1: Placebo	Placebo	-
Persistent or Paroxysmal AF Part 2: OPC-108459	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
Placebo Part 2	Placebo	-
Placebo Part 2	OPC-108459	-

Primary Outcome Measures

Name	Time	Method
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 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 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: 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: 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 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 2/1 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.

Secondary Outcome Measures

Name	Time	Method
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.
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	168 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.