Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation (CADENCE 215)

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

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.

Study Overview

• Status: Terminated
• Conditions: Atrial Fibrillation; Paroxysmal Atrial Fibrillation; Persistent Atrial Fibrillation
• Intervention / Treatment: Drug: OPC-108459; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 13953
    • Otsuka Investigational Site
  • Hamburg, Germany, 22291
    • Otsuka Investigational Site
  • Leipzig, Germany, 04289
    • Otsuka Investigational Site
  • Pirna, Germany, 01796
    • Otsuka Investigational Site
• Italy
  • Ancona, Italy, 60126
    • Otsuka Investigational Site
  • Bologna, Italy, 40138
    • Otsuka Investigational Site
  • Cremona, Italy, 26100
    • Otsuka Investigational Site
  • Como
    • San Fermo, Como, Italy, 22100
      • Otsuka Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Otsuka Investigational Site
  • Groningen, Netherlands, 9713GZ
    • Otsuka Investigational Site
• Spain
  • Barcelona, Spain, 08970
    • Otsuka Investigational Site
  • Granada, Spain, 18014
    • Otsuka Investigational Site
  • Madrid, Spain, 28034
    • Otsuka Investigational Site
  • Madrid, Spain, 28905
    • Otsuka Investigational Site
  • Madrid
    • Fuenlabrada, Madrid, Spain, 28942
      • Otsuka Investigational Site
• United Kingdom
  • Surrey
    • Chertsey, Surrey, United Kingdom, KT160PZ
      • Otsuka Investigational Site
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Otsuka Investigational Site
  • Florida
    • Hollywood, Florida, United States, 33021
      • Otsuka Investigational Site
    • Jacksonville, Florida, United States, 32209
      • Otsuka Investigational Site
    • Sarasota, Florida, United States, 34232
      • Otsuka Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Otsuka Investigational Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Otsuka Investigational Site
  • New York
    • Johnson City, New York, United States, 13790
      • Otsuka Investigational Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Otsuka Investigational Site
  • Texas
    • Houston, Texas, United States, 77024
      • Otsuka Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: OPC-108459; 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; Other Names: 269-11-215
PLACEBO_COMPARATOR: Persistent or Paroxysmal AF Part 1: Placebo	Drug: Placebo; Placebo dose, 10-minute constant rate IV infusion
EXPERIMENTAL: 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	Drug: OPC-108459; 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; Other Names: 269-11-215
PLACEBO_COMPARATOR: Placebo Part 2	Drug: OPC-108459; 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; Other Names: 269-11-215; Drug: Placebo; Placebo dose, 10-minute constant rate IV infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): October 1, 2015
• Study Completion (ACTUAL): October 1, 2015

Study Registration Dates

• First Submitted: November 29, 2011
• First Submitted That Met QC Criteria: November 30, 2011
• First Posted (ESTIMATE): December 1, 2011

Study Record Updates

• Last Update Posted (ACTUAL): April 10, 2017
• Last Update Submitted That Met QC Criteria: February 24, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Paroxysmal Atrial fibrillation; Persistent Atrial fibrillation; A-fib
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: 269-11-215