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

Primary Purpose

Atrial Fibrillation, Paroxysmal Atrial Fibrillation, Persistent Atrial Fibrillation

Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
OPC-108459
Placebo
Sponsored by
Otsuka Pharmaceutical Development & Commercialization, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Atrial Fibrillation focused on measuring Atrial fibrillation, Paroxysmal Atrial fibrillation, Persistent Atrial fibrillation, A-fib

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site
  • Otsuka Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Persistent or Paroxysmal AF Part 1: OPC-108459

Persistent or Paroxysmal AF Part 1: Placebo

Persistent or Paroxysmal AF Part 2: OPC-108459

Placebo Part 2

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
November 29, 2011
Last Updated
February 24, 2017
Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01483183
Brief Title
Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation
Acronym
CADENCE 215
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
February 2017
Overall Recruitment Status
Terminated
Why Stopped
Enrollment Difficulty
Study Start Date
November 2011 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Atrial Fibrillation, Paroxysmal Atrial Fibrillation, Persistent Atrial Fibrillation
Keywords
Atrial fibrillation, Paroxysmal Atrial fibrillation, Persistent Atrial fibrillation, A-fib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
40 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Persistent or Paroxysmal AF Part 1: OPC-108459
Arm Type
Experimental
Arm Description
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.
Arm Title
Persistent or Paroxysmal AF Part 1: Placebo
Arm Type
Placebo Comparator
Arm Title
Persistent or Paroxysmal AF Part 2: OPC-108459
Arm Type
Experimental
Arm Description
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
Arm Title
Placebo Part 2
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
OPC-108459
Other Intervention Name(s)
269-11-215
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo dose, 10-minute constant rate IV infusion
Primary Outcome Measure Information:
Title
Part 1: Maximum (Peak) Plasma Concentration (Cmax)
Description
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.
Time Frame
24 hours
Title
Part 1: Area Under the Concentration-time Curve From Time 0 to Time of the Last Measurable Concentration (AUCτ)
Description
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.
Time Frame
24 hours
Title
Part 1:Maximal Change From Baseline in QT Interval Corrected for Heart Rate Using the Fridericia Formula (QTcF) Within 24 Hour Infusion
Description
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.
Time Frame
24 hours
Title
Part 1: Maximal Change From Baseline in Ventricular Rate Within 24 Hour Infusion
Description
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.
Time Frame
24 hours
Title
Part 1: Maximal Change From Baseline in Blood Pressure Within 24 Hour Infusion
Description
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.
Time Frame
24 hours
Title
Part 2/1 Infusion: Cmax
Description
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.
Time Frame
24 hours
Title
Part 2/2 Infusions: Cmax
Description
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.
Time Frame
24 hours
Title
Part 2/1 Infusion: AUCt
Description
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.
Time Frame
24 hours
Title
Part 2/2 Infusions: AUCt
Description
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.
Time Frame
24 hours
Title
Part 2: QTcF
Description
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.
Time Frame
24 hours
Title
Part 2: Ventricular Rate
Description
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.
Time Frame
24 hours
Title
Part 2: Diastolic and Systolic Blood Pressure
Description
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.
Time Frame
24 hours
Title
Part 2: Percentage of Subjects With Normal Sinus Rhythm (NSR)
Description
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.
Time Frame
24 hours
Secondary Outcome Measure Information:
Title
Part 1: Percentage of Participants With NSR
Description
Percent of participants with NSR, defined as NSR for at least 1 minute within 30 minutes of the end of OPC-108459 infusion.
Time Frame
30 minutes
Title
Part 2: Time to NSR
Description
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.
Time Frame
24 hours
Title
Part 2: Duration of NSR
Description
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.
Time Frame
24 hours
Title
Part 2: Duration of NSR
Description
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.
Time Frame
168 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Otsuka Investigational Site
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20422
Country
United States
Facility Name
Otsuka Investigational Site
City
Hollywood
State/Province
Florida
ZIP/Postal Code
33021
Country
United States
Facility Name
Otsuka Investigational Site
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Otsuka Investigational Site
City
Sarasota
State/Province
Florida
ZIP/Postal Code
34232
Country
United States
Facility Name
Otsuka Investigational Site
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Otsuka Investigational Site
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Otsuka Investigational Site
City
Johnson City
State/Province
New York
ZIP/Postal Code
13790
Country
United States
Facility Name
Otsuka Investigational Site
City
Germantown
State/Province
Tennessee
ZIP/Postal Code
38138
Country
United States
Facility Name
Otsuka Investigational Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77024
Country
United States
Facility Name
Otsuka Investigational Site
City
Berlin
ZIP/Postal Code
13953
Country
Germany
Facility Name
Otsuka Investigational Site
City
Hamburg
ZIP/Postal Code
22291
Country
Germany
Facility Name
Otsuka Investigational Site
City
Leipzig
ZIP/Postal Code
04289
Country
Germany
Facility Name
Otsuka Investigational Site
City
Pirna
ZIP/Postal Code
01796
Country
Germany
Facility Name
Otsuka Investigational Site
City
San Fermo
State/Province
Como
ZIP/Postal Code
22100
Country
Italy
Facility Name
Otsuka Investigational Site
City
Ancona
ZIP/Postal Code
60126
Country
Italy
Facility Name
Otsuka Investigational Site
City
Bologna
ZIP/Postal Code
40138
Country
Italy
Facility Name
Otsuka Investigational Site
City
Cremona
ZIP/Postal Code
26100
Country
Italy
Facility Name
Otsuka Investigational Site
City
Amsterdam
ZIP/Postal Code
1105AZ
Country
Netherlands
Facility Name
Otsuka Investigational Site
City
Groningen
ZIP/Postal Code
9713GZ
Country
Netherlands
Facility Name
Otsuka Investigational Site
City
Fuenlabrada
State/Province
Madrid
ZIP/Postal Code
28942
Country
Spain
Facility Name
Otsuka Investigational Site
City
Barcelona
ZIP/Postal Code
08970
Country
Spain
Facility Name
Otsuka Investigational Site
City
Granada
ZIP/Postal Code
18014
Country
Spain
Facility Name
Otsuka Investigational Site
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
Otsuka Investigational Site
City
Madrid
ZIP/Postal Code
28905
Country
Spain
Facility Name
Otsuka Investigational Site
City
Chertsey
State/Province
Surrey
ZIP/Postal Code
KT160PZ
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

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

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