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

This study has been terminated.
(Enrollment Difficulty)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01483183
First Posted: December 1, 2011
Last Update Posted: April 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.
  Purpose

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.


Condition Intervention Phase
Atrial Fibrillation Paroxysmal Atrial Fibrillation Persistent Atrial Fibrillation Drug: OPC-108459 Drug: Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:

Primary Outcome Measures:
  • Part 1: Maximum (Peak) Plasma Concentration (Cmax) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 Blood Pressure Within 24 Hour Infusion [ Time Frame: 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 [ Time Frame: 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: Cmax [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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:
  • Part 1: Percentage of Participants With NSR [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.


Enrollment: 40
Study Start Date: November 2011
Study Completion Date: October 2015
Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: 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 Name: 269-11-215
Drug: Placebo
Placebo dose, 10-minute constant rate IV infusion

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 85 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01483183


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

Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT01483183     History of Changes
Other Study ID Numbers: 269-11-215
First Submitted: November 29, 2011
First Posted: December 1, 2011
Results First Submitted: October 4, 2016
Results First Posted: April 10, 2017
Last Update Posted: April 10, 2017
Last Verified: February 2017

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
Atrial fibrillation
Paroxysmal Atrial fibrillation
Persistent Atrial fibrillation
A-fib

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes