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

NCT01483183 | Terminated Phase 1 Results

• 1 other identifier: 269-11-215
• Study Type: interventional
• Target: 40
• Locations: 6 countries
• Sites: 25

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.

Conditions

Atrial Fibrillation; Paroxysmal Atrial Fibrillation; Persistent Atrial Fibrillation

Keywords

Atrial fibrillation; Paroxysmal Atrial fibrillation; Persistent Atrial fibrillation; A-fib

Outcome Measures

Primary Outcomes (13)

• 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 Outcomes (4)

• Part 1: Percentage of Participants With NSR

  30 minutes

• Part 2: Time to NSR

  24 hours

• Part 2: Duration of NSR

  24 hours

• Part 2: Duration of NSR

  168 hours

Study Arms (4)

Persistent or Paroxysmal AF Part 1: OPC-108459

EXPERIMENTAL

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

Persistent or Paroxysmal AF Part 1: Placebo

PLACEBO COMPARATOR

Drug: Placebo

Persistent or Paroxysmal AF Part 2: OPC-108459

EXPERIMENTAL

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

Placebo Part 2

PLACEBO COMPARATOR

Drug: OPC-108459; Drug: Placebo

Interventions

OPC-108459 DRUG

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

Also known as: 269-11-215

Persistent or Paroxysmal AF Part 1: OPC-108459; Persistent or Paroxysmal AF Part 2: OPC-108459; Placebo Part 2

Placebo DRUG

Placebo dose, 10-minute constant rate IV infusion

Persistent or Paroxysmal AF Part 1: Placebo; Placebo Part 2

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (25)

Otsuka Investigational Site

Washington D.C., District of Columbia, 20422, United States

Location

Otsuka Investigational Site

Hollywood, Florida, 33021, United States

Location

Otsuka Investigational Site

Jacksonville, Florida, 32209, United States

Location

Otsuka Investigational Site

Sarasota, Florida, 34232, United States

Location

Otsuka Investigational Site

Lexington, Kentucky, 40536, United States

Location

Otsuka Investigational Site

New Orleans, Louisiana, 70112, United States

Location

Otsuka Investigational Site

Johnson City, New York, 13790, United States

Location

Otsuka Investigational Site

Germantown, Tennessee, 38138, United States

Location

Otsuka Investigational Site

Houston, Texas, 77024, United States

Location

Otsuka Investigational Site

Berlin, 13953, Germany

Location

Otsuka Investigational Site

Hamburg, 22291, Germany

Location

Otsuka Investigational Site

Leipzig, 04289, Germany

Location

Otsuka Investigational Site

Pirna, 01796, Germany

Location

Otsuka Investigational Site

San Fermo, Como, 22100, Italy

Location

Otsuka Investigational Site

Ancona, 60126, Italy

Location

Otsuka Investigational Site

Bologna, 40138, Italy

Location

Otsuka Investigational Site

Cremona, 26100, Italy

Location

Otsuka Investigational Site

Amsterdam, 1105AZ, Netherlands

Location

Otsuka Investigational Site

Groningen, 9713GZ, Netherlands

Location

Otsuka Investigational Site

Fuenlabrada, Madrid, 28942, Spain

Location

Otsuka Investigational Site

Barcelona, 08970, Spain

Location

Otsuka Investigational Site

Granada, 18014, Spain

Location

Otsuka Investigational Site

Madrid, 28034, Spain

Location

Otsuka Investigational Site

Madrid, 28905, Spain

Location

Otsuka Investigational Site

Chertsey, Surrey, KT160PZ, United Kingdom

Location

MeSH Terms

Conditions

Atrial Fibrillation

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

The trial was terminated after Part 1 enrollment completed. It did not progress due to many factors including slow enrollment, limited site activity in pre-screening, absence of reproducible efficacy signal and increased costs.

Results Point of Contact

• Title: Global Medical Affairs
• Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.

800 562-3974

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2011
• First Posted: December 1, 2011
• Study Start: November 1, 2011
• Primary Completion: October 1, 2015
• Study Completion: October 1, 2015
• Last Updated: April 10, 2017
• Results First Posted: April 10, 2017

Record last verified: 2017-02

Locations

IT (4); NL (2); US (9); GB (1); DE (4); ES (5)