A Study to Assess the Safety of a Potential New Drug in Comparison to the Standard Practice of Dosing With Warfarin for Non-valvular Atrial Fibrillation

A Phase 2, Randomized, Parallel Group, Multi Center, Multi National Study for the Evaluation of Safety of Four Fixed Dose Regimens of DU-176b in Subjects With Non- Valvular Atrial Fibrillation

This study is to assess the safety of a potential new drug DU-176b for the prevention of stroke/systemic embolic event (SEE) in individuals with non-valvular atrial fibrillation (AF). The duration is 3 months of treatment and a 30 day follow-up visit.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; Thromboembolism
• Intervention / Treatment: Drug: Edoxaban (DU-176b); Drug: Edoxaban (DU-176b); Drug: Edoxaban (DU-176b); Drug: Edoxaban (DU-176b); Drug: warfarin

• Study Type: Interventional
• Enrollment (Actual): 1146
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belarus
  • Minsk, Belarus
• Belgium
  • Brussels, Belgium
  • Genk, Belgium
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina
  • Mostar, Bosnia and Herzegovina
  • Sarajevo, Bosnia and Herzegovina
  • Tuzla, Bosnia and Herzegovina
• Canada
  • Alberta
    • Calgary, Alberta, Canada
    • Edmonton, Alberta, Canada
  • British Columbia
    • Alberta, British Columbia, Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada
  • Ontario
    • Oshawa, Ontario, Canada
    • Thunder Bay, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
    • Sherbrooke, Quebec, Canada
• Chile
  • Antofagasta, Chile
  • Osorno, Chile
  • Santiago, Chile
  • Temuco, Chile
• Latvia
  • Daugavpils, Latvia
  • Riga, Latvia
  • Ventspils, Latvia
• Mexico
  • Cordoba, Mexico
  • Guadalajara Jalisco, Mexico
  • Mexico City, Mexico
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
• Russian Federation
  • Arkhangelsk, Russian Federation
  • Barnaul, Russian Federation
  • Chelyabinsk, Russian Federation
  • Ivanovo, Russian Federation
  • Kaliningrad, Russian Federation
  • Kazan, Russian Federation
  • Kemerovo, Russian Federation
  • Krasnodar, Russian Federation
  • Krasnoyarsk, Russian Federation
  • Moscow, Russian Federation
  • N.Novgorod, Russian Federation
  • Novosibirsk, Russian Federation
  • Orenburg, Russian Federation
  • Penza, Russian Federation
  • Perm, Russian Federation
  • Rostov on Don, Russian Federation
  • Samara, Russian Federation
  • Saratov, Russian Federation
  • St. Petersburg, Russian Federation
  • Tomsk, Russian Federation
  • Tula, Russian Federation
  • Tyumen, Russian Federation
  • Volgograd, Russian Federation
  • Yaroslavl, Russian Federation
• Slovakia
  • Bardejov, Slovakia
  • Bratislava, Slovakia
  • Kosice, Slovakia
  • Lucenec, Slovakia
  • Presov, Slovakia
• Ukraine
  • Cherkassy, Ukraine
  • Chernigov, Ukraine
  • Chernivtsy, Ukraine
  • Dnepropetrovsk, Ukraine
  • Donetsk, Ukraine
  • Ivano-Frankovsk, Ukraine
  • Kiev, Ukraine
  • Lutsk, Ukraine
  • Lviv, Ukraine
  • Odessa, Ukraine
  • Poltava, Ukraine
  • Ternopil, Ukraine
  • Vinnitsa, Ukraine
  • Zaporozhye, Ukraine
• United States
  • Alabama
    • Huntsville, Alabama, United States
  • California
    • Anaheim, California, United States
    • Beverly Hills, California, United States
    • Stockton, California, United States
  • Florida
    • Orlando, Florida, United States
    • Sarasota, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Canton, Georgia, United States
  • Indiana
    • Fort Wayne, Indiana, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Michigan
    • Cadillac, Michigan, United States
  • Montana
    • Kalispell, Montana, United States
  • Nebraska
    • Fremont, Nebraska, United States
  • New Mexico
    • Santa Fe, New Mexico, United States
  • New York
    • Albany, New York, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • Pennsylvania
    • Allentown, Pennsylvania, United States
    • Pottstown, Pennsylvania, United States
    • Sellersville, Pennsylvania, United States
  • Texas
    • Dallas, Texas, United States
  • Utah
    • Salt Lake City, Utah, United States
  • Washington
    • Bellevue, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, 18 to 80 years old.
2. Able to provide written informed consent.
3. Persistent non-valvular AF supported by abnormal electrocardiogram (ECG)
4. A congestive heart failure, hypertension, age ≥ 75 years, diabetes, and prior stroke (CHADS2) index score of at least 2

Exclusion Criteria:

1. Subjects with mitral valve disease or previous valvular heart surgery
2. Known contraindication to any anticoagulant including vitamin K antagonists such as warfarin
3. Known or suspected hereditary or acquired bleeding or coagulation disorder

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; DU-176b 30mg tablet once daily	Drug: Edoxaban (DU-176b); 30mg tablet once daily; Drug: Edoxaban (DU-176b); 60mg tablet once daily; Drug: Edoxaban (DU-176b); 30mg tablet two times a day; Drug: Edoxaban (DU-176b); 60mg tablet two times a day
Experimental: 2; DU-176b 60mg once daily	Drug: Edoxaban (DU-176b); 30mg tablet once daily; Drug: Edoxaban (DU-176b); 60mg tablet once daily; Drug: Edoxaban (DU-176b); 30mg tablet two times a day; Drug: Edoxaban (DU-176b); 60mg tablet two times a day
Experimental: 3; DU-176b 30mg b.i.d.	Drug: Edoxaban (DU-176b); 30mg tablet once daily; Drug: Edoxaban (DU-176b); 60mg tablet once daily; Drug: Edoxaban (DU-176b); 30mg tablet two times a day; Drug: Edoxaban (DU-176b); 60mg tablet two times a day
Experimental: 4; DU-176b 60mg tablets two times a day	Drug: Edoxaban (DU-176b); 30mg tablet once daily; Drug: Edoxaban (DU-176b); 60mg tablet once daily; Drug: Edoxaban (DU-176b); 30mg tablet two times a day; Drug: Edoxaban (DU-176b); 60mg tablet two times a day
Active Comparator: 5; warfarin tablets	Drug: warfarin; warfarin tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjudicated Incidence of Bleeding Events	Adjudicated Incidence of Bleeding Events during treatment period	3 months
Percent of Subjects With Liver-related Laboratory Marked Abnormalities (MA)	liver enzyme (ALT and/or AST) and/or bilirubin (TBL) abnormalities	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Major Adverse Cardiac Events MACE)	MACE is defined as the composite of stroke [ischemic or hemorrhagic], Systemic embolic event (SEE), Myocardial Infarction (MI), Cardiovascular (CV) death, and hospitalization for any cardiac condition	3 months
Effects on Biomarker D-dimer	Mean (SD) change from baseline in D-dimer	3 months
Effects on Biomarker Prothrombin Fragments	Mean (SD) change from baseline in Prothrombin Fragments 1 and 2 (F1 and F2)	3 months
Pharmacokinetics (Cmin, Cmax) of DU-176b in Subjects Receiving DU-176b	Median (min, max) values of Cmin,ss; Cmax,ss	3 months
Pharmacokinetics (AUC) of DU-176b in Subjects Receiving DU-176b	Median (min, max) values of AUCss	3 months
Effects on Pharmacodynamic Biomarker Anti-Factor Xa Activity in Subjects Receiving DU-176b	Mean (SD) change from baseline in biomarker anti-Factor Xa [FXa] activity on Day 28, 1-3 hours post dose.	Day 28
Effects on Pharmacodynamic Biomarker (Endogenous FX Activity) in Subjects Receiving DU-176b	Mean (SD) change from baseline in biomarker endogenous FX activity on Day 28, 1-3 hours post dose.	Day 28
Effects on Pharmacodynamic Biomarker PICT Activity in Subjects Receiving DU-176b	Mean (SD) change from baseline in biomarker prothrombinase induced clotting time [PICT] on Day 28, 1-3 hours post dose. PICT was determined by PICT aasay which is a plasma based functional assay to determine the anticoagulant activity on FXa and FIIa inhibition.	Day 28
Effects on Pharmacodynamic Biomarker PT in Subjects Receiving DU-176b	Mean (SD) change from baseline in biomarker prothrombin time (PT) on Day 28, 1-3 hours post dose.	Day 28
Effects on Pharmacodynamic Biomarker INR in Subjects Receiving DU-176b	Mean (SD) change from baseline in biomarker International Normalized Ratio (INR) on Day 28, 1-3 hours post dose.	Day 28

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: July 18, 2007
• First Submitted That Met QC Criteria: July 18, 2007
• First Posted (Estimate): July 20, 2007

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Non-valvular atrial fibrillation; Venous Thromboembolism; Anti-coagulant; Prevention of Blood Clots; Non-valvular
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Atrial Fibrillation; Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban; Warfarin
• Other Study ID Numbers: DU176b-PRT018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR