Late Phase 2 Study of DU-176b in Patients With Non-Valvular Atrial Fibrillation

A Randomized Dose-ranging Controlled Trial of DU-176b Versus Warfarin Potassium in Patients With Non-valvular Atrial Fibrillation

The primary objective of this study is to compare the incidence of hemorrhagic events in patients treated for non-valvular atrial fibrillation with DU-176b at each dose level versus warfarin potassium (warfarin). The secondary objective includes between-group comparisons with regard to incidence of thromboembolic events, pharmacodynamic parameters, and biomarkers for the efficacy evaluation, as well as incidence of adverse events and adverse reaction for the safety evaluation.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: DU-176b tablets; Drug: Warfarin potassium tablets

• Study Type: Interventional
• Enrollment (Actual): 536
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with non-valvular atrial fibrillation who meet all of the following requirements will be considered for admission to the study:

  • Age≧20years
  • Atrial fibrillation confirmed by at least 2 electrocardiographic(ECG) tracings taken at an interval of ≧1week during the year before enrollment

• Presence of any (at least )one of the following risk factors for embolism:

  • Hypertension
  • Diabetes mellitus
  • Congestive heart failure
  • Previous transient ischemic attack (TIA) or cerebral infarction (more than 30 days before giving informed consent )
  • Age≧75 years
  • At time of giving informed consent.
  • To be confirmed on ECG charts, etc.

Exclusion Criteria:

• Presence of any of the following conditions with increased risk of hemorrhage:

  • History of intracranial, intraocular (excluding bleeding beneath the bulbar conjunctiva ), intrathecal, retroperitoneal, or non-traumatic intraarticular hemorrhage
  • History of gastrointestinal hemorrhage during the year before giving informed consent
  • History of peptic ulcers during the 90 days before giving informed consent
  • Surgical treatment or trauma requiring hospitalization during the 30 days before giving informed consent
  • Hemoglobin level <10 g/dL platelet count <10 ×10000 /μL at screening examinations
  • Active hemorrhage* present at giving informed consent or at enrollment
  • Any invasive therapeutic or diagnostic procedure (e.g., surgery, tissue, biopsy, and tooth extraction) scheduled during the period from the time of informed consent until completion of the trial treatment.
  • Any congenital hemorrhagic disease
• History of cerebral infarction or TIA within 30 days before giving informed consent
• Current treatment with any anticoagulant(other than warfarin)
• Concurrent rheumatic valvular disease
• History of valvular surgery
• Concurrent infectious endocarditis
• Concurrent cardiac myxoma
• Confirmed left ventricular or left atrial thrombosis
• Any congenital condition with a tendency toward thrombosis
• Electrical or pharmacological defibrillation scheduled during the trial treatment
• Uncontrolled hypertension (persistently high systolic ［>160mmHg］or diastolic [>100mmHg] pressure)
• Uncontrolled diabetes mellitus

• Renal or hepatic dysfunction (as defined below ), confirmed at screening examinations

  • Serum creatinine>1.5mg/dL
  • AST(GOT)or ALT(GPT)≧twice the upper limit of the reference range
  • Total bilirubin ≧twice the upper limit of the reference range
• Current antiplatelet therapy for any concomitant illness that may be aggravated after discontinuation of the therapy.
• Any concurrent severe cardiac disease
• Known allergy to warfarin or any condition contraindicating its use
• Inability to discontinue current treatment with vitamin K
• Confirmed or potential pregnancy, wish to become pregnant during the study period, or current breast feeding
• Previous treatment with DU-176b
• Participation in a trial of any other drug during the 6 month before giving informed consent
• Any other condition that disqualifies the patient for the study in the opinion of the investigator/subinvestigator *This includes ecchymosis identified as at least one hematoma sized ≧5 cm in longer diameter, macroscopic hematuria, and microscopic hematuria defined as a ≧2+test or a 1+ test for occult blood with a urine sediment containing ≧10 red cells per high-power field (except for a 2+ occult blood test persisting for 1 year before giving informed consent).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; DU-176b low dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Experimental: 2; DU-176b intermediate dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Experimental: 3; DU-176b high dose	Drug: DU-176b tablets; DU-176b tablets taken once daily for up to 12 weeks
Active Comparator: 4; Warfarin	Drug: Warfarin potassium tablets; Warfarin potassium tablets taken once daily for up to 12 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Bleeding Events (Major Bleeding, Clinically Relevant Non-major Bleeding and Minor Bleeding ) Identified During the Period From the Entry Into the Treatment Period Until Completion or Termination of the Treatment.	The primary endpoint was the incidence of bleeding events (major bleeding, clinically relevant non-major bleeding, or minor bleeding) that occurred during the treatment period.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Thromboembolic Events (Cerebral Infarction and Systemic Embolism) Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment.		12 weeks
Incidence of Adverse Events and Adverse Reactions Identified During the Period From the Entry to the Treatment Period Until Completion or Termination of the Treatment		12 weeks
Pharmacodynamic Parameters (PT, PT-INR, and APTT)	PT - prothrombin time INR - International Normalized Ratio APTT - Activated Partial Thromboplastin time	12 weeks
Plasma DU-176 Concentration		12 weeks
Pharmacodynamic Biomarkers (F1+2, TAT, and D-dimer )		12 weeks

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Co., Ltd.

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: January 26, 2009
• First Submitted That Met QC Criteria: January 26, 2009
• First Posted (Estimate): January 27, 2009

Study Record Updates

• Last Update Posted (Actual): February 25, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Keywords: Atrial fibrillation; Factor Xa inhibition
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban; Warfarin
• Other Study ID Numbers: DU176b-C-J225

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