Evaluation of Edoxaban in Anticoagulant Naïve patients with normal renal function who are suffering from abnormal and irregular, often rapid heart rate defined as Atrial Fibrillation with no evidence of moderate or severe damage of the heart valves.

• Register: EUCTR
• Last refreshed on: 4 December 2018
• Main ID: EUCTR2016-001795-30-DK
• Date of registration: 19/10/2016
• Prospective Registration: Yes
• Primary sponsor: Daiichi Sankyo, Inc.
• Public title: Evaluation of Edoxaban in Anticoagulant Naïve patients with normal renal function who are suffering from abnormal and irregular, often rapid heart rate defined as Atrial Fibrillation with no evidence of moderate or severe damage of the heart valves.
• Scientific title: Evaluation of Edoxaban in Anticoagulant Naïve Patients with Non-Valvular Atrial Fibrillation (NVAF) and high Creatinine Clearance
• Date of first enrolment: 07/12/2016
• Target sample size: 600
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-001795-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Edoxaban 60mg QD with active and placebo tablets maintaining the blind; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Hungary, Latvia, Lithuania, Poland, Russian Federation, Serbia, Slovakia, Spain, Ukraine

Contacts

• Name: Clinical Trial Information Contact
• Affiliation: Daiichi Sankyo, Inc.

• Name: Clinical Trial Information Contact
• Affiliation: Daiichi Sankyo, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female patients older than the minimum legal adult age (country specific) who have signed an informed consent form for the study;
2. History of non-valvular AF documented by any electrical tracing (routine 12-lead electrocardiogram [ECG], Holter monitor [continuous ECG recording] rhythm strip, intracardiac electrogram, or pacemaker [PM] or implantable cardiac defibrillator [ICD] interrogation) within the prior 12 months and for which anticoagulation therapy is indicated and planned for the duration of the study;
3. Patient’s with CrCL > 100 mL/min as measured by the Cockcroft-Gault formula.
4. Patient has a CHADS2 score of = 2.
5. Patient’s weight is > 60 Kg.
6. Patient is naïve to anticoagulant therapy (defined as having received no dose of any oral anticoagulant (VKAs) or direct oral anticoagulant (DOAC) for 30 days prior to randomization.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 589
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 11

Exclusion criteria:
1. Patients with moderate or severe mitral stenosis, mitral valve rheumatic disease, unresected atrial myxoma, or a mechanical heart valve (patients with bioprosthetic heart valves and/or valve repair can be included) and/or other conditions, such as pulmonary embolism, considered to be a formal indication for conventional anticoagulation;
? However patients with AF and valvular heart diseases such as mitral valve prolapse, mitral valve regurgitation, and aortic valve disease are allowed in the study as long as they are of non-rheumatic nature
2. Patients with acute myocardial infarction, acute coronary syndrome, or percutaneous coronary intervention within the previous 30 days, or ischemic stroke within the previous 7 days; subjects with ischemic stroke more than 7 days prior to randomization can be included provided there is no evidence of haemorrhagic transformation
3. Patients with any contraindication to anticoagulant agents;
4. Patients with conditions associated with high risk of bleeding such as a past history of intracranial (spontaneous or traumatic), spontaneous intraocular, spinal, retroperitoneal or intra-articular bleeding; overt gastrointestinal bleeding or active ulcer within the previous year; recent severe trauma, major surgery, or deep organ biopsy within the previous 10 days; active infective endocarditis; uncontrolled hypertension (blood pressure [BP] above 170/100 mmHg); or hemorrhagic disorder including known or suspected hereditary or acquired bleeding or coagulation disorder;
5. Patients anticipated to receive dual antiplatelet therapy (eg, aspirin plus thienopyridine such as clopidogrel, prasugrel, or ticagrelor) or aspirin alone at a dose > 100 mg daily during the study;
6. Patients receiving or anticipated to continue fibrinolytics and patients anticipated to continue with prohibited concomitant medications, such as non-study anticoagulants, chronic oral or parenteral Non-Aspirin/Non-Steroidal Anti-Inflammatory Drugs (NSAID) for = 4 days/week;
7. Patients that are either receiving or are planned to receive the following oral P-gp inhibitors concomitantly: ciclosporine, dronedarone, erythromycin, or ketoconazole (topical formulations of ketoconazole or erythromycin are allowed);
8. Patients with severe hepatic impairment or hepatic disease associated with coagulopathy (eg, acute hepatitis, chronic active hepatitis, cirrhosis);
9. Patients with known liver disease and with a combination of alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) > 2 x upper limit of normal (ULN) and total bilirubin (TBL) > 1.5 x ULN;
10. Patients with hemoglobin < 10 g/dL or platelet count < 100,000 cells/mcL or white blood cell count < 3000 cells/mcL;
11. Patients with planned invasive procedures (other than routine endoscopy) or surgeries in which bleeding is anticipated during the study period;
12. Patients who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period;
13. Women of childbearing potential not using proper contraceptive measures, and women who are pregnant or breast feeding;
Note: Childbearing potential without proper contraceptive measures (ie, a method of contraception with a failure rate < 1 % during the course of the study (including the observational period). These methods of contraception according to the note for guidance on non-clinical safety studies for the conduct of human trials

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Non-Valvular Atrial Fibrillation (NVAF)
MedDRA version: 20.0 Level: PT Classification code 10003658 Term: Atrial fibrillation System Organ Class: 10007541 - Cardiac disorders

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Intervention(s)

Product Name: DU176b
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: EDOXABAN (as anhydrous free form)
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Product Name: DU176b
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: EDOXABAN (as anhydrous free form)
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Product Name: DU176b
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: EDOXABAN (as anhydrous free form)
CAS Number: 480449-71-6
Other descriptive name: EDOXABAN TOSYLATE MONOHYDRATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-

Primary Outcome(s)

Main Objective: The primary objective is to compare the exposure (based on average concentration at steady state (Cav), minimum concentration in plasma (Cmin), and anti-factor Xa [anti-FXa]) of edoxaban 75 mg once daily (QD) dose to edoxaban 60 mg QD dose in NVAF anticoagulant-naïve patients with CHADS2 score of = 2 and CrCL > 100 mL/min (as calculated by the Cockcroft-Gault formula) treated for up to 12 months.

Secondary Objective: -Provide an assessment of exposure based on a validated anti-FXa assay using edoxaban calibrators and controls and edoxaban concentration based on liquid chromatography/tandem mass spectrometry;
-Provide an overall assessment of the patients’ coagulation state based on the PD biomarkers: intrinsic FX, prothrombin time (PT) and activated partial thromboplastin time ( aPTT);
-Investigate the relationship between exposure Proprietary and Confidential
4 (anti-FXa activity, edoxaban concentrations) and PD biomarkers (intrinsic FX, PT, aPTT).
-Evaluate stroke/transient ischemic attack (TIA) and systemic embolic events (SEE);
-Evaluate the net clinical outcome (composite of stroke/TIA, SEE, myocardial infarction (MI), cardiovascular death, major bleeding);
-Evaluate the incidence of major (including intracranial) and Clinically Relevant Non-Major [CRNM]) bleeding;
-Evaluate the incidence of stroke/ TIA and SEE excluding haemorrhagic stroke.

Timepoint(s) of evaluation of this end point: Visit 2, 4, 6 and 9.

Primary end point(s): PK/PD Endpoints:
-edoxaban concentration (CAV, Cmin);
-anti-FXa;
-intrinsic FX, PT, aPTT.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Throughout study duration

Secondary end point(s): Efficacy Endpoints:
-composite of stroke/transient ischemic attack (TIA) and SEE (ischemic stroke, hemorrhagic stroke, TIA, and SEE).

Secondary ID(s)

2016-001795-30-LV

DU176b-C-E314

Source(s) of Monetary Support

Daiichi Sankyo, Inc.