Clinical Trials Register

Summary
EudraCT Number:	2016-001795-30
Sponsor's Protocol Code Number:	DU176b-C-E314
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-09-21
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2016-001795-30

A.3

Full title of the trial

Evaluation of Edoxaban in Anticoagulant Naïve Patients with Non-Valvular Atrial Fibrillation (NVAF) and high Creatinine Clearance

Hodnocení edoxabanu u pacientů s nevalvulární fibrilací síní (NVAF) a vysokou clearance kreatininu dosud neléčených antikoagulanty

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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.

A.4.1

Sponsor's protocol code number

DU176b-C-E314

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Daiichi Sankyo, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Daiichi Sankyo, Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo, Inc.
B.5.2	Functional name of contact point	Clinical Trial Information Contact
B.5.3	Address:
B.5.3.1	Street Address	211 Mt. Airy Road
B.5.3.2	Town/ city	Basking Ridge, NJ
B.5.3.3	Post code	07920-2311
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 732 590 5000
B.5.5	Fax number	+1 732 906-5690
B.5.6	E-mail	eu_cta@dsi.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DU176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EDOXABAN (as anhydrous free form)
D.3.9.1	CAS number	480449-71-6
D.3.9.3	Other descriptive name	EDOXABAN TOSYLATE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB182369
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DU176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EDOXABAN (as anhydrous free form)
D.3.9.1	CAS number	480449-71-6
D.3.9.3	Other descriptive name	EDOXABAN TOSYLATE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB182369
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 3
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DU176b
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EDOXABAN (as anhydrous free form)
D.3.9.1	CAS number	480449-71-6
D.3.9.3	Other descriptive name	EDOXABAN TOSYLATE MONOHYDRATE
D.3.9.4	EV Substance Code	SUB182369
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Non-Valvular Atrial Fibrillation (NVAF)

E.1.1.1

Medical condition in easily understood language

Abnormal and irregular, often rapid heart rate with no evidence of moderate or severe damage of the heart valves

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

-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.

E.2.3

Trial contains a sub-study

E.3

Principal 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.

E.4

Principal 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 for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner);
14. Patients with the following diagnoses or situations:
 Active cancer undergoing chemotherapy, radiation or major surgery within the next 3 months;
 Significant active concurrent medical illness or infection;
 Life expectancy < 12 months.
15. Patients who are unlikely to comply with the protocol (eg, unable to swallow tablets whole uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study);
16. Patients with a known drug or alcohol dependence within the past 12 months as judged by the Investigator;
17. Patients with any condition that, in the opinion of the Investigator, would place the patient at increased risk of harm if he/she participated in the study.

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 2, 4, 6 and 9.

E.5.2

Secondary end point(s)

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

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout study duration

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Edoxaban 60mg QD with active and placebo tablets maintaining the blind

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

139

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Bulgaria

Croatia

Czech Republic

Denmark

Estonia

Hungary

Latvia

Lithuania

Poland

Russian Federation

Serbia

Slovakia

Spain

Ukraine

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

360

F.4.2.2

In the whole clinical trial

600

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard Care

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-11-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-30

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-09

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