Clinical Trials Register

Summary
EudraCT Number:	2008-003698-42
Sponsor's Protocol Code Number:	D1250C00012
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2008-10-20
Trial 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

Spain - AEMPS

A.2

EudraCT number

2008-003698-42

A.3

Full title of the trial

Estudio Fase III, multicéntrico, aleatorizado , de grupos paralelos, doble ciego, doble enmascarado, controlado, para evaluar la eficacia y seguridad del inhibidor directo oral de la trombina AZD0837 comparado con Warfarina en la prevención del ictus y de acontecimientos embólicos sistémicos en pacientes con fibrilación auricular (ASSURE-AF)

A controlled, randomised, double-blind, double-dummy, parallel-group, phase III, multicenter study to evaluate efficacy and safety of the oral direct thrombin inhibitor AZD0837 compared to warfarin for the prevention of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (ASSURE-AF)

A.3.2

Name or abbreviated title of the trial where available

ASSURE-AF

A.4.1

Sponsor's protocol code number

D1250C00012

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	AstraZeneca AB
B.1.3.4	Country	Sweden
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	AZD 0837
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	631916-97-7
D.3.9.2	Current sponsor code	AZD0837 besylate
D.3.9.3	Other descriptive name	AR-H067639TM
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	175
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Comparator
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	Warfarin 1 mg tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Warfarin Sodium
D.3.9.1	CAS number	129066
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	1 mg
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Comparator
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	Warfarin 3 mg tablets
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Warfarin Sodium
D.3.9.1	CAS number	129066
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	3 mg
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)	Information not present in EudraCT
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	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
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	Information not present in EudraCT
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	Prolonged-release tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	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

prevención del ictus y de acontecimientos embólicos sistémicos en pacientes con fibrilación auricular

the prevention of stroke and systemic embolic events (SEE) in patients with non-valvular atrial fibrillation (AF)

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	LLT
E.1.2	Classification code	10003658
E.1.2	Term	Atrial fibrillation

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 of this study is to demonstrate that AZD0837 is non-inferior to warfarin, aiming for an INR 2.0 to 3.0, target 2.5, in the prevention of the composite outcome variable of stroke and SEE.

E.2.2

Secondary objectives of the trial

1. To demonstrate that AZD0837 is associated with a lower risk of bleeding events compared to warfarin, aiming for an International Normalised Ratio of 2.0 to 3.0, target 2.5
2. To demonstrate that AZD0837 is superior to warfarin, aiming for an International
Normalised Ratio of 2.0 to 3.0, target 2.5, in the composite outcome variable of stroke, systemic embolic events, cardiovascular mortality, clinically relevant non-major
bleeding and major bleeding events
3. To evaluate the overall safety profile of AZD0837 compared to warfarin by
assessment of adverse events, bleeding events, laboratory safety variables, physical
examination, electrocardiogram and vital signs

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Title of the genetic sub-study:
"A controlled, randomised, double-blind, double-dummy, parallel-group, phase III, multicenter study to evaluate efficacy and safety of the oral direct thrombin inhibitor AZD0837 compared to warfarin for the prevention of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (ASSURE-AF)"

Version and date:
version 1, dated 3-september-2008

Objectives of the genetic sub-study:
•To characterize the effect of genetic markers, CYP2C*2, CYP2C9*3 and
VKORC1(-1639G>A), of Warfarin clearance and Warfarin sensitivity and the
relationship to bleeding profile of Warfarin and to characterize “warfarin wobbler”
patients.
•To collect and store DNA, with appropriate informed consent, for future
retrospective research into genes that may influence the therapeutic response of
AZD0837 and Warfarin and/or genotype-phenotype predictions related to
thrombosis, thromboembolic events or AF.

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures
2. Female or male aged ≥18 years
3. Rhythm verification
Patient with paroxysmal AF: Clinically significant 5 paroxysmal AF with at least one
documented episode of AF 6 within 12 months. The AF can be documented by 12-
lead electrocardiogram (ECG), Holter, event recorder or telemetry, but not by
pacemaker. OR
Patient with permanent or persistent AF 5 : AF documented on two occasions >7 days
apart within 12 months. The AF can be documented by 12-lead ECG, Holter, event
recorder or telemetry, but not by pacemaker.
4. Stroke risk classification:
At least one of the following risk factors:
•Prior ischaemic stroke, TIA 7 and/or systemic embolism
•Patient aged ≥75 years
Alternatively at least two of the following risk factors if neither of the risk factors
above:
•Hypertension 8
•Symptomatic CHF and/or left ventricular ejection fraction (LVEF) ≤35%
•Diabetes mellitus

E.4

Principal exclusion criteria

1. Women of childbearing potential without a reliable form of contraception, as judged
by the Investigator, before and during participation in the study
2. Lactation
3. AF secondary to a current reversible disorder, (eg, hyperthyroidism, isolated
postoperative AF, drugs and pulmonary embolism)
4. Allergic and/or intolerant to VKA
5. Valvular heart disease if
•Any mitral valve prosthesis, or
•Mechanical valve prosthesis, or
•Mitral stenosis, or
Any other valvular heart disease considered to significantly increase the risk of
thromboembolic events or considered hemodynamically significant or expected to
require surgical intervention during the course of the study
6. Active infective endocarditis
7. Any condition other than AF requiring chronic anticoagulation treatment
8. Myocardial Infarction (MI), heart surgery (eg, coronary artery bypass grafting,
CABG) and/or percutaneous coronary intervention (PCI) within the 3 months prior
to enrolment. Any prior PCI requiring clopidogrel treatment at the time of
enrolment.
9. Stroke, TIA and/or systemic embolism within the previous 14 days prior to
randomisation
10. Known haemorrhagic disorders and/or conditions associated with increased risk of
major bleeding
11. Severe renal impairment (calculated creatinine clearance (CrCL) <30 mL/min)
12. Known hepatic disease and/or ALT >3xULN and/or bilirubin >2xULN
13. Uncontrolled hypertension, systolic blood pressure ≥180 mmHg
14. Anemia (Hb<100g/L = 6.2 mmol/L) and/or platelet count <100x10 9 /L
15. Planned pulmonary vein ablation procedure, PCI or major surgery. Planned
cardioversion (direct current (DC) or pharmacological) within 1 month of
randomisation.
16. Other serious disease that gives an estimated survival less than 12 months, any
condition making a patient too frail to participate in the study, and/or inability to
complete the study according to the protocol. Severe neurological deficit or
disability that would interfere with the detection and/or assessment of a new
cerebrovascular event.
17. Known drug addiction and/or alcohol abuse
18. Previous enrolment or randomisation of treatment in the present study and/or
participation in a previous study with AZD0837
19. Participation in another clinical study with IP and/or intervention during the last
3 months
20. Involvement in the planning and/or conduct of the study (applies to both
AstraZeneca staff and/or staff at the study site)

E.5 End points

E.5.1

Primary end point(s)

Stroke or systemic embolic event

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

Information not present in EudraCT

E.7.1.2

Bioequivalence study

Information not present in EudraCT

E.7.1.3

Other

Information not present in EudraCT

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

Yes

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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.8.6 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

Information not present in EudraCT

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

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

The end of the entire study is defined as ”the last visit of the last patient undergoing the study”.

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	No
F.1.1.1	In Utero	Information not present in EudraCT
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	Information not present in EudraCT
F.1.1.3	Newborns (0-27 days)	Information not present in EudraCT
F.1.1.4	Infants and toddlers (28 days-23 months)	Information not present in EudraCT
F.1.1.5	Children (2-11years)	Information not present in EudraCT
F.1.1.6	Adolescents (12-17 years)	Information not present in EudraCT
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	80
F.4.2	For a multinational trial
F.4.2.2	In the whole clinical trial	14600

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

2009-01-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2008-12-04

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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