Clinical Trials Register

Summary
EudraCT Number:	2013-003492-35
Sponsor's Protocol Code Number:	MED2-201301
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-03-17
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

Germany - BfArM

A.2

EudraCT number

2013-003492-35

A.3

Full title of the trial

Prevention of Silent Cerebral Thromboembolism
by Oral Anticoagulation with Dabigatran
after Pulmonary Vein Isolation for Atrial Fibrillation

A.3.1

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

Oral Anticoagulation after Successfull Pulmonary Vein Ablation

A.3.2

Name or abbreviated title of the trial where available

ODIn-AF Study

A.4.1

Sponsor's protocol code number

MED2-201301

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02067182

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	University of Bonn
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Boehringer Ingelheim Pharma GmbH & Co. KG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Clinical Study Core Unit Study Center Bonn
B.5.2	Functional name of contact point	Dr. Martin Coenen
B.5.3	Address:
B.5.3.1	Street Address	Sigmund-Freud-Str. 25
B.5.3.2	Town/ city	Bonn
B.5.3.3	Post code	53127
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4922828716045
B.5.5	Fax number	+4922828711603
B.5.6	E-mail	martin.coenen@ukb.uni-bonn.de

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	Yes
D.2.1.1.1	Trade name	Pradaxa
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Capsule, hard
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	DABIGATRAN ETEXILATE
D.3.9.1	CAS number	211915-06-9
D.3.9.4	EV Substance Code	SUB20521
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	150
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	Yes
D.2.1.1.1	Trade name	Pradaxa
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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.3.4	Pharmaceutical form	Capsule, hard
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	DABIGATRAN ETEXILATE
D.3.9.1	CAS number	211915-06-9
D.3.9.4	EV Substance Code	SUB20521
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	110
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

atrial fibriallation

E.1.1.1

Medical condition in easily understood language

cardiac arrhythmia

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 purpose of the ODIn-AF study is to demonstrate that the continued administration of dabigatran for 12 months is superior in the prevention of silent cerebral embolism to discontinuation of OAC in patients free from symptomatic AF-episodes with an elevated stroke risk (CHA2DS2VASc score ≥2) after successful antral pulmonary vein ablation (and re-ablation if necessary) for paroxysmal and persistent AF.

E.2.2

Secondary objectives of the trial

Comparison between the two treatments goups:
• Localisation, size and number of new micro- and macro-embolic lesions on cerebral MRI
• Incidence of clinically evident cardio-embolic events (stroke, TIA, systemic embolism)
• Incidence of clinically apparent neurological deficits
• Incidence of other thrombotic or thrombo-embolic events (myocardial in-farction, deep vein thrombosis, pulmonary embolism)
• Life-threatening / major / minor bleedings
• Hemorrhagic cerebral infarction
• All-cause mortality
• Cardiovascular mortality
• Correlation of cardio-embolic events to method used for PVI (cryo-balloon versus RF)
• Correlation of cardio-embolic events with arrhythmia recurrence (atrial fi-brillation or atrial flutter post ablationem with ECG documentation or symptoms)
• Correlation of cardio-embolic events with echocardiographic parameters (i.e. LA-size, LV function, LAA velocities)
• EQ-5D questionnaire
• MoCA test

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent
- Patients undergoing circumferential antral PV ablation for non-valvular (mitral regurgitation less than moderate- severe; no relevant mitral ste-nosis with a mean pressure gradient >5mmHg) symptomatic, paroxys-mal AF or persistent AF (duration < 12 months) with risk factors resulting in a CHA2DS2VASc score ≥2, using a cooled tip RF-, laser- or cryo-balloon-catheter.
- CHA2DS2VASc score ≥2

Randomization criteria:
- Sinus rhythm (as assessed by 72h Holter ECG) following the 3 months blanking and 3 months observation period after first or second pulmonary vein ablation procedure
- No clinical evidence of recurrent AF after completing 3 months blanking and 3 months observation period as assessed by symptoms
- No other relevant contraindication for OAC assessed by randomization MRI of the brain

E.4

Principal exclusion criteria

1. Severe mental retardation or psychiatrical disorder resulting in incapability to adequately understand nature, significance, implications and risks estimate the risks-and benefits of study parcipitation (i.e. bipolar disor-ders, severe depression, suicidal tendencies, among others) as judged by the local physician, ongoing, drug or alcohol addiction (> 8 drinks/week)
2. Pregnancy /breast feeding
3. Severely impaired renal function, GFR < 30 ml/min
4. Impaired liver function (ALT/AST transaminase count 3fold higher than normal values) or liver disease with reduced life expectancy <1 year
5. Valvular AF (less than moderate- severe; no relevant mitral stenosis with a mean pressure gradient >5mmHg)
6. Long standing persistent (>12 months) and permanent AF
7. NSTEMI/STEMI/implantated drug eluting stent with indication for dual antiplatelet therapy within 12 months before enrolment
8. History of complex left atrial ablation procedures. One previous PVI allowed.
9. Clinical indication for extended left atrial ablation procedures (lines, CFAE-, rotor-ablation)
10. History or presence of left atrial or ventricular thrombus
11. History of stroke / TIA independent from etiology
12. Acute major bleedings
13. Lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities
14. Need for concomitant anitcoagulation in addition to dabigatran
15. History of previous surgery resulting in contraindication for OAC
16. History of malignoma resulting in contraindication for OAC
17. Mechanical prosthetic heart valve or other indication for permanent OAC
18. Contraindication for MRI (i.e. metallical surgical implants unsuitable for MRI, cerebral port systems, wearing of magnetic or metallic objects that cannot be removed from the body (such as body piercing, implanted electrodes, contraceptive coil), inability to lie on the back for an extend-ed period of time, uncontrollable claustrophobia, hypersensitivity to noise etc.). Pacemaker and ICD-patients may be included at the dis-cretion of the local investigators/radiologists if MRI is warranted
19. Hypersensitivity against dabigatran or other ingredients of the medical product
20. Concomitant medication with dronedarone, ketoconazole, itraconazole, cyclosporine, tacrolimus or other interacting drugs as specified in the drug information
21. Simultaneous participation in any clinical trial involving administration of an investigational medicinal product within 30 days prior to clinical trial beginning
22. Females of childbearing potential, who are not using or not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices) unless they are surgically sterilized / hysterectomized or there are any other criteria considered sufficiently reliable by the investigator in individual cases
23. Conditions which interfere with the study treatment at the discretion of the investigator

E.5 End points

E.5.1

Primary end point(s)

Incidence of new micro- and macro-embolic lesions on cerebral MRI incl. flare and diffusion weighted imaging 12 months after randomization compared to baseline MRI at randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months after randomization

E.5.2

Secondary end point(s)

- Location, size and number of new micro- and macro-embolic lesions on cerebral MRI
- Incidence of clinically evident cardio-embolic events (stroke, TIA, systemic embolism)
- Incidence of clinically apparent neurological deficits
- Severeness neurological deficits
- Severeness of neurological deficits (modified ranking severity scale (mRS))
- Incidence of other thrombotic or thrombo-embolic events (myocardial infarction, deep vein throm-bosis, pulmonary embolism)
- Life-threatening / major / minor bleedings
- Hemorrhagic cerebral infarctions
- All-cause mortality
- Cardiovascular mortality
- Correlation of cardio-embolic events to method used for PVI (cryoballoon versus RF versus laser)
- Correlation of cardio-embolic events with arrhythmia recurrence (atrial fibrillation or atrial flutter post ablation with ECG documentation or symptoms)
- Correlation of cardio-embolic events with echocardiographic parameters (i.e. LA-size, LV function, LAA velocities)
- Quality of life questionnaire (AF-specific symptoms, EQ-5D)
- Neuropsychological questionnaire and assessment of neurocognitive deficits (MoCA test)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months after randomization

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

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

no treatment

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

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:

315

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

315

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

630

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)

After completion or termination of the study, study medication for each patient will be stopped and subse-quent treatment of the patients will be performed at the discretion of the treating physician.

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

2015-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-26

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-09-15

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