Clinical Trial Page

Summary
EudraCT Number:2014-002442-45
Sponsor's Protocol Code Number:AXAFA-AFNET5
National Competent Authority:Netherlands - Competent Authority
Clinical Trial Type:EEA CTA
Trial Status:Completed
Date on which this record was first entered in the EudraCT database:2015-03-05
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
A. Protocol Information
A.1Member State ConcernedNetherlands - Competent Authority
A.2EudraCT number2014-002442-45
A.3Full title of the trial
Anticoagulation using the direct factor Xa inhibitor apixaban during Atrial Fibrillation catheter Ablation: Comparison to vitamin K antagonist therapy.
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
During atrial fibrillation catheter ablation procedure treatment with anticoagulant drugs is necessary in order to prevent blood clotting and thereby decrease the risk of procedure related strokes. In this study two different types of anticoagulant drugs are being compared during and after the atrial fibrillation catheter ablation procedure: the novel direct factor Xa inhibitor apixaban and any of the standard vitamin K antagonists.
A.3.2Name or abbreviated title of the trial where available
AXAFA
A.4.1Sponsor's protocol code numberAXAFA-AFNET5
A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN87711003
A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02227550
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorKompetenznetz Vorhofflimmern e.V. [Atrial Fibrillation NETwork (AFNET)]
B.1.3.4CountryGermany
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportBrystol-Myers Sqibb
B.4.2CountryUnited States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationKompetenznetz Vorhofflimmern e.V. [Atrial Fibrillation NETwork (AFNET)]
B.5.2Functional name of contact pointAFNET
B.5.3 Address:
B.5.3.1Street AddressMendelstr. 11
B.5.3.2Town/ cityMünster
B.5.3.3Post code48149
B.5.3.4CountryGermany
B.5.4Telephone number+492519801340
B.5.5Fax number+492519801349
B.5.6E-mailinfo@kompetenznetz-vorhofflimmern.de
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name Eliquis
D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb/Pfizer EEIG
D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameApixaban
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNAPIXABAN
D.3.9.3Other descriptive nameApixaban
D.3.9.4EV Substance CodeSUB25425
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number2.5
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 2
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.2Country which granted the Marketing AuthorisationNetherlands
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product namePhenprocoumon
D.3.4Pharmaceutical form Tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNPHENPROCOUMON
D.3.9.1CAS number 435-97-2
D.3.9.3Other descriptive namephenprocoumon
D.3.9.4EV Substance CodeSUB09781MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number3
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 3
D.1.2 and D.1.3IMP RoleComparator
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.2Country which granted the Marketing AuthorisationNetherlands
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameAcenocoumarol
D.3.4Pharmaceutical form Tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNACENOCOUMAROL
D.3.9.1CAS number 152-72-7
D.3.9.4EV Substance CodeSUB05211MIG
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number1
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.IMP: 4
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation Yes
D.2.1.1.1Trade name Eliquis
D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb/Pfizer EEIG
D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product nameApixaban
D.3.4Pharmaceutical form Film-coated tablet
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNAPIXABAN
D.3.9.3Other descriptive nameApixaban
D.3.9.4EV Substance CodeSUB25425
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number5
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another 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.1.1Medical condition(s) being investigated
Atrial fibrillation catheter ablation
E.1.1.1Medical condition in easily understood language
Atrial fibrillation is a common cardiac rhythm disturbance. Although not directly life-threatening, it may have dangerous consequences: e.g., an up to fivefold increased risk of suffering a stroke.
E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 19.1
E.1.2Level PT
E.1.2Classification code 10003658
E.1.2Term Atrial fibrillation
E.1.2System Organ Class 10007541 - Cardiac disorders
E.1.2 Medical condition or disease under investigation
E.1.2Version 19.1
E.1.2Level LLT
E.1.2Classification code 10071667
E.1.2Term Persistent atrial fibrillation
E.1.2System Organ Class 10007541 - Cardiac disorders
E.1.2 Medical condition or disease under investigation
E.1.2Version 19.1
E.1.2Level LLT
E.1.2Classification code 10003661
E.1.2Term Atrial fibrillation paroxysmal
E.1.2System Organ Class 10007541 - Cardiac disorders
E.1.2 Medical condition or disease under investigation
E.1.2Version 19.1
E.1.2Level LLT
E.1.2Classification code 10066582
E.1.2Term Recurrent atrial fibrillation
E.1.2System Organ Class 10007541 - Cardiac disorders
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
To demonstrate that anticoagulation with the direct factor Xa inhibitor apixaban is not less safe than VKA therapy in patients undergoing catheter ablation of non-valvular AF in the prevention of peri-procedural complications.
E.2.2Secondary objectives of the trial
The substudy involving MRI scans after the ablation procedure aims to identify invisible damage such as 'silent'strokes in the test versus the comparator group.
E.2.3Trial contains a sub-study Yes
E.2.3.1Full title, date and version of each sub-study and their related objectives
MRI Sub-study (same version and same date as main study protocol)
E.3Principal inclusion criteria
I1. Non-valvular AF (ECG-documented) with a clinical indication for catheter ablation
I2. Clinical indication to undergo catheter ablation on continuous anticoagulant therapy
I3. Presence of at least one of the CHADS2 stroke risk factors
- Stroke or TIA
- age ≥ 75 years,
- hypertension, defined as chronic treatment for hypertension, estimated need for continuous antihypertensive therapy or resting blood pressure > 145/90 mm Hg,
- diabetes mellitus,
- symptomatic heart failure (NYHA ≥ II).
I4. Age ≥ 18 years
I5. Provision of signed informed consent
E.4Principal exclusion criteria
General exclusion criteria
E1. Any disease that limits life expectancy to less than 1 year
E2. Participation in another clinical trial, either within the past two months or still ongoing
E3. Previous participation in AXAFA
E4. Pregnant women or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception (oral contraception or intra-uterine device) or sterile women can be randomised.
E5. Breastfeeding women
E6. Drug abuse or clinically manifest alcohol abuse
E7. Any stroke within 14 days before randomisation
E8. Coadministration with drugs that are strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P glycoprotein (P-gp) or strong dual inducers of CYP3A4 and P-gp
Exclusion criteria related to a cardiac condition
E9. Valvular AF (as defined by the focussed update of the ESC guidelines on AF, i.e. severe mitral valve stenosis, mechanical heart valve). Furthermore, patients who underwent mitral valve repair are not eligible for AXAFA.
E10. Any previous ablation or surgical therapy for AF
E11. Cardiac ablation therapy for any indication (catheter-based or surgical) within 3 months prior to randomisation
E12. Clinical need for “triple therapy” (combination therapy of clopidogrel, acetylsalicylic acid, and oral anticoagulation)
E13. Other contraindications for use of VKA or apixaban
E14. Documented atrial thrombi less than 3 months prior to randomisation.
Exclusion criteria based on laboratory abnormalities
E15. Severe chronic kidney disease with an estimated glomerular filtration rate (GFR) < 15 ml/min
E.5 End points
E.5.1Primary end point(s)
The primary outcome parameter of AXAFA is a composite of
- all-cause death,
- stroke, and
- major bleeding events.
Stroke comprises ischemic strokes as defined by the FDA (including ischemic infarction with (transient) clinical symptoms that resolve completely within 24 hours, but have a matching lesion on brain imaging as well as ischemic infarction interrupted by death within 24 hours), subarachnoid hemorrhage and hemorrhagic stroke. Major bleeding events will be defined according to the Bleeding Academic Research Consortium (BARC) definition as BARC 2 or higher, i.e. all bleeding events that require an action by a health care professional. This outcome parameter comprises all relevant bleeding events in a clinical setting and has been used to optimise arterial vascular procedures such as percutaneous coronary interventions.
E.5.1.1Timepoint(s) of evaluation of this end point
Randomisation to end of follow-up, especially at 3-months on-site visit
E.5.2Secondary end point(s)
The secondary outcome parameters are defined as
- any bleeding event
- major bleeding events according to the ISTH and TIMI definitions,
- number of strokes, other systemic embolic events, and all-cause deaths,
- time from randomisation to ablation
- nights spent in hospital after ablation
- health-care related cost calculation estimated by quantification of interventions, nights spent in hospital, and the costs of outpatient treatment,
- number of hospitalizations (at least one over-night stay) for cardiovascular reasons ,
- treatment duration prior to ablation and total time on oral anticoagulation,
- number of patients with clinically indicated TEE
- ACT during ablation (assessed as mean, range, and number of ACT measurements within the target range)
- time to recurrent AF (determined clinically, and according to ECG and Holter ECG recording at the end of follow-up),
- rhythm status at the end of follow-up (assessed by Holter ECG),
- vascular access complications leading to prolongation of in-hospital stay or specific therapy,
- quality-of-life changes at month 3 compared to baseline (assessed by EQ-5D, SF-12 questionnaires, and by the Karnofsky scale),
- change of cognitive function at month 3 compared to baseline (assessed by Montreal Cognitive Assessment Scale; MoCA),
- MRI sub-study, only: Prevalence of clinically “silent” MRI-detected brain lesions within 48 hours after the ablation procedure,
- MRI sub-study, only: Impact of ablation-associated clinically overt strokes or MRI-detected but clinically “silent” acute brain lesions on cognitive function after ablation
E.5.2.1Timepoint(s) of evaluation of this end point
Randomisation to end of follow-up, especially at 3-months on-site visit
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety No
E.6.5Efficacy No
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) No
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other No
E.7.1.3.1Other trial type description
E.7.2Therapeutic exploratory (Phase II) No
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) Yes
E.8 Design of the trial
E.8.1Controlled Yes
E.8.1.1Randomised Yes
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group Yes
E.8.1.6Cross over No
E.8.1.7Other Yes
E.8.1.7.1Other trial design description
Investigator-initiated, prospective, parallel-group, randomised, open, blinded endpoint assessment
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Yes
E.8.2.2Placebo No
E.8.2.3Other Yes
E.8.2.3.1Comparator description
Vitamin K antagonist
E.8.2.4Number of treatment arms in the trial2
E.8.3 The trial involves single site in the Member State concerned No
E.8.4 The trial involves multiple sites in the Member State concerned Yes
E.8.4.1Number of sites anticipated in Member State concerned6
E.8.5The trial involves multiple Member States Yes
E.8.5.1Number of sites anticipated in the EEA40
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA Yes
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
Austria
Belgium
Denmark
Germany
Italy
Netherlands
Spain
United Kingdom
United States
E.8.7Trial 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.8.9.1In the Member State concerned years2
E.8.9.1In the Member State concerned months6
E.8.9.1In the Member State concerned days
E.8.9.2In all countries concerned by the trial years2
E.8.9.2In all countries concerned by the trial months6
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 200
F.1.3Elderly (>=65 years) Yes
F.1.3.1Number of subjects for this age range: 450
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations Yes
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception Yes
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state80
F.4.2 For a multinational trial
F.4.2.1In the EEA 610
F.4.2.2In the whole clinical trial 650
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)
At the end of the study course of each individual patient (planned or premature study discontinuation), the investigator is free to decide on which further anticoagulant medication to put the patient.
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2015-03-05
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2015-06-30
P. End of Trial
P.End of Trial StatusCompleted

Sponsors and Collaborators

Medical Conditions

Drug Interventions

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