Clinical trial NCT02427126: Apixaban for Treatment of Embolic Stroke of Undetermined Source
Official title: Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS Randomized Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Embolic Stroke of Undetermined Source
Keywords: ESUS
anticoagulation
Lead sponsor: University Hospital Tuebingen
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: Medtronic
name: ZKS and IKEaB Tübingen
First posted: 2015-04-27
Enrollment: 352
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Multicentre (national, Germany), randomized (2x2 factorial), open, parallel group, active controlled, efficacy study (phase III)

Detailed description: Based on the previous data, ATTICUS is designed as multicentre, national, parallel group, active controlled, phase III randomized (2x2 factorial), clinical trial to demonstrate the superiority of apixaban against the current standard of treatment (acetylsalicylic acid) for the longterm treatment after ESUS. ATTICUS will follow a dynamic treatment protocol implementing conversion from the acetylsalicylic acid arm to the apixaban arm in case of detection of relevant episodes of AF during the course of the study. ATTICUS is designed to test the superiority over acetylsalicylic acid to reduce new ischemic lesion detected by FLAIR/DWI MRI.

Eligibility criteria: Inclusion criteria Must be ≥ 18 years at the time of signing the informed consent.

* ESUS must be defined according to following criteria:

  * Stroke detected by CT or MRI that is not lacunar
  * Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischaemia
  * No major-risk cardioembolic source of embolism
  * No other specific cause of stroke identified
* \* At least one of the following non-major but suggestive risk factors for cardiac embolism:

  * LA size \>45mm (parasternal axis)
  * spontaneous echo contrast in LAA
  * LAA flow velocity \<=0.2m/s
  * atrial high rate episodes
  * CHA2DS2-Vasc score \>=4
  * persistent foramen ovale
* Understand and voluntarily sign an informed consent document
* Women of childbearing potential (WOCBP) must be using an adequate method of contraception.

Exclusion Criteria:

* History of hypersensitivity to the investigational medicinal product
* Participation in other clinical trials or observation period of competing trials.
* Arteria cerebri media stroke affecting \> 30% of c o r r e s p o n d i n g territory
* Diagnosis of haemorrhage or other pathology,
* Clear indication for anticoagulation
* Inability to control following risk factors for Hemorrhagic Transformation of fresh cerebral Infarction (HTI) during index hospital stay: presence of HTI at the time of anticoagulation, blood pressure \>140 mmHg systolic, abnormal blood glucose Clear indication for dual antiplatelet therapy
* Clear stroke-/non-stroke-indication for concomitant long-term therapy with antiplatelets (e.g. acetylsalicylic acid (ASA), Clopidogrel, or Prasugrel) or with non-steroidal anti-inflammatory drugs (NSAID).
* Concomitant systemic therapy with strong inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. azole antimycotics and human immunodeficiency virus (HIV)-protease inhibitors.
* Contraindication to investigational medications
* Planned or likely therapy with fibrinolytic agents within 48 hours of first study medication
* History of intracranial, intraocular, spinal, retroperitoneal or atraumatic intra-articular bleeding
* Gastrointestinal bleed or major surgery within 3 months
* Planned or likely revascularization (any angioplasty or vascular surgery) within the next 3 months
* TIA or minor stroke induced by angiography or surgery
* Severe non-cardiovascular comorbidity with life expectancy \< 3 months
* Severe renal failure, defined as Glomerular Filtration Rate (GFR) \<15ml/min
* Severe hepatic insufficiency (Child-Pugh score B to C),
* Active liver disease,
* Contraindications against performance of MRI (pacemaker/ICD), previous implantation non-MRI capable protheses
* Patients considered unreliable by the investigator, or having a life expectancy less than the expected duration of the trial

Primary outcomes:
measure: Imaging Endpoint: Occurrence of at least one new ischemic lesion at 12 months after study drug initiation when compared to baseline MRI before study drug initiation
timeFrame: 12 months
Secondary outcomes:
measure: Combination of recurrent ischaemic stroke, hemorrhagic stroke, systemic embolism
timeFrame: 12 months
measure: Combination of major adverse cardiovascular events (MACE) including recurrent stroke, myocardial infarction and cardiovascular death
timeFrame: 12 months
measure: Combination of major and clinically relevant non-major bleedings defined according to ISTH criteria
timeFrame: 12 months
measure: Change of cognitive function (MOCA)
timeFrame: 12 months
measure: Life quality (EQ-5D)
timeFrame: 12 months
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: MedicalPark Berlin Humboldtmühle GmbH & Co. KG
city: Bonn
country: Germany
facility: Neurologische Klinik, Universität Bonn
city: Coburg
country: Germany
facility: Regiomed Kliniken Coburg GmbH Abt. II
city: Friedrichshafen
country: Germany
facility: Neurologie, Klinikum Friedrichshafen GmbH
city: Göttingen
country: Germany
facility: Universitätsmedizin Göttingen Abt.Innere Medizin, Klinik für Kardiologie und Pneumologie,
city: Halle
country: Germany
facility: Krankenhaus Martha-Maria Halle-Döhlau
city: Kiel
country: Germany
facility: Klinik für Neurolgie,UKSH Campus Kiel
city: Ludwigsburg
country: Germany
facility: Klinik für Neurologie, Klinikum Ludwigsburg
city: Magdeburg
country: Germany
facility: Universitätsklinik für Neurologie, Magdeburg
city: Merseburg
country: Germany
facility: Carl von Basedow KlinikumSaalekreis gGmbH
city: Stuttgart
country: Germany
facility: Marienhospital Stuttgart, Klinik für Neurologie
city: Stuttgart
country: Germany
facility: Neurologische Klinik des Bürgerhospitals
city: Tubingen
country: Germany
facility: University Hospital
city: Ulm
country: Germany
facility: Universitäts- und Rehabilitationskliniken Ulm,Klinik für Neurologie
city: Villingen-Schwenningen
country: Germany
facility: Schwarzwald Baar Klinikum GmbH
city: Winnenden
country: Germany
facility: Rems-Murr-Klinikum WinnendenNeurologie
Study officials:
affiliation: Tübingen University Hospital
name: Tobias Geisler, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Tübingen University Hospital
name: Sven Poli, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Tübingen University Hospital
name: Schreieck Jürgen, Prof
role: PRINCIPAL_INVESTIGATOR
References: