Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS)

• ClinicalTrials.gov Identifier: NCT02427126
• Recruitment Status: Completed
• First Posted: April 27, 2015
• Last Update Posted: October 13, 2021
• Sponsor: University Hospital Tuebingen
• Collaborators: Bristol-Myers Squibb; Medtronic; ZKS and IKEaB Tübingen
• Information provided by (Responsible Party): University Hospital Tuebingen

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Embolic Stroke of Undetermined Source	Drug: Apixaban; Drug: Aspirin	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 352 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS Randomized Trial)
• Actual Study Start Date: December 2015
• Actual Primary Completion Date: August 2020
• Actual Study Completion Date: September 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Apixaban; Apixaban 5mg b.i.d. Study treatment: 12 months Follow-up: 30 days after last study drug intake	Drug: Apixaban; Apixaban is an oral anticoagulant currently approved for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation, for the treatment of deep vein thrombosis and pulmonary embolism, and for the prophylaxis of systemic embolism after orthopedic surgery; Other Name: Eliquis
Active Comparator: Aspirin; Acetylic Salicylic Acid 100mg o.d.; Study treatment: 12 months Follow-up: 30 days after last study drug intake	Drug: Aspirin; Acetylic Salicylic Acid 100mg o.d.; 12 Months

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 12 months ]
   The primary endpoint will be the occurrence of at least one new ischemic lesion identified by magnetic resonance imaging (axial T2-weighted fluid attenuated inversion recovery MRI (FLAIR) and/or axial diffusion weighted MRI (DWI)) at 12 months when compared to the baseline MRI (FLAIR, DWI) obtained at the time of study drug initiation. MRI at 12 months will be directly compared with the baseline MRI to assess for new ischemic lesions.

Secondary Outcome Measures :

1. Combination of recurrent ischaemic stroke, hemorrhagic stroke, systemic embolism [ Time Frame: 12 months ]
   The occurence of ischaemic stroke, hemorrhagic stroke, or systemic embolism during study participation (12months) will be quantified
2. Combination of major adverse cardiovascular events (MACE) including recurrent stroke, myocardial infarction and cardiovascular death [ Time Frame: 12 months ]
   The occurence of major adverse cardiovascular events (MACE) including recurrent stroke, myocardial infarction and cardiovascular death during study participation (12months) will be quantified
3. Combination of major and clinically relevant non-major bleedings defined according to ISTH criteria [ Time Frame: 12 months ]
   The occurence of major and clinically relevant non-major bleedings defined according to ISTH criteria during study participation (12months) will be quantified
4. Change of cognitive function (MOCA) [ Time Frame: 12 months ]
   MOCA test will be performed upon study enrollment and 12 months after enrollment and both tests will be compared
5. Life quality (EQ-5D) [ Time Frame: 12 months ]
   EQ-5D questionnaire will be raised upon study enrollment and 12 months after enrollment and both questionnaires will be compared

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Germany

MedicalPark Berlin Humboldtmühle GmbH & Co. KG

Berlin, Germany

Neurologische Klinik, Universität Bonn

Bonn, Germany

Regiomed Kliniken Coburg GmbH Abt. II

Coburg, Germany

Neurologie, Klinikum Friedrichshafen GmbH

Friedrichshafen, Germany

Universitätsmedizin Göttingen Abt.Innere Medizin, Klinik für Kardiologie und Pneumologie,

Göttingen, Germany

Krankenhaus Martha-Maria Halle-Döhlau

Halle, Germany

Klinik für Neurolgie,UKSH Campus Kiel

Kiel, Germany

Klinik für Neurologie, Klinikum Ludwigsburg

Ludwigsburg, Germany

Universitätsklinik für Neurologie, Magdeburg

Magdeburg, Germany

Carl von Basedow KlinikumSaalekreis gGmbH

Merseburg, Germany

Marienhospital Stuttgart, Klinik für Neurologie

Stuttgart, Germany

Neurologische Klinik des Bürgerhospitals

Stuttgart, Germany

University Hospital

Tubingen, Germany, D72076

Universitäts- und Rehabilitationskliniken Ulm,Klinik für Neurologie

Ulm, Germany

Schwarzwald Baar Klinikum GmbH

Villingen-Schwenningen, Germany

Rems-Murr-Klinikum WinnendenNeurologie

Winnenden, Germany

Sponsors and Collaborators

University Hospital Tuebingen

Bristol-Myers Squibb

Medtronic

ZKS and IKEaB Tübingen

Investigators

• Principal Investigator: Tobias Geisler, Prof; Tübingen University Hospital
• Principal Investigator: Sven Poli, Prof; Tübingen University Hospital
• Principal Investigator: Schreieck Jürgen, Prof; Tübingen University Hospital

More Information

• Responsible Party: University Hospital Tuebingen
• ClinicalTrials.gov Identifier: NCT02427126
• Other Study ID Numbers: 2014-005109-19
• First Posted: April 27, 2015
• Last Update Posted: October 13, 2021
• Last Verified: September 2021

Keywords provided by University Hospital Tuebingen:

ESUS; anticoagulation

Additional relevant MeSH terms:

Stroke; Embolic Stroke; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Ischemic Stroke; Aspirin; Apixaban; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors