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

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

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

Study Overview

• Status: Completed
• Conditions: Embolic Stroke of Undetermined Source
• Intervention / Treatment: Drug: Apixaban; Drug: Aspirin

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 Type: Interventional
• Enrollment (Actual): 352
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • MedicalPark Berlin Humboldtmühle GmbH & Co. KG
  • Bonn, Germany
    • Neurologische Klinik, Universität Bonn
  • Coburg, Germany
    • Regiomed Kliniken Coburg GmbH Abt. II
  • Friedrichshafen, Germany
    • Neurologie, Klinikum Friedrichshafen GmbH
  • Göttingen, Germany
    • Universitätsmedizin Göttingen Abt.Innere Medizin, Klinik für Kardiologie und Pneumologie,
  • Halle, Germany
    • Krankenhaus Martha-Maria Halle-Döhlau
  • Kiel, Germany
    • Klinik für Neurolgie,UKSH Campus Kiel
  • Ludwigsburg, Germany
    • Klinik für Neurologie, Klinikum Ludwigsburg
  • Magdeburg, Germany
    • Universitätsklinik für Neurologie, Magdeburg
  • Merseburg, Germany
    • Carl von Basedow KlinikumSaalekreis gGmbH
  • Stuttgart, Germany
    • Marienhospital Stuttgart, Klinik für Neurologie
  • Stuttgart, Germany
    • Neurologische Klinik des Bürgerhospitals
  • Tubingen, Germany, D72076
    • University Hospital
  • Ulm, Germany
    • Universitäts- und Rehabilitationskliniken Ulm,Klinik für Neurologie
  • Villingen-Schwenningen, Germany
    • Schwarzwald Baar Klinikum GmbH
  • Winnenden, Germany
    • Rems-Murr-Klinikum WinnendenNeurologie

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	12 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: Bristol-Myers Squibb; Medtronic; ZKS and IKEaB Tübingen
• Investigators: Principal Investigator: Tobias Geisler, Prof, Tubingen University Hospital; Principal Investigator: Sven Poli, Prof, Tubingen University Hospital; Principal Investigator: Schreieck Jürgen, Prof, Tubingen University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): August 1, 2020
• Study Completion (Actual): September 1, 2021

Study Registration Dates

• First Submitted: March 20, 2015
• First Submitted That Met QC Criteria: April 24, 2015
• First Posted (Estimate): April 27, 2015

Study Record Updates

• Last Update Posted (Actual): October 13, 2021
• Last Update Submitted That Met QC Criteria: October 12, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: anticoagulation; ESUS
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Ischemic Stroke; Stroke; Embolic Stroke; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Apixaban
• Other Study ID Numbers: 2014-005109-19