Biomarker Signature of Stroke Aetiology Study: The BIOSIGNAL-Study

• Conditions: Stroke, Acute

• Registration Number: NCT02274727
• Lead Sponsor: University of Zurich

Brief Summary

The three-year cumulative risk of a recurrent stroke, dependent on aetiology, is up to 25 per cent. At present, preventing recurrence relies on a broad approach to reduce risk factors associated with atherosclerosis, heart disease and metabolic disorders. However, more specific interventions, such as anticoagulation and surgery or stenting, need aetiologic information. BIOSIGNAL aims to determine where the most promising candidate biomarkers can help identify stroke aetiology and also predict overall MACE, including specifically recurrent stroke. In addition, the insights gained into the processes underlying different stroke subtypes may lead to more targeted diagnostic tools.

Detailed Description

Objectives and specific aims:

The investigators propose to prospectively evaluate the predictive value of the most promising blood bio-markers to identify treatable stroke etiologies on admission and risk of MACE and its components in consecutive ischemic stroke patients enrolled by several centers in Europe.

The clinical endpoints of the study are 1) recurrent cerebrovascular events (ischemic stroke and / or transient ischemic attack (TIA)) and major cardiac events (MACE) within one year after the index stroke and after 3-5 years of follow up (2021) 2) all types of atrial fibrillation (AF) detected on admission or by prolonged ambulatory cardiac rhythm monitors during the follow up period 3) presence of cerebrovascular atherosclerosis detected by ultrasound investigations and 4) overall mortality, functional outcome, cognitive impairment, occurrence of epilepsy, and newly diagnosed cancer, according to data collected in telephonic interviews in 2021 (only in Zurich and Basel) with the patients enrolled between 2014-2017.

Aim 1: To determine whether the proposed and novel biomarkers independently predict recurrent stroke and a composite outcome consisting of recurrent cerebrovascular event (ischemic stroke (AIS), intracranial hemorrhage (ICH) or transient ischemic attack (TIA), as well as myocardial infarction (MI), cardiovascular death (CVD)). i.e. major adverse cardiac events (MACE) among all patients. Hypothesis 1: Elevated levels of one or more of the proposed and novel biomarkers will independently predict MACE and its components during trial follow-up, assessed by structured interviews, as well as chart reviews 90 days, 1 year after the index stroke as well as in 2021 (only in Zurich and Basel).

Aim 2: To determine whether CE biomarkers are associated with atrial fibrillation among all patients. Hypothesis 2: Baseline values of one or more of the CE biomarkers will be independently associated with AF, including history of AF, AF detection at baseline, or AF detected during the follow up period by prolonged (at least 7-day) ambulatory cardiac rhythm monitors and structured interviews as well as chart reviews 90 days, 1 year after the index stroke as well as in 2021 (only in Zurich and Basel).

Aim 3: To determine whether LAA biomarkers are associated with a) the presence of cerebrovascular atherosclerosis among all patients. Hypothesis 3: Baseline values of one or more of LAA biomarkers will be independently associated with the presence of extra and intracranial atherosclerosis among patients with ischemic stroke.

Exploratory Aim 4: To determine whether the proposed and novel biomarkers will predict a) occurrence of epileptic seizures and diagnosis of epilepsy b) newly diagnosed cancer, c) functional outcome and cognitive impairment. Hypothesis 4: Baseline values of one or more of the proposed and potentially novel biomarkers will independently predict a) occurrence of epileptic seizures and the diagnosis of epilepsy b)occurrence of newly diagnosed cancer c) functional outcome and cognitive impairment assessed by a follow up structured telephone interview performed in 2021 with the patients enrolled between 2014-2017 (only in Zurich and Basel).

This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, and Good Clinical Practice (GCP) guidelines as well as all national legal and regulatory requirements.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2014-09
• Study First Submitted: 2014-10-17
• Study First Submitted QC: 2014-10-23
• Study First Posted: 2014-10-24
• Status Verified: 2021-11
• Last Update Submitted: 2021-11-05
• Last Update Posted: 2021-11-11
• Primary Completion: 2021-12
• Study Completion: 2021-12

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 1800

Inclusion Criteria

All consecutive patients (above the age of 18) who are admitted with a suspected ischemic stroke within 24 hours of symptom onset are eligible.

Ischemic stroke is defined as an acute localized ischemic lesion in the brain not attributable to central nervous system infection, tumor, demyelinating, or degenerative neurologic diseases due to an occlusive vascular disorder.

Detailed Inclusion Criteria:

1. Rapid onset of a focal neurologic deficit, with signs or symptoms persisting beyond 24 hours & NOT associated with:

   • infection
   • trauma
   • tumor of the brain
   • severe metabolic disorders
   • chronic degenerative neurologic disease

2. The development of an acute focal neurologic deficit persisting >24 hours in conjunction with brain imaging consistent with acute ischemic stroke.

The CT or MRI may either show a new infarct or no change from the study performed at entry, i.e. the diagnosis is clinical and does not require CT/MRI confirmation. Secondary hemorrhagic infarction is permissible.

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Exclusion Criteria

1. Hemorrhagic stroke
2. All patients discharged from the hospital with a diagnosis different from ischemic stroke (i.e. stroke mimics)

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Composite of Major adverse cardiac events (MACE)	Within 1 year after the index event. In Zurich and Basel also in 2021	Recurrent cerebrovascular events (ischemic stroke (AIS), intracranial hemorrhage (ICH) or transient ischemic attack (TIA)), as well as myocardial infarction (MI), cardiovascular death (CVD). i.e. major adverse cardiac events (MACE)

Secondary Outcome Measures

Name	Time	Method
History of AF	Diagnosed befor the stroke	Assessed by chart review and taking the patients history
The presence of cerebrovascular atherosclerosis among all patients.	During first hospitalisation (cross-sectional analysis, up to 14 days)	Assessed by duplex sonography.
Single components and combinations of MACE	Within one year after the index stroke	Recurrent cerebrovascular events (ischemic stroke (AIS), intracranial hemorrhage (ICH) or transient ischemic attack (TIA)), myocardial infarction (MI) or cardiovascular death (CVD)
Stroke aetiology	During first hospitalisation (cross-sectional analysis, up to 14 days)	According to TOAST and SS TOAST criteria
Newly Atrial Fibrillation (AF)	On admission and during a one year of follow-up by PCM. In Zurich and Basel also in 2021	Newly diagnosed atrial fibrillation in patients with no history of AF

Trial Locations

Locations (9)

University Hospital of Frankfurt; 🇩🇪 Frankfurt am Main, Germany

University Hospital of Bern/Inselspital; 🇨🇭 Bern, Switzerland

Stroke Center ; Neurocentro(EOC) della Svizzera Italiana; 🇨🇭 Lugano, Switzerland

Universitiy Hospital Vall d'Hebron; 🇪🇸 Barcelona, Spain

Kantonsspital Aarau, Department of Neurology; 🇨🇭 Aarau, Argau, Switzerland

University Hospital of Zurich, Department of Neurology; 🇨🇭 Zurich, Switzerland

Larissa University Hospital of Thessaly; 🇬🇷 Larissa, Greece

University Hospital of Basel; 🇨🇭 Basel, Switzerland

Stroke Center, Kantonsspital St.Gallen; 🇨🇭 St.Gallen, Switzerland