SECRETO: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome

Sponsor

SECRETO Study Consortium (Other)

Overall Status

Recruiting

CT.gov ID

NCT01934725

Collaborator

Finnish Medical Foundation (Other), Academy of Finland (Other), Helsinki and Uusimaa Hospital District (Other), Hospital District of Southwest Finland (Other), Pirkanmaa Hospital District (Other), Hospital District of North Ostrobothnia (Other), Hospital District of Northern Savo (Other), Sahlgrenska University Hospital, Sweden (Other)

1,200

Enrollment

Locations

217

Anticipated Duration (Months)

63.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

BACKGROUND: In industrialized countries a considerable and increasing proportion of strokes occur at younger ages. Stroke at young age causes marked disability at worst and thus long-standing socioeconomic consequences and exposes survivors for 4-fold risk of premature death compared with background population. Up to 50% of young patients with ischemic stroke remain without definitive etiology for their disease despite extensive modern diagnostic work-up (i.e. cryptogenic stroke). The group of cryptogenic strokes includes those with patent foramen ovale (PFO) or other abnormalities in the atrial septum in the heart as the only or concomitant finding. Population prevalence of PFO is high, 25%, and the mechanisms how PFO would be associated causally with ischemic stroke remain to be clarified. Moreover, there are only scarce data on clinical outcome, long-term risk of new vascular events, and prevention of such events in these patients.

DESIGN: Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO) is an international prospective multicenter case-control study of young adults (age 18-49) presenting with an imaging-positive first-ever ischemic stroke of undetermined etiology (aim N=2000). Patients are included after standardized diagnostic procedures (brain MRI, imaging of intracranial and extracranial vessels, cardiac imaging, and screening for coagulopathies) and age- and sex-matched to healthy controls in a 1:1 fashion. Up to 45 study sites worldwide will be needed to recruit the planned participant population during a 3-year period. Neurovascular imaging and echocardiography studies, and ECGs will be read centrally.

AIMS: SECRETO involves five principal fields of investigation: (1) Stroke triggers and clinical risk factors; (2) Long-term prognosis (new vascular events, functional and psychosocial outcomes); (3) Abnormalities of thrombosis and hemostasis; (4) Biomarkers of e.g. inflammation, atherogenesis, endothelial function, thrombosis, platelet activation, and hemodynamic stress to characterize postulated cryptogenic stroke mechanisms; and (5) genetic study, including genome-wide association and candidate gene studies as well as next-generation sequencing approach. All analyses consider cardiac functional and interatrial structural properties as a possible mediator. Furthermore, SECRETO Family Study (substudy) aims at collecting extensive family history of thrombotic events from informative patients being screened for SECRETO main study and collect genetic samples from all consenting family members for whole-genome sequencing.

SIGNIFICANCE: SECRETO will provide novel information on clinical and subclinical risk factors, both transient and chronic, predisposing to cryptogenic ischemic stroke in young adults. This study also reveals long-term prognosis of this understudied patient population and may discover new genetic background underlying the disease mechanism and provide potential targets for drug development.

Condition or Disease	Intervention/Treatment	Phase
Brain Infarction Ischemic Stroke Thrombosis Foramen Ovale, Patent

Study Design

Study Type:

Observational

Anticipated Enrollment :

1200 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Etiology, Triggers, and Outcome (SECRETO)

Actual Study Start Date :

Nov 1, 2013

Anticipated Primary Completion Date :

Jan 1, 2022

Anticipated Study Completion Date :

Dec 1, 2031

Arms and Interventions

Arm	Intervention/Treatment
Patients w/ cryptogenic ischemic stroke Patients aged 15 to 49 years with unexplained first-ever ischemic stroke
Stroke-free control subjects Stroke-free subjects age- and gender-matched to patients

Outcome Measures

Primary Outcome Measures

Nonfatal or fatal recurrent ischemic cerebrovascular event [10 years]
Ischemic stroke or transient ischemic attack

Secondary Outcome Measures

Composite of noncerebrovascular arterial or venous thrombotic events, or cerebral venous thrombosis [10 years]
Death from any cause [10 years]
New-onset atrial fibrillation [10 years]

Other Outcome Measures

Modified Rankin Scale [10 years]
Functional outcome will be assessed with modified Rankin Scale at mandatory 3-month visit and at annual follow-up contacts from year 1 to year 10.
Vocational outcome [10 years]
Vocational status will be assessed at each follow-up contact with Poststroke Working Activity Questionnaire and a set of questions designed for the study.
Cognitive outcome [3 months]
Cognition will be assessed at mandatory 3-month follow-up visit (Montreal Cognitive Assessment).
Anxiety and depression [10 years]
Poststroke anxiety and depression will be evaluated at 3-month visit, 1-year, 5-year, and 10-year follow-up contacts with Hospital Anxiety and Depression Scale.
Quality of life [10 years]
Quality of life will be assessed at 3-month visit, 1-year, 5-year, and 10-year follow-up contacts with EuroQol questionnaire.
Caregiver burden [3 months]
Poststroke burden to caregiver will be assessed at 3-month visit with Expanded Caregiver Strain Index Questionnaire.
Barthel Index [10 years]
Functional outcome will be assessed with Barthel Index at mandatory 3-month visit and at annual follow-up contacts from year 1 to year 10.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 49 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

PATIENTS:

Inclusion Criteria:

Age 18 to 49 at stroke onset
Patient hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology after complete timely diagnostic testing.

Exclusion Criteria:

Baseline mandatory tests not obtained in the first week following stroke onset, including:

Brain MRI
Routine blood tests, including complete blood count, CRP, fasting glucose, creatinine, aPTT, INR, total cholesterol, LDL-cholesterol, HDL-cholesterol, HbA1C, hemoglobin electrophoresis in individuals of African origin

Other baseline mandatory tests not obtained within the first two weeks following stroke onset, including:

Imaging of cervicocephalic arteries by CTA, MRA, or DSA
Transesophageal (highly recommended) or transthoracic echocardiography
24-hour Holter monitoring or continuous in-hospital ECG monitoring with automated arrhythmia detection for at least 24 hours
Screening for thrombophilia, including antiphospholipid antibodies and other coagulopathies (any abnormal finding must be retested at mandatory 3-month follow-up visit >12 weeks from initial testing or >4 weeks after cessation of anticoagulation at any later time point); mandatory tests include anticardiolipin antibodies, lupus anticoagulant, anti-β2-glycoprotein antibodies, factor V mutation (or aPC resistency ruled out), factor II mutation, homocysteine, antithrombin III, protein C, and protein S

No evidence of current brain ischemia
Current stroke due to cerebral venous thrombosis or as a complication of subarachnoid hemorrhage, angiography, or cardiac surgery
Patient otherwise not eligible for the study or adherent for follow-up (eg nonresident) or has concurrent disease affecting outcome (eg multiple sclerosis, cancer)
Informed consent not obtained from the patient or a proxy.

CONTROL SUBJECTS:

Inclusion Criteria:

Age 18 to 49 years
Absence of prior ischemic stroke as ascertained using the Questionnaire for Verifying Stroke-Free Status

Exclusion Criterion:

Informed consent not obtained

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Tartu University Hospital	Tartu	Estonia
2	Helsinki University Central Hospital	Helsinki	Finland	FI-00029
3	Kuopio University Hospital	Kuopio	Finland	70029
4	Oulu University Hospital	Oulu	Finland
5	Tampere University Hospital	Tampere	Finland
6	Turku University Central Hospital	Turku	Finland
7	Ernst-Moritz-Arndt University Medicine	Greifswald	Germany
8	"Attikon" Hospital, University of Athens, School of Medicine	Athens	Greece
9	University of Brescia	Brescia	Italy	25123
10	Arcispedale S. Maria Nuova	Reggio Emilia	Italy
11	Vilnius University Hospital Santariskiu klinikos	Vilnius	Lithuania
12	Radboud University Nijmegen Medical Centre	Nijmegen	Netherlands	6500 HB
13	Haukeland University Hospital	Bergen	Norway	5021
14	Hospital Santa Maria	Lisboa	Portugal	1649-035
15	Torrecárdenas University Hospital	Almería	Spain
16	Sahlgrenska University Hospital	Gothenburg	Sweden
17	Istanbul University Istanbul Faculty of Medecine	Istanbul	Turkey
18	Peterborough City Hospital	Peterborough	United Kingdom
19	Royal Stoke University Hospital	Stoke-on-Trent	United Kingdom

Investigators

Principal Investigator: Jukka Putaala, A/Prof., Helsinki University Central Hospital
Principal Investigator: Steven Kittner, Prof., University of Maryland Hospital