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

NCT01934725 | Active Not Recruiting DMC

• 1 other identifier: SECRETO
• Study Type: observational
• Target: 1,200
• Locations: 12 countries
• Sites: 18

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.

Conditions

Brain Infarction; Ischemic Stroke; Thrombosis; Foramen Ovale, Patent

Keywords

Ischemic Stroke; Brain Infarction; Patent Foramen Ovale; Stroke in the Young; Myocardial Infarction; Cerebral Venous Thrombosis; Pulmonary Embolism; Deep Vein Thrombosis; Subarachnoid Hemorrhage; Prognosis; Databases, Genetic

Outcome Measures

Primary Outcomes (1)

• Nonfatal or fatal recurrent ischemic cerebrovascular event

  Ischemic stroke or transient ischemic attack

  10 years

Secondary Outcomes (3)

• 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 Outcomes (7)

• Modified Rankin Scale

  10 years

• Vocational outcome

  10 years

• Cognitive outcome

  3 months

Study Arms (2)

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

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)
• Sampling Method: Probability Sample

Study Population

1. Patients aged 18 to 49 hospitalized due to first-ever imaging-positive ischemic stroke of undetermined etiology; 2. Age-, gender- and race-ethnicity-matched stroke-free control subjects

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• SECRETO Study Consortium: lead
• Finnish Medical Foundation: collaborator
• Academy of Finland: collaborator
• Hospital District of Helsinki and Uusimaa: collaborator
• Hospital District of Southwestern Finland: collaborator
• Pirkanmaa Hospital District: collaborator
• Hospital District of North Ostrobothnia: collaborator
• Northern Savo Hospital District: collaborator
• Sahlgrenska University Hospital: collaborator
• Sigrid Jusélius Foundation: collaborator

Study Sites (19)

Tartu University Hospital

Tartu, Estonia

Location

Helsinki University Central Hospital

Helsinki, FI-00029, Finland

Location

Kuopio University Hospital

Kuopio, 70029, Finland

Location

Oulu University Hospital

Oulu, Finland

Location

Tampere University Hospital

Tampere, Finland

Location

Turku University Central Hospital

Turku, Finland

Location

Ernst-Moritz-Arndt University Medicine

Greifswald, Germany

Location

"Attikon" Hospital, University of Athens, School of Medicine

Athens, Greece

Location

University of Brescia

Brescia, 25123, Italy

Location

Arcispedale S. Maria Nuova

Reggio Emilia, Italy

Location

Vilnius University Hospital Santariskiu klinikos

Vilnius, Lithuania

Location

Radboud University Nijmegen Medical Centre

Nijmegen, 6500 HB, Netherlands

Location

Haukeland University Hospital

Bergen, 5021, Norway

Location

Hospital Santa Maria

Lisbon, 1649-035, Portugal

Location

Torrecárdenas University Hospital

Almería, Spain

Location

Sahlgrenska University Hospital

Gothenburg, Sweden

Location

Istanbul University Istanbul Faculty of Medecine

Istanbul, Turkey (Türkiye)

Location

Peterborough City Hospital

Peterborough, United Kingdom

Location

Royal Stoke University Hospital

Stoke-on-Trent, United Kingdom

Location

Related Publications (10)

• Putaala J, Martinez-Majander N, Leppert M, Tulkki L, Pirinen J, Tolppanen H, Sarkanen T, Virtanen M, Jaakonmaki N, Jakala P, Hedman M, Redfors P, Bech-Hanssen O, Junttola U, Huhtakangas J, Ylikotila P, Lautamaki R, Schminke U, von Sarnowski B, Busch R, Yesilot N, Sezgin M, Waje-Andreassen U, Saeed S, Fonseca AC, Paula A, Amaya Pascasio L, Martinez-Sanchez P, Korv J, Muda P, Ferdinand P, Oxley C, Zakarkaite D, Ryliskiene K, Pezzini A, Lombardi CM, Licenik R, Zedde M, Grimaldi T, Tsivgoulis G, Sinisalo J, Gerdts E, Tatlisumak T; SECRETO Study Group. Burden of Modifiable Risk Factors in Young-Onset Cryptogenic Ischemic Stroke by High-Risk Patent Foramen Ovale. Stroke. 2025 Jun;56(6):1428-1440. doi: 10.1161/STROKEAHA.124.049855. Epub 2025 Apr 17.

  PMID: 40242852 DERIVED

• Kutal S, Tulkki LJ, Sarkanen T, Redfors P, Jood K, Nordanstig A, Yesilot N, Sezgin M, Ylikotila P, Zedde M, Junttola U, Fromm A, Ryliskiene K, Licenik R, Ferdinand P, Jatuzis D, Korv L, Korv J, Pezzini A, Sinisalo J, Lehto M, Gerdts E, Autere J, Fonseca AC, Waje-Andreassen U, Von Sarnowski B, Sairanen T, Tatlisumak T, Huhtakangas J, Jakala P, Putaala J, Martinez-Majander N. Association Between Self-Perceived Stress and Cryptogenic Ischemic Stroke in Young Adults: A Case-Control Study. Neurology. 2025 Mar 25;104(6):e213369. doi: 10.1212/WNL.0000000000213369. Epub 2025 Mar 5.

  PMID: 40043226 DERIVED

• Sindre RB, Gerdts E, Putaala J, Grymyr LMD, Midtbo H, Almeida AG, Bech-Hanssen O, Busch R, Eilertsen RK, Fonseca AC, Hedman M, Huhtakangas J, Jakala P, Lautamaki R, Lehto M, Martinez-Majander N, Redfors P, Sarkanen T, von Sarnowski B, Sinisalo J, Virtanen M, Waje-Andreassen U, Yesilot N, Ylikotila P, Cramariuc D. Association of Left Atrial Stiffness With Risk of Cryptogenic Ischemic Stroke in Young Adults. JACC Adv. 2024 Mar 14;3(4):100903. doi: 10.1016/j.jacadv.2024.100903. eCollection 2024 Apr.

  PMID: 38939654 DERIVED

• Zedde M, Grisendi I, Assenza F, Napoli M, Moratti C, Bonacini L, Di Cecco G, D'Aniello S, Pavone C, Merlino G, Putaala J, Valzania F, Pascarella R. The Prepetrous Segment of the Internal Carotid Artery as a Neglected Site of Symptomatic Atherosclerosis: A Single-Center Series. J Clin Med. 2024 Mar 15;13(6):1696. doi: 10.3390/jcm13061696.

  PMID: 38541922 DERIVED

• Tulkki L, Martinez-Majander N, Haapalahti P, Tolppanen H, Sinisalo J, Repo O, Sarkanen T, Numminen H, Ryodi E, Ylikotila P, Roine RO, Lautamaki R, Saraste A, Miettinen T, Autere J, Jakala P, Hedman M, Huhtakangas J, Junttola U, Putaala J, Pirinen J; SECRETO Study Group. 24-hour ambulatory blood pressure and cryptogenic ischemic stroke in young adults. Ann Med. 2023 Dec;55(1):2203513. doi: 10.1080/07853890.2023.2203513.

  PMID: 37086083 DERIVED

• Kuusisto JK, Poyhonen PAK, Pirinen J, Lehmonen LJ, Raty HP, Martinez-Majander N, Putaala J, Sinisalo J, Jarvinen V. Revisiting left atrial volumetry by magnetic resonance imaging: the role of atrial shape and 3D angle between left ventricular and left atrial axis. BMC Med Imaging. 2021 Nov 9;21(1):167. doi: 10.1186/s12880-021-00701-5.

  PMID: 34753444 DERIVED

• Poyhonen P, Kuusisto J, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Gerdts E, Putaala J, Sinisalo J, Jarvinen V. Right atrium and cryptogenic ischaemic stroke in the young: a case-control study. Open Heart. 2021 May;8(1):e001596. doi: 10.1136/openhrt-2021-001596.

  PMID: 34006504 DERIVED

• Poyhonen P, Kuusisto J, Jarvinen V, Pirinen J, Raty H, Lehmonen L, Paakkanen R, Martinez-Majander N, Putaala J, Sinisalo J. Left ventricular non-compaction as a potential source for cryptogenic ischemic stroke in the young: A case-control study. PLoS One. 2020 Aug 14;15(8):e0237228. doi: 10.1371/journal.pone.0237228. eCollection 2020.

  PMID: 32797064 DERIVED

• Pirinen J, Jarvinen V, Martinez-Majander N, Sinisalo J, Poyhonen P, Putaala J. Left Atrial Dynamics Is Altered in Young Adults With Cryptogenic Ischemic Stroke: A Case-Control Study Utilizing Advanced Echocardiography. J Am Heart Assoc. 2020 Apr 7;9(7):e014578. doi: 10.1161/JAHA.119.014578. Epub 2020 Mar 25.

  PMID: 32208831 DERIVED

• Martinez Majander N, Sinisalo J, Sundararajan S, Strbian D, Putaala J. Cryptic Loss of Consciousness in a 36-Year-Old Woman. Stroke. 2015 Jul;46(7):e164-6. doi: 10.1161/STROKEAHA.115.009405. Epub 2015 May 12. No abstract available.

  PMID: 25967578 DERIVED

Related Links

• Study website

Biospecimen

Retention: SAMPLES WITH DNA

Patients at baseline: 4 x 2.7 mL sodium citrate tube, aliquoted in 10 x 300 µL cryovials; 1 x 5 mL PPACK sodium citrate tube, aliquoted in 5 x 300 µL cryovials; 1 x 8 mL serum tube, aliquoted in 5 x 300 µL cryovials; 1 x 9 mL EDTA tube #1, aliquoted in 10 x 300 µL cryovials; 1 x 9 mL EDTA tube #2, full blood for DNA extraction. Patients at 3-month visit (fasting): 4 x 2.7 mL sodium citrate tube, aliquoted in 10 x 300 µL cryovials; 1 x 5 mL PPACK sodium citrate tube, aliquoted in 5 x 300 µL cryovials; 1 x 8 mL serum tube, aliquoted in 5 x 300 µL cryovials; 1 x 9 mL EDTA tube, aliquoted in 10 x 300 µL cryovials. Control subjects: 4 x 2.7 mL sodium citrate tube, aliquoted in 10 x 300 µL cryovials; 1 x 5 mL PPACK sodium citrate tube, aliquoted in 5 x 300 µL cryovials; 1 x 8 mL serum tube, aliquoted in 5 x 300 µL cryovials; 1 x 9 mL EDTA tube #1, aliquoted in 10 x 300 µL cryovials; 1 x 9 mL EDTA tube #2, full blood for DNA extraction.

MeSH Terms

Conditions

Brain Infarction; Ischemic Stroke; Thrombosis; Foramen Ovale, Patent; Myocardial Infarction; Intracranial Thrombosis; Pulmonary Embolism; Venous Thrombosis; Subarachnoid Hemorrhage

Condition Hierarchy (Ancestors)

Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Vascular Diseases; Cardiovascular Diseases; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Embolism and Thrombosis; Heart Septal Defects, Atrial; Heart Septal Defects; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Myocardial Ischemia; Intracranial Embolism and Thrombosis; Thromboembolism; Lung Diseases; Respiratory Tract Diseases; Embolism; Intracranial Hemorrhages; Hemorrhage

Study Officials

• Jukka Putaala, A/Prof.

  Helsinki University Central Hospital

  PRINCIPAL INVESTIGATOR

• Steven Kittner, Prof.

  University of Maryland Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Prof., MD, PhD, MSc

Study Record Dates

• First Submitted: August 29, 2013
• First Posted: September 4, 2013
• Study Start: November 1, 2013
• Primary Completion (Estimated): December 1, 2031
• Study Completion (Estimated): December 1, 2031
• Last Updated: May 16, 2025

Record last verified: 2025-05

Locations

PT (1); ES (1); LI (1); SE (1); IT (2); DE (1); GR (1); FI (5); NL (1); NO (1); GB (2); TU (1)