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

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2015 by SECRETO Study Consortium
Sponsor:
Collaborators:
Finnish Medical Foundation
Helsinki University Central Hospital
Academy of Finland
Information provided by (Responsible Party):
Jukka Putaala, SECRETO Study Consortium
ClinicalTrials.gov Identifier:
NCT01934725
First received: August 29, 2013
Last updated: December 4, 2015
Last verified: December 2015
  Purpose

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
Brain Infarction
Ischemic Stroke
Thrombosis
Foramen Ovale, Patent

Study Type: Observational
Study Design: 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)

Further study details as provided by SECRETO Study Consortium:

Primary Outcome Measures:
  • Nonfatal or fatal recurrent ischemic stroke [ Time Frame: 10 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Composite of noncerebrovascular arterial or venous thrombotic events, or cerebral venous thrombosis [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • Death from any cause [ Time Frame: 10 years ] [ Designated as safety issue: No ]
  • New-onset atrial fibrillation [ Time Frame: 10 years ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Modified Rankin Scale [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    Vocational status will be assessed at each follow-up contact with Poststroke Working Activity Questionnaire and a set of questions designed for the study.

  • Social outcome [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    Social status will be assessed at each follow-up contact with Oslo Social Support Scale and set of questions designed for the study.

  • Cognitive outcome [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Cognition will be assessed at mandatory 3-month follow-up visit (Montreal Cognitive Assessment).

  • Anxiety and depression [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Poststroke burden to caregiver will be assessed at 3-month visit with Expanded Caregiver Strain Index Questionnaire.

  • Barthel Index [ Time Frame: 10 years ] [ Designated as safety issue: No ]
    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.


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.


Estimated Enrollment: 4000
Study Start Date: November 2013
Estimated Study Completion Date: December 2026
Estimated Primary Completion Date: December 2026 (Final data collection date for primary outcome measure)
Groups/Cohorts
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

Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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
Criteria

PATIENTS:

Inclusion Criteria:

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

Exclusion Criteria:

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

    • Brain MRI
    • Routine blood tests, including complete blood count with differential, CRP, fasting glucose, creatinine, aPTT, INR, total cholesterol, LDL-cholesterol, HDL-cholesterol, HbA1C,hemoglobin electrophoresis in individuals of African origin
  2. Other baseline mandatory tests not obtained within the first two weeks following stroke onset, including:

    • Imaging of cervicocephalic arteries by CTA, MRA, or catheter angiography
    • Transesophageal (highly recommended) or transthoracic echocardiography
    • 24-hour Holter monitoring
    • 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
  3. No evidence of current brain ischemia
  4. Current stroke due to cerebral venous thrombosis or as a complication of subarachnoid hemorrhage, angiography, or cardiac surgery
  5. Patient otherwise not eligible for the study or adherent for follow-up (eg nonresident) or has concurrent disease affecting outcome (eg. multiple sclerosis, cancer)
  6. Informed consent not obtained from the patient or a proxy.

CONTROL SUBJECTS:

Inclusion Criteria:

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

Exclusion Criterion:

1. Informed consent not obtained

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01934725

Contacts
Contact: Jukka Putaala, MD, PhD, MSc +35894711 jukka.putaala@hus.fi
Contact: Turgut Tatlisumak, MD, PhD +35894711 turgut.tatlisumak@hus.fi

  Show 25 Study Locations
Sponsors and Collaborators
SECRETO Study Consortium
Finnish Medical Foundation
Helsinki University Central Hospital
Academy of Finland
Investigators
Principal Investigator: Jukka Putaala, MD, PhD, MSc Helsinki University Central Hospital
Principal Investigator: Sylvain Lanthier, MD, OD, CSPQ CHUM - Hôpital Notre-Dame
Principal Investigator: Steven Kittner, MD, MPH University of Maryland Hospital
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Jukka Putaala, Associate Prof., MD, PhD, MSc, SECRETO Study Consortium
ClinicalTrials.gov Identifier: NCT01934725     History of Changes
Other Study ID Numbers: SECRETO 
Study First Received: August 29, 2013
Last Updated: December 4, 2015
Health Authority: Finland: Ethics Committee
Individual Participant Data  
Plan to Share IPD: Undecided

Keywords provided by SECRETO Study Consortium:
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

Additional relevant MeSH terms:
Stroke
Infarction
Thrombosis
Brain Infarction
Foramen Ovale, Patent
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Ischemia
Pathologic Processes
Necrosis
Embolism and Thrombosis
Brain Ischemia
Heart Septal Defects, Atrial
Heart Septal Defects
Heart Defects, Congenital
Cardiovascular Abnormalities
Heart Diseases
Congenital Abnormalities

ClinicalTrials.gov processed this record on July 26, 2016