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

Status:	Recruiting
Conditions:	Peripheral Vascular Disease, Cardiology, Neurology
Therapuetic Areas:	Cardiology / Vascular Diseases, Neurology
Healthy:	No
Age Range:	18 - 49
Updated:	4/21/2016
Start Date:	November 2013
End Date:	December 2026
Contact:	Jukka Putaala, MD, PhD, MSc
Email:	jukka.putaala@hus.fi
Phone:	+35894711

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

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.

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

We found this trial at

sites

Massachusetts General Hospital

185 Cambridge Street
Boston, Massachusetts 02114

617-724-5200