Focal Cerebral Arteriopathy Steroid Trial

NCT ID: NCT06040255

Last Updated: 2024-08-21

Basic Information

• Recruitment Status: ENROLLING_BY_INVITATION
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-01
• Study Completion Date: 2030-01-31

Brief Summary

This comparative effectiveness trial (CET) in children with suspected focal cerebral arteriopathy (FCA) presenting with arterial ischemic stroke (AIS) or transient ischemic attack (TIA) will compare the use of early corticosteroid treatment (Arm A) versus delayed/no corticosteroid treatment (Arm B). Delayed corticosteroid treatment is given only for those demonstrating disease progression and is initiated as soon as the progression is detected (at any time after randomization). All participants will also receive standard of care therapy (aspirin and supportive care). Sites will randomize participants 1:1 to Arm A or B. Participants will be enrolled and randomized as soon as possible after their stroke/TIA up until 96 hours following the initial stroke/TIA event.

Detailed Description

FCA is an acute, monophasic, presumed inflammatory disease that causes unilateral stenosis of the intracranial anterior circulation. In the medical literature, it has also been called transient cerebral arteriopathy (TCA) and post-varicella arteriopathy when it occurs after chicken pox. Although rare (1 to 3 cases seen per year at a typical academic children's hospital in the US), it is one of the most common causes of arterial ischemic stroke in a previously healthy child. Pediatric stroke investigators identified an FCA treatment trial as the #1 priority of the field (Steinlin M, Dev Med Child Neurol 2017) because of its aggressive natural history: it often progresses dramatically over days to weeks with recurrent or expanding infarcts. A 2017 European retrospective cohort study suggested that corticosteroid treatment may improve outcomes for FCA (Steinlin M, Stroke 2017).

Europeans have begun the PASTA (Paediatric Arteriopathy STeroid Aspirin) trial (PI Steinlin): a "gold-standard" RCT to test the efficacy of corticosteroids for FCA. A 2018 survey of pediatric stroke investigators (participating in the NIH-funded Vascular effects of Infection in Pediatric Stroke, VIPS II, cohort study) revealed discomfort with randomization to "no steroids" as the majority now treat FCA with corticosteroids. However, despite attitudes favoring their use, corticosteroids were given to only 36% of 55 children with suspected FCA in the VIPS II cohort and (when given) were started a median of 3 days post-stroke (IQR 1.5, 6) (unpublished preliminary data). This incongruity reflects diagnostic uncertainty at stroke baseline: the characteristic arteriopathy evolution is needed for definitive diagnosis of FCA, and ≈1 in 5 children with suspected FCA at baseline have an alternate diagnosis. Hence, the pressing clinical question is: Should we treat all children with suspected FCA immediately or wait and treat only the subset that demonstrate disease progression?

Early treatment has the potential advantage of preventing FCA progression, but the disadvantage of over treatment of those with alternate diagnoses. With a comparative effectiveness approach, the FOCAS trial will compare these two treatment approaches. FOCAS will also collect the steroid treatment safety data needed to guide clinical decisions.

Conditions

Pediatric Stroke; Arteriopathy; Arterial Ischemic Stroke

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Arm A

Treat all children with suspected FCA with corticosteroids as soon as the diagnosis is made.

Group Type: ACTIVE_COMPARATOR

methylprednisolone, prednisolone, prednisone

Intervention Type: DRUG

Any generic or brand-name methylprednisolone at the appropriate dose may be used. Likewise, any generic or brand-name prednisolone, or prednisone, at the appropriate dose may be used.

Arm B

Treat only the subset of children that develop evidence of FCA disease progression.

Group Type: ACTIVE_COMPARATOR

methylprednisolone, prednisolone, prednisone

Intervention Type: DRUG

Any generic or brand-name methylprednisolone at the appropriate dose may be used. Likewise, any generic or brand-name prednisolone, or prednisone, at the appropriate dose may be used.

Interventions

methylprednisolone, prednisolone, prednisone

Any generic or brand-name methylprednisolone at the appropriate dose may be used. Likewise, any generic or brand-name prednisolone, or prednisone, at the appropriate dose may be used.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Age 1 year through 18 years at stroke/TIA ictus (ineligible as of 19th birthday).

2. Acute arterial ischemic stroke (AIS) or transient ischemic attack (TIA) in prior 4 days (96 hours).

1. AIS definition: neurological deficit with acute onset (including seizures) and acute infarct(s) corresponding to arterial territory(ies) on brain imaging.

2. TIA definition: neurological deficit with acute onset (not including seizures) consistent with ischemia of an arterial territory(ies) but without acute infarction on brain imaging.

a. Baseline imaging findings consistent with FCA: i. unilateral focal irregularity, banding, stenosis, wall thickening/enhancement, or occlusion of the distal internal carotid artery (ICA) and/or its proximal branches (A1, M1, posterior communicating artery, proximal PCA), OR ii. unilateral infarction in the territory of the lenticulostriate arteries with normal MRA.

b. Ability to return at 1-month (±7 days) post-stroke for an MRI/MRA (non-contrast) on a scanner of the same magnet strength as baseline MRI/MRA.*

4. Consent to study procedures.

• A repeat baseline MRI/MRA can be performed as a research scan within 24 hours of enrollment if needed to meet this requirement.

Exclusion Criteria

1. Prior stroke.

2. Another identified cause of stroke/TIA, other than FCA. (Intracranial dissection is considered a subtype of FCA and will be included if the patient is not predisposed to dissection for the reasons listed below.)

3. Presence of childhood stroke risk factors (known to be present at the time of enrollment):

1. Risk factors for arterial dissection: connective tissue disorder (e.g., Ehlers-Danlos type IV, Marfan syndrome, osteogenesis imperfect); severe head or neck trauma in the two weeks preceding AIS/TIA (defined as skull or cervical fracture, or an ICU admission for trauma).

2. Risk factors for moyamoya: genetic disorder or syndrome that predisposes to moyamoya (e.g., trisomy 21, neurofibromatosis type 1, tuberous sclerosis, sickle cell anemia, MOPD type II, PHACE syndrome); prior cranial radiation therapy.

3. Risk factors for secondary vasculitis or vasospasm: acute meningitis, systemic lupus erythematosus or other autoimmune disorder that can cause vasculitis, recent cocaine/amphetamine use (prior 7 days), recent subarachnoid hemorrhage (prior 14 days).

4. Risk factors for cardioembolism: complex congenital heart disease; recent cardiac surgery or catheterization (prior week); endocarditis or other cardiac valve disease with vegetations; right-to-left cardiac shunting lesion with deep vein thrombosis (DVT) or a known thrombophilia.

1. Baseline parenchymal imaging demonstrating remote or bilateral infarcts

2. Vascular imaging demonstrating bilateral arteriopathy or moyamoya collaterals

5. Contraindication to corticosteroid therapy (e.g., baseline immunosuppression, significant infection, etc.) as determined by the treating physicians.

6. Current or recent (within prior week) treatment with corticosteroids.

7. Pregnant, post-partum (within 6 months of childbirth), or nursing.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Cincinnati

OTHER

Sponsor Role: collaborator

Medical University of South Carolina

OTHER

Sponsor Role: collaborator

M.D. Anderson Cancer Center

OTHER

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: collaborator

University of Iowa

OTHER

Sponsor Role: collaborator

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

American Heart Association

OTHER

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Heather J Fullerton, MD, MAS

Role: PRINCIPAL_INVESTIGATOR

University of California, San Francisco

Locations

University of California San Francisco

San Francisco, California, United States

Countries

United States

References

Wintermark M, Hills NK, DeVeber GA, Barkovich AJ, Bernard TJ, Friedman NR, Mackay MT, Kirton A, Zhu G, Leiva-Salinas C, Hou Q, Fullerton HJ; VIPS Investigators. Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study. AJNR Am J Neuroradiol. 2017 Nov;38(11):2172-2179. doi: 10.3174/ajnr.A5376. Epub 2017 Oct 5.

Reference Type: BACKGROUND

PMID: 28982784 (View on PubMed)

Fullerton HJ, Stence N, Hills NK, Jiang B, Amlie-Lefond C, Bernard TJ, Friedman NR, Ichord R, Mackay MT, Rafay MF, Chabrier S, Steinlin M, Elkind MSV, deVeber GA, Wintermark M; VIPS Investigators. Focal Cerebral Arteriopathy of Childhood: Novel Severity Score and Natural History. Stroke. 2018 Nov;49(11):2590-2596. doi: 10.1161/STROKEAHA.118.021556.

Reference Type: BACKGROUND

PMID: 30355212 (View on PubMed)

Elkind MS, Hills NK, Glaser CA, Lo WD, Amlie-Lefond C, Dlamini N, Kneen R, Hod EA, Wintermark M, deVeber GA, Fullerton HJ; VIPS Investigators*. Herpesvirus Infections and Childhood Arterial Ischemic Stroke: Results of the VIPS Study. Circulation. 2016 Feb 23;133(8):732-41. doi: 10.1161/CIRCULATIONAHA.115.018595. Epub 2016 Jan 26.

Reference Type: BACKGROUND

PMID: 26813104 (View on PubMed)

Steinlin M, Bigi S, Stojanovski B, Gajera J, Regenyi M, El-Koussy M, Mackay MT; Swiss NeuroPediatric Stroke Registry. Focal Cerebral Arteriopathy: Do Steroids Improve Outcome? Stroke. 2017 Sep;48(9):2375-2382. doi: 10.1161/STROKEAHA.117.016818. Epub 2017 Jul 21.

Reference Type: BACKGROUND

PMID: 28733481 (View on PubMed)

Steinlin M, O'callaghan F, Mackay MT. Planning interventional trials in childhood arterial ischaemic stroke using a Delphi consensus process. Dev Med Child Neurol. 2017 Jul;59(7):713-718. doi: 10.1111/dmcn.13393. Epub 2017 Jan 25.

Reference Type: BACKGROUND

PMID: 28121022 (View on PubMed)

Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, deVeber GA; VIPS Investigators. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology. 2015 Oct 27;85(17):1459-66. doi: 10.1212/WNL.0000000000002065. Epub 2015 Sep 30.

Reference Type: BACKGROUND

PMID: 26423434 (View on PubMed)

Lanthier S, Armstrong D, Domi T, deVeber G. Post-varicella arteriopathy of childhood: natural history of vascular stenosis. Neurology. 2005 Feb 22;64(4):660-3. doi: 10.1212/01.WNL.0000151851.66154.27.

Reference Type: BACKGROUND

PMID: 15728288 (View on PubMed)

Chabrier S, Rodesch G, Lasjaunias P, Tardieu M, Landrieu P, Sebire G. Transient cerebral arteriopathy: a disorder recognized by serial angiograms in children with stroke. J Child Neurol. 1998 Jan;13(1):27-32. doi: 10.1177/088307389801300105.

Reference Type: BACKGROUND

PMID: 9477245 (View on PubMed)

Braun KP, Bulder MM, Chabrier S, Kirkham FJ, Uiterwaal CS, Tardieu M, Sebire G. The course and outcome of unilateral intracranial arteriopathy in 79 children with ischaemic stroke. Brain. 2009 Feb;132(Pt 2):544-57. doi: 10.1093/brain/awn313. Epub 2008 Nov 27.

Reference Type: BACKGROUND

PMID: 19039009 (View on PubMed)

Slavova N, Fullerton HJ, Hills NK, Breiding PS, Mackay MT, Steinlin M. Validation of the focal cerebral arteriopathy severity score (FCASS) in a Swiss cohort: Correlation with infarct volume and outcome. Eur J Paediatr Neurol. 2020 Sep;28:58-63. doi: 10.1016/j.ejpn.2020.07.015. Epub 2020 Aug 4.

Reference Type: BACKGROUND

PMID: 32826156 (View on PubMed)

Lo WD, Ichord RN, Dowling MM, Rafay M, Templeton J, Halperin A, Smith SE, Licht DJ, Moharir M, Askalan R, Deveber G; International Pediatric Stroke Study (IPSS) Investigators. The Pediatric Stroke Recurrence and Recovery Questionnaire: validation in a prospective cohort. Neurology. 2012 Aug 28;79(9):864-70. doi: 10.1212/WNL.0b013e318266fc9a. Epub 2012 Aug 15.

Reference Type: BACKGROUND

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Schechter T, Kirton A, Laughlin S, Pontigon AM, Finkelstein Y, MacGregor D, Chan A, deVeber G, Brandao LR. Safety of anticoagulants in children with arterial ischemic stroke. Blood. 2012 Jan 26;119(4):949-56. doi: 10.1182/blood-2011-06-361535. Epub 2011 Dec 7.

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Reference Type: DERIVED

PMID: 40351190 (View on PubMed)

Other Identifiers

UH3NS119702

Identifier Type: NIH

Identifier Source: org_study_id

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4UH3NS119702-02

Identifier Type: NIH

Identifier Source: secondary_id

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