Clinical trial NCT06040255: Focal Cerebral Arteriopathy Steroid Trial
Official title: Focal Cerebral Arteriopathy Steroid Trial
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE4
Conditions: Pediatric Stroke
Arteriopathy
Arterial Ischemic Stroke
Keywords: FCA
Focal cerebral arteriopathy
Pediatric stroke
Arterial ischemic stroke
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: University of Cincinnati
name: Medical University of South Carolina
name: M.D. Anderson Cancer Center
name: University of Colorado, Denver
name: University of Iowa
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: American Heart Association
First posted: 2023-09-15
Enrollment: 80
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.
3. Imaging inclusion criteria:

   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.
4. Imaging exclusion criteria:

   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.

Primary outcomes:
measure: Change in Focal Cerebral Arteriopathy Severity Score (FCASS)
timeFrame: Baseline to one month
Secondary outcomes:
measure: Focal Cerebral Arteriopathy Severity Score (FCASS) at 1 month (required)
timeFrame: Baseline to 1 month
measure: Focal Cerebral Arteriopathy Severity Score (FCASS) at 1 month at 12 months (when imaging is available)
timeFrame: Baseline to 12 months
measure: Relative infarct volume at 1 month (required)
timeFrame: 1 month after baseline
measure: Relative infarct volume at 12 months (when imaging is available)
timeFrame: 12 months after baseline
measure: Pediatric Stroke Outcome Measure (PSOM) at 6 months
timeFrame: 6 months after baseline
measure: Pediatric Stroke Outcome Measure (PSOM) at 12 months (when feasible)
timeFrame: 12 months after baseline
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
Study officials:
affiliation: University of California, San Francisco
name: Heather J Fullerton, MD, MAS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
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