High Dose Steroids in Children With Stroke

Background: Arterial ischemic stroke (AIS) is a rare but devastating condition affecting 2-5/100,000 children/year. Children do not recover better than adults with 2/3 suffering long term neurological, cognitive and behavioural problems. The economic cost of stroke is substantial. Arteriopathy is identified as AIS aetiology in 60-80% of previously healthy children and is the strongest predictor of recurrent events. 30-40% of these children will have a focal cerebral arteriopathy (FCA). FCA in childhood is shown to be an inflammatory vessel wall pathology provoked by infections. This encourages treatment with steroids, despite lack of evidence.

Rationale: There is increasing evidence that etiologically inflammatory processes play a crucial role in childhood stroke, and influence outcome. Retrospective analyses suggest improved outcome and less recurrence with steroid treatment. With the exception of sickle cell disease, this study will be the first randomized clinical trial in children with arterial ischemic stroke. It will provide high-level evidence for the most appropriate treatment for children with AIS due to FCA. Alignment of interventions and outcome as well as pooled analysis with the planned Focal Cerebral Arteriopathy Steroid (FOCAS) study in North America will allow pooled analysis results.This is very important in view of the marked neurological, social and economic burden of childhood AIS for patients and families. This project has been identified as the most important AIS treatment trial by a Delphi survey of international paediatric stroke experts and is one of the most important research priorities identified by parents. In addition, the study will provide insights into the pathogenesis of inflammatory vasculopathies.The objective of this trial is to show that children with first stroke event due to unilateral FCA treated with a combination of high dose steroid and aspirin will have better and quicker recovery of arteriopathy, better clinical functional outcome, and less recurrence compared to children treated with aspirin alone.

The proposed study is a prospective multicentre, parallel group, two-arm, randomized controlled, open-label clinical trial with blinded outcome assessment, comparing a high dose course of methylprednisolone / prednisolone plus standard of care with standard of care alone in children with unilateral arteriopathy and acute ischemic stroke.

Measurements and procedures: Participants will be randomized within 48 hours after diagnosis (maximum 96 hours after stroke onset) to standard of care (SC) alone (control group) or SC plus steroids (experimental group). SC will be harmonized among the study centres to include aspirin treatment. Patients will be assessed at 1, 3, 6 and 12 months. Magnetic imaging and angiography (MRI/MRA) will be done at 1, (3) and 6 months.

Number of Participants: 70 participants in total, 35 per treatment arm

Study duration: 48 months

Study Centre(s): International multi-centre study with approximately 20 to 30 centres

Participating countries:Switzerland, Germany, France, Austria, Great Britain \& Australia

Centres in additional countries might be considered.

Statistical Considerations: The sample size is based on the comparison of the primary outcome - the change in FCASS from baseline to 1 month - between the two treatment groups. The standard deviation from 13 patients of a retrospective study was calculated. The standard deviation of the baseline and follow-up FCASS was 3.0 and 3.3, respectively. The standard deviation of the change in FCASS from baseline was 2.8. Based on the standard deviation of 2.8 and a two-sample means test, 64 patients (32 in each group) are required to detect a difference of 2.0 with a power of 80% at a two-sided alpha-level of 0.05. To account for dropouts (8%), we enlarge the sample size to 70 patients (35 in each group). The primary analysis will follow the intention-to-treat (ITT) principle, i.e. all patients will be analysed in the allocated group regardless of any protocol violations such as cross-overs. The primary outcome (change in FCASS from baseline to 1 month) as well as other secondary continuous score outcomes that are measured multiple times during follow-up (RRQ, mRS, Pediatric Stroke Outcome Measure (PSOM), VABS, modAspect) will be assessed in a repeated-measure, mixed-effects linear model.

Good Clinical Practice (GCP) Statement: This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH-GCP) as well as all national legal and regulatory requirements.

• Functional impairment outcome measured by Pediatric Stroke Outcome Measure (PSOM) [Time frame: 1, 3, 6 and 12 months]
• Recovery assessed by Recovery and Recurrence Questionnaire (RRQ) [Time frame: 1, 3, 6, and 12 months]
• Degree of disability or dependence by modified Rankin Scale (mRS) [Time frame: 1, 3, 6, and 12 months]
• Clinical outcome by Vineland adaptive behavior scale (VABS) [Time frame: 6 and 12 months]
• Change in FCASS (Focal Cerebral Arteriopathy Severity Score) from baseline [Time frame: 6 months]
• Volume of stroke [Time frame: baseline, 1, 3 (if imaging is available) and 6 months]
• Residual vasculopathy [Time frame: 6 months]
• Stroke recurrence after index stroke [Time frame: 1, 6 and 12 months]
• Stroke recurrence after index stroke in relation to the initial degree of vessel stenosis [Time frame: 6 and 12 months]
• Stroke Quality of Life Measure (PSQLM) [Time frame: 12 month]
• Preschool Wechsler Intelligence Scale for Children (WISC V) / Wechsler Preschool and Primary Scale of Intelligence (WIPPSI IV) [Time frame: 12 month]
• Delis-Kaplan Executive Function System (D-KEFS) [Time frame: 12 month]