High Dose Steroids in Children with Stroke and Unilateral Focal Arteriopathy: A Multicentre Randomized Controlled Trial

The primary objective of this study is to assess whether a high-dose course of **methylprednisolone**/**prednisolone**, in addition to standard care including antithrombotic treatment, leads to improved outcomes in children with acute ischemic stroke and unilateral focal arteriopathy. This is clinically relevant as it may enhance the management of focal cerebral arteriopathy, potentially reducing the risk of stroke recurrence and improving overall clinical outcomes in pediatric patients.

Secondary objectives include determining if the high-dose steroid regimen:

• Improves functional clinical outcomes, as measured by the Recurrence and Recovery Questionnaire (RRQ), modified Rankin Scale (mRS), Paediatric Stroke Outcome Measure (PSOM), and Vineland Adaptive Behaviour Scale (VABS).
• Enhances neurocognitive outcomes.
• Reduces residual stenotic arteriopathy, assessed by the Focal Cerebral Arteriopathy Scaling System (FCASS).
• Decreases the final infarct volume, measured by the modified paediatric ASPECTS (modASPECTS).
• Decreases the recurrence risk of stroke.

The clinical trial involves a total of **35 participants** diagnosed with **focal cerebral arteriopathy** and childhood stroke. The study population includes both male and female subjects, aged between **6 months and 18 years** at the time of stroke. Participants were selected based on their ability to be randomized within 48 hours of diagnosis and a maximum of 96 hours after stroke onset. The trial specifically targets children with unilateral arteriopathy, characterized by newly acquired neurologic deficits and specific neuroimaging features such as unilateral stenosis or vessel irregularities within the central nervous system. The study population is considered vulnerable, given the age range and medical condition. Lifestyle considerations such as diet and physical activity are not specified in the available data. Key inclusion criteria include informed consent from the legal representative and, for female participants aged 13 and above, a negative pregnancy test. The trial aims to assess the impact of early anti-inflammatory treatment on the course of arteriopathy and the prevention of stroke recurrence.

The clinical trial is designed to evaluate the efficacy of high-dose **methylprednisolone**/**prednisolone** in children with acute ischemic stroke and unilateral focal cerebral arteriopathy (FCA). This study is a multicenter, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial aims to determine if the addition of early anti-inflammatory treatment can improve the clinical outcome and prevent stroke recurrence compared to standard care alone. The trial is expected to run from May 2022 to July 2026, with participant involvement lasting up to 12 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (6 months to 18 years), the ability to randomize within 48 hours of diagnosis, and specific neuroimaging features. Following the screening, participants will be randomized to receive either the investigational treatment or standard care. The primary endpoint is the change in FCA Severity Score (FCASS) from baseline to one month. Secondary endpoints include neurological deficits over time, neurocognitive outcomes, recurrence-free survival, and changes in FCASS at three and six months.

Study visits will include follow-up assessments at one, three, six, and 12 months to monitor the primary and secondary endpoints. The end-of-study visit will occur at 12 months, marking the conclusion of participant involvement. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The trial will utilize both oral and intravenous administration routes for the investigational products, with a maximum treatment period of three to four weeks, depending on the specific product used.

The clinical trial involves the administration of several **experimental medications**. One of the primary medications is **Prednisolone**, available in various dosages including 1 mg, 5 mg, 10 mg, 20 mg, and 50 mg, all in tablet form. The tablets are administered orally with a maximum daily dose of 40 mg and a total maximum dose of 840 mg over a treatment period of up to 4 weeks. Prednisolone is a glucocorticoid used for its anti-inflammatory properties, and it is provided by MIBE GMBH ARZNEIMITTEL and MERCK GESELLSCHAFT MBH.

Another key medication used in the trial is **Methylprednisolone**, which is administered in the form of a solution for injection or infusion. The available dosages include 16 mg, 32 mg, 250 mg, 500 mg, and 1000 mg. The route of administration is intravenous, with a maximum daily dose of 1000 mg and a total maximum dose of 3000 mg over a treatment period of up to 3 days. Methylprednisolone is provided by MIBE GMBH ARZNEIMITTEL and PFIZER CORPORATION AUSTRIA GES.M.B.H. This medication is also a glucocorticoid, used for its potent anti-inflammatory effects.

Additionally, the trial includes the use of **Methylprednisolone Sodium Succinate** and **Methylprednisolone Hydrogen Succinate**, both administered intravenously as a solution for injection or infusion. These formulations are used in similar dosing regimens as Methylprednisolone, with a focus on rapid anti-inflammatory action in acute settings.

**Prednisolone Metasulfobenzoate Sodium** is administered as an effervescent tablet, with the same dosing schedule as other prednisolone formulations. This form is provided by CHEPLAPHARM ARZNEIMITTEL GMBH and is designed for ease of administration and rapid absorption.

In addition to the experimental medications, the trial includes a **comparator treatment** involving **Betamethasone Sodium Phosphate**, administered orally. This medication serves as a standard-of-care therapy, with a maximum daily dose of 40 mg and a total maximum dose of 840 mg over a 4-week period. The inclusion of this comparator allows for the evaluation of the experimental treatments against established therapeutic options.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed regimens. The trial aims to assess the efficacy of high-dose glucocorticoids in improving clinical outcomes in children with acute ischemic stroke and unilateral focal arteriopathy.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the change in **FCA Severity Score (FCASS)** from baseline to 1 month. This score will be used to evaluate the improvement in focal arteriopathy in children with acute ischemic stroke and unilateral focal arteriopathy. Secondary endpoints include the assessment of neurological deficits over time, which will be measured using the Pediatric Stroke Outcome Measure (PSOM), the Recovery and Recurrence Questionnaire (RRQ), the modified Rankin Scale (mRS), and the Vineland Adaptive Behaviour Scale (VABS) at 6 and 12 months. Additionally, neurocognitive outcomes will be evaluated at 12 months, along with recurrence-free survival, changes in FCASS at 3 and 6 months, and residual vasculopathy at 6 months.

The efficacy parameters will be collected and analyzed at specified timepoints, including baseline, 1 month, 3 months, 6 months, and 12 months. The use of validated scales and tools such as PSOM, RRQ, mRS, and VABS ensures the reliability and accuracy of the assessments. These measures will provide comprehensive data on the clinical outcomes and the potential benefits of high-dose **methylprednisolone/prednisolone** treatment in addition to standard care. The analysis will focus on determining whether the additional anti-inflammatory treatment results in better clinical outcomes compared to standard care alone.