Clinical trial NCT04873583: High Dose Steroids in Children With Stroke
Official title: High Dose Steroids in Children With Stroke and Unilateral Focal Arteriopathy: A Multicentre Randomized Controlled Trial PASTA (Paediatric Arteriopathy Steroid Aspirin) Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Paediatric Stroke
Keywords: Ischemic
Stroke
Pediatric
Steroids
Unilateral
Focal
Arteriopathy
Neurology
Cerebral
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: University of Bern
First posted: 2021-05-05
Enrollment: 70
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multi-center, randomized, controlled, non-blinded trial
Primary purpose: TREATMENT

Brief summary: This clinical trial deals with focal cerebral arteriopathy and childhood stroke, a rare but devastating condition.

Focal cerebral arteriopathy (FCA) is an inflammatory vessel wall disease provoked by infection and there is increasing evidence that inflammatory processes play a crucial role in childhood stroke, influencing the outcome of the disease.

Analysis of existing data suggests that outcomes are improved and that there is less stroke recurrence in children treated with steroids to reduce the acute inflammatory processes. This clinical trial will be conducted in over 20 hospitals in several countries in order to investigate this.

Participants will be randomly separated into two groups. The first group will be treated with standard of care (including aspirin) combined with high dose steroids. The second group will be treated with standard of care (including aspirin) but without steroid treatment.

The objective is to investigate if children treated with a combination of high dose steroid and aspirin will have a better and quicker recovery of FCA, better clinical functional outcome, and less recurrence compared to children treated with aspirin alone.

This project has been identified by international pediatric stroke experts as the most important topic for a clinical trial in the field and is as well one of the most important research priorities identified by parents. The study results will also provide insight into the evolution of inflammatory vessel disease.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent of the legal representative of the trial participant documented by signature
2. Age \> 6 months \& \< 18 years at time of stroke
3. Randomisation possible within 48 hours of diagnosis and maximum 96 hours after stroke onset
4. Unilateral arteriopathy according to the following criteria:

   * Newly acquired neurologic deficits
   * Specific neuroimaging (MRA) features of either

     * unilateral stenosis, or
     * unilateral vessel irregularities within the Central Nervous System (CNS)
5. Unless otherwise defined in the national addendum: Female participants age ≥ 13: Negative pregnancy test (blood or urine)

Exclusion Criteria:

1. Previous stroke
2. Known syndromal disorders, as e.g. Trisomy 21, Neurofibromatosis type 1
3. Known genetic vasculopathies as e.g. posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies and eye anomalies syndrome (PHACES), actin alpha 2 (ACTA II)
4. Moyamoya or sickle cell disease
5. Small vessel cerebral vasculitis (primary CNS vasculitis)
6. Bilateral arteriopathy
7. Arterial dissection(s)
8. Evidence of underlying systemic disorders, as e.g. lupus, rheumatoid problems
9. Secondary CNS angiitis due to infections (meningitis, endocarditis, borreliosis), or generalised angiitis due to rheumatic or other autoimmune problems
10. Progressive large to medium childhood primary angiitis of the CNS (cPACNS ) with 2 of the following 3 criteria:

    1. pre-existing progressive neurocognitive dysfunction
    2. bilateral MRI lesions/vessel involvement
    3. small vessel arterial stenosis
11. On steroid treatment at disease onset
12. Contraindication to steroid treatment as e.g. a congenital or acquired immunodeficiency
13. Inability to follow the procedures of the study, e.g. due to language problems
14. Participation in another interventional study within the 30 days preceding the indication stroke and during the present study

Primary outcomes:
measure: Change in Focal Cerebral Arteriopathy Severity Score (FCASS) from baseline
timeFrame: 1 month (30 days)
Secondary outcomes:
measure: Functional impairment outcome measured by Pediatric Stroke Outcome Measure (PSOM)
timeFrame: 1, 3, 6 and 12 months
measure: Recovery assessed by Recovery and Recurrence Questionnaire (RRQ)
timeFrame: 1, 3, 6, and 12 months
measure: Degree of disability or dependence by modified Rankin Scale (mRS)
timeFrame: 1, 3, 6, and 12 months
measure: Clinical outcome by Vineland adaptive behavior scale (VABS)
timeFrame: 6 and 12 months
measure: Change in FCASS (Focal Cerebral Arteriopathy Severity Score) from baseline
timeFrame: 6 months
measure: Volume of stroke
timeFrame: baseline, 1, 3 (if imaging is available) and 6 months
measure: Residual vasculopathy
timeFrame: 6 months
measure: Stroke recurrence after index stroke
timeFrame: 1, 6 and 12 months
measure: Stroke recurrence after index stroke in relation to the initial degree of vessel stenosis
timeFrame: 6 and 12 months
measure: Stroke Quality of Life Measure (PSQLM)
timeFrame: 12 month
measure: Preschool Wechsler Intelligence Scale for Children (WISC V) / Wechsler Preschool and Primary Scale of Intelligence (WIPPSI IV)
timeFrame: 12 month
measure: Delis-Kaplan Executive Function System (D-KEFS)
timeFrame: 12 month
measure: Continuous performance task (CPT-III)
timeFrame: 12 month
Other outcomes:
Locations:
city: Randwick
country: Australia
facility: Sydney Childrens Hospital Randwick
state: New South Wales
city: Westmead
country: Australia
facility: Sydney Childrens Hospital Network
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Childrens Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Melbourne Childrens Hospital
state: Victoria
city: Wien
country: Austria
facility: Universitätsklinik für Kinder und Jugendheilkunde Wien
city: Marseille
country: France
facility: L'ASSISTANCE PUBLIQUE-HOPITAUX DE MARSEILLE (AP-HM) - Hôpital de la Timone
state: Aix-en-Provence
city: Strasbourg
country: France
facility: Pediatric Neurology Strasbourg - Hautepierre University Hospital
state: Alsace
city: Bron
country: France
facility: Hôpital Femme Mère Enfant Lyon
state: Auvergne-Rhône-Alpes
city: Le Kremlin-Bicêtre
country: France
facility: Hôpitaux Universitaires Paris Sud
state: Ile De France
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
state: Ile De France
city: Lille
country: France
facility: Hôpital Roger Salengro, CHRU de Lille
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg Zentrum für Kinder- und Jugendmedizin Klinik für Neuropädiatrie und Muskelerkrankungen
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen Neuropädiatrie, Allgemeinpädiatrie, Endokrinologie, Diabetologie, Sozialpädiatrie
state: Baden-Wüttemberg
city: München
country: Germany
facility: LMU Klinikum
state: Bayern
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
state: Nordrhein-Westfahlen
city: Münster
country: Germany
facility: Universitäts Kinderklinik Münster
state: Nordrhein-Westfahlen
city: Berlin
country: Germany
facility: Charité-Universitätsmedizin Berlin
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden, Departement Kinder- und Jugendmedizin
state: Graubünden
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale di Bellinzona e Valli
state: Ticino
city: Sion
country: Switzerland
facility: Hôpital du Valais
state: Valais
city: Lausanne
country: Switzerland
facility: Centre Hôpitalier Universitaire Vaud (CHUV), Unité de Neurologie
state: Vaud
city: Basel
country: Switzerland
facility: Universitätskinderklinik beider Basel
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Geneva
country: Switzerland
facility: Hôpitale Universitaire de Genève, Neuropediatrie, Hôpital des Enfants
city: Luzern
country: Switzerland
facility: Luzerner Kantonsspital, Kinderspital, Neuropädiatrie
city: Saint Gallen
country: Switzerland
facility: Stiftung ostschweizerisches Kinderspital
city: Zürich
country: Switzerland
facility: Kidnerspital Zürich
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital - Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
state: Hampshire
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: Lancashire
city: Newcastle
country: United Kingdom
facility: Royal Victoria Infirmary
state: Tyne And Wear
city: Bristol
country: United Kingdom
facility: University Hospital Bristol
Study officials:
affiliation: Bern university hospital, Inselspital Bern, Kinderklinik
name: Maja Steinlin, Dr. med.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.