| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Focal cerebral arteriopathy and childhood stroke
Focal cerebral arteriopathy (FCA) is an inflammatory vessel wall disease
provoked by infection. |
Accident vasculaire cérébral consécutif à une vasculopathie inflammatoire durant l'enfance.
La vasculopathie cérébrale est une maladie inflammatoire des parois vasculaires provoquée par une infection. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Childhood stroke and inflammatory blood vessel wall disease caused by infection. |
| maladie des vaisseaux sanguins après un accident relative aux vaisseaux sanguins cérébraux (AVC) chez l'enfant. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055221 |
| E.1.2 | Term | Ischemic stroke |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003209 |
| E.1.2 | Term | Arteriopathy |
| E.1.2 | System Organ Class | 100000004866 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The purpose of this study is to evaluate if additional early anti-inflammatory treatment may influence the course of arteriopathy and improve clinical outcome and may prevent stroke recurrence in children with stroke and unilateral focal arteriopathy.
The primary objective of this study is to determine if a high dose course of methylprednisolone/prednisolone in addition to standard of care including antithrombotic treatment results in better improvement of focal arteriopathy in children with acute ischemic stroke and focal arteriopathy compared to standard of care alone.
|
L'objectif de l'étude est d'évaluer si un traitement anti-inflammatoire précoce supplémentaire peut influencer l'évolution de l'artériopathie et améliorer l'issue clinique et éviter des récidives d'AVC chez les enfants avec AVC et une artériopathie unilatérale.
L'objectif primaire de cette étude est de déterminer si, chez les enfants avec un AVC ischémique aïgu et une artériopathie, une dose forte de méthylprednisolone/prednisolone en plus de la norme des soins comprenant un traitement antithrombotique aboutit à une meilleure amélioration de l'artériopathie que la norme des soins seul.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to determine if a high dose course of methylprednisolone/prednisolone in addition to standard of care including antithrombotic treatment:
• Improves functional clinical outcomes (measured by Recurrence and Recovery Questionnaire (RRQ), modified Rankin Scale (mRS), Paediatric Stroke Outcome measure (PSOM), and Vineland Adaptive Behaviour Scale (VABS))
The Recurrence and Recovery Questionnaire (RRQ) and the Paediatric Stroke Outcome measure (PSOM), although not identical, assess closely related aspects of recovery
• Improves neurocognitive outcome
• Reduces residual stenotic arteriopathy measured by FCASS (Focal Cerebral Arteriopathy Scaling System)
• Decreases the final infarct volume measured by the modASPECTS (modified paediatric ASPECTS, Alberta stroke program early CT score)
• Decreases recurrence risk of stroke |
Les objectifs secondaires sont de déterminer si une forte dose de méthylprednisolone/prednisolone en plus de la norme des soins comprenant un traitement antithrombotique:
•Améliore l'issue clinique fonctionnel (mesurée par "Recurrence and Recovery Questionnaire" (RRQ), "modified Rankin Scale" (mRS), "Paediatric Stroke Outcome measure" (PSOM), et "Vineland Adaptive Behaviour Scale" (VABS))
• Améliore l'issue neurocognitive
• Diminue l'artériopathie sténosées résiduelle mesurée par FCASS (Focal Cerebral Arteriopathy Scaling System).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion 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 CNS
5. Female participants age ≥ 13: Negative pregnancy test (blood)
|
Critères d'inclusion
1. Consentement éclairée par le représentant légale du participant de l'étude documenté par signature.
2. Age: > 6 mois & < 18 ans au moment de l'AVC
3. Randomisation possible dans les 48 h du diagnose et maximum 96 h après le début de l'AVC
4. Artériopathie unilatérale selon les critères suivantes:
• Nouvelle déficit neurologique
• Caractéristiques spécifiques de neuroimagerie (MRA) de soit
- sténose unilatérale, ou
- Irrégularités unilatéraux des vaisseaux au niveau du SNC
5. Participantes féminines âgées de ≥ 13: Test (sanguin) négatif de grosses
|
|
| E.4 | Principal exclusion criteria |
Exclusion criteria:
1. Previous stroke
2. Known syndromal disorders, as e.g. Trisomy 21, Neurofibromatosis type 1
3. Known genetic vasculopathies as e.g. PHACES syndrome, ACTA II
4. Moyamoya or sickle cell disease
5. Small vessel cerebral vasculitis (primary CNS vascularitis)
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:
a. pre-existing progressive neurocognitive dysfunction
b. bilateral MRI lesions/vessel involvement
c. 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
|
Critères d'exclusion:
1. Antécédant d’AVC
2. Troubles syndromiques connus, comme par ex. Trisomie 21, Neurofibromatose de type 1
3. Vasculopathies génétiques connues comme par ex. Syndrome PHACES, ACTA II
4. Moyamoya ou drépanocytose
5. Vascularite cérébrale des petits vaisseaux (vascularite primaire du SNC)
6. Artériopathie bilatérale
7. Dissection(s) artérielle(s)
8. Indices de troubles systémiques sous-jacents, comme par ex. lupus, problèmes rhumatoïdes
9. Angéite secondaire du SNC due à une infection (méningite, endocardite, borréliose) ou angéite généralisée due à des problèmes rhumatismaux ou d’autres problèmes auto-immuns
10. Grande à moyenne angéite infantile primaire progressive du SNC (cPACNS ) avec 2 des 3 critères suivants :
a. dysfonctionnement neurocognitif progressif antérieur
b. lésions IRM /atteinte vasculaire bilatérale(s)
c. sténose artérielle des petits vaisseaux
11. Sous traitement de stéroïdes au début de la maladie
12. Contre-indication au traitement par stéroïdes, par ex. une immunodéficience congénitale ou acquise
13. Incapacité à suivre les procédures de l'étude, par ex. en raison de problèmes linguistiques
14. Participation à une autre étude interventionnelle dans les 30 jours précédant l'AVC et au cours de l’étude |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome is
• change in FCA Severity Score (FCASS) from baseline to 1 month
|
Le résultat principal est
• le changement de FCASS (Focal Cerebral Arteriopathie Severity Score - Score de gravité pour artériopathie cérébrale) du point de départ à 1 mois |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary outcome is a change (of FCASS) and is hence measured at two timepoints
* baseline
* 1 month |
Le résultat principal est un changement (de FCASS). Il est donc mésuré à deux moments précis
* au point de départ
* à 1 mois |
|
| E.5.2 | Secondary end point(s) |
Secondary outcomes are
a) Functional impairment outcome measured by PSOM at 1, 3, 6 and 12 months.
The neurological outcome will be assessed using the PSOM (paediatric stroke outcome measure). The PSOM has been specifically developed and validated for paediatric stroke patients and addresses paediatric specific domains such as development, behaviour and cognition in addition to sensory-motor and language function.
b) Recovery assessed by RRQ (Recurrence and Recovery Questionnaire)) at 1, 3, 6, and 12 months.
The Paediatric Recurrence and Recovery Questionnaire (RRQ) was specifically developed and validated for paediatric stroke patients and addresses paediatric- specific problems of manifestation of stroke and also difficulties in reliable clinical examination.
c) Degree of disability or dependence by mRS (modified Rankin Scale) at 1, 3, 6, and 12 months.
d) Clinical outcome by Vineland adaptive behaviour scale (VABS) at 6 and 12 months.
The VABS is a well validated instrument to monitor cognitive and behaviour problems of children by interview. It is used widely in studies with children, as e.g. in a similar steroid treatment trial in infantile spasms.
e) For Children 2 -18 years, Quality of Life evaluation will be done at 12 month, using the Pediatric Stroke Quality of Life Measure (PSQLM)
f) Neurocognitive outcome measured at 12 months
• Intelligence: For Children between 2 -18 years intelligence will be assessed by Preschool Wechsler Intelligence Scale for Children (WISC V) / Wechsler Preschool and Primary Scale of Intelligence (WIPPSI IV, as age appropriate) (range=40-160, the higher the score the better the performance)
• Executive Function: Children > 8 years will undergo specific evaluation of executive function (EF). They will be assessed with the Delis-Kaplan Executive Function System (D-KEFS) Trail Making Test, Delis-Kaplan Executive Function System (D-KEFS) Color-Word-Interference Test (range=1-19, the higher the score the better the performance)
• Attention: Children > 8 years will undergo specific evaluation of attention. They will be assessed with the Continuous performance task (CPT-III). (range=20-80, the higher the score the better the performance)
g) Change in FCASS from baseline to 6 months.
Two neuroradiologists will independently score the FCASS; a panel of three neuroradiologists will adjudicate disagreements.
For participants with available imaging at 3 months, the change in FCASS form baseline to 3 months will additionally be evaluated.
h) Volume of stroke at baseline, 1, 3 (if imaging is available) and 6 months measured by modASPECTS in diffusion-weighted MRI (DWI) and fluid-attenuated inversion recovery (FLAIR) images.
ModASPECTS provides a semi quantitative measure of infarct volume in childhood stroke where each abnormal area is assigned one point. Higher scores represent greater volumes, with a maximum possible score of 30 (15 per hemisphere). ModASPECTS is shown to correlate with volume measurements of stroke area.
i) Residual vasculopathy at 6 months measured by FCASS
j) Stroke recurrence during the first 12 months after index stroke, assessed at 1, 6 and 12 months.
Stroke recurrence is defined as
(i) new focal neurological deficit(s)
(ii) worsening of the neurological deficits by > 4 pedNIHSS points lasting for more than 24 hours with new or increased diffusion restriction at the time of recurrence (with or without FLAIR/T2 lesions) in the corresponding vascular territory, or
(iii) new areas of clinically silent infarction, remote from the initial infarct (at 1 and 6 months).
The neurological deficit has to be verified by a child neurologist. The infarction on MRI will be assessed by two independent paediatric neuroradiologists and ultimately determines presence or absence of stroke. Stroke recurrence will be measured as proportion in each group.
k) Stroke recurrence at 6 and 12 months after index stroke in relation to the initial degree of vessel stenosis as measured by change in FCASS from baseline to follow-up. Stroke recurrence will be measured as proportion in each category of vessel stenosis. |
Les résultats secondaires les plus importants sont
a) Déficience fonctionnelle mesurée par PSOM (paediatric stroke outcome measure) à 1, 3, 6 et 12 mois.
b) Rétablissement évalué par RRQ (Recurrence and Recovery Questionnaire)) at à 1, 3, 6 et 12 mois.
c) Degré de déficience ou de dépendance estimé par mRS (modified Rankin Scale) à 1, 3, 6 et 12 mois.
d) Issue clinique par VABS (Vineland Adaptive Behaviour Scale) à 6 et 12 mois. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary outcomes are evluated at 1, 3, 6 and 12 months respectively, see E.5.2. |
| Les résultats principaux sont évalués à 1, 3, 6 et 12 mois. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| None. Investigational arm: Steroids and standard of care; Control arm: Standard of care |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| France |
| Switzerland |
| Germany |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The study end is defined as the moment of database lock, after the last participant had the last visit (LPLV).
During the period of data cleaning and completeness checks performed in the clinical database after LPLV, there is a chance that the site has to contact a participant to clarify an issue or collect missing information. |
Le moment de fermeture de la base de données est défini comme la fin de l'essaie.
Pendant la période de vérification des données et de leur intégralité qui suit le "dernier patient, dernière visite", il se peut que les sites doivent encore contacter des participants pour des clarifications ou pour collecter des informations manquantes. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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