Clinical trial NCT05835674: CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial
Official title: Multi-center Prospective Cohort Study CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cerebral Palsy
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Aarhus University Hospital
name: Aalborg University Hospital
name: Herlev Hospital
First posted: 2023-04-28
Enrollment: 500
Sex: ALL
Minimum age (years): 3
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Infants below 12 months of age with risk of cerebral palsy.

Brief summary: Background. Early diagnosis of cerebral palsy is important as intervention becomes possible at a time where neuroplasticity is at the highest. Current mean age at diagnosis is 13 months in Denmark. Recent research has documented that implementation of an early-diagnosis set-up can lower diagnostic age of cerebral palsy. The aim of the current study is to show that the response to the early intervention program added to standard care is superior to standard care alone in a Danish multi-site setting in children from both a newborn and infant detectable risk pathway.

Methods The current study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included (Goal Oriented ParentaL supported home ActivitY program), aims at testing feasibility of an early diagnosis and intervention set-up in four paediatric centers. In a prospective cohort study design, we will consecutively include a total of 500 infants. We will systematically collect data at inclusion and follow a subset of participants with definite cerebral palsy or high risk of cerebral palsy until they are two years of age. The focus is on eight areas related to implementation and the perspective of the families: Early MRI; early genetic testing; implementation of the General Movements Assessment method; early prediction of cerebral palsy; comparative analysis of the Hand Assessment for Infants method and evaluation by Hammersmith Infant Neurological Examination, MRI, and the General Movements method; analysis of the GO-PLAY early intervention; parental perspective of early intervention; and parental perspective of having an early diagnosis.

Discussion Early screening for CP is increasingly possible and an interim diagnosis of "high risk of CP" is recommended but not currently used in our clinical care. There is a need to accelerate identification in mild or ambiguous cases to facilitate appropriate therapy early. The majority of studies on early diagnosis focus on identifying CP in infants below five months corrected age. Little is known about early diagnosis in the 50% of all CP cases that are discernible later in infancy, which is also addressed in this study. The study aims at improving care of patients with cerebral palsy even before they have the diagnosis established.

Detailed description: Cerebral palsy (CP) is the most common cause of lifelong motor impairment in children and is defined by the Surveillance of Cerebral Palsy in Europe (SCPE) as "a group of permanent but not unchanging disorders of movement and/or posture and of motor function, which are due to a non-progressive interference, lesion, or abnormality of the developing/immature brain". An early diagnosis is important in order to start relevant intervention, when neuroplasticity is highest. Research suggests that early intervention programs have a positive influence on cognitive and motor outcomes and is a parental request.

In 2004, the Danish Cerebral Palsy Follow-up Program (CPOP) was introduced, with the aim of establishing a standardized follow-up program. The CPOP guarantees that children with CP are followed annually and aims to document, monitor, and improve the quality of health care for children with CP in Denmark. A previous Danish nationwide study from birth years 1995-2003 found that the median corrected diagnostic age of Danish children with CP was 11 months based on first mention in the patient journal. In an novel analysis we have found that for children with CP in birth years 2010-2013 the diagnostic age was 13 months based on first registered diagnosis. The best predictive tools for early diagnosis of CP has been found to be the Prechtl Qualitative Assessment of General Movements (GMA), Hammersmith Infant Neurological Examination (HINE) and cerebral MRI. These tools can be used to diagnose CP before the corrected age of five months. The method Hand Assessment for Infants (HAI) has in recent publications been found promising to complement these tests, but little evidence on HAI has been published. Feasibility of an early-diagnosis set-up of a systematic approach with neurological assessment, GMA/HINE and neuroimaging has been evaluated in several studies, but not yet in Denmark and not in a setting where both the newborn- and infant-detectable risk pathways were included. Neonates may have obvious risk factors at birth/in the neonatal period, but in the present study infants with findings suggesting CP emerging in the first year of life are also included.

For more than 80% of children with CP neuroimaging performed with MRI is abnormal. It has been recommended for many years to use MRI while diagnosing CP. A review from 2007 showed that 86% of the MRIs performed on children with CP were abnormal and for the majority gave clues to the pathogenesis of CP. In a previous Australian study of children with CP specific MRI patterns varied depending on parity, gestational age, level of neonatal care, Apgar score and time to established respiration. Diagnostic MRI of newborns and infants with suspected brain damage are today based on structural images with the focus on identifying major structural brain pathology, such as periventricular leukomalacia or white matter damage. However, advanced research MRI-sequences can be sensitive to detect brain damage and may provide important biological information about myelination, microstructure, and connectivity of the white matter fibre tracts, as well as the metabolic profile, including markers of neuronal integrity and glial markers, of the brain tissue. MRI will be offered earlier than regular clinical practice for participants in this research project and for a subset of patients repeat MRI will be possible.

Many gene variants may play a role in the development of CP. Previous research with genetic testing has shown that genetic aetiology, while often seen in children with no previous gestational or neonatal risk factor, is not limited to this group nor those with other neurodevelopmental comorbidities such as epilepsy or intellectual disability. One study has suggested an association between CP and genes that hinder early brain development and also predispose to susceptibility to environmental risk factors. The cause for the various CP types, including the most prevalent spastic subtype and the rare ataxic or dyskinetic CP, are different. In some cases, the cause is obvious, such as asphyxia during labour, cerebral bleeding, or infection, but in many cases the cause is unknown. However, in an increasing number of patients it is now possible to identify the underlying cause, since it has become clear that several treatable metabolic and genetic diseases such as dopa-responsive dystonia may be misdiagnosed as CP. Identifying the cause makes it possible to provide genetic counselling and direct specific treatment, e.g., with nutrient-specific diets or medications, which can interrupt disease progression and hinder further injury. In the current study extensive genetic testing with whole genome sequencing will be performed in participants with definite CP or high risk of CP.

Receiving an early diagnosis of CP or high risk of CP is a parent priority and both parents and care providers agree that early access to interventions is important for the child. Parents of children with CP may experience high stress levels, depression, and chronic sorrow symptoms. Intensive home-based approaches addressing cognitive and motor improvement increasingly involve parents as treatment providers, supervised by therapists. This can lead to both a positive parental outcome such as motivation, knowledge, and increased competences, as well as negative outcomes, because parents may be overwhelmed by the burden of responsibility and the feeling of insufficiency and lack of confidence.

The current study CP-EDIT (Early Diagnosis and Intervention Trial) with the GO-PLAY intervention included ( Goal Oriented ParentaL supported home ActivitY program, that will be registered separately at ClinTrials), aims at testing feasibility of an early diagnosis and intervention set-up in four neuropaediatric centers in Denmark with focus on eight areas related to implementation and the perspective of the families: Early MRI, early genetic testing, implementation of the GMA method, early prediction of CP, comparative analysis of the HAI and HINE, MRI, and GMA methods, analysis of the GO-PLAY early intervention, and parental perspective of intervention and early diagnosis.

Eligibility criteria: Inclusion Criteria:

Group A: 'Newborn-detectable risk-pathway'

* Preterm birth with gestational age below 32 or birth weight below 1500 g and clinical concern
* Moderate to severe brain injury (Papile grade 3 to 4 intraventricular haemorrhage, cystic periventricular leukomalacia, neonatal stroke, term hypoxic-ischaemic encephalopathy (≥35 weeks gestation at birth) or other significant neurological condition)
* History (e.g. neonatal seizures, Extra Corporal Membrane Oxygenation, meningitis, kernicterus, severe hypoglycemia) or neurological risk factors (brain malformation, increased tone)
* Parental concern and one of the factors above

Group B: 'Infant detectable risk-pathway'

* Inability to sit independently by age 9 months
* Hand function asymmetry or crawl asymmetry
* Inability to take weight through the plantar surface of the feet
* History (as above) or neurological risk factors
* Parental concern and one of the factors above

Exclusion Criteria:

* 1) Infants with progressive or neurodegenerative disorders or genetic disorders not associated with CP, 2) Infants with other disability diagnoses e.g. Down Syndrome.

Primary outcomes:
measure: MRI
timeFrame: MRI at enrollment in cohort II
measure: Whole genome sequencing
timeFrame: Genetics at enrollment in cohort III
measure: Hammersmith Infant Neurological Examination (HINE)
timeFrame: At enrollment visit
measure: General Movement Assessment (GMA)
timeFrame: At enrollment visit if < 5 months of corrected age
measure: Screening Hand Assessment for Infants (SHAI)
timeFrame: At enrollment visit
measure: Clinical assessment of CP diagnosis
timeFrame: at 24 months corrected age
Secondary outcomes:
measure: Motor function - The Gross Motor Function Classification System - Expanded & Revised (GMFCS - E&R)
timeFrame: at 24 months corrected age
measure: Motor function - The Mini-Manual Ability Classification System (Mini-MACS)
timeFrame: at 24 months corrected age
Other outcomes:
measure: Motor Optimality Score - Revised (MOS-R)
timeFrame: At enrollment visit if < 5 months of age
measure: Alberta Infant Motor Scale (AIMS)
timeFrame: At enrollment, six and 12 months corrected age
measure: Peabody Developmental Motor Scales - Second edition (PDMS-2)
timeFrame: at 24 months corrected age
measure: Gross Motor Function Measure (GMFM-66)
timeFrame: at 24 months corrected age
measure: Bayley Scales of Infant and Toddler Development 4-cognitive
timeFrame: at 24 months corrected age
measure: HINE
timeFrame: at visit six, 12, 18, and 24 months corrected age
measure: Hand Assessment in Infants (HAI)
timeFrame: at 12 months corrected age
measure: The Depression Anxiety Stress Scales (DASS-21)
timeFrame: at enrollment visit, and 12, 24 months corrected age
measure: The Parental stress scale (PSS)
timeFrame: at enrollment visit, and 12 and 24 months corrected age
measure: The Ages & Stages Questionnaire (ASQ-3)
timeFrame: at 24 months corrected age
measure: The Measure of Processes of Care 20 (MPOC-20)
timeFrame: at 24 months corrected age
Locations:
city: Aalborg
country: Denmark
facility: University Hospital Aalborg
city: Aarhus
country: Denmark
facility: University Hospital Aarhus
city: Herlev
country: Denmark
facility: University Hospital Herlev
city: Copenhagen
country: Denmark
facility: University Hospital Rigshospitalet, Dept. Paediatrics
state: Østerbro
Study officials:
affiliation: Department of Paediatrics, University Hospital Rigshospitalet, Denmark
name: Christina Hoei-Hansen, professor
role: STUDY_CHAIR
References: