CP-EDIT: Cerebral Palsy - Early Diagnosis and Intervention Trial

NCT ID: NCT05835674

Last Updated: 2023-04-28

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 500 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-04-01
• Study Completion Date: 2028-03-31

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.

Conditions

Cerebral Palsy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Cohort I

500 participants screened by history and interview with parents to assess if they are to proceed to cohort II. This will be assessed by steering committee.

No interventions assigned to this group

Cohort II

Participants (n=300) who meet the inclusion criteria from Cohort I, is assessed at enrollment visit and will proceed to cohort III if they meet any two of the following criteria:

1. Neuroimaging predictive of a motor disability

2. GMA test with absent fidgety GMs at fidgety age

3. HINE scores <57 at 3months or <60 at 6months or <63 at 9 months or < 66 at 12 months

Infants will also be included if they meet both of the following criteria:

1. Unilateral brain injury on neuroimaging predictive of CP

2. Clinical signs of asymmetry

Studies/objectives related to Cohort II

1. Evaluation of MRI

2. GMA implementation - To assess the feasibility of GMA in a multi-center Danish hospital setting.

3. Prediction of CP - To determine the clinical utility of the MRI, HINE, HAI, and GMA to predict a confirmed diagnosis of CP at 24 months

4. GMA/HINE/MRI vs. HAI - To compare diagnostic accuracy of HAI and GMA/HINE/MRI.

No interventions assigned to this group

Cohort III

Participants (n=160) will be included in cohort III if infants are considered CP or at high risk of CP Participants are followed at enrolment, and ages six, 12, 18 and 24 months. Blood sample for trio-whole genome sequencing is offered to participants with definite or high risk of CP.

Studies/objectives related to Cohort III

e) Evaluation of genetics f) GO-PLAY. To analyse the effect of the GO-PLAY intervention with early family-centred set-up for children with definite or high risk of CP.

g) Parents perspective on intervention. To explore parents' perspectives on barriers and facilitators involved in early intervention.

h) Parents perspectives of early diagnosis - To analyse interviews of parents' perspectives of gains and concerns when having an early diagnosis of high risk of CP.

Early intervention program

Intervention Type: DIAGNOSTIC_TEST

At enrollment visit: History and examination, MRI, evaluation of comorbidities, medication and genomic testing. HINE, GMA (if below 5 mo), AIMS, SHAI, PSS and DASS-21 questionnaire.

At 6 mo visit: Examination and evaluation of comorbidities, medication and HINE and AIMS

At 12 mo visit: Examination and evaluation of comorbidities, medication and HINE, AIMS, HAI, PSS and DASS-21 questionnaire.

At 18 mo visit: Examination and evaluation of comorbidities, medication and HINE

At 24 mo visit: Examination and evaluation of comorbidities, medication and HINE, PDMS-2, GMFM-66, BSID-IV-cog, MPOC-20 ,PSS, and DASS-21 questionnaire. GMFCS and Mini MACS if CP.

Interventions

Early intervention program

At enrollment visit: History and examination, MRI, evaluation of comorbidities, medication and genomic testing. HINE, GMA (if below 5 mo), AIMS, SHAI, PSS and DASS-21 questionnaire.

At 6 mo visit: Examination and evaluation of comorbidities, medication and HINE and AIMS

At 12 mo visit: Examination and evaluation of comorbidities, medication and HINE, AIMS, HAI, PSS and DASS-21 questionnaire.

At 18 mo visit: Examination and evaluation of comorbidities, medication and HINE

At 24 mo visit: Examination and evaluation of comorbidities, medication and HINE, PDMS-2, GMFM-66, BSID-IV-cog, MPOC-20 ,PSS, and DASS-21 questionnaire. GMFCS and Mini MACS if CP.

Intervention Type: DIAGNOSTIC_TEST

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.

• Minimum Eligible Age: 3 Months
• Maximum Eligible Age: 12 Months
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Aarhus University Hospital

OTHER

Sponsor Role: collaborator

Aalborg University Hospital

OTHER

Sponsor Role: collaborator

Herlev Hospital

OTHER

Sponsor Role: collaborator

Rigshospitalet, Denmark

OTHER

Sponsor Role: lead

Responsible Party

Christina Høi-Hansen

Professor, MD, DMSc

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christina Hoei-Hansen, professor

Role: STUDY_CHAIR

Department of Paediatrics, University Hospital Rigshospitalet, Denmark

Locations

University Hospital Aalborg

Aalborg, , Denmark

Site Status: RECRUITING

University Hospital Aarhus

Aarhus, , Denmark

Site Status: RECRUITING

University Hospital Herlev

Herlev, , Denmark

Site Status: RECRUITING

University Hospital Rigshospitalet, Dept. Paediatrics

Copenhagen, Østerbro, Denmark

Site Status: RECRUITING

Countries

Denmark

Central Contacts

Christina E Hoei-Hansen

Role: CONTACT

Phone: +4535455095

Email: christina.hoei-hansen@regionh.dk

Lene Weber

Role: CONTACT

Phone: +4535455090

Email: lene.weber@regionh.dk

Facility Contacts

Mette Johansen, PT

Role: primary

Gija Rackauskaite, MD

Role: primary

Rebecca Fabricius, MD

Role: primary

Christina Høi-Hansen, Prof.

Role: primary

Lene Weber, PT

Role: backup

Other Identifiers

H-22013292

Identifier Type: -

Identifier Source: org_study_id