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

NCT05835674 | Recruiting

• 1 other identifier: H-22013292
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 4

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.

Conditions

Cerebral Palsy

Outcome Measures

Primary Outcomes (6)

• MRI

  MRI scans will be described clinically by radiologists at the participating hospitals. The findings will be categorised according to SCPE criteria (Surveillance of Cerebral Palsy in Europe). In participants where ultrasound or CT scanning of the patients have already been performed as part of clinical follow-up, the results will be gathered, and additional MRI may be optional. Repeat MRI at ages 12 and 24 months will be optional for participants in cohort III as part of the complementary NIBS-CP project (NeuroImaging of Babies during natural Sleep to assess typical development and Cerebral Palsy), which 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 at enrollment in cohort II

• Whole genome sequencing

  Blood samples will be obtained from participants with definite or high risk of CP (n=160) upon inclusion in CP-EDIT cohort III after informed, written consent has been obtained by the parents. The parents will also be asked to provide a blood sample and written consent for genome sequencing (trio-analysis). A clinical geneticist and clinical laboratory geneticist will perform the data analysis and result interpretation. Results will be categorised as either: I) Pathogenic CP-explaining variant, II) Likely pathogenic CP-explaining variant, III) Variant of uncertain significance, IV) Likely benign variant, V) Benign variants (according to the ACMG guidelines) and VI) Pathogenic variant, non-CP disease. Only data from the proband will undergo a full analysis. De novo variants in gene with no known clinical association may be submitted to GeneMatcher.

  Genetics at enrollment in cohort III

• Hammersmith Infant Neurological Examination (HINE)

  The HINE is a standardized neurological examination for infants aged 3-24 months. It includes three sections: 1) Neurological Examination - Assessment of cranial nerve function, posture, movements, tone, reflexes and reactions 2) Motor Milestones - head control, sitting, grasping, rolling, crawling, standing and walking and 3) State of Behavior - consciousness, emotional state and social orientation. The HINE global score ranges from a minimum of 0 to a maximum score of 78. A score \< 73 indicates high risk of CP and \< 40 indicates abnormal outcome, usually CP. HINE cut off scores for high risk infants indicating CP are: score \< 57 at 3 months, \<60 at 6 months, \< 63 at 9 months and, \< 66 at 12 months. The HINE asymmetry-score, also provides insight into CP topography (unilateral vs bilateral) and CP motor severity (ambulant vs non-ambulant, GMFCS I-III vs IV-V). The HINE is performed by a neuro pediatrician or physiotherapist.

  At enrollment visit

• General Movement Assessment (GMA)

  GMA is an observation that evaluates the quality of an infant's early spontaneous movement patterns. GMA is categorised in writhing movements (from preterm until 6-9 weeks post term age) and fidgety movements (from 9 to 20 weeks post term age). Absent fidgety movements (FM) at 3 months post-term age is highly predictive of CP in 'high-risk' infants and may be a marker for other adverse neurodevelopmental outcomes. FMs are classified as follows: Normal, defined as circular movements of small amplitude, moderate speed, and variable acceleration of neck, trunk, and limbs in all directions. Abnormal FMs: (a) absent, when normal FMs are never observed from age 9 to 20 weeks post term age; (b) sporadic , when FMs can be detected but less than 3 sec. (c) exaggerated, when FMs are of large amplitude, high speed, and jerkiness are seen.

  At enrollment visit if < 5 months of corrected age

• Screening Hand Assessment for Infants (SHAI)

  SHAI is developed to facilitate screening for risk of unilateral CP in infants aged 3-12 month at risk of CP. The sHAI measures the manual actions performed with each hand separately, test procedure comprises a semi-structured video-recorded play session lasting 5 min, with assessment of 6 unimanual items (including quality of holding, grasping from easy position, object location, finger movements and quality of movement). All items are scored on a three-point rating scale (0-2) and the scores of the unimanual items are summed to the Each Hand Sum score (EaHS) with a range of 0-12 raw scores. The EaHS of the better functioning hand and the lesser functioning hand is used to calculate an asymmetry index (0-100) where a higher percentage indicates a larger asymmetry.

  At enrollment visit

• Clinical assessment of CP diagnosis

  Definitely CP' encompasses participants that fulfil SCPE CP clinical criteria and guided by fulfilling the following: 4/5 for children \<5 months, and 3/4 for children ≥ 5 months of the following at screening. 1. Delayed motor development without signs of neuromuscular disease (floppy infant, absent reflexes) 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 4. MRI or ultrasound of brain with a lesion in one or more of the following structures: sensori-motor cortex, basal ganglia, posterior limb of the internal capsule, pyramidal tracts 5. Focal neurological symptoms (hyperreflexia, clonus, dystonia, ataxia, intention tremor) or clinical signs of asymmetry

  at 24 months corrected age

Secondary Outcomes (2)

• Motor function - The Gross Motor Function Classification System - Expanded & Revised (GMFCS - E&R)

  at 24 months corrected age

• Motor function - The Mini-Manual Ability Classification System (Mini-MACS)

  at 24 months corrected age

Other Outcomes (11)

• Motor Optimality Score - Revised (MOS-R)

  At enrollment visit if < 5 months of age

• Alberta Infant Motor Scale (AIMS)

  At enrollment, six and 12 months corrected age

• Peabody Developmental Motor Scales - Second edition (PDMS-2)

  at 24 months corrected age

Study Arms (3)

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.

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.

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.

Diagnostic Test: Early intervention program

Interventions

Early intervention program 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.

Cohort III

Eligibility Criteria

• Age: 3 Months - 12 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Infants below 12 months of age with risk of cerebral palsy.

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead
• Aarhus University Hospital: collaborator
• Aalborg University Hospital: collaborator
• Herlev Hospital: collaborator

Study Sites (4)

University Hospital Aalborg

Aalborg, 9000, Denmark

RECRUITING

University Hospital Aarhus

Aarhus, 8000, Denmark

RECRUITING

University Hospital Herlev

Herlev, 2730, Denmark

RECRUITING

University Hospital Rigshospitalet, Dept. Paediatrics

Copenhagen, Østerbro, 2100, Denmark

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Blood samples. Whole genome sequencing will be performed.

MeSH Terms

Conditions

Cerebral Palsy

Condition Hierarchy (Ancestors)

Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Christina Hoei-Hansen, professor

  Department of Paediatrics, University Hospital Rigshospitalet, Denmark

  STUDY CHAIR

Central Study Contacts

Christina E Hoei-Hansen

CONTACT

+4535455095; christina.hoei-hansen@regionh.dk

Lene Weber

CONTACT

+4535455090; lene.weber@regionh.dk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, MD, DMSc

Study Record Dates

• First Submitted: March 31, 2023
• First Posted: April 28, 2023
• Study Start: April 1, 2023
• Primary Completion: March 31, 2025
• Study Completion (Estimated): March 31, 2028
• Last Updated: April 28, 2023

Record last verified: 2023-04

Locations

DK (4)