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Premature BirthNCT04617587

Novel Epigenetic Biomarker for Prematurity Related Neurodevelopmental Disorders in Childhood

A study testing Early Intervention in people with Premature Birth, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Preterms are early exposed to a stressful environment (i.e. excessive sensory stimulation and paucity of parental contact) with subsequent detrimental effects on brain maturation and neurodevelopmental outcomes. In contrast, early interventions seem to reduce stress exposure and promote neurodevelopment. Read more about this study

Who is it for?
Ages 24 to 32 weeks
Conditions the study is for
Premature Birth
What is being tested?
Early Intervention
Could I receive a placebo?
No, everyone receives an active treatment
How many people
104 participants
Where
1 siteItaly
Study dates
3 Dec 2020to 30 Mar 2025
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 24 to 32 weeks
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Gestational age at birth between 24+0 and 32+6 weeks
  • Mothers age over 18 years
  • Good comprehension of the Italian language
  • Written informed consent signed by both parents

Who cannot join

  • Infants with major genetic disorders and malformations
  • Parents declined study participation
  • Single-parent family
  • Parents with obvious cognitive or psychiatric disorders and drug addiction

Trial locations and contacts

1 site in 1 country.

Italy1 site

  • NICU, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

    Milan, 20122

Other trials in Italy

About this study

Official title: Structural Variations of the Neural Genome as Prognostic Biomarkers for Prematurity Related Neurodevelopmental Disorders in Childhood

Preterms are early exposed to a stressful environment (i.e. excessive sensory stimulation and paucity of parental contact) with subsequent detrimental effects on brain maturation and neurodevelopmental outcomes. In contrast, early interventions seem to reduce stress exposure and promote neurodevelopment. The brain functional plasticity in response to environmental experiences can be partly attributed to changes in DNA methylation. In this context, LINE-1 (L1) promoter (18% of human genome) methylation/demethylation has been associated with L1 somatic mobilization in the brain genomes, contributing to experience-driven brain plasticity; this mechanism being deregulated in important neurological disease. This study aims at identifying and characterizing the role of L1 DNA repeats as a novel biomarker to predict long-term neurodevelopmental outcome in preterm infants. In addition, the study's secondary goal will be to define a preventive approach, based on early intervention strategies, for improving long-term neurodevelopmental outcomes.

Read the detailed description

Around 25-50% of very preterm infants suffer from neurodevelopmental delays (motor, cognitive and behavioral problems), which are most likely related to brain micro-structural defects and impaired neuronal maturation and connectivity. These alterations in brain maturation occurring during the neonatal period may be implicated in long-term neurobehavioral disorders later experienced by preterm babies.

There is increasing evidence that also stressful events (excessive sensory stimulation, paucity of parental contact and painful procedures) experienced in the Neonatal Intensive Care Unit (NICU) by preterm neonates can affect neurodevelopment through epigenetic mechanisms.

The brain is a genomic mosaic, owing to somatic mutations that arise throughout development. It is already established that mobile genetic elements, including LINE-1 (L1), are one source of somatic mosaicism, inducing copy number variations in neural genome. Environmental experiences can drive brain plasticity at a molecular level, with changes in DNA methylation. In particular, L1 promoter methylation/demethylation is already associated with L1 mobilization in the brain genomes and its deregulation is linked with important neurological diseases. A preliminary study has shown the correlation between L1 promoter methylation levels and preterm birth. In addition, maternal care during early life has been reported to drive variability in L1 mobilization and methylation of the neural hippocampal genome in mice models.

Several studies have reported how individualized developmental care in the NICU can ameliorate preterm infants' medical outcome and subsequent neurodevelopment. More recently, early intervention (EI) strategies based on parental training and multisensory stimulation, such as infant massage and visual stimulation, have been demonstrated to enhance child's neurodevelopment. These programs have the greatest potential to reduce environmental stress in preterms, promoting brain plasticity, optimizing dyadic interaction and ameliorating neurodevelopmental outcomes.

Conditions
Premature Birth
Being tested
Early Intervention
Keywords
Premature Birth, DNA Methylation, L1 Elements, Epigenometics, Early Intervention, Brain Development, Neurodevelopment, Parent-infant interaction, Massage therapy, Visual interaction
Medical subject headings
Premature Birth

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Early InterventionBehavioural

    The early intervention (EI) is delivered during the NICU stay. It is a multisensory intervention which consists in three parts: parental training, massage therapy and visual interaction. The EI is first focused on parental training, according to PremieStart Protocol, in order to train parents to: recognize signs of infant stress and alert-available behavior through the identification of infant's behavioral states; adopt principles of graded stimulation; sustain infant's attention and respond to infant's cues; optimize interactions and avoid overwhelming infants through facilitation strategies. The program is held in eight main sessions and one additional post-discharge session. In addition, parents are trained and invited to daily promote preterm baby massage therapy and visual interaction (visual fixation/tracking and visual attention).

Study groups in NCT04617587
Study groupRoleWhat they receive
Early InterventionExperimentalAll the enrolled preterm infants are assigned to receive the early neurodevelopmental intervention during the NICU stay.
Receives: Behavioral: Early Intervention

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. L1 Promoter Methylation Levels on Biological Materials

    Epigenetic analysis is performed on biological materials: cord blood sample and buccal swab at birth, peripheral blood sample and buccal swab at NICU discharge/term equivalent age, buccal swab collected during the follow up assessment at 12 and 24 months of corrected age.

    Measured: Up to 24 months corrected age

Secondary outcomes (6)

  1. Conventional and advanced brain Magnetic Resonance Imaging (MRI)

    Evaluation of brain development and maturation

    Measured: Term equivalent age, approximately 40 weeks postmenstrual age

  2. Neurological Examination

    Hammersmith Neonatal Neurological Examination (HNNE)

    Measured: Term equivalent age, approximately 40 weeks postmenstrual age

  3. General Movements Examination

    Prechtl's Qualitative Assessment of General Movements

    Measured: Term equivalent age, approximately 40 weeks postmenstrual age

  4. Visual Assessment

    Neonatal Visual Assessment Battery developed by Ricci et al. The assessment evaluates the following items: ocular spontaneous motility, ability to fix and follow a target, reaction to colour, visual acuity and visual attention at distance.

    Measured: Term equivalent age, approximately 40 weeks postmenstrual age

  5. Neurodevelopmental Outcome

    Children development assessed using the Griffiths Mental Development Scales, performed at 12 and 24 months of corrected age. Mean score is 100. General score has a Standard deviation of 12 and sub scales have a Standard Deviation of 16.

    Higher scores indicate better outcomes.

    Measured: Up to 24 months corrected age

  6. Behavioral Outcome

    Children behavior assessed using the Child Behavior Checklist (CBCL). It is a parent report form to screen for emotional, behavioral and social problems.

    Lower scores indicate better outcomes. A T score above 75 is considered pathological while a T score between 65 and 74 is considered borderline.

    Measured: 24 months corrected age

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Nov 2020
  2. Study start3 Dec 2020
  3. Primary completion21 Mar 2025
  4. Study completion30 Mar 2025

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
104 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04617587
Sponsor's protocol ID
GR-2018-12365280
Status last verified
Apr 2025
First submitted
23 Oct 2020
Last updated
1 May 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: The dataset generated for this study will be made available on request in an anonymized version or in a grouped form in order to prevent patient identification.

Publications

  • Fontana C, De Carli A, Ricci D, Dessimone F, Passera S, Pesenti N, Bonzini M, Bassi L, Squarcina L, Cinnante C, Mosca F, Fumagalli M. Effects of Early Intervention on Visual Function in Preterm Infants: A Randomized Controlled Trial. Front Pediatr. 2020 Jun 4;8:291. doi: 10.3389/fped.2020.00291. eCollection 2020.

    PubMed 32582595

  • Newnham CA, Milgrom J, Skouteris H. Effectiveness of a modified Mother-Infant Transaction Program on outcomes for preterm infants from 3 to 24 months of age. Infant Behav Dev. 2009 Jan;32(1):17-26. doi: 10.1016/j.infbeh.2008.09.004. Epub 2008 Nov 20.

    PubMed 19026450

  • Bedrosian TA, Quayle C, Novaresi N, Gage FH. Early life experience drives structural variation of neural genomes in mice. Science. 2018 Mar 23;359(6382):1395-1399. doi: 10.1126/science.aah3378.

    PubMed 29567711

  • Ricci D, Romeo DM, Serrao F, Cesarini L, Gallini F, Cota F, Leone D, Zuppa AA, Romagnoli C, Cowan F, Mercuri E. Application of a neonatal assessment of visual function in a population of low risk full-term newborn. Early Hum Dev. 2008 Apr;84(4):277-80. doi: 10.1016/j.earlhumdev.2007.10.002. Epub 2007 Nov 8.

    PubMed 17996405

  • Guzzetta A, Baldini S, Bancale A, Baroncelli L, Ciucci F, Ghirri P, Putignano E, Sale A, Viegi A, Berardi N, Boldrini A, Cioni G, Maffei L. Massage accelerates brain development and the maturation of visual function. J Neurosci. 2009 May 6;29(18):6042-51. doi: 10.1523/JNEUROSCI.5548-08.2009.

    PubMed 19420271

Questions about this trial

What is this clinical trial studying?

A study testing Early Intervention in people with Premature Birth, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 May 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

L1 Promoter Methylation Levels on Biological Materials (time frame: Up to 24 months corrected age). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04617587, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2025.

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