Clinical trial NCT06512649: Early Recognition and Intervention in Siblings at High-risk for Neurodevelopmental Disorder
Official title: Early Recognition and Intervention in Siblings at High-risk for Neurodevelopmental Disorder
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Neurodevelopmental Disorders
Autism Spectrum Disorder
Lead sponsor: Fondazione Don Carlo Gnocchi Onlus
Sponsor class: OTHER
Collaborators: name: University of Milano Bicocca
name: Politecnico di Milano
name: Catholic University of the Sacred Heart
name: University of Turin, Italy
First posted: 2024-07-22
Enrollment: 48
Sex: ALL
Minimum age (years): 6
Maximum age (years): 8
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: H1The primary goal of this intervention study is to learn if very early parent-mediated intervention in children at risk for neurodevelopmental disorders in the first year of life can be implemented in routine care, positively impacting early sensory-motor and socio-communicative developmental trajectories and reducing the developmental gap in children with signs of concern.

H2: It is here postulated that early intervention with active parental involvement can reduce parental stress, as well as improve parental understanding and responsiveness to the child's communication cues.

H3: An important part of our work will be analysing data about early social and joint attention behaviours in recruited children and comparing them at different time points. The hypothesis is to find early differences between groups at baseline and to detect a change before and after the intervention. For this reason, in our study design, we decided to use technologies to collect data on quantitative measures during play-structured and laboratory sessions to understand changes in developmental trajectories.

H4: Given the potential role of genetic and immunological mechanisms in ASD, one of the study's secondary aims is to investigate the impact of an early intervention programme on epigenetic changes and inflammatory and immune response.

After enrolment and baseline assessments (T0), children will be allocated to the three groups:

* Group 1 - Clinical Monitoring Group (CM): Siblings of TD children subjects with no signs of concern
* Group 2 - Active Monitoring Group (AM): Siblings of ASD children with no signs of concern
* Group 3 - Early Intervention Group (EI): Siblings classified as "with signs of concern" at baseline evaluation.

All children will be re-evaluated after 6 months (T1) and after 12 months (T2).

Detailed description: Researchers will contact interested parents to assess eligibility and provide detailed study information. Parents will provide written consent before completing baseline assessments (T0) and based on the scores at the main outcome measures, children will be assigned to the correct group. Infants with no signs of concern and siblings of TD children will be allocated to Group 1 (CM); infants with no signs of concern (scores at the Griffiths-3 and CSBS-ITC in the normal range) and siblings of ASD children will be allocated to Group 2 (AM); infants with General Quotient score below 85 using Griffiths-3 and/or at least one score above the "concern" cutoff using the CSBS-ITC will be allocated to Group 3 (EI). Families allocated to Groups 2 and 3 will start the intervention within one month from the baseline assessment. Families allocated to Group 1 will perform only the evaluations at different time points. Assessments will be conducted at baseline (T0), which will be when the parents give their consent and within the 8 months of life of the child, after 6 months from the start of the intervention (T1) and after 12 months from the start of the intervention (T2).

Technological assessment of social behaviour and joint attention:

- video recording of ESCP through Kinect Azure camera to collect and analyse quantitative data related to joint attention.

The administration of the ECSP-I will be video-recorded through an Azure Kinect camera to extract automatically gaze orientation and quantitatively assess Joint Attention.

- Eye-tracker acquisitions An experimental Eye-Tracker Screening (ETS) protocol for children will also be developed. Specifically, short videos will be used to measure the children's ability to process familiar/unfamiliar faces and to respond to social stimuli, particularly referential gaze. The children's eye movements will be analysed using the eye-tracker (Tobii Pro Fusion) and extracted using the appropriate software.

At recruitment (T0), anamnestic, sociodemographic data and auxological and clinical parameters at birth will be collected.

Biomolecular assessment Saliva samples will be collected using 3 different kits, respectively for DNA or RNA extraction, and for protein detection, through spongy swabs that are inserted into the baby's mouth, leading the saliva collection non-invasive, simple, fast, and most importantly, painless. Saliva samples will be collected from all the probands (at T0, T1 and T2) and from their siblings and parents at T0 to assess parent-to-child genetic transmission in relation to the risk of ASD. If possible, a sample of approximately 40 mL of blood (from the parents) will be collected.

Biological samples from family quartet will be collected as follow:

1. In all the enrolled children, their older siblings and parents, genetic analysis will be conducted by a Next-Generation Sequencing (NGS) gene-targeted panel approach to analyse genes involved in synaptogenesis and immunogenetic regulation.
2. Epigenetic analysis of the miRNome in saliva collected from all enrolled children at all time-points will be performed by NGS. Epigenetic analysis will allow to define a panel of microRNAs that can differentiate between ASD children and children with typical development.
3. Analysis of inflammatory cytokines and neurotrophic factors using an automated immunoassay system (ELLA, Biotech) will be performed in probands at T0, T1 and T2. Parents will also be characterized for cytokine and lymphocyte subset at T0.

Correlations between clinical parameters and all biological variables (genetic, epigenetic, inflammatory) will be performed to correlate molecular biomarkers with neurodevelopmental changes in follow-up and pre-post intervention.

Sample size

Since the importance of ECSP-I in this project, as behavioural outcome measures as a tool for reaching quantitative data through technology, we calculate the sample size to detect an association between the ECSP-I score and the groups (1, 2 and 3) at each time point. The calculation was performed based on preliminary data (not already published) from the Italian Version of ESCP (ECSP-I). Assuming a standard deviation of 0.56 for the ECSP-I scale and a significance level α= 0. 01, obtained by applying the Bonferroni correction for multiple comparisons, performed in pairs between groups, to the type I error, we obtained a sample size of 14 subjects per group to detect a difference of 0.8 between the means of each group using a 2-tailed Student's t-test for independent samples, with a power of 80%. Assuming a drop-out rate of 10%, the required sample size increases to 16 subjects per group, that is 48 subjects in total.

Statistical analysis

Analysis (using STATA or SPSS 28.00) will follow standard methods for trials using comparisons between the three groups. First, a study of the maturation trajectories of the infants will be carried out, with a description of the pre-post intervention changes in the tests carried out. Secondly, quantitative evaluations of joint attention data and molecular markers will be performed, detected, and described through mean and standard deviation in case of Gaussian distribution of variables, or median and interquartile range in case of non-Gaussian distribution. The normality of distributions will be assessed by applying the Shapiro-Wilk test. For categorical variables, absolute frequencies and percentages will be reported. Genetic analysis of intra-familial allelic inheritance will be conducted by AFBAC (Affected Family-Based Controls) and TDT (Transmission Disequilibrium Test) . The immunological parameters obtained from the groups of ASD children and children with typical development will be analysed using a nonparametric Mann-Whitney test that will allow to identification of specific immunological biomarkers of ASD-associated neuroinflammation. Moreover, clinical parameters will be correlated with immunological biomarkers characteristic of ASD children. Finally, epigenetic analysis will allow us to define a panel of microRNAs that can differentiate between ASD children and children with typical development. Using computer algorithms, the potential targets, pathways, and biological functions deregulated by this group of miRNAs will be analysed. These data will also be analysed concerning the clinical parameters evaluated in the study and both the genetic and inflammatory characterization of the subjects studied.

Eligibility criteria: Inclusion Criteria:

* Age at recruitment less than or equal to 8 months.
* Sibling diagnosed with autism spectrum disorder
* Normal neurological examination

Exclusion Criteria:

* Focal neurological signs/symptoms or suspicion of genetic-metabolic disorders
* Genetically determined suspected or known conditions in brother/sister
* Significant familial language barrier

Primary outcomes:
measure: Griffiths Scales of Child Development, 3rd Edition (Griffiths-3)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Communication and Symbolic Behaviour Scales - Infant-Toddler Checklist (CSBS-IT-C)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Early Social Communication Scale (Échelle de la Communication Sociale Précoce, Italian adaptation, ECSP-I)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Satisfaction Survey
timeFrame: T1 (T0 + 6 months)
Secondary outcomes:
measure: Vineland Adaptive Behaviour Scales-II - Second Edition (Vineland-II)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Questionnaire Sensory Profile - Second Edition (SP-2)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: McArthur-Bates questionnaire, child's first vocabulary (PVB) - gestures and words
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Infant Behavior Questionnaire-Revised (IBQ-R) and Early Childhood Behavior Questionnaire (ECBQ)
timeFrame: T0 (recruitment); T2 (T0 + 12 months)
measure: Autism Diagnostic Observation Schedule, Second Edition (ADOS-2)
timeFrame: T2 (T0 + 12 months)
measure: Autism Diagnostic Interview-Revised (ADI-R)
timeFrame: T2 (T0 + 12 months)
measure: Parent interactions with children: Checklist of Observations Linked to Outcomes (PICCOLO)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Questionnaire Parent Stress Index - Short Form (PSI-SF)
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Kinect
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Eye-tracker
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Laboratory- genetic analysis
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Laboratory- epigenetic analysis
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
measure: Laboratory- inflammatory cytokines and neurotrophic factors
timeFrame: T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)
Other outcomes:
Locations:
city: Milano
country: Italy
facility: Santa Maria Nascente
Study officials:
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