Early Recognition and Intervention in Siblings at High-risk for Neurodevelopmental Disorder
NCT Number: NCT06512649
Acronym: ERI-SIBS
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Neurodevelopmental Disorders|Autism Spectrum Disorder
Interventions: BEHAVIORAL: Early intervention|BEHAVIORAL: Active monitoring
Sponsor: Fondazione Don Carlo Gnocchi Onlus
Collaborators: University of Milano Bicocca|Politecnico di Milano|Catholic University of the Sacred Heart|University of Turin, Italy
Sex: ALL
Age: CHILD
Enrollment: 48
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2023-05-31
Completion Date: 2026-05-31
Locations: Santa Maria Nascente, Milano, 20148, Italy

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).

Primary Outcome Measures: Griffiths Scales of Child Development, 3rd Edition (Griffiths-3), Griffiths-3 is the gold standard to provide an overall measure of a child's development (0-6 years); it permits the definition of an individual profile of strengths and needs of the child across five areas: foundations of learning, language and communication, eye and hand coordination, personal-social-emotional, gross motor

UNIT OF MEASURE: Developmental quotients (range 20-150, normality 85-115), T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Communication and Symbolic Behaviour Scales - Infant-Toddler Checklist (CSBS-IT-C), is a tool for developmental screening, designed to measure 7 language predictors in children 6 to 24 months of age. The questions of the checklist may be presented in an interview format with adequate explanations to clarify what is being asked. It takes about 5 to 10 minutes to complete and permits the detection of signs of concern for ASD in infants and toddlers

UNIT OF MEASURE: weighted score, number: range 3-17; no concern \> 7, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Early Social Communication Scale (Échelle de la Communication Sociale Précoce, Italian adaptation, ECSP-I), the ECSP-I is a structured assessment designed to provide measures of individual differences in nonverbal communication skills in children from 3 to 30 months of age. The administration requires 15-20 min involving the presentation of approximately 23 standardised situations which provide opportunities for social communication. The ECSP-I demonstrates strong reliability and both construct and discriminant validity

Unit of measure: number. Optimal and average level (mean, range 1-4)., T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Satisfaction Survey, Parents of children in Groups 2 and 3 will also be asked to anonymously complete a satisfaction survey (created ad hoc for this project) immediately after the intervention to assess their satisfaction with the services provided. The questionnaire takes 5 minutes to complete.

unit of measure: likert scale, range 0-5, T1 (T0 + 6 months)
Secondary Outcome Measures: Vineland Adaptive Behaviour Scales-II - Second Edition (Vineland-II), This assessment measures personal and social adaptation skills in everyday-life. It is applicable to children from birth through 18 years, 11 months. Standardization included national samples of children with and without disabilities.

The scales yield normative standard scores (M = 100; SD = 15) that indicate level of adaptive functioning, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Questionnaire Sensory Profile - Second Edition (SP-2), The SP-2 is a norm-referenced collection of five parent- and teacher-report questionnaires that assess sensory processing in children about everyday sensory events; for this study, the age-appropriate version was used, that is the Toddler Module (from 7 to 35 months); Unit of measure: items are rated on a 5-point Likert scale from 5 (almost always) to 1 (almost never). Point are scored as Standard Deviation through automatized scoring provided by the editor, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|McArthur-Bates questionnaire, child's first vocabulary (PVB) - gestures and words, The PVB assesses major features of communicative development, including words' comprehension and production, use of gesture, and first sentences' comprehension. The PVB/words and gestures form is a checklist filled by the parents'. The questionnaire is validated on an Italian sample, and it allows to calculate quotients related to the different subareas investigated

Unit of measure: centile according to age (range 5-95) and quotients (number), T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Infant Behavior Questionnaire-Revised (IBQ-R) and Early Childhood Behavior Questionnaire (ECBQ), The IBQ-R (3-12 months) and ECBQ (18-36 months) are parent-report questionnaires for the assessing of temperament in infancy and later childhood; items are rated on a 7-point scale (from 1 that is 1 never to 7 that is always) (Cozzi et al., 2013; Gartstein \& Rothbart, 2003), T0 (recruitment); T2 (T0 + 12 months)|Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), The ADOS-2 is a semi structured, standardized assessment of communication social interaction, play/imaginative use of materials and restricted/repetitive patterns of interest to assess the presence of ASD symptoms. The administration involves direct observations using hierarchical manualized procedures and progressive prompts. Every behaviour/symptom is assessed using a likert scale (0-3) and coded on an algorithm based on DSM-5 diagnostic criteria. We will use Toddler Module, for 12 to 30 months-aged children, or the Module 2 if language in sentences is present.

We will consider the total score (unit of measure number, range 0-28), social affect score (unit of measure number, range 0-20), and restricted and repetitive behaviours score (unit of measure number, range 0-8)., T2 (T0 + 12 months)|Autism Diagnostic Interview-Revised (ADI-R), The ADI-R is a semi-structured interview conducted by a trained researcher or psychologist with the child's parents or other caregivers, based on DSM-IV criteria. The ADI-R focuses on the developmental history of the child and on the actual description given by the parents.

Every behaviour/symptom is assessed using a likert scale (0-3) and coded on an algorithm. We will use algorithms specifically developed for toddlers, that give a clinical cutoff and a rate of risk for ASD.

unit of measure: number, T2 (T0 + 12 months)|Parent interactions with children: Checklist of Observations Linked to Outcomes (PICCOLO), this is an observational measure in which a parent-child interaction is video recorded and trained observers code-specific parenting behaviours known to predict children's early social, cognitive, and language development. Specifically, the PICCOLO examines four domains of parenting behaviours, including affection, responsiveness, encouragement, and teaching. The PICCOLO demonstrates strong reliability and both construct and predictive validity.

Each domain is scored on a 0-2 likert scale.

Unit of measure: number, range 0-14 for each subscale, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Questionnaire Parent Stress Index - Short Form (PSI-SF), It is a questionnaire completed by the parents, composed by thirty-six items are divided into three domains: Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI), and Difficult Child (DC), which combine to form a Total Stress scale.

UNIT of MEASURE: centiles, number. Range 1-99, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Kinect, video recording of ESCP through Kinect Azure camera to collect and analyse quantitative data to estimate the gaze orientation.

* time spent by the child looking at the therapist
* joint attention lenght, (the time during which the child and the therapist simultaneously focus on the same object or each other).

Unit of measure: absolute time values (seconds) and a relative measurement in relation to the total session duration (percentage)).

To date, there are no normative data available in the literature for these specific metrics., T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Eye-tracker, An experimental Eye-Tracker Screening (ETS) protocol will be implemented using the Tobii Pro Fusion 120Hz to analyze children's eye movement patterns. The indices that will be used include Total Fixation Duration (TFD) and Time to First Fixation (TFF).

TFD will measure children's general attention to specific areas, such as faces and objects (i.e. target and distractor).TFF will assess children's ability to follow the gaze of the familiar or unfamiliar faces towards the target, thereby verifying their response to referential gaze (i.e., the gaze-following mechanism).

Both indices, TFD and TFF, will be measured in milliseconds., T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Laboratory- genetic analysis, genetic analysis will be conducted by a Next-Generation Sequencing (NGS) gene-targeted panel approach to analyse genes involved in synaptogenesis and immunogenetic regulation.

Gene association will be reported as genotypes and alleles NUMBER and percentages, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Laboratory- epigenetic analysis, Epigenetic analysis of the miRNome by NGS. Epigenetic analysis will allow to define a panel of microRNAs that can differentiate between ASD children and children with typical development.

MiRNA concentrations will be reported as COPIES/NANOGRAMS of extracted RNA, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)|Laboratory- inflammatory cytokines and neurotrophic factors, Analysis of inflammatory cytokines and neurotrophic factors using an automated immunoassay system (ELLA, Biotech).

Cytokine and neurotrophic factors concentration measured in saliva and plasma samples will be reported as PICOGRAMS/ML.

Results calculations will be based on standard curves and internal controls provided by commercial kits, T0 (recruitment), T1 (T0 + 6 months); T2 (T0 + 12 months)