VIPPSTAR-G1 Digital Early Intervention for Visual Impairment

The VIPPSTAR-G1 study is a multicenter, multinational clinical trial evaluating a caregiver-mediated digital early intervention designed to promote visual function and neurodevelopment in infants at risk of or with visual impairment (VI), within a framework that promotes and strengthens the parent-child/caregiver-child relationship. The study is conducted within the framework of the VIPPSTAR Horizon Europe project and integrates telemedicine, digital health technologies, and individualized developmental support into routine clinical care.

Visual function plays a fundamental role in early neurodevelopment. Vision represents the primary means through which infants explore and interact with the environment, while environmental experiences simultaneously shape the maturation and plasticity of visual pathways and broader neurodevelopmental networks. Visual impairment in infancy is therefore associated not only with altered visual functioning but also with increased risk for motor, cognitive, communicative, adaptive, and socio-emotional developmental difficulties.

Visual impairment includes peripheral visual impairment (PVI), caused by ocular or anterior visual pathway disorders, and cerebral visual impairment (CVI), resulting from damage or dysfunction affecting post-geniculate visual pathways and visual cortical networks. These disorders often co-occur. CVI has become one of the leading causes of childhood visual disability in industrialized countries, particularly among infants born preterm or with neonatal neurological complications.

Although early individualized intervention and visually enriched experiences are considered essential to support neuroplasticity and developmental outcomes, implementation of intensive family-centered intervention programs in real-world healthcare systems remains challenging because of limited accessibility, geographic barriers, shortage of specialized services, and socioeconomic constraints affecting families. Digital and telemedicine-based interventions may help overcome these limitations by enabling remote delivery of evidence-based developmental support integrated into everyday family routines.

The VIPPSTAR-G1 protocol evaluates a caregiver-mediated home-based intervention delivered through a dedicated digital platform. The platform provides individualized developmental activities, audiovisual guidance materials, e-learning resources, remote supervision, and continuous communication with clinicians. The intervention is designed to promote naturalistic developmental learning and parent-child interaction within the child's daily environment.

The protocol includes two distinct study populations conducted under a shared methodological framework:

Study Sample 1 - Randomized Controlled Trial Cohort It constitutes the definitive randomized controlled trial (RCT) component of the protocol. This cohort includes 102 newborns at risk of visual impairment recruited from Neonatal Intensive Care Units (NICUs), nurseries, and neuropsychiatry outpatient clinics across participating sites in Italy, Belgium, and Moldova.

Eligible infants are randomized in a 1:1 ratio to: the VIPPSTAR caregiver-mediated digital intervention plus standard care, or standard clinical care alone. Randomization is stratified by recruitment site and biological sex using computer-generated permuted blocks implemented through the REDCap randomization module.

The primary objective of the RCT cohort is to evaluate the efficacy of the intervention in improving: 1)visual acuity, and 2)smooth pursuit eye movements.

Secondary objectives include assessment of: visual processing speed and ocular motor functioning through gaze metrics and qualitative assessments, developmental quotient, adaptive behavior, language development, everyday visual-related behavior, parental stress, quality of life, feasibility, acceptability and usability of the intervention. Primary confirmatory efficacy analyses will be conducted exclusively in Study Sample 1.

Study Sample 2 - Exploratory Pilot Cohort It is an additional exploratory pilot subgroup including 48 infants and toddlers up to 42 months of age with established peripheral or cerebral visual impairment or both.

The objective of this cohort is to evaluate: feasibility, acceptability, usability, adherence, implementation procedures, and preliminary clinical effects of the intervention in a broader clinical population beyond neonates at risk of visual impairment.

Participants in the pilot subgroup follow the same assessment and intervention framework and assessment schedule used in the main RCT cohort. However, this exploratory cohort is not powered for confirmatory efficacy analyses. Data derived from this subgroup will primarily be analyzed descriptively and used to inform future refinement and scalability of the intervention model.

Intervention Description The intervention is a non-pharmacological, non-invasive, caregiver-mediated developmental program delivered remotely through the VIPPSTAR digital platform over a 6-months period.

The platform includes: individualized developmental activities, video demonstrations, audio instructions, e-learning educational materials, secure communication systems, weekly online supervision sessions with clinicians, monitoring tools for adherence and feasibility.

Activities are personalized according to each child's developmental profile, visual functioning, and clinical needs, and are integrated into everyday family routines such as play, caregiving interactions, and home activities.

Clinicians monitor intervention delivery through the digital platform and adapt activities over time according to child responses and caregiver feedback.

Participants allocated to the control group receive standard clinical care according to local institutional practice, including routine follow-up visits and access to clinical communication channels when needed.

Study Timeline and Assessments Participants undergo evaluations at: baseline before randomization (T0), post-intervention after 24 weeks (T1), 6-month follow-up after intervention completion (T2).

Assessments include: neuro-ophthalmological evaluation including ophthalmological assessment and basic visual functions/ocular motor function evaluation; visual processing speed/ eye-tracking based ocularmotor parameters, developmental testing including the assessment of developmental quotient, adaptive behavior assessment, language assessment, parental stress questionnaires, quality-of-life measures, feasibility, acceptability and usability measures.

Outcome assessors and statisticians remain blinded to treatment allocation whenever feasible.

Outcomes

The co-primary outcomes for the RCT cohort are:

Change improvement of visual acuity Change in smooth pursuit function

Secondary outcomes evaluate broader neurodevelopmental, neuro-ophthalmological parameters, adaptive behavior, parental stress, quality of life, and feasibility of the digital intervention.

Data Management and Data Sharing Study data are collected and managed through a centralized REDCap platform hosted at the University of Brescia. All data are pseudo-anonymized and handled in compliance with GDPR and applicable national regulations.

De-identified individual participant data (IPD) underlying published study results may be shared upon reasonable request after publication of the primary analyses. Statistical code, metadata, and data dictionaries may also be shared for academic, non-commercial research purposes.

In preparation for multicenter data exchange and digital platform implementation, the consortium is establishing the necessary Data Sharing Agreements, Data Processing Agreements, and software governance procedures among participating institutions and technology providers to ensure secure, compliant, and ethically governed handling of study data.

Ethical Considerations The study has received ethics approval from Comitato Etico Territoriale Lombardia 6 (Approval No. VIPPSTAR G1 - NP 6758; approved 4th June 2026). Written informed consent is obtained from parents or legal guardians before participation.

Given the non-invasive and caregiver-mediated nature of the intervention, the study is considered minimal risk. Safety monitoring procedures are implemented throughout the study period, including systematic monitoring of adverse events, participant burden, and intervention tolerability.

Inclusion criteria

Study Sample 1 - Infants at Risk of Visual Impairment

• Gestational age ≤32 weeks OR full-term/newborns>32 weeks of age with neonatal distress (Apgar ≤5 at 10 minutes)
• NAVEG score ≥3
• At least one neurological or neuroimaging abnormality:

• 3 abnormal signs at ATNAT neurological examination OR Abnormal cranial ultrasound findings OR Abnormal MRI findings

Exclusion criteria

Study Sample 1 - Infants at Risk of Visual Impairment

• Epileptic encephalopathy
• Parents unable to understand local language

Inclusion criteria

Study Sample 2 - Infants/Toddlers With Visual Impairment

• Age ≤42 months
• Diagnosis of peripheral or cerebral visual impairment
• Moderate or severe visual impairment documented by standardized visual acuity testing Exclusion Criteria: Study Sample 2 - Infants/Toddlers With Visual Impairment
• Age >42 months
• Refractory epilepsy or epileptic encephalopathy
• Participation in another interventional study within previous 12 months
• Parents unable to understand local language