Background <p>Early prodromal signs of Autism Spectrum Disorder (ASD) can be detected within the first year of life, a period of heightened neuroplasticity. Pre-emptive, parent-mediated interventions delivered during this window may improve developmental outcomes and reduce ASD symptom severity, but evidence from adequately powered randomized trials in Europe remains limited.</p> <p>Early prodromal signs of Autism Spectrum Disorder (ASD) can be detected within the first year of life, a period of heightened neuroplasticity. Pre-emptive, parent-mediated interventions delivered during this window may improve developmental outcomes and reduce ASD symptom severity, but evidence from adequately powered randomized trials in Europe remains limited.</p> Objectives <p>The primary objective of this trial is to determine the efficacy of FIRRST (Fostering Infant Responsivity and Reciprocity – Support to Thrive), a parent-mediated pre-emptive telehealth intervention, in reducing ASD symptom severity in infants with ASD prodromes, as measured by change in Autism Diagnostic Observation Schedule–Second Edition (ADOS-2) Calibrated Severity Scores. Secondary objectives are to evaluate effects on infant developmental skills, caregiver–child interaction, parental well-being, neurophysiological markers, and cost-effectiveness.</p> Methods <p>This is a multicenter, single-blinded, randomized, parallel-group superiority trial conducted in Italy. A total of 132 infants aged 9–14&#xa0;months with ASD prodromes will be recruited by clinicians at participating university hospital–based centers and randomly allocated (1:1) to FIRRST or a Parent Education control condition. Key inclusion criteria include risk-range scores on the Social Attention and Communication Surveillance–Revised (SACS-R); exclusion criteria include known genetic, neurological, or severe sensory impairments. Randomization will be stratified by age (&lt; 12 vs ≥ 12&#xa0;months), sex, and ASD symptom severity. FIRRST consists of weekly telehealth sessions delivered by trained licensed health professionals over 24&#xa0;weeks. Outcomes will be assessed at baseline, post-intervention (24&#xa0;weeks), and follow-up (48&#xa0;weeks).</p> Outcomes <p>The primary outcome is change in ADOS-2 Calibrated Severity Scores from baseline to post-intervention. Secondary outcomes include developmental level (Griffiths-III), caregiver–child interaction (MONSI-CC), parental well-being (PSI-4), and neurophysiological measures derived from high-density electroencephalography. Safety outcomes include monitoring and descriptive reporting of adverse events. A cost-effectiveness analysis will be conducted from the healthcare system perspective.</p> Trial registration <p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/study/NCT06817746">NCT06817746</a>. Registered on November 2024.</p>