SIRENA protocol: an Italian, prospective, multicentre cohort study of children and adults with islet autoimmunity and early-stage type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D) is a progressive autoimmune disease with identifiable presymptomatic stages. Islet autoantibody screening, expanded in Italy by Law 130/2023, identifies children and adults at high risk of progression. Structured longitudinal follow-up is needed to characterise disease trajectories, reduce diabetic ketoacidosis (DKA) at diagnosis and identify candidates for emerging disease-modifying therapies such as teplizumab. METHODS AND ANALYSIS: Standardized Italian netwoRk Enrolling iNdividuals with islet-Autoantibodies (SIRENA) is a prospective, multicentre cohort study coordinated by the Italian Society for Pediatric Endocrinology and Diabetology, distributed across more than 40 paediatric and adult diabetes centres. Asymptomatic children and adults with at least one confirmed islet autoantibody and not meeting the American Diabetes Association (ADA) diagnostic criteria for diabetes will be consecutively enrolled and followed for up to 10 years. Clinical, biochemical, immunological and patient- and caregiver-reported data will be collected through a Research Electronic Data Capture-based electronic case report form, standardised to the Observational Medical Outcomes Partnership Common Data Model and shared with the European pre-T1D Registry. The primary outcome is progression to clinical (stage 3) T1D, defined per ADA criteria as hyperglycaemia with or without symptoms. Secondary outcomes include biochemical (stage 3a) versus symptomatic (stage 3b) onset, transitions across earlier stages, the incidence of each stage, DKA frequency and severity at onset, metabolic trajectories, preventive-therapy exposure, comorbidities and the psychosocial impact of early diagnosis. Analyses will use descriptive, competing-risks time-to-event (cumulative incidence and Fine-Gray) and regression approaches. ETHICS AND DISSEMINATION: The protocol was approved by the National Ethics Committee of the National Health System (Istituto Superiore di Sanità). Written informed consent will be obtained from adults or, for minors, their parents or legal guardians. Findings will be disseminated through peer-reviewed publications and scientific meetings. SIRENA will generate real-world Italian evidence to refine follow-up strategies, strengthen paediatric-adult care integration and position Italy within the European pre-T1D Registry and the European action for the Diagnosis of Early Non-clinical Type 1 diabetes For disease Interception infrastructure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT07503366.