An efficient, UK-wide, real-world-data-enabled, adaptive, 2-randomisation, controlled trial to determine clinical efficacy, effect size, and safety of widely used enteral feeds in reducing necrotising enterocolitis, mortality, and cognitive impairment in preterm babies born below 29 weeks' gestation

RESEARCH QUESTIONS We will assess, in extremely preterm babies (born <29 weeks gestation), the efficacy and safety of 1) pasteurised human donor milk (pHDM) compared with Preterm Formula when a supplement for milk from a baby’s own mother (Own Mother's Milk) is required, and 2) routine cow-milk based protein-carbohydrate fortification of human milk feeds (Own Mother’s Milk and pHDM) in improving “survival to 34 weeks gestational age without surgical necrotising enterocolitis (NEC)” (primary outcome), language and cognition at age 2-years, and other outcomes. We will determine 3) if the feeds differ in the NHS value they generate, and in a subset of participants 4) if the supplements have different mechanisms of effect on brain development. BACKGROUND NEC, an acquired inflammation of the immature gastrointestinal tract, is a leading cause of death and neuro-impairment in extremely preterm babies. There are around 3000 such births and around 260 NEC deaths and/or surgeries each year in the UK, with 3 times more developing less severe disease. Own Mother’s Milk is protective but over 85% of extremely preterm babies require supplementary feeds; a third to a half receive pHDM and around two-thirds, Preterm Formula. The feeds differ markedly in nutrient and non-nutrient composition and cost (Preterm Formula and Fortifier £5/litre; pHDM £125-£200/litre). The hope is that pHDM reduces NEC; the fear is that highly processed cow-milk based Preterm Formula and Fortifier increase risk, but also that human milk nutrient content alone is inadequate for optimal brain development. AIMS AND OBJECTIVES Our principal aim is to resolve these important, longstanding uncertainties that have led to highly variable practice, anxiety for parents, confusion for staff, and risks to patient safety. Objectives 1 and 2 are to determine the efficacy and safety of pHDM, Preterm Formula, and Fortifier. Objective 3 is to study cerebral white matter microstructure as an effect mechanism. As the feeds are already in wide use, clinicians will view the study as providing definitive evidence, hence Objective 4 is to determine their value to the NHS. Objective 5 is to make our efficient methods available to other researchers to test other treatments. Our proposal is a game-changer for newborn care, ambitious, efficient, feasible, and priority-ranked by parents, patients, and clinicians. METHODS We will conduct a UK-wide, real-world-data-enabled, digital technology-facilitated, 2-randomisation, group-sequential, open-label, randomised, controlled trial embedded in routine clinical care, employing statistical, operational, and technical efficiencies. We will reduce burden and cost by using our well-established National Neonatal Research Database as principal data source and a digital version of a standard-of-care parent questionnaire to assess cognitive and language development. We will involve and engage parents from diverse backgrounds in all study aspects. TIMELINE Study duration is 5 years. Primary and in-hospital secondary outcomes will be available in year-4; mechanistic, economic, cognitive and language outcomes in year-5. IMPACT AND DISSEMINATION Results will be immediately practice changing in the UK and globally. They will be shared with NHS clinicians, commissioners, managers and policymakers, professional organisations, charities, and patient groups through academic and lay publications, conferences, workshops, social media, and strong personal networks.