Title: Precision-medicine platform trials to improve the care of sick and preterm newborn babies
Funder: Medical Research Council

Abstract: Background: Our goal over many years has been to improve the life-long health of sick and preterm babies through research to identify best care practices and facilitate the development of medicines that meet their needs. Around 70,000 preterm babies are born each year in the UK (of whom 6000 are born very preterm, more than two months early), and around 15 million world-wide. Nutrition is an essential requirement for their growth. However, the types of feed that preterm babies receive, and medicines to improve their ability to digest milk, and protect their bowel against infection and other damage, can also improve life-long outcomes because they have effects that extend beyond growth. These include brain development which is an important determinant of adult achievement, and the risk of developing conditions like high blood pressure, heart disease and diabetes. Aim and objectives: The primary aim of this application is to speed completion of a detailed study, developed with parents, patients, clinical teams, academic researchers, and industry, to test 3-4 new and existing nutritional treatments to see if they are effective in very preterm babies. The treatments we are considering include types of milk feeds, and new medications to improve bowel growth and development, and help healing in injury caused by a serious bowel inflammation called necrotising enterocolitis. The study will be designed to find out if the treatments work differently in boys and girls, and babies born at different gestational ages and birth weights. We aim to include neonatal units in the UK and other countries including low-resource settings. We also aim to study the way in which the treatments work, specifically if they affect bowel and brain development. Other objectives are to improve methods to test multiple treatments simultaneously, and best practice for parent-clinician-industry partnerships. The development of studies such as this is complex and can take considerable time, which is why we are applying for accelerated development support. Methods: We will deliver objectives in 7 work-packages. These are to finalise i) the selection of treatments, ii) the research team including NHS, academic and industry partners, iii) study design, including how many babies need to take part to detect an effect of each treatment reliably, and iv) studies to show how the treatments work. We will develop v) a detailed plan to involve parents and other stakeholders; vi) applications to regulatory authorities for permission to carry out the study; and vii) put in place operational requirements to enable us to start the study immediately. The main outcomes are whether the treatments reduce the risk of necrotising enterocolitis and/or improve language development and understanding at the age of two years. Timelines: If the accelerated development application is successful, we will submit a full stage 1 funding application in May 2023, and if this successful, a stage 2 application in September 2023, with a planned start date in 2024. Impact and communication: Preterm care is an area of great global need. For example, only one medicine has ever been specifically developed for preterm babies. We have identified considerable interest in this proposal among potential NHS, academic, and industry partners; hence communication of outputs will be wide; ability to conduct UK and international preterm research will be improved, and impact on preterm care will be high.

Lay abstract: Background: Our goal for many years has been continuous improvement in personalised care pathways for sick and preterm infants through efficient, cost-effective, collaborative clinical research. Around 70,000 preterm babies (of whom 6000 are very preterm, below 32 weeks gestation) are born each year in the UK, and around 15 million globally. Early nutritional interventions have long-term effects that extend beyond growth, in addition to being an essential requirement for short-term survival and development. Early nutritional interventions have potential to improve the substantially increased risk of preterm populations to impaired cognitive development, the principal determinant of adult educational, economic, and societal attainment, and chronic non-communicable diseases characteristically associated with aging that are the principal causes of reduced longevity and healthy lifespan. However, which interventions are suitable for which infants, and mechanisms of action, are unknown. These are important knowledge gaps as effects differ by precision medicine factors, key among which are sex, and degree of immaturity and intrauterine growth restriction. Aim: The aim of this application is to accelerate completion of a master protocol, agreed by parent-patient groups, clinicians, and NHS/academic/industry partners, for a precision-medicine platform trial to be conducted in the UK and other high- and low-income settings. This will test the efficacy of nutritional interventions in very preterm neonates, and mechanistic hypotheses. It will advance generalisable learning around platform study design, UK and international regulation, and best practice in relation to parent-patient-clinician-industry involvement. We will test novel agents and interventions in variable clinical use. Each has proof of concept, but definitive proof of efficacy, safety, effect sizes, and precision medicine effects are uncertain. We propose to test 3-4 interventions but will include ability to incorporate additional arms and domains Objectives and methods: We will deliver objectives in 7 work-packages; final selection of i) interventions and ii) research team including NHS, academic and industry co-applicants and collaborators; iii) detailed simulation study to inform platform design; iv) mechanistic study protocols, v) stakeholder communications plan, vi) research ethics application/s for UK and non-UK sites, and vii) operational readiness. Primary measures of efficacy relate to survival without severe necrotising enterocolitis (NEC) at 36 weeks postconceptional age and survival without severe cognitive impairment at age two-years. Mechanistic hypotheses will test the effect of interventions on NEC, an acquired acute inflammatory condition of the preterm gastrointestinal tract and major cause of death and long-term impairment, and brain development, a major determinant of cognitive outcome Timelines: The platform trial will be submitted as a Stage 1 application in May 2023, with anticipated stage 2 application in September 2023, planned start date in 2024, and end date in 2029 Impact and dissemination: Preterm research is an area of great clinical and research need. We have identified considerable interest from potential academic, NHS and industry partners; hence impact and dissemination will be wide. As there have been no neonatal precision-medicine platform trials to-date, this study will position the UK as a global leader in neonatal research and development.

Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH