Title: Multicentre open label, pragmatic randomised controlled trial of early surfactant therapy versus expectant management in late preterm and early term infants with respiratory distress
Funder: Department of Health and Social Care

Abstract: This research will focus on babies born two to six weeks before their due date. Every year in the UK there are around 40,000 babies born between 34 and 36 weeks of pregnancy. These babies are said to be 'late preterm'. There are also over 130,000 born between 37-38 weeks of pregnancy or 'early term' each year in the UK. Babies born even just a few weeks early are not fully developed, which can cause problems early in life._x000D_ Many late preterm and early term babies have breathing problems after birth, which can be severe. Some need to go onto a breathing machine (ventilator) soon after birth; many do not, but still need some help with breathing. They often go onto ‘non-invasive’ breathing support which means that machines give oxygen through soft, short tubes in the nose or small masks over the nose. The lungs of healthy full term babies produce surfactant, a substance that makes it easier for them to breathe. Late preterm or early term babies often do not make enough, or their natural surfactant does not work properly. We can give extra surfactant into the lungs of these babies by putting a tube in the windpipe, but this procedure can be uncomfortable for babies and they sometimes need to go onto a ventilator for a period of time afterwards. Not all babies need extra surfactant, but it is hard to predict which will get better with non-invasive support alone and which will go on to develop severe breathing problems and need to have intensive care for longer. We want to know if it is better to give surfactant early, when a baby first starts to need help with breathing, or wait to see if they improve without surfactant and only give it if they do not improve._x000D_ Breathing problems mean that the baby and mother are separated while the baby needs to be cared for on a neonatal unit. Often both mother and baby stay in hospital for longer than expected. There have been no research studies looking at the use of surfactant in late preterm and early term babies with breathing problems. Because of this, practice varies according to doctors’ experience and preferences. We want to know if giving surfactant early can reduce the number of days that babies with breathing problems need to stay in hospital, and reduce their chances of developing very severe breathing problems._x000D_ Babies who are starting non-invasive support because of breathing difficulties will be able to take part in this study. A computer will decide, at random, if the baby will get surfactant or not. When the study ends, we will compare the groups to see how long the babies in each group are in hospital, and how many babies in each group develop severe breathing problems. We will also look at the costs of treatment in each group._x000D_ We will give parents information explaining the study and get their written consent for their baby to take part. We will appoint a group of parents to help design a study that is acceptable to families. They will review parent leaflets to check they are clear and easy to understand, and will advise the research team during the trial. We will present results of the study at medical conferences and publish them in high quality medical journals. We will make sure that parents of babies in the study can get feedback at the end of the study and Bliss, the charity for babies born premature or sick and other parent organisations will help us tell other parents and the public about the results.

Lay abstract: Research Question: In babies born at 34-38 weeks’ gestation with respiratory distress, where the clinical plan is to give non-invasive respiratory support(P), does early use of surfactant(I) compared with expectant management(C) result in shorter hospital stay and reduced failure to respond to treatment(O)?_x000D_ Background: Respiratory distress is common in late preterm (LP) and early term (ET) babies and their childhood respiratory outcomes are worse than those of full term babies. The commonest reason for neonatal unit (NNU) admission is respiratory distress syndrome due to surfactant deficiency. No evidence-based guidance exists for early respiratory management in this population and clinical practice varies widely. Many babies receive non-invasive respiratory support after birth. Some recover spontaneously but others go on to need mechanical ventilation and prolonged intensive care. It is difficult to predict which babies will deteriorate. Some clinicians use surfactant early to prevent respiratory deterioration; others choose to wait and give surfactant only if needed. The best strategy to prevent severe neonatal respiratory disease and reduce adverse long-term respiratory outcomes is not known._x000D_ Aim: To investigate whether, in LP and ET infants with respiratory distress, early use of surfactant versus expectant management results in shorter duration of hospital stay and reduced disease severity. _x000D_ Objectives:_x000D_ A.To compare length of hospital stay and number of babies with failure to respond to treatment in LP and ET babies receiving early surfactant, versus those receiving expectant management._x000D_ B.To investigate the effectiveness and cost-effectiveness of early surfactant therapy on important secondary outcomes_x000D_ C.To examine the impact of early surfactant therapy on parent/carer health-related quality of life _x000D_ D.To examine, using economic evaluation, whether any benefits associated with early surfactant therapy are justified by resource implications needed to deliver the treatment._x000D_ E.To undertake an internal pilot study to assess recruitment and retention of participants, delivery of interventions, assess protocol adherence, monitor safety and evaluate completeness of data collection._x000D_ Methods: We will conduct a multicentre, randomised controlled trial of early surfactant versus expectant management in LP and ET babies admitted to a NNU with respiratory distress, where a clinical decision has been taken to provide non-invasive respiratory support. Eligible babies whose mothers give consent and who have been allocated to the treatment arm at randomisation will receive 100-200mg/kg surfactant, in line with usual clinical practice, and non-invasive respiratory support according to local practice. Babies allocated to the control arm will receive non-invasive respiratory support alone. Babies in either trial arm may receive 'rescue' surfactant at the attending clinician's discretion if they meet pre-defined criteria for severe respiratory disease. Following the trial, we will study hospital admissions to one year using data linkage._x000D_ Timeline: 6 months set up, 30 months accrual(with internal pilot) 6 months analysis and dissemination; duration 42 months. Health economic analysis at 1 year corrected age._x000D_ Impact and dissemination: Results will be disseminated via Bliss and other parent organisations. Dissemination to professionals will be via professional bodies, conferences and peer-reviewed publications. Results will inform national guidance to ensure cost-effective, evidence-based care for LP and ET babies.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH