Title: A multi-centre randomised placebo-controlled trial of prophylactic enteral supplementation with bovine lactoferrin to prevent late-onset invasive infection in very preterm or very low birth weight infants.
Funder: Department of Health and Social Care

Abstract: • Study design: Multi-centre randomised placebo-controlled parallel-group trial with prospective economic evaluation. • Setting: 30 neonatal units in the UK. Participating centres are within established neonatal networks including the UK Neonatal Infection Surveillance Network (neonIN), the Northern, Yorkshire, Trent and Midlands Neonatal Networks, managed clinical networks in Northern Ireland and Scotland, and units with local investigators affiliated to the UK Neonatal Nutrition Group. • Target population: Infants are eligible if (a) gestational age at birth is <32 weeks and (b) they are less than 72 hours old and (c) parent gives written informed consent. Infants who are not receiving any enteral feeds while <7 days old are still eligible and will begin study supplements when minimal enteral nutrition (>12 ml/kg/day) is given. Infants with (a) severe congenital anomalies or (b) infants unlikely to receive any enteral input by 14 days or (c) infants who, in the opinion of the treating clinician, have no realistic prospect of survival are not eligible to participate. • Randomisation: Web-based randomisation via a secure website with telephone back-up hosted by the NPEU Clinical Trials Unit. We will use a bespoke minimisation algorithm to ensure balance on important prognostic factors including recruiting site, sex and gestational age at birth. • Health technology being assessed: Enteral bovine lactoferrin (150 mg/kg/day to a maximum of 300 mg/day - Tatua Dairy, New Zealand) or sucrose placebo added once daily to milk feeds from when minimal enteral feeding is started and continuing until 34 weeks' post-menstrual age. • Outcomes: The primary outcome is the incidence of microbiologically-confirmed or clinically suspected late-onset invasive infection from trial entry until hospital discharge. Invasive infection will be defined using modified UK neonIN and European Medicines Agency consensus definitions [microbial culture from fluid sampled aseptically from a normally sterile site (NOT urine) or clinical and laboratory features of infection with clinician intention to give antibiotics for at least 5 days (see Protocol for full definition)]. Secondary outcomes are: all-cause mortality prior to hospital discharge; NEC: Bell’s stage II or III; Severe ROP treated medically or surgically; BPD: where the infant is still receiving mechanical ventilator support or supplemental oxygen at 36 weeks’ postmenstrual age; a composite of invasive infection, major morbidity (NEC, ROP, or BPD as defined above) and mortality; total number of days of administration of antibiotics administered per infant from 72 hours until death or discharge from hospital; total number of days of administration of antifungal agents per infant; total length of stay until discharge home; Length of stay in (i) intensive care, (ii) high dependency care, (iii) special care. • Costs analysis: The health service resources used by the infant and the family during the infant’s hospital stay will be identified, measured, valued and combined with clinical effectiveness data. If differences in outcomes between the trial groups are detected, these will be used to generate an incremental cost per additional benefit e.g. per infection-free survival to discharge. • Sample size: Calculations are based on a range of plausible primary outcome control event rates (CER) from 24% to 18%, based on estimates from Europe, North America and Australasia. In summary, with 90% power and a two-sided 5% significance level, to detect an absolute risk reduction (ARR) of 5—5.8% (relative risk reduction of 24—28%) would require a trial with a total of up to 2,200 participants if the CER is 18%, 2,070 if the CER is 21%, and 2,076 if the CER is 24%. This target sample size of 2,200 will allow for an anticipated loss to follow-up of up to 5%. This sample size will also be sufficient to exclude important effects on secondary outcomes with 90% power, e.g. a 7% ARR in antibiotic exposure (from 45% to 38%). • Recruitment rate: The participating neonatal units admit on average 60 very low birth weight infants per annum. Based on 40% recruitment, 30 units will be able to recruit a total sample size of up to 2,160 infants over 3 years (an average of 2 infants per unit per month).

Lay abstract: In the UK, about 1-2% of infants are born very preterm (< 32 weeks'). Over the past 20 years, advances in care practices have substantially improved outcomes for this very vulnerable population. In particular, more effective prevention and treatment of lung disease means that very preterm infants are now more likely to survive beyond the first few days after birth. However, very preterm infants often require several weeks of intensive care and are exposed to invasive procedures that increase their risk of acquiring serious infections. About one-fifth to one-quarter of very preterm infants acquire a serious infection and these infants have higher likelihoods of developing other problems including major lung and bowel conditions, and of dying or being disabled. Identifying better methods to prevent infection in very preterm infants has the potential to have a major impact on death and disability rates. In addition, because very preterm infants who acquire infection spend nearly 3 weeks longer in hospital, reducing the incidence of infection has important potential benefits for neonatal care services. By lowering the average length of hospital admission, preventing infection will increase cot availability in neonatal units and therefore reduce overcrowding and the need for transfer of expectant mothers or their sick or preterm newborn infants to units distant from their homes and families. This proposal is to undertake a study to evaluate whether giving very preterm infants supplemental lactoferrin, a natural antibiotic protein processed from cow milk, in their diet prevents serious infections. Lactoferrin is present in the breast milk of all mammals including humans but for a variety of reasons very preterm infants receive only small amounts. A recent Italian study has provided preliminary evidence that giving very low birth-weight infants supplemental lactoferrin mixed with their milk may reduce rates of some infections in some infants. However, this study was not large enough to provide evidence sufficiently convincing to change practice. Additionally, several important differences between the care practices and the types of infections encountered limit the applicability of the Italian trial findings to the UK setting. To address this question definitively, we propose to conduct a randomised trial in which about 2,200 very preterm infants cared for in 30 neonatal units across the UK participate. With informed consent from parents, clinicians in each unit will recruit and randomly allocate infants to receive either (i) active treatment (lactoferrin mixed with a small volume of breast or formula milk) or (ii) sham treatment (sugar placebo) in their diet. Parents will be offered information about the trial and have up to 72 hours to consider whether they wish their baby to take part. In all units, staff are experienced in recruiting to similar trials (often with shorter time frames for consideration by parents). These teams have collectively succeeded in recruiting large numbers of infants on target to three recent studies and are aware of the needs and sensitivities of parents in the early newborn period. Treatment with lactoferrin or placebo will continue until the infants are no longer at high risk of acquiring serious infections (the equivalent of 34 weeks' gestation). The clinicians, caregivers and parents or carers will not be aware whether each individual infant is receiving lactoferrin or placebo - a 'blinded' randomised controlled trial, the most robust method of assessing the effects of a treatment. As well as comparing serious infection rates between the two groups, we will assess the effects of lactoferrin supplementation on the risk of other serious diseases and death, on the need for infants to receive multiple or prolonged courses of antibiotics (a major cause of antibiotic resistance in neonatal units), and on the length of hospital stay. The trial team includes a network of clinicians whose daily work is intensive and developmental care for very preterm infants and who have a background and expertise in neonatal infection, nutrition and long term outcomes. Having broad representation from clinicians across the UK aligned to patient representation via BLISS (the special care baby charity) aims to ensure relevance and applicability of the trial findings to the needs of all very preterm infants and their families. The trial will be coordinated, managed and monitored by a team at the National Perinatal Epidemiology Unit Clinical Trials Unit (NPEU CTU) in Oxford. The NPEU CTU has considerable experience of running large randomised controlled trials, and monitoring trial delivery and governance. As well as improving the methodological rigour of the trial (by reducing the numbers of steps with potential for error), centralised trial management will reduce the overall cost to deliver the trial. The other key staff members needed to ensure trial delivery are dedicated research neonatal nurses or midwives located in each of the participating centres. These will be funded for the equivalent of one day per week to manage local aspects of the trial including staff education and training, and explaining processes to parents or carers. By being responsible for the day-to-day smooth running of the trial in participating sites and the management of administration and data collection in each unit, these staff should enhance participation, improve consistency, and raise the profile of clinical research within neonatal units. As well as the benefits to this trial, this should enhance the potential of the NHS to undertake future studies and trials which are essential to drive continued improvement in care and outcomes for very preterm infants and their families. In addition, an experienced health economist is part of the trial team and will undertake an economic evaluation to make sure the intervention is cost-effective, that is, assessing not only whether lactoferrin prevents infection but also that it is most cost-efficient way of using scarce NHS resources to improve health and care outcomes for very preterm infants.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH