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.

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 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).