Title: Speed of Increasing milk Feeds Trial (SIFT)
Funder: Department of Health and Social Care

Abstract: • Design: Multi-centre pragmatic randomised controlled parallel-group trial. • Setting: 30 tertiary level neonatal units and their associated continuing care & data collection sites within the UK and Ireland using established neonatal clinical and trial networks. Participating centres are within established neonatal networks including the UK Neonatal Infection Surveillance Network, the Northern, Yorkshire, Trent, Midlands, South Central South Coast, and Norfolk, Suffolk and Cambridgeshire Neonatal Networks, and managed clinical and research networks in Northern Ireland and Scotland. • Target Population: Infants born before 32 completed weeks' gestation or <1500g birthweight, and receiving <30ml/kg/day of milk and where the clinical team are uncertain over the best rate of increase in feeds. Consent will be obtained in the first 48 hours and randomisation will take place at the time the clinician is ready to start increasing the feed volume. Infants with severe congenital anomalies, those not likely to survive or be contactable at follow up will not be eligible. • Health Technologies Being Assessed: Based on survey data indicating acceptable limits of current clinical practice (1), we will compare two rates of increasing the daily volume of milk feeds: 18ml/kg/day increment (slow) and 30 ml/kg/day (fast). If milk is increased as intended, full milk feeds (tolerating 150ml/kg/day) will be reached 4 days sooner in the fast group. • Primary outcome - The primary outcome is the proportion of infants surviving without moderate or severe neurodevelopmental disability at 24 months of age corrected for prematurity. In order to report the proportion of infants surviving without disability a composite parent report questionnaire will be used to identify children with (i) moderate/severe vision impairment, (ii) moderate/severe hearing impairment, and (iii) moderate/severe motor impairment and moderate/severe cognitive impairment defined as PARCA-R PRC scores <44 respectively (2). A child who has any one or more of these will be classified with disability. Definitions for motor and sensory impairments will be as defined in the report published by BAPM in 2008. • Secondary outcomes: incidence of late onset sepsis (after 72 hours of age) before discharge. Sepsis is defined as microbiologically-confirmed or clinically strongly-suspected infection, as defined by the NEONIN dataset; incidence of necrotising enterocolitis; time to reach full milk feeds (defined as 150ml/kg/day for 72 hours); growth to discharge (measured by weight and head circumference); duration of parenteral feeding before discharge; length of time in intensive care; length of hospital stay and survival without serious disability at 24 months corrected age. • Cost analysis: The health service resources used and the costs to the family during the infant’s hospital stay will be identified, measured, valued and combined with clinical effectiveness data and used to generate an incremental cost per additional benefit. • Proposed Sample Size: The event rate for the primary outcome is expected to be 25%. To detect an absolute risk reduction (ARR) of 5.4% from 25% to 19.6% with 90% power, assuming a 2-sided 5% significance level will require ~2500 infants (a minimum of 1236 per arm) (3). This sample size would also have 90% power to detect an increase in the incidence of stage II or III NEC from 6.3% to 9.8% with a 2-sided 5% significance level. Based on previous trials, we anticipate attrition of no more than 20% at two years, reducing the sample evaluated at 2 years to ~2000 babies. We estimate the proportion of infants born before 32 weeks' gestation surviving to 2 years with no or mild disability in the control group to be 69%. The trial will have 90% power to detect an (absolute) increase in survival with no or mild disability of 6% from 69% to 75%. An inflation factor of 1.12 was applied to the sample size to allow for multiple births, expected to have correlated outcomes, receiving the same allocation. This was based on an estimate of 25% for the proportion of multiple births and an intraclass correlation coefficient of 0.9 for the primary outcome at 2 years, based on a similar outcome in a preterm population (4). The total number of babies that will be recruited will be 2800. • Randomisation: Web-based randomisation via a secure web site (www.npeu.ox.ac.uk/SIFT) with a telephone back-up available 24/7 (365 days per year) hosted by the NPEU CTU. Randomisation will ensure balance on important prognostic factors using a minimisation algorithm to including factors such as the collaborating hospital, gestational age at birth and ‘age’ at starting feeding. • Project Timetable and Milestones: Jan 2013 – Jul 2013 obtain R&D approvals from 30 participating sites; Jul 2014 – Dec 2014 obtain approvals and set up 30 additional recruiting sites; Jun 2013- Jun 2015 recruitment and data collection; Jun 2013 – Dec 2016 data collection and cleaning; Jun 2016- Apr 2017 neonatal outcomes analysis and reporting; Jun 2015- Feb 2018 Neurodevelopmental follow up; Jun 2015-Jul 2018 final data collation and verification, data lock, final analysis, reporting and dissemination. • Recruitment rate: Participating units have previously successfully recruited to similar, higher intensity neonatal trials in more selected infants. A modest participation rate of just 10.4% of the UK’s 8000 eligible infants per year, giving 833 recruits a year would take 3 years to complete recruitment of 2500 babies. In 30 neonatal units, this would require an average of 2.3 infants a month per unit. With more than a quarter of the Tertiary units in the UK involved we anticipate that this rate is realistic. I2S2 an NPEU run trial, recruiting infants of less than 31 weeks' gestation is averaging 3 recruits per unit per month. In July 2014, approval was granted to set up an additional 30 recruiting sites in the UK, to help facilitate recruitment to the trial. • Statistical Analysis: Babies will be analysed according to allocation regardless of the feeding regime they actually received (ITT analysis). For the incidence of sepsis, NEC, survival without serious disability at 2 years and other dichotomous outcomes, relative risks and 95% confidence intervals will be calculated. Analysis of time to event outcomes such as time to reach full enteral feeding will use survival analysis techniques. Pre-specified subgroup analyses will include birth weight and gestational age. The consistency of the effect of advancing feeds across subgroups will be assessed using the statistical test of interaction. • Independent Data Monitoring Committee: The DMC will review the progress of the trial at least annually and provide advice on the conduct of the trial to the Trial Steering Committee. • References: (1) EM Boyle. UK and North American Neonatal Feeding Survey: A survey of practice in the feeding of preterm and very low birth weight infants with particular reference to necrotising enterocolitis; Ph.D. Thesis; University of Edinburgh 2011. (2) Johnson S, Wolke D & Marlow N. Developmental assessment of preterm infants at 2 years: Validity of parent reports. Developmental Medicine and Child Neurology 2008; 50:58-62. (3) Vermont Oxford Database, data for 31 Neonatal Units in the United Kingdom, database accessed 29/9/11. (4) Johnson S, Evans TA, Draper ES, Field DJ, Manktelow BN, Marlow N, et al. Neurodevelopmental outcomes following late and moderate prematurity: population-based cohort study. Arch Dis Child Fetal Neonatal Ed. 2015; 100(4):F301–8.

Lay abstract: Survival of preterm infants has increased greatly over recent years, so a major aim now is to improve the long-term outlook for these babies and to avoid serious complications. Over 8000 babies are born very prematurely (more than 8 weeks before their due date) in the UK each year so this is an important issue for the NHS. The way babies are fed in early life affects short and long-term health and survival, parental experience and access to their infants, health care associated costs, and the availability of neonatal intensive care space. Because the bowels of premature babies have not matured, they cannot digest large volumes of milk feeds straight away. Until the gut matures, nutrition is provided by intravenous (iv) drip while the amount of milk feed is gradually increased over time. Increasing the amount of milk rapidly may increase the risk of serious or life-threatening gut complications. On the other hand, increasing slowly means that iv nutrition is needed for longer. As this can only be given down intravenous lines, there is an associated increase in the number of infections proportional to the number of days the line is present in the bloodstream of these babies. Infection is a common cause of death and disease affecting just over a quarter of very low birthweight preterm babies in the UK, and these and gut complications cause more than one third of all deaths in preterm babies who survive their first week of life. Infection or necrotising enterocolitis (NEC), where portions of the bowel undergo necrosis (tissue death), also double the risk of poor long-term outcome for preterm infants. Intravenous feeding also contributes to liver damage, vitamin, salt and nutrition imbalances. Providing iv nutrition safely and effectively is complicated and a recent large NHS confidential enquiry showed that only a quarter of all preterm infants had their iv feeding managed optimally. Recent surveys show large variations between units in intravenous feeding and milk feeding practices and it is therefore clear that doctors currently do not agree on the best way to deal with this. Despite the universal importance of milk feeding preterm babies, there have been very few studies to help doctors learn how best to balance these risks, and what the best way to increase feeds in these babies is - this study sets out to address this missing information. We will compare two different daily rates of increase in milk feeds, one ‘fast’ and one ‘slow’, but both within the rates currently used in UK neonatal units. We aim to find out if either rate gives better outcomes for the infants. We will measure a variety of important outcomes, such as survival, infection, bowel problems, growth and long-term physical and mental development, as well as the impacts on families and the NHS including costs. Increasing feed volumes more quickly may mean babies and their parents need to stay in hospital for less time and could mean that more babies are able to be cared for in the neonatal intensive care unit closest to home, something very important to families. This study will be led by an experienced team of doctors and researchers who have run similar studies before, and will use an established network of neonatal units that have taken part in previous studies. We are confident that there will be enough families happy to take part in the study. The costs requested will support clinical teams to recruit babies, record data and collect outcome information. A clinical trials unit that has helped develop the trial will plan and set up the trial, create and maintain necessary databases, implement web-based randomisation (allocation of babies to either fast or slow increases in their feeds), provide ongoing monitoring and support, perform data analysis, support trial monitoring committees, and contribute to release of the results. The study requires ethics approval, but will compare strategies already in current use so we do not anticipate any problems with this. Importantly parents and patient representatives have been involved in the design phase of the study and will be represented on the monitoring committees.

Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH