Title: Nutritional Evaluation and Optimisation in Neonates (NEON) trial of amino acid regimen and intravenous lipid composition in preterm parenteral nutrition: a randomised double blind controlled trial
Funder: Department of Health (England)

Abstract: Design: Multicentre UK randomised double blind controlled trial (RCT). Eligible infants will be randomised within 12 hours of birth to receive parenteral nutrition (PN) with Recommended Daily Intake of amino acids (intervention) or PN with incremental increase in amino acids (control) and either 20% lipid (control) or 20% SMOF lipid (intervention). Intralipid is a first generation intravenous emulsion that is the currently widely used formulation. SMOF lipid a third generation emulsion (soy bean medium chain triglycerides olive and fish oil) has an improved ratio of n6 to n3 fatty acids that has been shown to be liver protective. Randomisation will be stratified by gestational age and centre. Enteral feeding will be commenced within 24 hours and advanced according to a pre-specified protocol that has previously been used by us in a RCT to control for potential differences arising from different feeding regimens. Dietary intakes will be captured from birth until discharge prospectively. PN will continue until the infant is tolerating full milk feeds. Enteral nutrition will be in the form of maternal expressed breast milk. If this is in short supply standard preterm formula milk will be used as supplement. Research ethics approval and informed parental consent will be sought. The trial will be conducted in accordance with Good Clinical Practice. A Data Monitoring Committee and Trial Steering Committee will be set up. User input has been sought.Setting: Neonatal Intensive Care units in North West London. Participants within this perinatal network cover wide socio economic and ethnic groups and are representative of those in the rest of the NHS. Target Population: Preterm infants less than 31 weeks of gestation. These are infants who require nutritional support in the form of PN. Exclusion criteria: Infants with major congenital or life threatening anomalies.Intervention being evaluated: The intervention being evaluated is PN. PN is the only means of delivering nutrition in extremely preterm infants in the immediate period after birth because of gastrointestinal immaturity and also when enteral feeding is contraindicated. Current practice in neonates is variable inconsistent and not evidence based. Current practice results in significant deficits in protein which cannot be made up. Although RDI have been described for this group of infants (based on fetal growth rates from studies on fetal cadavers) the impact on body composition of providing this from birth has not previously been studied.Measurements of outcomes and duration of follow up: Primary outcome measure: Body composition at term or near term age equivalent including lean body mass and adipose tissue mass measured by whole body magnetic resonance imaging (MRI) and Hepatic magnetic resonance spectroscopy (MRS) to measure intrahepatocellular lipid content (IHCL). Secondary outcome measures: 1. Adipose tissue quantity and distribution. 2. Anthropometry; 3. Brain MRI (brain growth measured by cerebral volumes); 4. Metabolic index of insulin sensitivity at term age equivalent (QUICKI) calculated using fasting serum glucose and insulin; While measurement of weight head circumference and length are inexpensive and routinely used to monitor growth they do not reflect the composition of weight gain in relation to lean body and adipose tissue mass. It is not only the quantity but the distribution of lean and adipose tissue that is associated with metabolic health. The distribution of lean and adipose tissue mass is strongly influenced by diet and in turn affect metabolic health. Therefore measurements of lean and adipose tissue mass are more clinically meaningful outcomes to measure following nutritional intervention. There are many ways to measure body composition. Several methods rely on assumptions and while they can measure absolute quantity of a certain tissue they cannot measure the distribution. MRI and MRS are non invasive and validated against the respective gold standards of cadaver dissection and liver biopsy. MRI has the advantage of directly quantifying quantity and distribution of lean and adipose tissue mass. We have developed the use of this technique in this age group. We have access to a dedicated neonatal research MRI facility. QUICKI is a marker of insulin resistance. HOMA is the gold standard for measuring insulin resistance but is invasive and cannot be justified in this patient group. QUICKI had been validated against HOMA and been used in neonates before. Similarly head circumference is used as a surrogate for brain growth but correlates poorly with brain volume as measured by MRI. Subject to future funding there will be follow up at 6 years for a neuro developmental assessment and anthropometry and body composition at 10 years (MRI and hepatic MRS). Sample size and Planned Analyses: The mean (standard deviation) of lean body mass of preterm infant is 2.1 (0.4)kg. 64 infants in each group would allow us to detect a 0.2 kg difference in lean mass between the groups using 80% power and 5% significance level. The same number will allow a detection of 40% decrease in IHCL in the intervention group of SMOF lipid. Assuming a 10% mortality prior to term and 10% drop out rate 80 infants will be recruited in to each group. This is a 2 * 2 factorial randomised trial. Analysis will be performed at the margins of the 2 by 2 table and an interaction ratio calculated.Project timetables including recruitment rate: Ethics approval Clinical Trial Authorisation R&D approvals and final protocol will take six months. Recruitment will be over a period of 2 and a half years. The final six months will be spent analysing the data. We will recruit from our own and other hospitals within this perinatal network that have previously collaborated with us. In one RCT we recruited 40 infants over a 1 year period and in the second 160 over 18 months. We do not anticipate difficulties with recruiting the required number of infants (160 over 30 months) as there are a total of 120 infants born a year at less than 31 weeks of gestation in the hospitals that we will recruit from and in our previous studies have had a recruitment rate of approximately 70%. This study has already been presented at the North West London Perinatal Network R&D meeting to inform the design of the study.


Research activity codes: 6.7 PHYSICAL
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH