The Limited versus Extended Trophic Feeding (LET-FEED) Trial: Study Protocol of a Multi-Center Individually Randomized Controlled Clinical Trial

Abstract Background : Nearly 30% of all very preterm (VP; defined as those born before 32 weeks’ gestation) newborns develop late onset sepsis (LOS), a life-threatening infection that occurs after 72 hours from birth. Early human milk feeding is associated with reduced risk of LOS. Systematic reviews have reported that the strategy of starting enteral feeds shortly after birth, with advancement in volume before four days from birth, decreases the risk of LOS. However, limited evidence exists to guide advancement before four days. Thus, clinicians are uncertain whether advancing enteral feeds at one versus three days after birth affects outcomes. Methods: This is a multi-center, open-label, parallel-group, individual randomized controlled trial comparing two different trophic feeding regimens in preterm infants born between 25 0/7 and 31 6/7 weeks of gestation and with birthweights <1500 grams. Neonates will be randomly assigned (1:1 allocation) to either limited trophic feeding (20 to 25 mL/kg birthweight/day for one day) or extended trophic feeding (20 to 25 mL/kg birthweight/day for three days) prior to advancing enteral feeds until full feeding volume (≥140 mL/kg day). The primary outcome is LOS, defined as positive blood, urine, and/or cerebrospinal fluid cultures in the presence of compatible clinical signs of sepsis occurring after 72 hours from birth and before hospital discharge, and treated with antibiotics for ≥ 5 days. Secondary outcomes will include length of hospital stay, all-cause in-hospital mortality, duration of intravenous fluids and central line utilization, necrotizing enterocolitis, severe intraventricular hemorrhage, bronchopulmonary dysplasia, or retinopathy of prematurity requiring intervention. Growth metrics will be evaluated using change in weight, length, and head circumference z-scores from birth to 36 weeks’ postmenstrual age. Discussion: The LET-FEED trial will investigate whether advancement of enteral feeds after 1 or 3 days of trophic feeds leads to improved outcomes without evidence of harm among VP newborns. As the trial is a multi-center clinical trial conducted across geographically diverse regions of the US, the findings will have external validity and generalizability to many settings, increasing the potential for directly actionable results. Trial Registration: The present study is registered at ClinicalTrials.gov with identifier No: NCT06893939.