PrePhage pilot trial: a study protocol for infant-to-infant fecal filtrate transfer to prevent necrotizing enterocolitis in preterm infants

Necrotizing enterocolitis (NEC) is a leading cause of complications in preterm infants, affecting 7% of those with very low birth weight (< 1500 g) and carrying a 24% mortality rate. The disease may involve multiple underlying pathologies of which one may be acute inflammation linked to changes in the gut microbiota composition, suggested by changes in gut viral and bacterial diversity preceding NEC onset. Fecal microbiota transplantation has been proposed to mitigate these changes, but it may lead to bacterial translocation and sepsis. As an alternative, transplantation of sterile fecal filtrate, containing bacteriophages, has shown protective effects against NEC in preterm piglets without serious side effects. This study aims to test fecal filtrate transfer (FFT) in preterm infants at risk of NEC in a pilot study. A double-blinded, randomized controlled pilot trial comparing orally administered FFT from healthy, full-term donor infants to saline in 20 preterm infants (gestational age 26 + 0 to 30 + 6 weeks) was designed. The primary objective is to assess the feasibility of using fecal samples from healthy, term donor infants, who undergo a comprehensive selection and screening process, including feces, urine, blood, and maternal milk samples, for FFT to preterm infants. The secondary objective is to assess clinical outcomes, sepsis rates, NEC incidence, nutritional intake, feeding tolerance, stool patterns and mortality, although the study is not powered to reach conclusions. Finally, we will analyze the bacterial and viral compositions of fecal samples from donors and FFT recipients, to test if FFT significantly alters recipient gut microbiome. Additionally, the feasibility of inclusion of donors and recipients will be evaluated quantitatively and qualitatively. This trial will determine the feasibility of a full-scale clinical trial, validate the novel screening program, address practical challenges in FFT implementation, and establish preliminary data on the safety of infant-to-infant fecal transfers while assessing potential health risks for recipients. ClinicalTrials.gov registration: (NCT05272579 and NCT05272566).