GERD management in neonatal ICU infants: study protocol for a randomized controlled trial comparing maturation, added rice starch formula and proton pump inhibitors

The prevalence of gastroesophageal reflux disease (GERD) diagnosis among infants in the neonatal intensive care unit (NICU) is high and varies across USA NICUs. GERD diagnosis is challenging as symptoms can be physiological and association is difficult to determine without objective testing methods. Precision diagnostics using 24-hour pH-impedance (pH-Imp) studies with symptom correlation to reflux events have been developed and validated for this population. Current empiric-based, non-standardized GERD management practices are highly variable and are widely untested for safety and efficacy in high-risk NICU infants. The rationale for this randomized controlled trial (RCT) is to compare the efficacy and safety of three widely used interventions for infants that meet the criteria for acid-mediated GERD, objectively diagnosed by 24-hour pH-Imp. This is a prospective, single-center RCT aiming to enroll convalescing NICU infants between 35- and 47-weeks postmenstrual age with objectively diagnosed GERD using a unique parallel 3-arm design comparing the short-term effects of three common management strategies: natural maturation vs. proton pump inhibitors (PPI) vs. added rice starch (AR) formula. Using established 24-hour pH-Imp inclusion criteria, subjects will be randomized to one of the three arms for a 4-week treatment course allocated 1:1:1, stratified by acid reflux index (ARI) (3–7% and > 7%) and feeding method at inception (full oral versus any tube feeds). Primary outcome measures include maintenance or improvement in oral feeding and symptom improvement measured at 4 weeks or discharge whichever is sooner. A second pH-Imp study will be done on treatment to examine treatment efficacy on GERD metrics. The primary clinical endpoints are oral feeding improvement and absence of troublesome symptoms. The mechanistic hypotheses that pH-Imp mechanisms are distinct between assigned therapies, and between clinical success and failure will also be tested. The goal of this study is to refine novel diagnostic pH-Imp criteria for infant GERD diagnosis and compare the efficacy of the three unproven therapies, examine pathophysiological mechanisms for clinical outcomes, define duration of therapy, and assess consequences of interventions. ClinicalTrials.gov. Brief Title: GERD Infant Feeding Therapeutics Trial (GIFT Trial). NCT Number: NCT06114836. Unique Protocol ID: STUDY00003300.