2.1. Trial Design
RECRUITMENT, RECRUITMENT
This prospective, longitudinal, double-blind, randomized controlled clinical trial took place at three clinical sites in the United States (Rhode Island Hospital, RIH; Pennington Biomedical Research Center, PBRC; and Boston Children’s Hospital, BCH) with a two-parallel-group design and a non-randomized reference group of breastfed infants. Randomization was performed using the Medidata RTSM module (dynamic randomization, second-best probability = 15%) and stratified by site and gender. The intervention period was 12 months, and infants were followed up to 2 years of life with the following schedule: V1 (6 ± 1 weeks of life), V2 (3 months ± 2 weeks), V3 (6 months ± 2 weeks), V4 (9 months ± 2 weeks), V5 (12 months ± 2 weeks), V6 (18 months ± 3 weeks), and V7 (24 months ± 4 weeks). The BCH site was closed before study end due to recruitment issues. The two enrolled infants from that site dropped out.Recruitment occurred from 2017 to 2020, with the First Subject First Visit (FSFV) in March 2017, the Last Subject First Visit (LSFV) in March 2020, completion of the 12-month intervention period for all randomized participants in February 2021, and the Last Subject Last Visit (LSLV) in February 2022. After completion of the intervention phase for all participants, a staged statistical analysis (SSA) was approved by the Institutional Review Boards and performed for main outcomes of the 3- and 6-month data only. For the SSA, a collaborator at one of the clinical sites and an external contract research organization were unblinded; however, only aggregated information was shared with the sponsor to ensure blinding until trial completion. The SSA results have been reported in our previous publication that describes recruitment, randomization, blinding, data, and biological sample collection [