The study was a randomized, double-blind, placebo-controlled trial of prophylaxis with trimethoprim–sulfamethoxazole (Sulfatrim Pediatric suspension from Actavis and Sulfamethoxazole and Trimethoprim Oral Suspension from Hi-Tech Pharmacal) in children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection (index infection). The project steering committee designed the trial, which was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and was conducted under an Investigational New Drug application (number 75,739) to the Food and Drug Administration. The study rationale and design have been published previously,12 (link)–16 (link) and the protocol is available with the full text of this article at NEJM.org. The writing group wrote the manuscript and vouches for the completeness and accuracy of the data and analyses and the fidelity of the study to the protocol.
We enrolled children at 19 clinical sites across the United States who were 2 to 71 months of age and had grade I to IV vesicoureteral reflux. We excluded children whose index infection occurred more than 112 days before randomization and children with coexisting urologic anomalies, contraindications for the use of trimethoprim–sulfamethoxazole, or certain medical conditions (see the Supplementary Appendix, available at NEJM.org). We followed the children for 2 years to ascertain the primary outcome of febrile or symptomatic recurrence and secondary outcomes of renal scarring, failure of prophylaxis, and antimicrobial resistance. We also assessed bladder and bowel dysfunction according to a standardized measure (see the Supplementary Appendix).12 (link),17 (link),18 (link) An NIDDK data and safety monitoring board and an institutional review board at each site approved the protocol. Parents or legal guardians of the children provided written informed consent before enrollment.