PROJECT SUMMARY Opinion-based clinical practice guidelines for management of hyperphosphatemia recommend lowering serum phosphate towards normal in order to improve on the dismal clinical outcomes of patients with end-stage kidney disease (ESKD). However, no randomized clinical trial tested whether phosphate reduction improves clinical outcomes or whether it might provoke unexpected harm. These gaps provided the equipoise needed to initiate “HiLo” as an NIH Health Care Systems Research Collaboratory pragmatic clinical trial in partnership with DaVita. HiLo is testing the hypothesis that targeting a higher serum phosphate (“Hi,” ≥6.5 mg/dl) vs a lower serum phosphate (“Lo,” <5.5 mg/dl) will be superior on the primary hierarchical composite outcome of all-cause mortality and all-cause hospitalization. We initially designed HiLo as a cluster-randomized trial in which entire dialysis units were randomized. Upon review of 434 of the first 558 participants who entered the cluster-randomized trial through 2021, we identified imbalances in baseline characteristics and enrollment rates between the Hi and Lo arms. These findings raised concern that biased recruitment due to post-randomization consent could jeopardize internal validity. In response, we worked with the Data Safety Monitoring Board (DSMB) and DaVita to redesign HiLo as an individual-randomized trial. We resumed recruitment in 2022. The HiLo study team was informed on Friday, November 17, 2023 that the DSMB and NIDDK made the decision to terminate the study due to futility of enrollment and futility of separation between the invention and control arm participants’ mean serum phosphate levels. In this closeout award, we will separately analyze the cluster-randomized and individually-randomized participants and also perform an additional analysis in which the individually-randomized participants are considered a cluster of their own and combined with the other cluster-randomized participants in a single analysis. We will report these results as part of a final manuscript that details the closure of HiLo and conveys lessons learned for PCTs in ESKD.