Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis

Abstract

Rationale & ObjectiveHyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes.Study DesignMulticenter, pragmatic, cluster-randomized clinical trial.Setting & ParticipantsHiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis.InterventionPhosphate binder prescriptions and dietary recommendations to achieve the “Hi” serum phosphate target (≥6.5 mg/dL) or the “Lo” serum phosphate target (<5.5 mg/dL).OutcomesPrimary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome.ResultsThe trial is currently enrolling.LimitationsHiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes.ConclusionsHiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome.Trial RegistrationRegistered at ClinicalTrials.gov with study number NCT04095039. Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes. Multicenter, pragmatic, cluster-randomized clinical trial. HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis. Phosphate binder prescriptions and dietary recommendations to achieve the “Hi” serum phosphate target (≥6.5 mg/dL) or the “Lo” serum phosphate target (<5.5 mg/dL). Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome. The trial is currently enrolling. HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes. HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome.

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