HiLo: Pragmatic Trial of Higher vs Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis

• ClinicalTrials.gov Identifier: NCT04095039
• Recruitment Status: Not yet recruiting
• First Posted: September 19, 2019
• Last Update Posted: September 19, 2019
• Sponsor: Duke University
• Collaborators: Northwestern University; University of Pennsylvania; University of Utah; Davita Clinical Research; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

HiLo will be a pragmatic, open-label, multicenter, cluster-randomized trial of ~4400 patients with ESRD undergoing in-center maintenance hemodialysis at 120-150 units maintained by two dialysis organizations that care for a substantial proportion of the US dialysis population. The 1st objective of HiLo is to test the following primary and secondary hypotheses of HiLo:

Primary hypothesis: Compared to the current standard approach of targeting serum phosphate levels of <5.5 mg/dl, less stringent control of serum phosphate to target levels of >6.5 mg/dl will yield a reduction in the hierarchical composite outcome of time to all-cause mortality and all-cause hospitalization among patients with ESRD undergoing hemodialysis.

Secondary hypothesis: The main secondary hypotheses are that less stringent control of serum phosphate will reduce risk of all-cause mortality as well as the risk of all-cause hospitalization (individually) compared to the current standard approach of strict phosphate control (superiority analysis). In addition, the trial will test the secondary hypotheses that less stringent control of serum phosphate will result in increased serum albumin and protein catabolic rate (PCR), as markers of diet and nutrition.

The 2nd objective of HiLo is to conduct a second-generation pragmatic clinical trial in dialysis. In partnership with two dialysis provider organizations, demonstrate the following for a trial embedded in clinical care delivery:

1. Feasibility of obtaining informed consent using electronic devices (e-consent)
2. Use of a single IRB of record for hundreds of dialysis facilities
3. Successful implementation of a trial-driven treatment algorithm by dietitians at the participating dialysis units
4. Harmonization of data from a large for-profit dialysis provider, a large not-for profit dialysis provider, and an academically-owned small dialysis provider
5. Effective monitoring of trial implementation using a centralized approach

Condition or disease	Intervention/treatment	Phase
Mortality	Procedure: Hemodialysis	Not Applicable

Detailed Description:

Pragmatic Trial Demonstration Goals

The HiLo Trial is one of the pragmatic trial demonstration projects of the NIH Health Care Systems (HCS) Research Collaboratory. These demonstration projects are intended to be large clinical trials that are conducted within the clinical care environment and evaluate interventions implemented by care providers and relying as much as possible on data obtained as part of routine clinical care. HiLo has the following demonstration project goals:

1. To implement an electronic consent process;
2. To use of a single IRB of record to oversee hundreds of dialysis facilities;
3. To implement a trial-driven treatment algorithm by dietitians at the participating dialysis units
4. To harmonize across 2 different dialysis providers data elements obtained though clinical care;
5. To monitor safety without using individual adverse event reporting.

HiLo will cluster-randomize dialysis facilities using stratification to achieve balance across the two arms. Stratification will be by dialysis provider organization (DaVita or University of Utah) and by unit size (above or below the provider's median facility census). Within each stratum, the facilities will be randomly assigned. Once a facility is randomized, all of its individually enrolled patients will be assigned the same treatment.

Participants will be followed for up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months.

Two phosphate titration protocols will be used that have the same "look and feel" as those used in practice in an effort to sustain a mean time-averaged difference in serum phosphate between the two arms of ≥1 mg/dl:

1. Low serum phosphate target that is consistent with current standard of care: The goal is to titrate and maintain serum phosphate to <5.5 mg/dl.
2. Higher serum phosphate target that is the intervention strategy: The goal is to titrate and maintain serum phosphate to >6.5 mg/dl by setting a serum phosphate threshold >7.0 mg/dl when binders will be initiated, as has been done previously.

A mean serum phosphate of 4.8-5.2 is anticipated in the low arm and 6.5-6.8 in the high arm, as observed in two pilot clinical trials.Since serum phosphate is 4-7 mg/dl in most patients with ESRD, ≥1 mg/dl difference equates with a ≥33% difference within the modifiable range of time-averaged phosphate exposure. Specific binder choices will be relegated to the discretion of local providers based on local practice.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 4400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: HiLo: Pragmatic Trial of Higher vs Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis
• Estimated Study Start Date: November 1, 2019
• Estimated Primary Completion Date: April 30, 2023
• Estimated Study Completion Date: April 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Hi Arm; Patients to allow blood serum phosphate levels to rise to 6.5 mg/dl or above	Procedure: Hemodialysis; Patients in both arms will undergo hemodialysis to remove phosphate from the blood; however, patients in the Hi Arm will only be titrated down to no lower than 6.5mg/dl
No Intervention: Lo Arm; Patients to titrate blood serum phosphate levels to the standard <5.5mg/dl

Outcome Measures

Primary Outcome Measures :

1. Hierarchical Composite Mortality and all cause hospitalization [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   Hierarchical composite of time to all-cause mortality and all-cause hospitalization rate (total counts per person-years of follow-up).

Secondary Outcome Measures :

1. Time to all-cause mortality [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   Time to all-cause mortality
2. all-cause hospitalization rate [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   all-cause hospitalization rate, expressed as total counts per person-years of follow-up.
3. Total Inpatient Hospital Days [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   total inpatient hospital days per person-years of follow-up;
4. serum albumin [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   serum albumin as markers of diet and nutrition.
5. protein catabolic rate (PCR) [ Time Frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months ]
   protein catabolic rate (PCR) as markers of diet and nutrition.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adults over 18 years of age
• Undergoing 3 times weekly in-center hemodialysis for at least 3 months
• Able to provide written informed consent

Exclusion Criteria:

• None

Contacts and Locations

Contacts

Contact: Myles Wolf, MD, MMSc; 919-684-9788; myles.wolf@duke.edu

Contact: Davy A Andersen, MHA; 919-668-9997; davy.andersen@duke.edu

Sponsors and Collaborators

Duke University

Northwestern University

University of Pennsylvania

University of Utah

Davita Clinical Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Investigators

• Principal Investigator: Myles Wolf, MD, MMSc; Duke Nephrology

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT04095039 History of Changes
• Other Study ID Numbers: Pro00100325; UG3DK118748 ( U.S. NIH Grant/Contract )
• First Posted: September 19, 2019
• Last Update Posted: September 19, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Will share data in accordance with the NIH data sharing guidelines
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: The Study Protocol SAP will be presented in a methods paper which is planned to be submitted to statistical professionals journals in the coming months. The CSR and the deidentified clinical database will be provided to the NIDDK data repository w/in 3 months of database lock.
• Access Criteria: Access criteria will be maintained by the NIDDK.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Duke University:

All-cause hopitalization