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

HiLo will be a pragmatic, open-label, multicenter, clinical trial with individual level randomization 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 and an academically-owned small dialysis provider
5. Effective monitoring of trial implementation using a centralized approach

Study Overview

• Status: Terminated
• Conditions: Mortality
• Intervention / Treatment: Procedure: Hemodialysis

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 individually randomize participants using facility-level stratification to achieve balance across the two arms. Stratification will be 1:1 within each facility.

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.

Planned Enrollment and randomization Enrollment of the first subject - 03/13/2020 (Actual) 25% of planned enrollment recruited - 06/30/2022 (Anticipated) 50% of planned enrollment recruited - 10/30/2022 (Anticipated) 75% of planned enrollment recruited - 03/31/2023 (Anticipated) 100% of planned enrollment recruited - 09/30/2023 (Anticipated) 6.4. Completion of primary endpoint data analyses - 11/30/2024 (Anticipated) 6.5. Reporting of results in ClinicalTrials.gov - 1/31/2025 (Anticipated)

• Study Type: Interventional
• Enrollment (Actual): 812
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35218
      • DaVita Ensley
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • DaVita Phoenix Dialysis
  • Arkansas
    • Camden, Arkansas, United States, 71701
      • DaVita Ouachita Valley
    • El Dorado, Arkansas, United States, 71730
      • DaVita South Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • DaVita Fayetteville
    • Mena, Arkansas, United States, 71953
      • DaVita Mena
    • Springdale, Arkansas, United States, 71953
      • DaVita Springdale
  • California
    • Long Beach, California, United States, 90806
      • DaVita El Dorado Dialysis
    • San Diego, California, United States, 27560
      • DaVita San Diego South
  • Connecticut
    • Hamden, Connecticut, United States, 06518
      • DaVita Hamden
    • Middletown, Connecticut, United States, 06457
      • DaVita Middlesex
    • New Britain, Connecticut, United States, 06052-2016
      • DaVita New Britain
    • Torrington, Connecticut, United States, 06790-6268
      • DaVita Torrington
  • Florida
    • Kissimmee, Florida, United States, 34747
      • DaVita Celebration Dialysis
  • Georgia
    • LaGrange, Georgia, United States, 30240
      • DaVita Troup County Dialysis
    • Thomaston, Georgia, United States, 30286
      • DaVita Thomaston Dialysis
  • Illinois
    • Chicago, Illinois, United States, 60617
      • DaVita Stony Island
    • Joliet, Illinois, United States, 60435
      • DaVita West Joliet
  • Indiana
    • Vincennes, Indiana, United States, 47591
      • DaVita Vincennes Dialysis
  • Massachusetts
    • Cambridge, Massachusetts, United States, 02138
      • DaVita Northeast Cambridge
    • Medford, Massachusetts, United States, 02155
      • DaVita Wellington Circle
  • Michigan
    • Highland Park, Michigan, United States, 48203
      • DaVita Highland Park
  • Minnesota
    • Arden Hills, Minnesota, United States, 55112
      • DaVita Arden Hills
    • Bloomington, Minnesota, United States, 55420
      • DaVita Bloomington
    • Burnsville, Minnesota, United States, 55337
      • DaVita Burnsville
    • Cass Lake, Minnesota, United States, 56633
      • DaVita Cass Lake
    • Coon Rapids, Minnesota, United States, 55433
      • DaVita Coon Rapids
    • Cottage Grove, Minnesota, United States, 55016
      • DaVita Cottage Grove
    • Dilworth, Minnesota, United States, 56529
      • DaVita Moorehead
    • Eden Prairie, Minnesota, United States, 55344
      • DaVita Eden Prairie
    • Faribault, Minnesota, United States, 55021
      • DaVita Faribault
    • Fridley, Minnesota, United States, 55421
      • DaVita East River Road
    • Glencoe, Minnesota, United States, 55336
      • DaVita Glencoe
    • Hastings, Minnesota, United States, 55033
      • DaVita Historical Hastings
    • Lakeville, Minnesota, United States, 55044
      • DaVita Lakeville
    • Maple Grove, Minnesota, United States, 55369
      • DaVita Maple Grove
    • Minneapolis, Minnesota, United States, 55409
      • DaVita Minneapolis Uptown
    • Minnetonka, Minnesota, United States, 55345
      • DaVita Minnetonka
    • New Ulm, Minnesota, United States, 56073
      • DaVita New Ulm
    • Northfield, Minnesota, United States, 55057
      • DaVita Northfield
    • Redwood Falls, Minnesota, United States, 56283
      • DaVita Redwood Falls
    • Richfield, Minnesota, United States, 55423
      • DaVita Richfield
    • Rochester, Minnesota, United States, 55904
      • DaVita Rochester
    • Saint Louis Park, Minnesota, United States, 55426
      • DaVita St. Louis Park
    • Saint Paul, Minnesota, United States, 55103
      • DaVita St. Paul
    • Saint Paul, Minnesota, United States, 55106
      • DaVita Sun Ray
    • Saint Paul, Minnesota, United States, 55114
      • DaVita University Riverside
    • Savage, Minnesota, United States, 55378
      • DaVita Scott County
    • W. Saint Paul, Minnesota, United States, 55118
      • DaVita West St. Paul
    • Wyoming, Minnesota, United States, 55092
      • DaVita Wyoming
  • Nebraska
    • Omaha, Nebraska, United States, 68154
      • DaVita Omaha West Dialysis
  • Nevada
    • Las Vegas, Nevada, United States, 89149
      • DaVita Centennial
    • Pahrump, Nevada, United States, 89048
      • DaVita Pahrump
  • New York
    • Bronx, New York, United States, 10461
      • DaVita Bronx
    • West Seneca, New York, United States, 14127
      • DaVita Orchard Park Dialysis
  • North Carolina
    • Burlington, North Carolina, United States, 27215
      • Burlington Dialysis
    • Burlington, North Carolina, United States, 27217-2928
      • North Burlington Dialysis
    • Durham, North Carolina, United States, 27701
      • Durham Dialysis
    • Durham, North Carolina, United States, 27705
      • Bull City Dialysis
    • Durham, North Carolina, United States, 27705
      • Durham West Dialysis
    • Durham, North Carolina, United States, 27713
      • Southpoint Dialysis
    • Goldsboro, North Carolina, United States, 27534
      • DaVita Goldsboro South Dialysis
    • Henderson, North Carolina, United States, 27536
      • Vance County Dialysis
    • Louisburg, North Carolina, United States, 27549
      • Kerr Lake
    • Reidsville, North Carolina, United States, 27320
      • DaVita Reidsville Dialysis
    • Roxboro, North Carolina, United States, 27573
      • DaVita Roxboro Dialysis
    • Southern Pines, North Carolina, United States, 28387
      • DaVita Southern Pines Dialysis
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • DaVita Fargo
  • Ohio
    • Fairborn, Ohio, United States, 45324
      • DaVita Midwest Fairborn
  • Oklahoma
    • Moore, Oklahoma, United States, 73160
      • DaVita Moore
    • Tahlequah, Oklahoma, United States, 74464
      • DaVita Tahlequah
  • Pennsylvania
    • McKeesport, Pennsylvania, United States, 15132-3953
      • DaVita McKeesport West
    • Radnor, Pennsylvania, United States, 19406
      • DaVita Radnor
  • Tennessee
    • Maryville, Tennessee, United States, 37804
      • DaVita Blount Dialysis
  • Texas
    • Tyler, Texas, United States, 75703
      • Renal Center of Waterton
  • Utah
    • American Fork, Utah, United States, 84003
      • American Fork Dialysis
    • Bountiful, Utah, United States, 84010
      • DaVita Bountiful Dialysis
    • Layton, Utah, United States, 84041
      • DaVita Farmington Bay Dialysis
    • Payson, Utah, United States, 84651
      • Payson Dialysis
    • Provo, Utah, United States, 84604
      • Provo Dialysis
    • Salt Lake City, Utah, United States, 84108
      • DaVita Kolff
    • Sandy, Utah, United States, 84070
      • DaVita Sandy Dialysis
    • Taylorsville, Utah, United States, 84129
      • Sandy Dialysis
  • Washington
    • Federal Way, Washington, United States, 98003
      • DaVita Federal Way Dialysis

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

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

Exclusion Criteria:

• Pregnancy
• In-center Nocturnal
• Calciphylaxis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Pennsylvania; Northwestern University; Davita Clinical Research; American Association of Kidney Patients
• Investigators: Principal Investigator: Myles Wolf, MD, MMSc, Duke Nephrology

Publications and helpful links

General Publications

• Edmonston DL, Isakova T, Dember LM, Brunelli S, Young A, Brosch R, Beddhu S, Chakraborty H, Wolf M. Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis. Am J Kidney Dis. 2021 Jun;77(6):920-930.e1. doi: 10.1053/j.ajkd.2020.10.008. Epub 2020 Dec 3.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2020
• Primary Completion (Actual): November 17, 2023
• Study Completion (Actual): November 17, 2023

Study Registration Dates

• First Submitted: September 10, 2019
• First Submitted That Met QC Criteria: September 17, 2019
• First Posted (Actual): September 19, 2019

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: All-cause hospitalization
• Other Study ID Numbers: Pro00100325; 5UH3DK118748-03 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Will share data in accordance with the NIH data sharing guidelines
• IPD Sharing 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.
• IPD Sharing Access Criteria: Access criteria will be maintained by the NIDDK.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No