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All-cause MortalityNCT04095039

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

A study testing Hemodialysis in people with All-cause Mortality and Hospitalization, run by Duke University at 84 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
All-cause Mortality, Hospitalization
What is being tested?
Hemodialysis
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
793 participants
Where
84 sitesUnited States
Study dates
11 Mar 2020to 17 Nov 2023
Phase
Interventional
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • Pregnancy
  • In-center Nocturnal
  • Calciphylaxis

Trial locations and contacts

84 sites in 1 country.

84 sites in 1 country

United States84 sites
  • American Fork Dialysis

    American Fork, Utah, 84003

  • DaVita Arden Hills

    Arden Hills, Minnesota, 55112

  • DaVita Ensley

    Birmingham, Alabama, 35218

  • DaVita Bloomington

    Bloomington, Minnesota, 55420

  • DaVita Bountiful Dialysis

    Bountiful, Utah, 84010

  • Burlington Dialysis

    Burlington, North Carolina, 27215

  • North Burlington Dialysis

    Burlington, North Carolina, 27217-2928

  • DaVita Burnsville

    Burnsville, Minnesota, 55337

  • DaVita Northeast Cambridge

    Cambridge, Massachusetts, 02138

  • DaVita Ouachita Valley

    Camden, Arkansas, 71701

  • DaVita Cass Lake

    Cass Lake, Minnesota, 56633

  • DaVita Stony Island

    Chicago, Illinois, 60617

  • DaVita Coon Rapids

    Coon Rapids, Minnesota, 55433

  • DaVita Cottage Grove

    Cottage Grove, Minnesota, 55016

  • DaVita Moorehead

    Dilworth, Minnesota, 56529

  • Durham Dialysis

    Durham, North Carolina, 27701

  • Bull City Dialysis

    Durham, North Carolina, 27705

  • Durham West Dialysis

    Durham, North Carolina, 27705

  • Southpoint Dialysis

    Durham, North Carolina, 27713

  • DaVita Eden Prairie

    Eden Prairie, Minnesota, 55344

  • DaVita South Arkansas

    El Dorado, Arkansas, 71730

  • DaVita Midwest Fairborn

    Fairborn, Ohio, 45324

  • DaVita Fargo

    Fargo, North Dakota, 58104

  • DaVita Faribault

    Faribault, Minnesota, 55021

  • DaVita Fayetteville

    Fayetteville, Arkansas, 72703

  • DaVita Federal Way Dialysis

    Federal Way, Washington, 98003

  • DaVita East River Road

    Fridley, Minnesota, 55421

  • DaVita Glencoe

    Glencoe, Minnesota, 55336

  • DaVita Goldsboro South Dialysis

    Goldsboro, North Carolina, 27534

  • DaVita Hamden

    Hamden, Connecticut, 06518

  • DaVita Historical Hastings

    Hastings, Minnesota, 55033

  • Vance County Dialysis

    Henderson, North Carolina, 27536

  • DaVita Highland Park

    Highland Park, Michigan, 48203

  • DaVita West Joliet

    Joliet, Illinois, 60435

  • DaVita Celebration Dialysis

    Kissimmee, Florida, 34747

  • DaVita Troup County Dialysis

    La Grange, Georgia, 30240

  • DaVita Lakeville

    Lakeville, Minnesota, 55044

  • DaVita Centennial

    Las Vegas, Nevada, 89149

  • DaVita Farmington Bay Dialysis

    Layton, Utah, 84041

  • DaVita El Dorado Dialysis

    Long Beach, California, 90806

  • Kerr Lake

    Louisburg, North Carolina, 27549

  • DaVita Maple Grove

    Maple Grove, Minnesota, 55369

  • DaVita Blount Dialysis

    Maryville, Tennessee, 37804

  • DaVita McKeesport West

    McKeesport, Pennsylvania, 15132-3953

  • DaVita Wellington Circle

    Medford, Massachusetts, 02155

  • DaVita Mena

    Mena, Arkansas, 71953

  • DaVita Middlesex

    Middletown, Connecticut, 06457

  • DaVita Minneapolis Uptown

    Minneapolis, Minnesota, 55409

  • DaVita Minnetonka

    Minnetonka, Minnesota, 55345

  • DaVita Moore

    Moore, Oklahoma, 73160

  • DaVita New Britain

    New Britain, Connecticut, 06052-2016

  • DaVita New Ulm

    New Ulm, Minnesota, 56073

  • DaVita Northfield

    Northfield, Minnesota, 55057

  • DaVita Omaha West Dialysis

    Omaha, Nebraska, 68154

  • DaVita Pahrump

    Pahrump, Nevada, 89048

  • Payson Dialysis

    Payson, Utah, 84651

  • DaVita Phoenix Dialysis

    Phoenix, Arizona, 85004

  • Provo Dialysis

    Provo, Utah, 84604

  • DaVita Radnor

    Radnor, Pennsylvania, 19406

  • DaVita Redwood Falls

    Redwood Falls, Minnesota, 56283

  • DaVita Reidsville Dialysis

    Reidsville, North Carolina, 27320

  • DaVita Richfield

    Richfield, Minnesota, 55423

  • DaVita Rochester

    Rochester, Minnesota, 55904

  • DaVita Roxboro Dialysis

    Roxboro, North Carolina, 27573

  • DaVita St. Louis Park

    Saint Louis Park, Minnesota, 55426

  • DaVita St. Paul

    Saint Paul, Minnesota, 55103

  • DaVita Sun Ray

    Saint Paul, Minnesota, 55106

  • DaVita University Riverside

    Saint Paul, Minnesota, 55114

  • DaVita Kolff

    Salt Lake City, Utah, 84108

  • DaVita San Diego South

    San Diego, California, 27560

  • DaVita Sandy Dialysis

    Sandy City, Utah, 84070

  • DaVita Scott County

    Savage, Minnesota, 55378

  • DaVita Southern Pines Dialysis

    Southern Pines, North Carolina, 28387

  • DaVita Springdale

    Springdale, Arkansas, 71953

  • DaVita Tahlequah

    Tahlequah, Oklahoma, 74464

  • Sandy Dialysis

    Taylorsville, Utah, 84129

  • DaVita Bronx

    The Bronx, New York, 10461

  • DaVita Thomaston Dialysis

    Thomaston, Georgia, 30286

  • DaVita Torrington

    Torrington, Connecticut, 06790-6268

  • Renal Center of Waterton

    Tyler, Texas, 75703

  • DaVita Vincennes Dialysis

    Vincennes, Indiana, 47591

  • DaVita West St. Paul

    West Saint Paul, Minnesota, 55118

  • DaVita Orchard Park Dialysis

    West Seneca, New York, 14127

  • DaVita Wyoming

    Wyoming, Minnesota, 55092

Other trials in United States

About this study

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.

Read more

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
Read the 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 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)

Being tested
Hemodialysis
Keywords
All-cause Mortality, All-cause hospitalization, Phosphate management, Hemodialysis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • HemodialysisProcedure or surgery

    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

Study groups in NCT04095039
Study groupRoleWhat they receive
Hi ArmExperimentalPatients to allow blood serum phosphate levels to rise to 6.5 mg/dl or above
Receives: Procedure: Hemodialysis
Lo ArmNo interventionPatients to titrate blood serum phosphate levels to the standard <5.5mg/dl

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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) for the individually randomized cohort

    Measured: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months

Secondary outcomes (4)
  1. Time to All-cause-mortality

    Time to all-cause-mortality from baseline for both cluster-randomized and individually randomized cohorts.

    Measured: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months

  2. Hospitalization Days

    Total days hospitalized (Data reflects participants with valid, non-missing hospitalization start and end dates.)

    Measured: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months

  3. Serum Albumin

    serum albumin as markers of diet and nutrition.

    Measured: Baseline (days -30 - 0)

  4. Protein Catabolic Rate (PCR)

    protein catabolic rate (PCR) as markers of diet and nutrition (g/kg/day).

    Measured: Baseline (days -30 - 0)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Sep 2019
  2. Study start11 Mar 2020
  3. Primary completion17 Nov 2023
  4. Study completion17 Nov 2023

Why it stopped: Futility of enrollment and futility of separation between study arms

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
793 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04095039
Sponsor's protocol ID
Pro00100325
Other IDs
5UH3DK118748-05
Status last verified
Jul 2023
First submitted
10 Sep 2019
Last updated
24 Apr 2025
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Will share data in accordance with the NIH data sharing guidelines

Publications

  • Edmonston D, Isakova T, Dember LM, Waymyers S, Andersen D, Chan KE, Chakraborty H, Wolf M. Higher versus Lower Phosphate Targets for Patients Undergoing In-Center Hemodialysis: A Randomized Controlled Trial. J Am Soc Nephrol. 2025 Dec 1;36(12):2445-2455. doi: 10.1681/ASN.0000000765. Epub 2025 Jul 10.

    PubMed 40638247
  • Fajol A, Faul C. The Pathologic Actions of Phosphate in CKD. Kidney360. 2025 Apr 17;6(6):1040-1049. doi: 10.34067/KID.0000000820.

    PubMed 40241437
  • 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.

    PubMed 33279558

Questions about this trial

What is this clinical trial studying?

A study testing Hemodialysis in people with All-cause Mortality and Hospitalization, run by Duke University at 84 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 24 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 84 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Yes. Results are posted in the registry (first posted 8 Jan 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Hierarchical Composite Mortality and All Cause Hospitalization (time frame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04095039, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Apr 2025.

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