Clinical trial NCT04095039: HiLo: Pragmatic Trial of Higher vs Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis
Official title: HiLo: Pragmatic Trial of Higher vs Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: All-cause Mortality
Hospitalization
Keywords: All-cause Mortality
All-cause hospitalization
Phosphate management
Hemodialysis
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Northwestern University
name: University of Pennsylvania
name: Davita Clinical Research
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: American Association of Kidney Patients
First posted: 2019-09-19
Enrollment: 793
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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. 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

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)

Eligibility criteria: 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

Primary outcomes:
measure: Hierarchical Composite Mortality and All Cause Hospitalization
timeFrame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months
Secondary outcomes:
measure: Time to All-cause-mortality
timeFrame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months
measure: Hospitalization Days
timeFrame: up to 27 (enter at enrollment end) - 45 (enter at enrollment start) months
measure: Serum Albumin
timeFrame: Baseline (days -30 - 0)
measure: Protein Catabolic Rate (PCR)
timeFrame: Baseline (days -30 - 0)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: DaVita Ensley
state: Alabama
city: Phoenix
country: United States
facility: DaVita Phoenix Dialysis
state: Arizona
city: Camden
country: United States
facility: DaVita Ouachita Valley
state: Arkansas
city: El Dorado
country: United States
facility: DaVita South Arkansas
state: Arkansas
city: Fayetteville
country: United States
facility: DaVita Fayetteville
state: Arkansas
city: Mena
country: United States
facility: DaVita Mena
state: Arkansas
city: Springdale
country: United States
facility: DaVita Springdale
state: Arkansas
city: Long Beach
country: United States
facility: DaVita El Dorado Dialysis
state: California
city: San Diego
country: United States
facility: DaVita San Diego South
state: California
city: Hamden
country: United States
facility: DaVita Hamden
state: Connecticut
city: Middletown
country: United States
facility: DaVita Middlesex
state: Connecticut
city: New Britain
country: United States
facility: DaVita New Britain
state: Connecticut
city: Torrington
country: United States
facility: DaVita Torrington
state: Connecticut
city: Kissimmee
country: United States
facility: DaVita Celebration Dialysis
state: Florida
city: LaGrange
country: United States
facility: DaVita Troup County Dialysis
state: Georgia
city: Thomaston
country: United States
facility: DaVita Thomaston Dialysis
state: Georgia
city: Chicago
country: United States
facility: DaVita Stony Island
state: Illinois
city: Joliet
country: United States
facility: DaVita West Joliet
state: Illinois
city: Vincennes
country: United States
facility: DaVita Vincennes Dialysis
state: Indiana
city: Cambridge
country: United States
facility: DaVita Northeast Cambridge
state: Massachusetts
city: Medford
country: United States
facility: DaVita Wellington Circle
state: Massachusetts
city: Highland Park
country: United States
facility: DaVita Highland Park
state: Michigan
city: Arden Hills
country: United States
facility: DaVita Arden Hills
state: Minnesota
city: Bloomington
country: United States
facility: DaVita Bloomington
state: Minnesota
city: Burnsville
country: United States
facility: DaVita Burnsville
state: Minnesota
city: Cass Lake
country: United States
facility: DaVita Cass Lake
state: Minnesota
city: Coon Rapids
country: United States
facility: DaVita Coon Rapids
state: Minnesota
city: Cottage Grove
country: United States
facility: DaVita Cottage Grove
state: Minnesota
city: Dilworth
country: United States
facility: DaVita Moorehead
state: Minnesota
city: Eden Prairie
country: United States
facility: DaVita Eden Prairie
state: Minnesota
city: Faribault
country: United States
facility: DaVita Faribault
state: Minnesota
city: Fridley
country: United States
facility: DaVita East River Road
state: Minnesota
city: Glencoe
country: United States
facility: DaVita Glencoe
state: Minnesota
city: Hastings
country: United States
facility: DaVita Historical Hastings
state: Minnesota
city: Lakeville
country: United States
facility: DaVita Lakeville
state: Minnesota
city: Maple Grove
country: United States
facility: DaVita Maple Grove
state: Minnesota
city: Minneapolis
country: United States
facility: DaVita Minneapolis Uptown
state: Minnesota
city: Minnetonka
country: United States
facility: DaVita Minnetonka
state: Minnesota
city: New Ulm
country: United States
facility: DaVita New Ulm
state: Minnesota
city: Northfield
country: United States
facility: DaVita Northfield
state: Minnesota
city: Redwood Falls
country: United States
facility: DaVita Redwood Falls
state: Minnesota
city: Richfield
country: United States
facility: DaVita Richfield
state: Minnesota
city: Rochester
country: United States
facility: DaVita Rochester
state: Minnesota
city: Saint Louis Park
country: United States
facility: DaVita St. Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: DaVita St. Paul
state: Minnesota
city: Saint Paul
country: United States
facility: DaVita Sun Ray
state: Minnesota
city: Saint Paul
country: United States
facility: DaVita University Riverside
state: Minnesota
city: Savage
country: United States
facility: DaVita Scott County
state: Minnesota
city: W. Saint Paul
country: United States
facility: DaVita West St. Paul
state: Minnesota
city: Wyoming
country: United States
facility: DaVita Wyoming
state: Minnesota
city: Omaha
country: United States
facility: DaVita Omaha West Dialysis
state: Nebraska
city: Las Vegas
country: United States
facility: DaVita Centennial
state: Nevada
city: Pahrump
country: United States
facility: DaVita Pahrump
state: Nevada
city: Bronx
country: United States
facility: DaVita Bronx
state: New York
city: West Seneca
country: United States
facility: DaVita Orchard Park Dialysis
state: New York
city: Burlington
country: United States
facility: Burlington Dialysis
state: North Carolina
city: Burlington
country: United States
facility: North Burlington Dialysis
state: North Carolina
city: Durham
country: United States
facility: Durham Dialysis
state: North Carolina
city: Durham
country: United States
facility: Bull City Dialysis
state: North Carolina
city: Durham
country: United States
facility: Durham West Dialysis
state: North Carolina
city: Durham
country: United States
facility: Southpoint Dialysis
state: North Carolina
city: Goldsboro
country: United States
facility: DaVita Goldsboro South Dialysis
state: North Carolina
city: Henderson
country: United States
facility: Vance County Dialysis
state: North Carolina
city: Louisburg
country: United States
facility: Kerr Lake
state: North Carolina
city: Reidsville
country: United States
facility: DaVita Reidsville Dialysis
state: North Carolina
city: Roxboro
country: United States
facility: DaVita Roxboro Dialysis
state: North Carolina
city: Southern Pines
country: United States
facility: DaVita Southern Pines Dialysis
state: North Carolina
city: Fargo
country: United States
facility: DaVita Fargo
state: North Dakota
city: Fairborn
country: United States
facility: DaVita Midwest Fairborn
state: Ohio
city: Moore
country: United States
facility: DaVita Moore
state: Oklahoma
city: Tahlequah
country: United States
facility: DaVita Tahlequah
state: Oklahoma
city: McKeesport
country: United States
facility: DaVita McKeesport West
state: Pennsylvania
city: Radnor
country: United States
facility: DaVita Radnor
state: Pennsylvania
city: Maryville
country: United States
facility: DaVita Blount Dialysis
state: Tennessee
city: Tyler
country: United States
facility: Renal Center of Waterton
state: Texas
city: American Fork
country: United States
facility: American Fork Dialysis
state: Utah
city: Bountiful
country: United States
facility: DaVita Bountiful Dialysis
state: Utah
city: Layton
country: United States
facility: DaVita Farmington Bay Dialysis
state: Utah
city: Payson
country: United States
facility: Payson Dialysis
state: Utah
city: Provo
country: United States
facility: Provo Dialysis
state: Utah
city: Salt Lake City
country: United States
facility: DaVita Kolff
state: Utah
city: Sandy
country: United States
facility: DaVita Sandy Dialysis
state: Utah
city: Taylorsville
country: United States
facility: Sandy Dialysis
state: Utah
city: Federal Way
country: United States
facility: DaVita Federal Way Dialysis
state: Washington
Study officials:
affiliation: Duke Nephrology
name: Myles Wolf, MD, MMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.