Futility of enrollment and futility of separation between study arms

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

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)

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

Will share data in accordance with the NIH data sharing guidelines

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 will be maintained by the NIDDK.