HiLo: Pragmatic Trial of Higher vs Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis
Phase: NA
Conditions: All-cause Mortality, Hospitalization
Sponsor: Duke University

 
 
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HiLo: Pragmatic trial of higher vs lower serum phosphate targets in patients 
undergoing hemodialysis 
 
Funding Source 
National Institute of Digestive, Diabetes 
and Kidney Disease (NIDDK)  
NIH Grant Number  
UH3DK118748 
Duke University Protocol Number  
Pro00100325 
Principal Investigator  
Myles Wolf, MD, MMSc  
Clinical Trials.gov Number  
NCT04095039 
Date; Version 
September 24,2021; Version 5.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
THIS DOCUMENT CONTAINS INFORMATION THAT IS PRIVILEGED OR 
CONFIDENTIAL AND MAY NOT BE DISCLOSED UNLESS SUCH DISCLOSURE IS 
REQUIRED BY APPLICABLE LAWS AND REGULATIONS. THE INFORMATION IN 
THIS DOCUMENT IS THE PROPERTY OF THE DUKE CLINICAL RESEARCH 
INSTITUTE (DCRI) AND MAY NOT BE REPRODUCED, PUBLISHED, OR 
DISCLOSED TO OTHERS WITHOUT WRITTEN AUTHORIZATION FROM DCRI.

 
 
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PROTOCOL APPROVAL PAGE 
 
Study Title: HiLo: Pragmatic trial of higher vs lower serum phosphate targets in patients 
undergoing hemodialysis 
 
Version: 5.0 
 
Date of Issue:  September 24 2021 
 
Study Funding Source: National Institute of Digestive, Diabetes and Kidney Disease 
(NIDDK) 
 
 
We, the undersigned, have read and approve this protocol and agree on its content. 
 
 
______________________________________________ 
 
 
NIDDK Representative 
 
______________________________________________ 
Date 
 
 
 
______________________________________________ 
 
 
Principal investigator 
 
______________________________________________ 
Date 
 
 
 

 
 
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PROTOCOL VERSION AND AMENDMENT TRACKING 
Version 
Number/Amendment 
Approval Date 
Summary of Changes 
1.0 
November 19, 2018 
Initial Submission 
2.0 
August 16, 2019 
Added protocol number; removed DCI as recruiting 
center; updated primary outcome / analytical 
approach to a hierarchical composite of all-cause 
mortality and all-cause hospitalizations; adjusted 
randomization stratification to above and below 
provider’s median facility census; updated sample 
size language; added interim analysis and stopping 
rules 
3.0 
November 1, 2019 
Added pregnancy exclusion 
4.0 
February 02,2021 
Clarified inclusion as at least 3 months of dialysis 
treatment, not specific to in-center hemodialysis; 
added Calciphylaxis and Nocturnal in-center dialysis 
as exclusion criteria 
5.0 
September 21 2021 
Changed randomization and analysis to individual 
level randomization from cluster-randomized design 
 
 
 
 
 

 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
HiLo: Pragmatic trial of higher vs lower serum phosphate 
targets in patients undergoing hemodialysis 
Short Title 
HiLo 
Protocol Number 
Pro00100325 
Funding Source 
National Institutes of Diabetes and Digestive and Kidney 
Diseases 
Study Design 
Pragmatic, open-label, clinical outcomes trial with individual-
level randomization 
Principal Investigator 
Myles Wolf, MD, MMSc 
Study Objectives 
1. To determine whether less stringent control of serum 
phosphate to target levels of ≥6.5 mg/dl versus the 
current standard approach of targeting serum phosphate 
levels of <5.5 mg/dl will result in lower rates of the 
hierarchical composite outcome of all-cause mortality 
and all-cause hospitalization among patients with ESRD 
undergoing hemodialysis. 
2. To demonstrate the capacity to conduct a second-
generation, large-scale, randomized pragmatic clinical 
trial that requires individual-level informed consent in 
partnership with two dialysis provider organizations. 
Intervention / Comparator  
Arms 
High protocol: Target a serum phosphate range of ≥6.5 mg/dl
Low protocol: Target serum phosphate of <5.5 mg/dl 
Enrollment Period 
24 months 
Duration 
45 months 
Dialysis Provider(s) 
Outpatient hemodialysis facilities operated by: 
1. DaVita, Inc. 
2. University of Utah 
Data Coordinating Center 
Duke Clinical Research Institute (DCRI) 
Number of Facilities, Patients 
100-150 facilities, ~4400 patients 
Main Eligibility Criteria 
Dialysis Facility Eligibility  
 
Willingness of the medical director, treating 
nephrologists and dietitians to adopt either the high or 
low phosphate target ranges for participating patients 
 
Willingness of the facility manager to allow dietitians to 
participate in training and regularly scheduled 
teleconferences throughout the duration of HiLo 
 
Facility dietitian comfort with the phosphate targets and 
willingness to implement the trial procedures and attend 
training and teleconferences throughout the duration of 
HiLo 
Patient Eligibility 
Inclusion criteria:  
 
Adults ≥18 years  

 
 
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 
Undergoing 3 times weekly in-center hemodialysis and 
having received dialysis treatment for at least 3 months 
 
Able to provide informed consent 
Exclusion criteria:  
 
Females who are pregnant or who plan to become 
pregnant while in the study 
 
Calciphylaxis 
 
Nocturnal in-center dialysis 
Outcomes 
Primary: hierarchical composite outcome of all-cause 
mortality and all-cause hospitalization rate 
 
Main Secondary Outcomes: all-cause mortality; all-cause 
hospitalization rate   
Additional Secondary Outcomes: total inpatient hospital days 
PPY of follow-up; serum albumin and protein catabolic rate 
(PCR), as markers of diet and nutrition.  
Duration of Intervention 
45 months 
Analytic Approach 
Primary efficacy analysis will use the intention to treat (ITT) 
sample that includes all randomized patients. 
Primary outcome: The primary analysis of HiLo is the 
comparison of the Finkelstein-Schoenfeld scores across the 
two serum phosphate arms on the hierarchical composite 
endpoint of time to all-cause mortality and hospitalization 
rate. 
Main secondary outcomes: Cox regression will be used to 
estimate the effect of phosphate target arm on time-to-all-
cause mortality; per person year hospitalization rate ratios 
will be compared between the two serum phosphate arms. 
Additional secondary outcomes: Use mixed effect models to 
examine individual participants’ total number of days spent in 
the hospital per total length of follow-up according to two 
serum phosphate arms.  
Study Oversight 
An independent Data and Safety Monitoring Board (DSMB) 
appointed by NIDDK will review trial progress, data quality, 
and safety throughout the course of the trial in accordance 
with a Data and Safety Monitoring Board Charter. 
 
 
 

 
 
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TABLE OF CONTENTS 
Contents 
Protocol Approval Page .................................................................................................... 2 
Protocol Version and Amendment Tracking ...................................................................... 3 
Protocol Synopsis ............................................................................................................. 4 
Table of Contents .............................................................................................................. 6 
List of Tables ..................................................................................................................... 9 
List of Figures .................................................................................................................... 9 
Abbreviations .................................................................................................................. 10 
 
Background and Rationale .................................................................................. 11 
1.1 
Background and Rationale for the HiLo Trial Question ........................... 11 
1.2 
Rationale for Pragmatic Trial Design ....................................................... 11 
 
Objectives, Outcomes, and Goals ....................................................................... 14 
2.1 
Primary Objectives................................................................................... 14 
2.2 
Secondary Objectives .............................................................................. 14 
2.3 
Primary Outcome ..................................................................................... 14 
2.4 
Secondary Outcomes .............................................................................. 14 
2.4.1 
Pragmatic Trial Demonstration Goals ....................................... 15 
 
Study Organization .............................................................................................. 16 
3.1 
Study Leadership ..................................................................................... 16 
3.2 
Dialysis Provider Organizations ............................................................... 16 
3.3 
Data Coordinating Center: The Duke Clinical Research Institute 
(DCRI)...................................................................................................... 16 
3.4 
Subcommittees ........................................................................................ 16 
 
Study Design ....................................................................................................... 18 
4.1 
Overview of Study.................................................................................... 18 
4.2 
Study Setting ........................................................................................... 18 
4.3 
Facility and Participant Selection ............................................................. 18 
4.3.1 
Facility Eligibility ........................................................................ 18 
4.3.2 
Participant Eligibility .................................................................. 18 
4.4 
Participant Timeline ................................................................................. 19 
4.5 
Randomization ......................................................................................... 19 
4.6 
Intervention .............................................................................................. 19 
4.6.1 
Frequency of Serum Phosphate Measurements ...................... 19 
4.6.2 
Phosphate Binder Choices ....................................................... 19 
4.6.3 
Titrations Strategies .................................................................. 19 
4.6.4 
Thresholds of Phosphate Control ............................................. 22 
4.6.5 
Approach to Phosphate Binders ............................................... 22 

 
 
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4.6.6 
Approach to Diet ....................................................................... 22 
4.6.7 
Approach to Management of Hypercalcemia and Secondary 
Hyperparathyroidism ................................................................. 22 
4.7 
Dialysis Provider Staff Roles ................................................................... 23 
4.7.1 
Role of Dietitians in Implementing HiLo Interventions in 
Facilities .................................................................................... 23 
4.7.2 
Role of Treating Nephrologists ................................................. 23 
4.8 
Adherence ............................................................................................... 24 
 
Study Procedures ................................................................................................ 25 
5.1 
Facility Selection ...................................................................................... 25 
5.2 
Participant Identification ........................................................................... 25 
5.3 
Participant Enrollment .............................................................................. 26 
5.3.1 
Informed Consent ..................................................................... 26 
5.3.2 
HIPAA Authorization ................................................................. 26 
5.4 
Data Collection and Tracking ................................................................... 26 
5.5 
Participant Withdrawal ............................................................................. 28 
 
Potential Risks ..................................................................................................... 29 
6.1.1 
Breach to Participant Confidentiality ......................................... 29 
6.1.2 
Risks Related to Hyperphosphatemia Management ................. 29 
 
Safety Assessments ............................................................................................ 30 
7.1 
Adverse Event Reporting and Follow-up ................................................. 30 
 
Statistical Analysis Plan and Determination of Sample Size ............................... 31 
8.1 
Sample Size............................................................................................. 31 
8.2 
Statistical Design ..................................................................................... 31 
8.3 
Primary Outcome Analysis ...................................................................... 31 
8.4 
Major Secondary Analyses ...................................................................... 31 
8.5 
Other Planned Secondary Analyses ........................................................ 32 
8.5.1 
Interim Analyses ....................................................................... 32 
 
Data and Safety Monitoring ................................................................................. 33 
9.1 
Data and Safety Monitoring Board ........................................................... 33 
9.2 
Stopping Rules ........................................................................................ 33 
 
Data Management and Quality Control ............................................................... 34 
10.1 
Data Extraction and Transfer ................................................................... 34 
10.2 
Data Quality Procedures .......................................................................... 34 
10.3 
Data Security ........................................................................................... 34 
 
Study Responsibilities ......................................................................................... 35 
11.1 
Investigator Responsibility/Performance ................................................. 35 
11.2 
Training .................................................................................................... 35 
11.3 
Clinical Monitoring ................................................................................... 35 
11.4 
Study Documentation .............................................................................. 36 
11.5 
Source Documentation ............................................................................ 36 
11.6 
Protocol Deviations .................................................................................. 36 
11.7 
Protocol Changes .................................................................................... 36 
11.8 
Data Transmittal and Record Retention .................................................. 36 

 
 
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11.9 
Study Closeout ........................................................................................ 37 
11.10  Data Sharing ............................................................................................ 37 
 
Ethical Considerations ......................................................................................... 38 
12.1 
Role of DCRI............................................................................................ 38 
12.2 
Informed Consent .................................................................................... 38 
12.3 
Confidentiality of Participants .................................................................. 38 
12.4 
Authorization for Use and Disclosure of Protected Health Information 
(HIPAA).................................................................................................... 39 
12.5 
Institutional Review Board Review .......................................................... 39 
12.6 
Financial Disclosure/ Conflict of Interest .................................................. 40 
 
References .......................................................................................................... 41 
 

 
 
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LIST OF TABLES 
Table 1: HiLo Subcommittees ......................................................................................... 16 
Table 2: Serum Phosphate Thresholds ........................................................................... 22 
 
 
 
 
 
LIST OF FIGURES 
Figure 1: Schematic of Study Design ................................ Error! Bookmark not defined. 
Figure 2: Example Treatment Algorithm for Low Phosphate Group................................ 20 
Figure 3: Example Treatment Algorithm for High Phosphate Group ............................... 21 
 
 

 
 
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ABBREVIATIONS 
 
 
CVD 
Cardiovascular disease 
DCRI 
Duke Clinical Research Institute 
DSMB 
Data and Safety Monitoring Board 
EHR 
Electronic health record 
ESRD 
End-stage renal disease 
ICD-10 
International Classification of Disease (ICD)-10 codes 
IRB 
Institutional Review Board 
KDIGO 
Kidney disease improving global outcomes 
MOP 
Manual of Procedures 
PCR 
Protein catabolic rate 
PID 
Participant identifier  
PPY 
Per-patient year 
TSAT 
Transferrin saturation 
 

 
 
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BACKGROUND AND RATIONALE 
1.1 
Background and Rationale for the HiLo Trial Question 
For patients with end-stage renal disease (ESRD) undergoing dialysis, clinical outcomes 
have improved modestly in recent years, but rates of hospitalization (~2 per patient-year) 
and mortality (15–20%) remain unacceptably high.1  Poor outcomes are driven primarily 
by increased risk of cardiovascular disease (CVD),1 but interventions that are proven to 
improve clinical outcomes in the general population by targeting traditional CVD risk 
factors have mostly failed in patients with ESRD.2-4  The lack of efficacy of traditional 
interventions has led the nephrology community to invoke and target putative ESRD-
specific risk factors for CVD and death.  
Hyperphosphatemia is a ubiquitous complication of ESRD that is independently 
associated with increased risks of CVD and death.5-9  Experimental data suggest that 
hyperphosphatemia may contribute to arterial calcification, and left ventricular hypertrophy 
which are associated with increased risk of CVD events and death in ESRD.10-
15  Hyperphosphatemia also exacerbates increases in parathyroid hormone and fibroblast 
growth factor 23 levels, each of which are associated with CVD and mortality in ESRD.6,16-
22  Based on this body of observational human and preclinical data, the nephrology 
community has advanced hyperphosphatemia as a putative – but unproven by 
randomized controlled trial – contributor to adverse outcomes in ESRD. 
Starved for therapeutic advances to improve outcomes in ESRD, opinion-based clinical 
practice guidelines suggest that phosphate levels be maintained at ~5.0 mg/dl in ESRD 
using phosphate binders and low phosphate diet.  However, there have been no 
randomized outcomes trials to evaluate the optimal serum phosphate target and no 
placebo-controlled trials tested the effects of FDA-approved phosphate binders on clinical 
outcomes.23,24  Thus, major questions in the field that affect daily clinical practice in every 
dialysis facility across the US remain unanswered: “Do phosphate binders, as currently 
deployed, improve clinical outcomes in ESRD?”  More fundamentally, “Does lowering of 
serum phosphate towards the normal range improve outcomes in ESRD?”   
While patients who adhere to burdensome binder and dietary regimens may realize 
theoretical benefits of strict phosphate control, excessive treatment to achieve an 
unnecessarily low serum phosphate may actually worsen outcomes by: 1) paradoxically 
increasing risk by inducing calcium, lanthanum or iron overload;25-28 2) promoting 
gastrointestinal side effects that exacerbate malnutrition, which is a potent risk factor for 
death in ESRD;29 and 3) eroding patients’ quality of life by adding phosphate-related 
demands to an already high pill burden.30,31  All of these potential risks may have escaped 
detection precisely because of the lack of randomized outcomes trials.  Thus, clinical 
equipoise is the scientific premise for conducting the HiLo trial. 
1.2 
Rationale for Pragmatic Trial Design 
There is increasing interest in pragmatic, or real-world, trials because of their potential for 
efficient, yet rigorous, evidence generation, and the relevance of the findings to broad 
populations of individuals with the condition of interest rather than highly selected 
subgroups.  Several aspects of ESRD care are ideally suited to conducting large-scale 
pragmatic clinical trials based in dialysis facilities.  Patients are treated in their facilities 
thrice weekly for 3–4 hours per session during which study education, informed consent 

 
 
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and trial activities can occur.  Laboratory tests are performed in a regimented fashion at 
central laboratories and all results are integrated into dialysis providers’ electronic health 
records (EHR) that can serve as databases for interventional studies.  Dialysis provider 
organizations use protocols to standardize care across their facilities; for example, 
protocols to manage bone and mineral metabolism and anemia are the norm.  This 
enables standardized integration of protocol-driven randomized interventions into the 
fabric of daily clinical practice while also providing a natural mechanism for rapid 
translation of trial results into future clinical practice.  These attributes supported execution 
of the pragmatic “TiME” trial in >250 dialysis facilities across the US as one of the initial 
NIH Collaboratory Demonstration Projects.32  Our team will leverage best practices and 
many lessons learned from TiME to execute HiLo, which will answer a critical clinical 
question while simultaneously advancing the fertile field of pragmatic trials in ESRD. 
The design and implementation approach of HiLo will incorporate the following pragmatic 
features: 
1. Liberal eligibility criteria: This will accelerate enrollment and promote 
generalizability of the results. 
2. Use 
of 
an 
internet-based, 
centralized 
informed 
consent 
process 
administered at dialysis units: A historical obstacle to executing HiLo 
pragmatically is the need for individual-level patient consent.  Requiring numerous 
study personnel in scores of dialysis units across the country would be too costly 
for a pragmatic budget.  However, new pragmatic trial advances that are being 
pioneered by PCORNet and the Duke Clinical Research Institute (DCRI) enable 
an approach to obtaining informed consent via tablets and associated web-based 
communications applications, such as Skype, that require a small centralized team 
of study personnel.  The DCRI is successfully using this approach for the 
ADAPTABLE trial,33 which will serve as a precedent and model for HiLo. 
3. Leveraging clinical practice to implement the intervention: Dietitians 
employed by dialysis organizations are present in all dialysis units and routinely 
use protocols to manage bone and mineral metabolism parameters.  Phosphate 
management protocols will be tailored specifically to HiLo that have the same “look 
and feel” as those used in clinical practice by the dietitians, who will implement the 
protocols.   
4. Flexible implementation of the intervention using already approved 
medications: Consistent with current practice, the HiLo protocol will dictate the 
target serum phosphate, but specific binder choices will remain at the discretion of 
local providers.  Since HiLo participants will be treated with standard or lower 
doses of phosphate binders already used in clinical practice, they will not incur 
increased costs of study medications.   
5. Use of clinical laboratory data to implement and continuously monitor the 
intervention: To titrate phosphate treatment and support centralized monitoring, 
the trial will use serum phosphate levels that are already measured at least 
monthly in routine care.  DCRI Bioinformatics will build automated algorithms to 
monitor achievement of serum phosphate targets at the levels of randomization 
group and individual participant.  Reliance on clinically acquired rather than trial-

 
 
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driven phosphate levels will reduce cost and enhance the generalizability of HiLo’s 
results to the non-trial setting.   
6. Use of EHRs to extract clinical data and ascertain endpoints: HiLo will derive 
all trial data from the rich clinical and laboratory databases that are maintained and 
updated daily by the dialysis providers.  Monthly secure data transfers from the 
dialysis provider organizations to DCRI will be orchestrated by DCRI 
Bioinformatics and will include demographic and clinical data, repeated measures 
data on serum phosphate and many other lab tests, and clinical data, including all 
hospitalizations and deaths.  Since hospitalization and mortality data are captured 
with high precision in real time in the dialysis organizations’ databases, this will 
eliminate costs related to outcomes adjudication.  Using a similar approach to data 
acquisition, the TiME trial found a high degree of completeness for most data 
elements.  
7. Collection of Patient Reported Outcomes:  In support of an ancillary study 
awarded to Northwestern University the HiLo study team will collect patient 
responses to 6 surveys (Kidney Disease and Quality of Life (KDQOLTM-36), 
PROMIS Gastrointestinal Belly Pain 5a, PROMIS Gastrointestinal Constipation 9a, 
PROMIS Gastrointestinal Diarrhea 6a, PROMIS Gastrointestinal Gas and Bloating 
13a, and PROMIS Gastrointestinal Nausea and Vomiting 4a) and transmist de-
identified responses to Northwestern University via secure file transfer platform 
requiring multi-factor authentication.  The goal of the ancillary study is to determine 
the impact of change in care on patients’ perceived quality of life.  Survey 
responses will be collected at baseline (time of consent), six months from consent, 
and one year from consent.  Surveys will be sent from the Duke REDCap system 
for patients who chose to complete surveys online.  Duke will provide the contact 
phone number to Northwestern University for patients who chose to complete the 
surveys over the phone.  Northwestern University will collect phone responses and 
conduct all analyses regarding PRO data.  
8. Ability to merge HiLo data with Medicare claims data: Treatment of the majority 
of patients with ESRD is supported by Medicare, regardless of age.  Since virtually 
all HiLo participants will be Medicare beneficiaries, it will be possible to merge the 
HiLo database with Medicare claims data to obtain International Classification of 
Disease (ICD)-10 codes from all hospitalizations experienced by HiLo participants.  
This will enable us efficient conduct of secondary analyses of cause-specific 
hospitalization to determine whether HiLo trial effects are primarily driven by 
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OBJECTIVES, OUTCOMES, AND GOALS 
HiLo will be a pragmatic, open-label, multicenter, individual-randomized trial of ~4400 
patients with ESRD undergoing in-center maintenance hemodialysis at 100-150 units 
maintained by two dialysis organizations that care for a substantial proportion of the US 
dialysis population.   
2.1 
Primary Objectives 
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. 
2.2 
Secondary Objectives 
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 
 
2.3 
Primary Outcome 
Hierarchical composite of time to all-cause mortality and all-cause hospitalization rate 
(total counts per person-years of follow-up). 
2.4 
Secondary Outcomes  
Time to all-cause mortality; and all-cause hospitalization rate, expressed as total counts 
per person-years of follow-up. 
 
Additional secondary outcomes: total inpatient hospital days per person-years of follow-
up; serum albumin and protein catabolic rate (PCR), as markers of diet and nutrition.  

 
 
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2.4.1 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 through 
clinical care; 
5. 
To monitor safety without using individual adverse event reporting. 
 
 
 

 
 
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STUDY ORGANIZATION 
3.1 
Study Leadership 
Principal Investigator: Myles Wolf, MD, MMSc 
Co-Investigators: Tamara Isakova, MD, MMSc, Geoffrey Block, MD, Laura Dember, MD, 
Matthew Roe, MD, Hrishikesh Chakraborty, DrPH 
3.2 
Dialysis Provider Organizations  
HiLo will be conducted in partnership with 2 dialysis provider organizations and 
represented by: 
 
DaVita, Inc.: Steven Brunelli, MD, MSCE 
 
Dialysis Program at University of Utah Health: Srinivasan Beddhu, MD 
3.3 
Data Coordinating Center: The Duke Clinical Research Institute 
(DCRI) 
DCRI will serve as the Data Coordinating Center for HiLo and it will support trial design, 
operations, site management, IRB reporting, bioinformatics, biostatistics, data safety 
monitoring board meeting preparation, and dissemination of HiLo’s results.  
3.4 
Subcommittees 
The following subcommittees will be established to address specific aspects of trial 
conduct and analysis. 
Table 1: HiLo Subcommittees 
Subcommittee 
Operational Support from DCRI 
Protocol & Manual of Operations 
Protocol & MOP development 
Regulatory documentation for Central 
IRB 
Informed Consent and Recruitment & 
Retention 
Informed consent development  
Piloting informed consent 
Creation of participant tracking 
algorithms  
Creation of materials to promote 
engagement 
Phosphate Intervention & Monitoring  
Algorithms development  
Piloting algorithms 
Communications, Education & 
Training  
Creation of education materials and 
toolkits 
Creation of communication platforms 
Design & Analysis  
Data extraction & synchronization   
Data quality monitoring  
 

 
 
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Resource Sharing & Publications  
Assist with dissemination of information 
Support for resource sharing  

 
 
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STUDY DESIGN 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration regulations and guidelines, International Conference on Harmonisation 
guidelines on Good Clinical Practice (ICH E6, the principles of which have their origin in 
the Declaration of Helsinki), and all other applicable national and local laws and 
regulations. 
4.1 
Overview of Study 
HiLo is a pragmatic, multicenter, open-label, clinical outcomes trial with individual-level 
randomization. HiLo will compare the effects on hospitalization, mortality, diet, and 
nutrition of two different phosphate management strategies in ~4400 patients being 
treated with maintenance hemodialysis at 100-150 facilities operated by (1) a large 
national for-profit dialysis corporation (DaVita, Inc.) and (2) a smaller regional academic 
program (University of Utah).  HiLo will randomize individuals to either liberal control of 
serum phosphate, targeting ≥6.5 mg/dl, or strict control of serum phosphate, targeting <5.5 
mg/dl.     
4.2 
Study Setting  
The trial will be conducted in ~100-150 facilities operated by 2 dialysis provider 
organizations.  The dialysis facilities will be distributed throughout the United States. 
4.3 
Facility and Participant Selection 
4.3.1 Facility Eligibility 
Dialysis facilities will be eligible for participation if they meet the following criteria: 
 
Willingness of the medical director, treating nephrologists and dietitians to adopt 
either the high or low phosphate target range for participating patients;  
 
Willingness of the facility manager to allow dietitians to participate in training and 
regularly scheduled teleconferences throughout the duration of HiLo; and 
 
Facility dietitian comfort with the phosphate targets and willingness to implement 
the trial procedures and attend training and teleconferences throughout the 
duration of HiLo. 
4.3.2 Participant Eligibility 
The eligibility criteria are broad in order to maximize the generalizability of the trial findings. 
 
 
Inclusion criterion:  
o Adults ≥18 years  
o Undergoing 3 times weekly in-center hemodialysis and having received 
dialysis treatment for at least 3 months 
o Able to provide informed consent  
 
 
Exclusion criteria:  
o Females who are pregnant or who plan to become pregnant while in the 
study 
o Calciphylaxis 
o Nocturnal in-center dialysis 

 
 
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4.4 
Participant Timeline 
Participants will be followed for up to 27 (enter at enrollment end) – 45 (enter at enrollment 
start) months. 
4.5 
Randomization 
Following consent, patients will be randomized in a 1:1 ratio to the two treatment arms. 
The randomization will be stratified by site in random sized blocks.  
4.6 
Intervention 
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.34 
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.34,35  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.   
4.6.1 Frequency of Serum Phosphate Measurements  
Dialysis clinics measure serum phosphate monthly and typically repeat levels biweekly 
during active binder titration, per their standard of care.  No additional dedicated laboratory 
testing will be conducted for HiLo.  
4.6.2 Phosphate Binder Choices 
All classes of FDA-approved phosphate binders that are used in routine dialysis practice 
will be available for use in HiLo with the choices of specific binders left to the patients’ 
provider teams.  
4.6.3 Titrations Strategies 
Below are example initial phosphate titration algorithms. DCRI will work with the dialysis 
providers to optimize the algorithms, within the framework of the dialysis providers’ current 
procedures, during the first 6 months of the UG3 phase of the trial: 
 
 
 

 
 
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Figure 1: Example Treatment Algorithm for Low Phosphate Group 
Check Phosphate 
Level
Phosphate <4 
mg/dl?
Phosphate >5.5 
mg/dl?
No Action Required
Reduce Dose of 
Binder
At Maximal 
Dose?
Advance Dose of 
Binder
Add Another Binder 
Class
No
Yes
No Action Required
Yes
No
Yes
No
Low Arm
 
 
 
 
 
 

 
 
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Figure 2: Example Treatment Algorithm for High Phosphate Group 
 
Check Phosphate 
Level
Phosphate <6.5 
mg/dl?
No Action Required
Reduce Dose of 
Binder
No
Yes
High Arm
 
 
 
 
 
 

 
 
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4.6.4 Thresholds of Phosphate Control 
The 2 arms will have different thresholds of serum phosphate at which therapeutic 
changes will be considered. 
Table 2: Serum Phosphate Thresholds   
Arm 
Phosphate 
Target 
Action 
Threshold
Action, Upper 
Threshold 
Action, Lower 
Threshold 
Low 
<5.5 mg/dl 
≥5.5 mg/dl  
Binder therapy 
increased 
Binder therapy 
decreased 
High 
≥6.5 mg/dl 
<6.5 mg/dl 
 
4.6.5 Approach to Phosphate Binders 
To achieve desired serum phosphate targets, dialysis facilities randomized to the low arm 
will manage serum phosphate levels in accordance with current standard of care.  Dialysis 
facilities randomized to the high arm will manage serum phosphate levels in accordance 
with the intervention strategy that allows for less intensive serum phosphate control and 
more liberalized serum phosphate targets.  DCRI will work with the dialysis providers to 
on their approach to these titrations, based on the current procedures being implemented 
at their dialysis units. Further details will be available in the study Manual of Procedures.  
4.6.6 Approach to Diet 
Throughout the duration of the study, in-center dietitians will provide feedback and 
recommendations about diet during in-person meetings using the same general 
approaches and frequency that they use in clinical care.  During these meetings, 
participants’ dietary intake will be reviewed and standard recommendations for healthy 
nutrition for dialysis patients will be conveyed.  Dietitians at dialysis facilities will provide 
all participants with identical dietary phosphate recommendations but the frequency of 
their delivery will vary, tailored to the facility’s randomized phosphate arm (high vs. low) 
and the current serum phosphate level of the participant relative to the facility’s 
randomized target (within, above or below range).  For example, participants at the units 
randomized to the low arm whose serum phosphate is above target may receive more 
frequent and intensive dietary counseling to reduce phosphate intake, for example, by 
minimizing intake of high phosphate processed foods.  Conversely, participants in the 
units randomized to the high phosphate arm who are below target may be advised to 
liberalize their diet to increase phosphate intake, for example, by increasing intake of dairy 
products. DCRI will work with the dialysis providers on their approach to dietary 
recommendations, based on the current procedures being implemented at their dialysis 
units.  
4.6.7 Approach to Management of Hypercalcemia and Secondary 
Hyperparathyroidism 
Clinicians will manage hypercalcemia and secondary hyperparathyroidism as they do in 
usual clinical care, for example, by altering the binder regimen to reduce calcium intake, 
or using calcimimetics or vitamin D analogs to lower PTH.   

 
 
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4.7 
Dialysis Provider Staff Roles 
4.7.1 Role of Dietitians in Implementing HiLo Interventions in Facilities 
Dietitians at dialysis units will be the on-the-ground personnel who will implement the HiLo 
protocols for phosphate management.  The decision to have dietitians implement the 
protocols is based on multiple considerations: 
1. Dietitians are employed by dialysis organizations, are present in all dialysis units, and 
usually serve as the primary decision makers for titration of phosphate-related 
treatments. Relying on clinical personnel to implement the trial intervention is 
consistent with the goals of pragmatic trials. 
2. The HiLo phosphate algorithms will feel “natural” to both dietitians and patients. 
Dietitians have well established relationships with the patients who will participate in 
HiLo, they see them in the dialysis unit at least monthly, and are comfortable 
discussing phosphate management with them.  The existing rapport between dietitians 
and patients will facilitate adherence to the interventions.  
3. Dietitians are among the most motivated caregivers on dialysis teams.  Anecdotally, 
they are often the most committed and scientifically inquisitive members of care teams, 
constantly seeking better approaches to enhance patient care in general, and diet and 
nutrition in particular, including phosphate management.  To fully engage dietitians in 
the design and conduct of HiLo, DCRI will: (1) recruit 2 dietitian representatives to the 
HiLo Steering Committee to provide input into design and implementation; (2) identify 
a group of dietitians who will serve as local champions for HiLo and interact directly 
with dietitians at the units within their respective regions; and (3) drive interest among 
dietitians by having a HiLo presence at the DaVita and DCI national meetings and 
distributing HiLo newsletters throughout the conduct of the trial.  DCRI will hold regular 
conference calls during the planning and conduct of the trial with participating dietitians 
for training updates and to review protocol adherence using a strategy of friendly 
competition across centers to maximize intervention fidelity.  DCRI has initiated 
discussions with our dialysis partners about methods for recognizing and incentivizing 
participating dietitians.  
 
4.7.2 Role of Treating Nephrologists 
Although dialysis facilities will be randomized to high or low serum phosphate targets, the 
specific phosphate binding medications will be prescribed by the treating nephrologist(s) 
thus allowing for individualization of the prescription based on other considerations.  Also 
consistent with standard practice, patients can have input into the prescribed medications 
through discussions with the treating nephrologist(s).   
Participants may be discontinued from their study arm at the discretion of the dialysis 
provider physician.  These participants will continue to be followed and will be included in 
the intent-to-treat analyses. 
 

 
 
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4.8 
Adherence 
In accordance with the clinical monitoring plan the DCRI will continuously monitor serum 
phosphate and remediate deviations from targets using webinars first and then in-person 
training visits, if needed.  Sites will be notified by the DCRI whenever point-of-care serum 
phosphate measurements are repeatedly in the “action required” range; such notifications 
will be linked to a reminder of the facility’s treatment group assignment and the facility’s 
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STUDY PROCEDURES 
All of the HiLo Trial processes will be described in detail in the Manual of Procedures 
(MOP).  The MOP will include trial activities occurring at the dialysis facilities, dialysis 
provider organization data warehouses, and the DCC at DCRI.  The DCC is responsible 
for maintaining the manual and any associated documents, and will ensure that all relevant 
collaborators are informed about study procedures.  
5.1 
Facility Selection 
In aggregate, our partnering dialysis provider organizations offer >3000 individual 
freestanding dialysis facilities to choose from in order to assemble a final roster of 
participating sites in HiLo.  DCRI will work with our partners from the dialysis provider 
organizations to develop a strategy to select a suitable roster of dialysis facilities for HiLo; 
general considerations will include:  
 
Regional diversity across the US to maximize generalizability; 
 
Stability of candidate facilities, e.g. to exclude those with a dwindling census that 
could close; 
 
Willingness of medical directors, facility managers and dietitians to endorse the 
clinical equipoise that justifies HiLo and adopt either serum phosphate target for their 
patients;  
 
While provider organizations will support HiLo, facility managers should endorse the 
suitability of their dietitians to participate in training and regularly scheduled 
teleconferences throughout the duration of HiLo; 
 
Facility dietitian comfort with the different phosphate targets and willingness to 
implement the trial procedures and attend training and teleconferences throughout 
the duration of HiLo. 
5.2 
Participant Identification 
Patients receiving care at participating dialysis facilities who meet the eligibility criteria will 
be identified through the electronic data systems of the dialysis provider organizations by 
the HiLo Trial Information Technology (IT) teams at the provider organizations.  A unique 
research participant identifier (PID) for each participant will be generated.  The PID will 
not be related to the patient’s medical record number or any other identifier.  Each dialysis 
provider organization will maintain the key to the unique identifiers for participants enrolled 
from their organizations.  The keys to the unique identifiers will not be transmitted to the 
DCRI.  During the data extraction process, all personal identifiers will be replaced by the 
PID.

 
 
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5.3 
Participant Enrollment 
Since HiLo includes a phosphate target that differs from current practice guidelines,24 the 
greater-than-minimal-risk research requires individual-level consent.  HiLo initially used a 
cluster-randomized design in which participating dialysis centers were randomized to 
either the intervention or control arm.  After completing enrollment in 30 dialysis units (14 
Hi and 16 Lo sites), there was concern for biased enrollment. Therefore, the remainder of 
the trial will utilize individual-level randomization to ensure that arm assignment does not 
influence patients’ willingness to participate. Patients enrolled in the cluster-randomized 
design will remain in the study through completion. For the individual randomized phase, 
the HiLo study will randomize approximately 3,800 additional participants (1,900 per arm). 
5.3.1 Informed Consent 
The trial will require that participants provide informed consent because the research 
poses greater than minimal risk.  Electronic consent (eConsent) is rapidly becoming a new 
standard to improve efficiency, effectiveness and compliance of the informed consent 
process.  Leveraging DCRI experience in other pragmatic trials, the study team will create 
an eConsent form and study educational materials that will be available at all participating 
dialysis facilities and also contain links to centralized clinical experts at DCRI that will be 
available to engage potential participants and answer their questions.   
5.3.2 HIPAA Authorization  
HIPAA Authorization forms will be obtained with informed consent. 
5.4 
Data Collection and Tracking 
The electronic data systems of the dialysis provider organizations contain detailed clinical 
information from every dialysis treatment and the results of laboratory tests and 
hospitalization dates.  These data are maintained in central electronic data warehouses.  
For HiLo, a pre-specified subset of data elements will be extracted from the central data 
warehouses and securely (encrypted) transferred to the DCRI database at regular 
intervals.  No laboratory studies will be performed specifically for the trial.  The following 
data elements will be obtained from clinical care data for all trial participants at the 
indicated frequency:  
Demographic and comorbidity data at study entry:  
 
Dialysis facility zip code 
 
Age  
 
Sex  
 
Race 
 
Ethnicity  
 
Height 
 
Weight  
 
Dialysis vintage 
 
Co-morbid illnesses noted on admission to the dialysis facility (ICD-9/10 codes)  
 
Cause of end-stage renal disease  
For patients who decide not to participate in the trial, de-identified demographic and 
comorbidity data will be transmitted to the DCRI to allow comparison of characteristics of 
participating and non-participating patients. 
 

 
 
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Dialysis treatment data:  
 
Dialysis adequacy, single pool Kt/V, modality change: all available data 
 
Pre-dialysis and post-dialysis weights: every session 
 
Vascular access type (presence or absence of catheter): once per month  
 
Laboratory data: monthly  
In alignment with usual practice, all values available for the following laboratory test 
results will be made available to the DCRI by electronic data transfer on a monthly basis. 
 
Hemoglobin  
 
Albumin  
 
Calcium  
 
Phosphate  
 
Protein catabolic rate 
 
Serum ferritin 
 
Transferrin saturation 
 
Laboratory data: once every 3 months 
 
Intact parathyroid hormone 
 
Hospitalizations data: all 
Medications: all 
All available data on medications will be made available to DCRI by electronic data transfer 
on a monthly basis, including but not limited to: 
 
Phosphate binders 
 
Activated vitamin D 
 
Home medications 
 
Calcium 
 
Calcimimmetics (oral and IV) 
 
Status change: all 
 
Date of transfer to another dialysis facility 
 
Date of kidney transplantation 
 
Date of transfer to peritoneal dialysis 
 
Date of withdrawal from dialysis 
 
Date of death 
 
The study team will also be collecting and transmitting patient reported outcomes (as 
well as name and phone number for patients that wish to complete the surveys via 
telephone) to Northwestern University.  
 
Kidney Disease and Quality of Life (KDQOLTM-36) 
 
PROMIS Gastrointestinal Belly Pain 5a 
 
PROMIS Gastrointestinal Constipation 9a 
 
PROMIS Gastrointestinal Diarrhea 6a 
 
PROMIS Gastrointestinal Gas and Bloating 13a 

 
 
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 
PROMIS Gastrointestinal Nausea and Vomiting 4a 
 
Name 
 
Phone Number 
 
5.5 
Participant Withdrawal 
Participants may decide to withdraw from the study at any time.  Patients who initially 
participate but later elect to withdraw from the trial will have no data transmitted to the 
DCRI after the date of withdrawal. Additionally, participants who increase dialysis 
frequency to more than three times weekly, including participants in the high arm who 
become pregnant, will be withdrawn from the study by the dialysis provider.  
Data transmitted to the DCRI prior to withdrawal will remain in the trial database.  Contact 
information for the research personnel from the relevant dialysis provider organization will 
be available at participating dialysis facilities throughout the duration of the trial to facilitate 
communication such as a decision to withdraw from the trial.  Participants who elect to 
discontinue phosphate binder medications or protocol-based treatment algorithms will 
remain as trial participants and continue to have data transmitted to the DCRI unless they 
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POTENTIAL RISKS 
6.1.1 Breach to Participant Confidentiality   
Due to necessity of data merges from with data systems outside the enrolling site, breach 
to confidentiality is a potential risk.  To minimize this risk, primary identifiers will be retained 
only within the data systems where required to conduct the study; these will be omitted as 
data travel downstream and only study IDs will be in the analysis datasets.  Further de-
identification and anonymization methods will be used when making data available for 
outside investigators.  DCRI is part of the Duke HIPAA covered entity and has experience 
working with PHI in the research context; DCRI is extremely prudent in keeping patient 
data secure and confidential. 
6.1.2 Risks Related to Hyperphosphatemia Management  
Observational studies have linked hyperphosphatemia in patients with ESRD to increased 
risks of CVD and death.5-9  Phosphate binders are the mainstay of management of 
hyperphosphatemia in patients undergoing dialysis treatment.  Use of these medications 
can lead to gastrointestinal side effects, including nausea, vomiting, abdominal pain, 
bloating, dyspepsia, diarrhea, and constipation.37  Use of calcium-based phosphate 
binders can also lead to hypercalcemia.37  It is anticipated that gastrointestinal side effects 
will be reduced in the high phosphate target arm and they will remain similar to pre-
intervention levels in the low phosphate target arm.  Risks related to hyperphosphatemia 
management in both arms will be managed according to usual clinical care, which typically 
entails adjustment of phosphate binder dose and/or substitution of drug class.    
 

 
 
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SAFETY ASSESSMENTS 
7.1 
Adverse Event Reporting and Follow-up 
Among patients undergoing hemodialysis, adverse events of moderate or higher severity 
are extremely common and usually result in hospitalization (or death).  Based on this 
information, and given that hospitalization is the primary outcome of HiLo, additional 
information on adverse events will not be collected.  Periodically reports will be generated 
related to laboratory-based events and allow the DSMB to review in a blinded manner the 
rates of these events in high versus low target groups.  All laboratory parameters are 
measured either monthly or quarterly for all patients as part of routine clinical care: 
 
 
Hypophosphatemia, defined as serum phosphate <2.0 mg/dL; 
 
Hyperphosphatemia, defined as serum phosphate >7.5 mg/dl;  
 
Hypercalcemia, defined as total uncorrected serum calcium >10.5 mg/dL; 
 
Excessive iron supplementation, defined as serum ferritin >1000 ng/ml and 
transferrin saturation (TSAT) >50% (to assess for the potential effects of excess 
iron-based binder use); and 
 
Secondary hyperparathyroidism, defined as parathyroid hormone (PTH) levels 9 
times the upper limit of normal for the assay, based on the threshold articulated 
in the international KDIGO guidelines.    
 
 

 
 
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STATISTICAL ANALYSIS PLAN AND DETERMINATION OF 
SAMPLE SIZE 
8.1 
Sample Size 
The primary analysis of HiLo is the comparison of rank sum scores on the hierarchical 
composite endpoint of time to all-cause mortality and hospitalization rate. Simulations 
were employed to estimate the power of the planned analysis. The assumptions for the 
simulation include: 
 
48-month study with a 24-month enrollment period 
 
Annual loss to follow-up rate of 5% 
 
15% annual mortality rate in the standard of care arm and a hazard ratio of 0.85 
comparing the intervention arm to the standard of care arm 
 
35% of participants are “non-susceptible” to hospitalizations (will not have any 
hospitalizations during the course of the study).  
 
In the susceptible population, an average of 1.8 hospitalizations per year in the 
standard of care arm and 1.53 hospitalizations per year in the intervention arm 
(15% difference). 
 
1000 different study populations with 3800 participants were simulated under the above 
assumptions and analyzed using the planned analysis method. The power was estimated 
as the percentage of significant results out of the 1000. The results of the simulation 
provided an estimated power above 95%. Under these same assumptions, there would 
be at least 80% power to detect a treatment difference for both mortality and 
hospitalization when analyzed as separate endpoints. These results indicate that the trial 
will have sufficient power to detect a treatment effect with a population size of 3800 
participants. 
8.2 
Statistical Design 
In the primary analysis of efficacy, the intention to treat (ITT) sample will be used that 
includes all randomized patients. 
8.3 
Primary Outcome Analysis 
The primary outcome for HiLo is the hierarchical composite endpoint of time to all-cause 
mortality and the all-cause hospitalization rate in that order. Participants will have a rank 
score calculated using all pairwise comparisons and subsequently tested by the method 
proposed by Finkelstein and Schoenfeld.38 Participants will be hierarchically compared 
first on time to all-cause mortality, and compared on hospitalization rate only if the mortality 
comparison is not possible (e.g., both participants in an individual comparison survive 
throughout the follow-up period). 
8.4 
Major Secondary Analyses 
The other main secondary outcome for HiLo is time-to-all-cause death, which will be 
compared between the serum phosphate treatment arms.  Standard Cox regression 
methods will be employed to estimate the effect of phosphate treatment arm on time-to-
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8.5 
Other Planned Secondary Analyses 
As an alternative approach to analyzing the secondary outcome of hospitalization, the 
analysis will be repeated after substituting individual participants’ total number of days 
spent in the hospital per total length of follow-up in HiLo.  Additional secondary outcomes 
related to nutrition are change from baseline in serum albumin, and PCR.  Mixed effect 
models will be used for all available longitudinal observations in the ITT population to 
compare change from baseline in these secondary continuous variables between the two 
arms.  Supplemental analyses will consider the “as treated” sample.   
8.5.1 Interim Analyses 
One interim analysis will be completed when 50% of patients have been enrolled and have 
at least 24 months of median follow-up time accrued to assess efficacy on the primary 
outcome. Throughout the trial, the mean separation in serum phosphate between the 
treatment groups will be continuously monitored, targeting a mean separation of at least 
0.75 mg/dL and ideally, a mean separation of at least 1.0 mg/dL.  

 
 
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DATA AND SAFETY MONITORING  
9.1 
 Data and Safety Monitoring Board 
 
The NIDDK will convene a Data and Safety Monitoring Board (DSMB) to oversee the HiLo 
Trial.  The DSMB will include individuals with expertise in dialysis, nutrition, clinical trials, 
and biostatistics.  Members of the DSMB will not be involved in the conduct of the trial.  
The DSMB will review trial progress, data quality, blinded reports of rates of laboratory-
based events in the high versus low target groups, and safety throughout the course of 
the trial in accordance with a Data and Safety Monitoring Board Charter. The DSMB will 
meet regularly and make recommendations to NIDDK about study progress, safety and 
trial continuation.  DSMB reports will be submitted to the central Institutional Review Board 
(IRB). 
9.2 
Stopping Rules  
The DSMB can make recommendations to stop the trial based on safety or other concerns.   
There will be no pre-specified stopping rules for efficacy or futility, however the DSMB will 
review the results of the interim analysis (see Section 8.5.1) with the following being 
considered:  
 
Futility of serum phosphate separation 
 
Futility of enrollment  
 

 
 
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DATA MANAGEMENT AND QUALITY CONTROL 
10.1 
Data Extraction and Transfer 
The dialysis provider organization data warehouse teams already have processes in place 
to ensure that data are captured appropriately from the various originating units.  DCRI 
will develop a module to ensure that records transmitted from the central warehouse are 
accurately incorporated in the study database.  Pre-specified data elements will be 
transmitted to DCRI from the 2 dialysis provider organizations on a monthly basis.  The 
transferred data will be cumulative – each month the information technology groups at the 
provider organization will generate and transfer a complete data set for overwriting the 
previous one.  The dialysis provider IT groups will notify DCRI when each data transfer is 
occurring so the DCRI IT team can confirm that the transfer was successful.  Standardized 
file formats for transmitted data will be defined during the UG3 phase in order to enable 
automation of extraction, transfer, and loading processes.   
10.2 
Data Quality Procedures 
Primary responsibility for data quality will reside with the dialysis provider organization 
data warehouse teams.  Data from individual dialysis units are regularly transmitted for 
inclusion into central data warehouses for each of the participating dialysis organizations.  
The data being extracted and transmitted from these central warehouses is expected to 
be an accurate representation of the source data collected at each dialysis unit.   
10.3 
Data Security 
DCRI will use a web-based validated, electronic reporting platform.  All data files being 
exchanged will be transferred using secure servers.  During the data extraction by the 
dialysis providers, all personal identifiers other than dates of service and date of birth (IDs; 
such as medical record number, hospital account number, names) will be replaced by a 
unique study participant identifier.  The provider organizations will manage the individual 
study IDs and ensure they are unique across all participants.  This will be accomplished 
by establishing mutually exclusive ranges of values for study IDs between the two 
providers.  In the case of relevant dates of services or procedures or dates of birth, one of 
the standard methods for de-identifying dates will be used, such as elapsed time from 
starting event versus actual starting and ending dates or age versus birth date. 
For security reasons, and in compliance with regulatory guidelines, it is imperative that 
only the persons who own the user IDs and passwords access the system using their own 
unique access codes. Access codes are nontransferable. Study personnel who have not 
undergone training may not use the system and will not be issued user ID and password 
until appropriate training is completed. 
 

 
 
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STUDY RESPONSIBILITIES 
11.1 
Investigator Responsibility/Performance 
By signing this protocol, DCRI and the study PI agree to be responsible for implementing 
and maintaining quality control and quality assurance systems to ensure that all work 
incidental to this protocol is conducted and data are generated, documented, and reported 
in compliance with the protocol; accepted standards of Good Clinical Practice (GCP); and 
all applicable federal, state, and local laws, rules and regulations relating to the conduct 
of the clinical study. 
The principal investigator (PI) ensure that all personnel responsible for study conduct are 
provided current copies of the study protocol. 
The PI will ensure that NIDDK is provided with copies of all institutional review board (IRB) 
actions regarding the study. 
11.2 
Training 
The training of appropriate dialysis provider personnel will be the responsibility of DCRI. 
To ensure protocol understanding and compliance, DCRI will present a formal training 
session to dialysis provider personnel, to include instructions for study procedures, 
informed consent, and regulatory requirements.  
The dialysis provider leadership are responsible for ensuring that his or her staff conduct 
the study according to the protocol. 
11.3 
Clinical Monitoring 
DCRI will employ a “risk-based monitoring” (RBM) strategy that ensures human subject 
protection and data quality are held in the utmost regard. Data-Driven Trial Management 
(DDTM) is a targeted analysis–based surveillance effort designed to proactively minimize 
risk and improve quality. 
DCRI focuses on a simple and pragmatic project management strategy based on the 
following quality by design principles with human subject protection and data quality and 
integrity as the foundation of project planning and execution: 1) the correct participants 
are consented and enrolled, 2) acceptable protocol adherence is met, 3) complete data is 
obtained, and 4) good clinical practices (GCP) are followed. 
Integrated DCRI systems support our RBM strategies allowing us to closely monitor and 
track agreed upon key risk indicators and follow-up quickly with necessary interventions.  
Based on our significant data quality experience, the DCRI has established strategies and 
supporting tools to deliver high quality data that is critical for all trials including long term, 
event driven trials. By integrating the varied data sources and providing seamless 
reporting of trial data status, the study team is enabled to proactively manage trials. 
As part of a concerted effort to follow the study in a detailed and orderly manner in 
accordance with established principles of GCP and applicable regulations, a DCRI team 
member will maintain frequent contact with point persons from the dialysis providers.  

 
 
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11.4 
Study Documentation 
Study documentation includes all electronic medical record data, the study database, 
sponsor-investigator correspondence, and regulatory documents (e.g., signed protocol 
and amendments, IRB or EC correspondence and approval, approved and signed 
participant consent forms, etc.). 
The DCRI will prepare and maintain complete and accurate study documentation in 
compliance with GCP standards and applicable federal, state, and local laws, rules and 
regulations. 
By signing the protocol, the PI acknowledges that, within legal and regulatory restrictions 
and institutional and ethical considerations, study documentation will be promptly and fully 
disclosed to NIDDK by the investigator upon request and also shall be made available at 
the investigator’s site upon request for inspection, copying, review, and audit at 
reasonable times by representatives of NIDDK or responsible government agencies as 
required by law.  
The PI agrees to promptly take any reasonable steps that are requested by NIDDK as a 
result of an audit to cure deficiencies in the study documentation and the study database. 
11.5 
Source Documentation 
For this study, the source documentation is the electronic health record (EHR) at the 
dialysis providers.  
11.6 
Protocol Deviations 
Because this is a pragmatic trial intended to evaluate effectiveness of the phosphate 
targets under real-world conditions, protocol deviations will be limited to: 1) enrollment of 
individuals who do not meet eligibility criteria or provide informed consent, and 2) breach 
of participant confidentiality. Deviations will be reported to DCRI and to the IRB.   
11.7 
Protocol Changes 
All modifications to the protocol will be approved by the Steering Committee and submitted 
to the IRB for approval prior to implementation.  Changes will be incorporated into the 
protocol as amendments.  Protocol amendments and new versions of the protocol will be 
distributed to all HiLo personnel and partners. 
11.8 
Data Transmittal and Record Retention 
The clinical data generated at the dialysis facility is retained at the data warehouse of the 
dialysis provider organization in accordance with each organizations standard operating 
procedures.  
The trial database at the DCRI will be maintained for a period of 2 years following 
completion of the study, after which it will be archived.  A copy of the data will be 
transferred to the NIDDK Repository in accordance with NIDDK policy.  Data elements 
that are unique to one of the dialysis provider organizations, infrequent values, or any 
other elements that have potential for identifying a provider organization, dialysis facility, 
or participant will not be included in the repository data. 

 
 
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The DCRI will maintain the electronic trial master file and all other study-specific 
documentation for at least 2 years after the formal discontinuation of this study. The DCRI 
will notify NIDDK prior to the destruction of any study documentation.  Such documentation 
is subject to inspection by NIDDK as well as other regulatory agencies, as provided by 
law. 
11.9 
Study Closeout 
Upon completion of the study (defined as all participants have completed all follow-up 
visits, and all data transfer are complete), DCRI will notify the site of closeout. The DCRI 
monitor will ensure that the electronic trial master files are up-to-date and complete. DCRI 
will then notify the IRB of the site closures. Following the analysis of the study data and 
writing of the final study report/manuscript, DCRI will notify the IRB of study closure. 
11.10 
Data Sharing  
A data sharing policy will be developed by the HiLo Steering Committee.  The policy will 
be consistent with the data sharing policy of the NIDDK.  Data that can potentially be linked 
to a specific participating dialysis provider organization will not be transmitted to NIH data 
repositories.  This includes all data elements that are collected by only one of the two 
dialysis provider organizations and data categories with counts below a specified 
threshold.  All PHI will be removed from any shared data sets including dates, ages >89 
years and any other sparsely represented values that could potentially be identifying. 

 
 
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ETHICAL CONSIDERATIONS 
By signing this protocol, the principal investigator (PI) agrees to conduct the study in 
compliance with the protocol, DCRI standard operating procedures and/or guidelines, 
International Conference on Harmonisation guidelines on Good Clinical Practice (ICH E6, 
the principles of which have their origin in the Declaration of Helsinki), and all other 
applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study. 
12.1 
Role of DCRI 
As the study sponsor, DCRI has overall responsibility for the conduct of the study, 
including assurance that the study meets the regulatory requirements of the FDA. DCRI 
will ensure adherence to the sponsor’s general responsibilities as listed in21 Code of 
Federal Regulations [CFR] 312.50 and other responsibilities including monitoring (21 CFR 
312.56), and protocol amendments (21 CFR 312.30).  
12.2 
Informed Consent 
The PI and dialysis providers have both ethical and legal responsibility to ensure that each 
participant being considered for inclusion in this study is given a full explanation of the 
study. Informed consent will be obtained from all participants before any study-related 
procedures are performed.  
Informed consent will be documented through an electronic consent process approved by 
the same IRB/EC responsible for approval of this protocol. The ICF will conform to FDA 
regulations in 21 CFR Part 50 and to the institutional requirements for informed consent 
and applicable regulations.  
The study details and consent process will be reviewed with the prospective study 
participants, and study staff will be available to answer questions regarding procedures, 
risks, and alternatives.  
Once the appropriate essential information has been provided to the participant, and it is 
felt that the participant understands the implications of participating, the participant will 
sign and date and IRB-approved electronic consent. The participant will receive a copy of 
the signed ICF. The signed and dated consent will be maintained electronically as a part 
of the study documentation.  
The participant will be informed in a timely manner through their dialysis provider if new 
information becomes available that may be relevant to the participant’s willingness to 
continue participation in the trial.  
12.3 
Confidentiality of Participants 
Participant confidentiality will be maintained throughout the clinical study in a way that 
ensures the information can always be tracked back to the source data. For this purpose, 
a unique participant identification (ID) code (ID number and participant name code) will be 
used that allows identification of all data reported for each participant. 
Participant information collected in this study will comply with the standards for protection 
of privacy of individually identifiable health information as promulgated by HIPAA (Health 
Insurance Portability and Accountability Act) and as mandated in Title 45 CFR Parts 160 
and 164. All records will be kept confidential, and the participant’s name will not be 

 
 
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released at any time. Participant records will not be released to anyone other than DCRI 
or its designees and responsible regulatory authorities when requested. In all cases, 
caution will be exercised to assure the data are treated confidentially and that the 
participant’s privacy is guaranteed. 
12.4 
Authorization for Use and Disclosure of Protected Health 
Information (HIPAA) 
An authorization for use and disclosure of protected health information (PHI) under the 
HIPAA Privacy Rule (45 CFR § 164.102 et seq) will be obtained from every trial participant 
before or at the time of enrollment. It will be presented to, and signed by, the participant 
at the same time or prior to the electronic consent form.  The dialysis provider is 
responsible for obtaining participants’ authorizations and signatures and for explaining the 
elements of the HIPAA authorization form, if necessary. 
HIPAA authorization will be a separate form from the electronic consent. A signed copy of 
the HIPAA document will be filed in the participant’s medical records. Participants will be 
given the other signed duplicate for their personal records. 
The HIPAA authorization form will contain all elements required under the HIPAA Privacy 
Rule. By law, IRB approval of the HIPAA authorization form for use in this study is not 
required, and no such approval will be sought or requested.  
The dialysis provider will promptly inform DCRI of any restrictions on the use or disclosure 
of PHI of any participant to which the dialysis provider has agreed under the Privacy Rule. 
The dialysis provider will also promptly inform DCRI of any written revocation of any 
participant’s HIPAA authorization. 
12.5 
Institutional Review Board Review 
The appropriate IRB/EC must approve the protocol and informed consent documents, 
agree to monitor the conduct of the study, and agree to review study progress periodically, 
at intervals not to exceed 1 year. DCRI will ensure that the IRB/EC has approved the study 
before the study may begin. 
In addition, the investigator must provide the following documentation to NIDDK: 
1. IRB/EC annual re-approval of the protocol, per current Title 21 CFR 312.66 
regulations and 1997 International Conference on Harmonisation guidelines. 
2. IRB/EC approval of revisions to the informed consent documents or any 
amendments to the protocol. Any revisions to the protocol that may increase 
participant risk exposure must be approved before implementation. 
Administrative changes (such as a change in address or phone number) must 
be sent to IRBs/ECs but do not require their approval.  
The Duke University Institutional Review Board will serve as the IRB of record for the HiLo 
Trial and provide regulatory oversight for the trial activities at the dialysis facilities and 
DCRI.  Authorization agreements between the Duke IRB and the dialysis provider 
organizations will be established. 

 
 
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12.6 
Financial Disclosure/ Conflict of Interest 
Financial and other competing interests for the investigators are documented, provided to 
the IRB, updated annually, and maintained at DCRI. 

 
 
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