Ultrafiltration Profiling and Outcomes Among Individuals on Maintenance Hemodialysis
Phase: NA
Conditions: End Stage Renal Disease
Sponsor: University of North Carolina, Chapel Hill

 
Ultrafiltration Profiling and Outcomes Among Individuals on Maintenance Hemodialysis 
 
NCT Number: NCT03301740 
Document: Study Protocol & Statistical Analysis Plan 
Document Date: April 4, 2018 
 
 

Ultrafiltration profiling and cardiovascular risk among 
individuals on maintenance hemodialysis 
Protocol Identifying Number: 001 
Principal Investigator: Jennifer E. Flythe 
IND/IDE Sponsor: N/A 
Funded by: NIH/ NIDDK 
Draft or Version Number:  v.8 
April 4, 2018 
 

ii 
 
Table of Contents 
LIST OF ABBREVIATIONS ....................................................................................................................................... 1 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
PROTOCOL SUMMARY ........................................................................................................................................... 2 
SCHEMATIC OF STUDY DESIGN .......................................................................................................................... 2 
1 
KEY ROLES .................................................................................................................................................... 2 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................ 2 
2.1 
Background Information ...................................................................................................................... 3 
2.2 
Rationale ............................................................................................................................................... 3 
UF profiling, the practice of varying UF rates to maximize fluid removal during periods of greatest 
hydration and plasma oncotic pressure, is one treatment modification that may reduce UF-related harm 
without necessitating reduction in interdialytic fluid intake or longer HD treatments. While UF profiling has 
been available for decades, it has not been adequately studied independently of sodium profiling. Sodium 
profiling uses a higher dialysate sodium concentration to increase plasma osmolality. While sodium 
profiling (± UF profiling) often reduces hypotension, it disadvantageously sodium-loads the patient. The 
resultant positive sodium balance leads to increased thirst, weight gain, and interdialytic hypertension. 
Sodium profiling has been dismissed as a viable treatment option due to these disadvantageous side 
effects. Alternatively, UF profiling may reduce UF-related hemodynamic instability and associated 
cardiovascular consequences without altering sodium balance. Hypotensive episodes occur when UF 
rates exceed plasma refill rates. UF profiling allows for lower UF rates later in the HD treatment when 
plasma refill rates are the slowest and hemodynamic instability risk the highest. Thus, UF profiling has the 
potential to improve hemodynamic stability without untoward sodium gains..................................................... 3 
2.3 
Potential Risks and Benefits .............................................................................................................. 3 
2.3.1 
Known Potential Risks ..................................................................................................... 3 
2.3.2 
Known Potential Benefits ................................................................................................ 3 
3 
OBJECTIVES AND PURPOSE .................................................................................................................... 4 
4 
STUDY DESIGN AND ENDPOINTS ........................................................................................................... 4 
4.1 
Description of the Study Design ........................................................................................................ 4 
The study is a 4-period cross-over trial (see schematic of study design) in which participants are 
successively alternated between study arms across 4 periods with intervening washout periods, and 
treatment order is randomized. The study control arm is conventional HD: the patient’s standard HD 
prescription (no UF profiling). The study experimental arm is conventional HD + linear UF profiling. Linear 
UF profiling will be specified as a linearly decreasing UF rate with a UF rate starting at 1.33 times the rate 
that would be needed at a constant UF rate to achieve the desired post-weight (Fresenius 2008K 
machine profile 2). After providing consent, patients will be randomly allocated to experimental or control 
treatment for period 1. Patients will undergo 9 treatments during each phase for a total of 18 conventional 
HD treatments and 18 UF profiled treatments. Patients will undergo 3 wash-out HD treatments between 
phases. The study will be double-blinded in that patients will not be informed of the treatment paradigm. 
Investigators, including those performing TTE interpretation, will be blinded to treatment paradigm. 
Ultrasonographers performing intra-HD TTEs will be blinded to treatment paradigm. ..................................... 4 
4.2.1 
Primary Endpoint .............................................................................................................. 4 
4.2.2 
Secondary Endpoints ...................................................................................................... 4 
4.2.3 
Exploratory Endpoints ..................................................................................................... 5 
5 
STUDY ENROLLMENT AND WITHDRAWAL ........................................................................................... 5 
5.1 
Participant Inclusion Criteria .............................................................................................................. 5 
5.2 
Participant Exclusion Criteria ............................................................................................................. 5 
5.3 
Strategies for Recruitment and Retention ........................................................................................ 6 
5.4 
Participant Withdrawal or termination ............................................................................................... 6 
5.4.1 
Reasons for Withdrawal or Termination ....................................................................... 6 
5.4.2 
Handling of Participant Withdrawals or termination .................................................... 6 

iii 
 
5.5 
Premature Termination or Suspension of Study ............................................................................. 7 
6 
STUDY AGENT/ INTERVENTION .............................................................................................................. 7 
6.1 
Study INTERVENTION and Control Description ............................................................................ 7 
6.1.1 
DESCRIPTION ................................................................................................................. 7 
Intervention (UF profile during HD): The study intervention arm is linear UF profiling (linearly decreasing 
UF rate with a UF rate starting at 1.33 times the rate that would be needed at a constant UF rate to 
achieve the desired post-weight; pre-programmed “profile 2” on a Fresenius 2008K machine, the machine 
used in all participating clinics). ................................................................................................................................ 7 
Routine care/ control (conventional HD): The study control arm is conventional HD (the patient’s standard 
HD prescription without UF profiling). ...................................................................................................................... 7 
6.1.2 
Duration of Therapy ......................................................................................................... 7 
6.2 
Study agent Accountability Procedures ............................................................................................ 7 
7 
STUDY PROCEDURES AND SCHEDULE ................................................................................................ 7 
7.1 
Study Procedures/Evaluations ........................................................................................................... 7 
7.1.1 
Study specific procedures ............................................................................................... 7 
7.1.2 
Standard of care study procedures ............................................................................... 8 
7.2 
Laboratory Procedures/Evaluations .................................................................................................. 8 
7.2.1 
Clinical Laboratory Evaluations ...................................................................................... 8 
7.2.2 
Other Assays or Procedures .......................................................................................... 8 
7.2.3 
Specimen Preparation, Handling, and Storage ........................................................... 9 
7.2.4 
Specimen Shipment ......................................................................................................... 9 
7.3 
Study Schedule .................................................................................................................................... 9 
7.3.1 
Screening .......................................................................................................................... 9 
7.3.2 
Enrollment/Baseline ......................................................................................................... 9 
7.3.3 
Follow-up ........................................................................................................................... 9 
7.3.4 
Final Study Visit ................................................................................................................ 9 
7.3.7 
Schedule of Events Table ............................................................................................... 9 
7.4 
Justification for Sensitive Procedures ............................................................................................. 10 
7.5 
Concomitant Medications, Treatments, and Procedures ............................................................. 10 
7.5.1 
Precautionary Medications, Treatments, and Procedures ....................................... 10 
7.6 
Prohibited Medications, Treatments, and Procedures ................................................................. 10 
7.7 
Prophylactic Medications, Treatments, and Procedures ............................................................. 10 
7.8 
Rescue Medications, Treatments, and Procedures ..................................................................... 10 
7.9 
Participant Access to Study Agent At Study Closure ................................................................... 10 
8 
ASSESSMENT OF SAFETY ...................................................................................................................... 11 
8.1 
Specification of Safety Parameters ................................................................................................. 11 
8.1.1 
Definition of Adverse Events (AE) ............................................................................... 11 
8.1.2 
Definition of Serious Adverse Events (SAE) .............................................................. 11 
8.1.3 
Definition of Unanticipated Problems (UP) ................................................................. 12 
8.2 
Classification of an Adverse Event ................................................................................................. 12 
8.2.1 
Severity of Event ............................................................................................................ 12 
8.2.2 
Relationship to Study EXPERIMENTAL TREATMENT............................................ 12 
8.2.3 
Expectedness ................................................................................................................. 12 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up .......................................... 12 
8.4 
Reporting Procedures ....................................................................................................................... 13 
8.4.1 
Adverse Event Reporting .............................................................................................. 13 
8.4.2 
Serious Adverse Event Reporting ............................................................................... 13 

iv 
 
8.4.3 
Unanticipated Problem Reporting ................................................................................ 13 
8.4.4 
Events of Special Interest ............................................................................................. 13 
8.4.5 
Reporting of Pregnancy ................................................................................................ 13 
8.5 
Study Halting Rules ........................................................................................................................... 13 
8.6 
Safety Oversight ................................................................................................................................ 13 
9 
CLINICAL MONITORING ............................................................................................................................ 14 
10 
STATISTICAL CONSIDERATIONS .......................................................................................................... 14 
10.1 
Statistical and Analytical Plans ........................................................................................................ 14 
10.2 
Statistical Hypotheses ....................................................................................................................... 14 
10.3 
Analysis Datasets .............................................................................................................................. 14 
10.4 
Description of Statistical Methods ................................................................................................... 14 
10.4.1 
General Approach .......................................................................................................... 14 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 14 
10.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 15 
10.4.4 
Safety Analyses .............................................................................................................. 15 
10.4.5 
Adherence and Retention Analyses ............................................................................ 15 
10.4.6  
Baseline Descriptive Statistics ..................................................................................... 15 
10.4.7 
Planned Interim Analyses ............................................................................................. 15 
10.4.9 
Multiple Comparison/Multiplicity................................................................................... 15 
10.4.10 
Tabulation of Individual Response Data ..................................................................... 15 
10.4.11 
Exploratory Analyses ..................................................................................................... 16 
10.5 
Sample Size ....................................................................................................................................... 16 
10.6 
Measures to Minimize Bias .............................................................................................................. 16 
10.6.1 
Enrollment/ Randomization/ Masking Procedures .................................................... 16 
10.6.2 
Evaluation of Success of Blinding ............................................................................... 16 
10.6.3 
Breaking the Study Blind/Participant Code ................................................................ 16 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................... 16 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .............................................................................. 17 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................... 17 
13.1 
Ethical Standard ................................................................................................................................. 17 
13.2 
Institutional Review Board ................................................................................................................ 17 
13.3 
Informed Consent Process ............................................................................................................... 17 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants.... 17 
13.3.2 
Consent Procedures and Documentation .................................................................. 18 
13.4 
Participant and data Confidentiality ................................................................................................ 18 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data .............................. 18 
13.5 
Future Use of Stored Specimens .................................................................................................... 18 
14 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 19 
14.1 
Data Collection and Management Responsibilities ...................................................................... 19 
14.2 
Study Records Retention .................................................................................................................. 19 
14.3 
Protocol Deviations............................................................................................................................ 20 
14.4 
Publication and Data Sharing Policy ............................................................................................... 20 
15 
STUDY ADMINISTRATION ........................................................................................................................ 20 
15.1 
Study Leadership ............................................................................................................................... 20 
16 
CONFLICT OF INTEREST POLICY .......................................................................................................... 20 
17  
LITERATURE REFERENCES.................................................................................................................... 21 

v 
 
APPENDIX .................................................................................................................... Error! Bookmark not defined. 
TTE Protocol .............................................................................................................................................................. 22 
Symptom Assessment…………………………………………………………………………………………………………………………………………….24 
 

Ultrafiltration profiling and cardiovascular risk among individuals on maintenance hemodialysis    
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LIST OF ABBREVIATIONS 
 
IRB 
Institutional Review Board 
HD 
hemodialysis 
UF 
ultrafiltration 
BP 
blood pressure 
TTE 
transthoracic echocardiography 
GLS 
global longitudinal strain 
EF 
ejection fraction 
BP 
blood pressure 
PI 
principal investigator 
AE 
adverse event 
SAE 
serious adverse event 
UP 
unanticipated problem 
 
STATEMENT OF COMPLIANCE 
This document is a protocol for a clinical research study. The study will be conducted in compliance with all 
stipulations of this protocol, the conditions of the Scientific Review Committee approval, and the conditions of the 
IRB approval. Additionally, the trial will be conducted in accordance with the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the NIH/ NIDDK terms of the award. The PI will assure that no 
deviation from, or changes to the protocol will take place without documented approval from the IRB, except 
where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel involved in the 
conduct of this study have completed Human Subjects Protection Training. 
I agree to ensure that all staff members involved in the conduct of this study are informed about their obligations 
in meeting the above requirements. 
PI:  Jennifer E. Flythe, MD, MPH 
 
Signature:  
 
 
Date: 4/04/2018 
 
 

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PROTOCOL SUMMARY 
Title: 
Ultrafiltration (UF) profiling and cardiovascular risk among individuals on 
maintenance hemodialysis 
Précis: 
More rapid fluid removal (i.e. higher UF rate) is associated with adverse 
cardiovascular outcomes among maintenance hemodialysis (HD) patients. UF 
profiling may reduce UF-related cardiovascular complications. We will conduct a 
4-period cross-over trial with 30 participants in which participants are alternated 
between UF profiling and standard HD therapy and key cardiovascular and 
patient-reported outcomes are assessed. 
Objectives: 
 
To investigate the comparative effect of UF profiling during HD and non-profiled 
conventional HD on select cardiovascular and patient-reported outcomes 
Primary Endpoints 
1) intradialytic hypotension, 2) troponin T change, 3) TTE-measured global 
longitudinal strain change 
Population: 
Adult individuals on maintenance HD for ≥3 months who have mean UF rates >10 
mL/h/kg in the screening period who receive HD at a UNC-associated dialysis clinic 
(Carolina Dialysis Carrboro, Siler City, Pittsboro, Mebane, or Sanford)  
Phase: 
Phase 2 
Number of Sites enrolling 
participants: 
5 (all sites are UNC-based: Carolina Dialysis Carrboro and Siler City) 
Description of Study 
Experimental 
Intervention: 
Linear UF profiling is an HD technique in which the UF rate (fluid removal rate) is 
linearly decreased over the course of HD (starting UF rate= 1.33x the rate that 
would be needed at a constant UF rate to achieve the desired post-dialysis 
weight). The practice maximizes fluid removal during periods of greatest 
hydration and plasma oncotic pressure. 
Study Duration: 
15 months 
Participant Duration: 
4 months (+ 6 week screening period)  
 
SCHEMATIC OF STUDY DESIGN 
1 
KEY ROLES 
Jennifer E. Flythe, MD, MPH (Principal Investigator); UNC School of Medicine; 919-445-2656; jflythe@med.unc.edu 
Alan Hinderliter, MD (Co-Investigator); UNC School of Medicine; 919-843-5447; alan_hinderliter@med.unc.edu 
Ronald J. Falk, MD (Co-Investigator); UNC School of Medicine; 919-843-6485; ronald@falk@med.unc.edu 
Julia Narendra, MPH (Study Coordinator); UNC School of Medicine; 919-445-2686; julia3@email.unc.edu 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 

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2.1 
BACKGROUND INFORMATION  
United States HD patients have unacceptably poor outcomes with mortality rates greater than eight-fold those of 
individuals without kidney failure and symptom burdens on-par with those of cancer patients. Many difficult to 
modify factors such as co-morbid disease, chronic inflammation and poor nutrition contribute to the high 
morbidity and mortality experienced by HD patients. However, HD treatment factors also affect outcomes. 
Modifications of the HD procedure itself may represent feasible strategies to improve clinical outcomes. The rate 
of fluid removal during HD (UF rate) is a critical contributor to cardiovascular complications in HD patients. Higher 
UF rates are linked to greater morbidity and mortality. The mechanism likely relates to BP perturbations, 
myocardial ischemia, systemic inflammation, and other end-organ ischemic damage. In cases where fluid removal 
outpaces vascular refill rates, UF induces both subclinical end-organ hypoperfusion and frank hypotension. 
Hypoperfusion leads to regional myocardial hypoxia as evidenced by “stunning” on TTE and troponin elevation. 
Hemodialysis procedural strategies, such as UF profiling, the practice of varying UF rates to maximize fluid removal 
during periods of greatest hydration and plasma oncotic pressure, may reduce UF-related cardiovascular 
complications and patient-reported symptoms. See section 2.2 for UF profiling rationale. The objective of this 
study is to investigate the comparative effect of UF profiling during HD and non-profiled conventional HD on select 
cardiovascular and patient-reported outcomes. 
2.2 
RATIONALE  
UF profiling, the practice of varying UF rates to maximize fluid removal during periods of greatest hydration and 
plasma oncotic pressure, is one treatment modification that may reduce UF-related harm without necessitating 
reduction in interdialytic fluid intake or longer HD treatments. While UF profiling has been available for decades, it 
has not been adequately studied independently of sodium profiling. Sodium profiling uses a higher dialysate 
sodium concentration to increase plasma osmolality. While sodium profiling (± UF profiling) often reduces 
hypotension, it disadvantageously sodium-loads the patient. The resultant positive sodium balance leads to 
increased thirst, weight gain, and interdialytic hypertension. Sodium profiling has been dismissed as a viable 
treatment option due to these disadvantageous side effects. Alternatively, UF profiling may reduce UF-related 
hemodynamic instability and associated cardiovascular consequences without altering sodium balance. 
Hypotensive episodes occur when UF rates exceed plasma refill rates. UF profiling allows for lower UF rates later in 
the HD treatment when plasma refill rates are the slowest and hemodynamic instability risk the highest. Thus, UF 
profiling has the potential to improve hemodynamic stability without untoward sodium gains. 
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  
The risks involved in this study are small. Patients will complete 2 study arms (2 phases of each): UF profiling and 
conventional dialysis. Both forms of dialysis are used in clinical practice and are considered standard of care. Other 
than the different fluid removal paradigms, patients will undergo routine dialysis as prescribed by their treating 
nephrologists. All HD carries a risk of low blood pressure, heart rhythm abnormality, electrolyte abnormality, and 
bleeding. Patients are exposed to these risks each time they undergo dialysis. Participation in this study will not 
increase these baseline risks. There are no known risks associated with UF profiling. All study monitoring is low risk 
and part of routine dialysis care. Blood draws for laboratory testing will be low volume and will not exceed a total 
of 20 mL/ patient. Blood draws will be performed by experienced dialysis nurses, and blood will be taken from the 
cannulated dialysis access (thus no additional cannulations will be necessary). The main risk associated with the 
blood tests is bruising or bleeding at the access.  
2.3.2 KNOWN POTENTIAL BENEFITS  

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There is no additional direct benefit to the subjects participating. The results of this study may potentially benefit 
to future patients and their peers on dialysis. If individual participants experience improvement in UF-related 
cardiovascular risk or symptoms with UF profiling, UF profiling could be incorporated into their individual clinical 
dialysis prescriptions.  
3 
OBJECTIVES AND PURPOSE 
The objective of this study is to investigate the comparative effect of UF profiling during HD and non-profiled 
conventional HD on select cardiovascular and patient-reported outcomes. 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
The study is a 4-period cross-over trial (see schematic of study design) in which participants are successively 
alternated between study arms across 4 periods with intervening washout periods, and treatment order is 
randomized. The study control arm is conventional HD: the patient’s standard HD prescription (no UF profiling). The 
study experimental arm is conventional HD + linear UF profiling. Linear UF profiling will be specified as a linearly 
decreasing UF rate with a UF rate starting at 1.33 times the rate that would be needed at a constant UF rate to 
achieve the desired post-weight (Fresenius 2008K machine profile 2). After providing consent, patients will be 
randomly allocated to experimental or control treatment for period 1. Patients will undergo 9 treatments during 
each phase for a total of 18 conventional HD treatments and 18 UF profiled treatments. Patients will undergo 3 
wash-out HD treatments between phases. The study will be double-blinded in that patients will not be informed of 
the treatment paradigm. Investigators, including those performing TTE interpretation, will be blinded to treatment 
paradigm. Ultrasonographers performing intra-HD TTEs will be blinded to treatment paradigm. 
4.2.1 PRIMARY ENDPOINT 
1) Intradialytic hypotension: measured on a per-treatment basis; defined as nadir systolic BP <90 mmHg 
2) Troponin T change: measured at the 7th treatment of each phase; defined as pre-HD – post-HD troponin T 
(ng/mL) and percentage change (troponin T rise) ≥10% 
3) Left ventricular global longitudinal strain (GLS) on TTE: measured at baseline and 30 minutes before HD end 
during 7th treatment in the first phase of  each treatment type (once during conventional and once during UF 
profiled treatment); defined as % GLS change (intradialytic GLS – baseline GLS), see Appendix A for TTE protocol. A 
change ≥2.5% indicates a clinically important change in GLS. 
4.2.2 SECONDARY ENDPOINTS 
1) Systolic BP change: measured on a per-treatment basis; defined as pre-HD – nadir intra-HD systolic BP (mmHg) 
2) Nadir systolic BP: measured on a per-treatment basis; defined as the minimum intradialytic systolic BP (mmHg) 
3) Target weight achievement: measured on a per-treatment basis: defined as post-HD weight within 1 kg of 
prescribed target weight. 
4) Weight difference: measured on a per-treatment basis; defined as target weight – post-HD weight (kg) 
5) Patient acceptance: measured after treatment 9 of each phase; response to the following question, “If 
recommended by your physician, would you be willing to adopt the HD prescription you have received during the 
last 9 treatments?” 

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6) TTE ejection fraction (EF): measured 30 minutes before HD end during 7th treatment in the first phase of  each 
treatment type (once during conventional and once during UF profiled treatment); defined as % EF change 
(baseline – intradialytic EF), see Appendix A for TTE protocol 
7) Patient-reported symptoms: measured after the 1st HD treatment each week; see Appendix B for data 
collection form. 
4.2.3 EXPLORATORY ENDPOINTS 
1) Early diastolic myocardial velocity (Em): measured 30 minutes before HD end during 7th treatment in the first 
phase of  each treatment type (once during conventional and once during UF profiled treatment); calculated as the 
average of early diastolic velocities recorded at the medial and lateral mitral annulus, see Appendix A for TTE 
protocol 
2) Tricuspid annulus systolic excursion velocity (St): measured 30 minutes before HD end during 7th treatment in 
the first phase of  each treatment type (once during conventional and once during UF profiled treatment); 
measured as the distance of tricuspid annular movement between end-diastole to end-systole (cm), see Appendix 
A for TTE protocol 
3) Blood volume monitor slope (by hour): measured during the 1st (last) HD treatment of each week, hour-by-hour 
basis; defined as change in blood volume (%) on an hourly basis 
4) Blood volume monitor slope (by treatment): measured during the 1st (last) HD treatment of each week, from 
start to end of HD treatment; defined as change in blood volume (%) over the entire HD treatment 
5) Plasma refill: measured 10 minutes before HD end during 7th treatment of each phase; defined as the 
percentage increase in hematocrit 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
 
UF rate >10 mL/h/kg in >30% of treatments in a 4-week screening period (require ≥6 outpatient 
treatments in this period) 
 
Age 18-85 years 
 
Ability to converse comfortably in English or Spanish 
 
Receipt of in-center maintenance HD at Carolina Dialysis Carrboro, Siler City, Pittsboro, Mebane, or 
Sanford clinics 
 
≥90 days on HD 
 
Free of bloodstream infection during 4-week screening period 
 
Willingness to undergo all study testing 
 
Evidence of a signed and dated informed consent document 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Patients meeting any of the following exclusion criteria will not be eligible for randomization. 
 
Systolic BP unable to be measured by arm cuff 
 
>1 hospitalization during 4-week screening period 
 
Unstable angina per treating nephrologist 

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 
End-stage cirrhosis per treating nephrologist 
 
New York Heart Association class IV heart failure per treating nephrologist 
 
Pregnant 
 
Dialysis treatment schedule increases to more than 4 times per week 
 
Incarcerated 
 
Anticipated kidney transplant within 6 months per treating nephrologist 
 
Non-adherence to HD prescription (>2 unexplained absences during 4-week screening period) 
 
Sodium profiling or UF profiling in standing HD prescription 
 
Decisionally challenged, unable to provide informed consent 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The recruitment goal is 36 participants (to account for drop-out) with study completion goal of 30 participants. The 
PI, a nephrologist, will identify eligible subjects from participating dialysis clinic (Carolina Dialysis Carrboro, Siler 
City) patient rosters and offer opportunity to participate in the study. If the patient does desire to participate in 
the research study, informed consent will be obtained by the PI or research staff.  A study information sheet will be 
made available in the clinic for patients who desire additional information about the study. Participants will receive 
$20 for their time spent participating in the baseline TTE procedure because it is the only TTE performed outside of 
participants’ regular dialysis treatment time. Participants will be compensated $45 for each 9 week treatment 
period and $20 for the baseline period TTE ($200 for full study completion). 
Participants may miss study treatments. Missed study treatments will be considered “missed” and will not be 
made-up. For example, if a patient misses treatment #9 from arm 1, the patient will start wash-out treatments at 
the next treatment and will have missing data for treatment #9. The permeated design of the study arms 
(alternating conventional, UF profile, conventional, UF profile) was selected to maximize opportunities for data 
collection under each treatment paradigm.  If participants are lost to follow-up (death, withdrawn consent, move 
to a new dialysis center), additional participants will be recruited until a study size of 30 participants is reached. 
Based on the composition of the patient populations at the participating UNC sites, the expected sex breakdown is 
50% male and 50% female and the expected enrollment of Hispanic or Latino participants is 10%. No exclusion by 
sex or by ethnic/ racial background will be made. There are no expected differences in the response to UF profiling 
across sex or racial/ ethnic groups. Children (individuals < 18 years) and vulnerable participants are not included in 
the study. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
 
Active (voluntary) withdrawal of consent by the study participant 
 
Transfer of care to a non-participating dialysis clinic 
 
An investigator may terminate participation in the study if: 
o 
Non-adherence to study data collection procedures (refusal of TTE, blood draw or symptom 
monitoring) 
o 
Violation of the inclusion/ exclusion criteria determined after the fact 
o 
Any clinical AE, laboratory abnormality or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 

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While participants will be encouraged to complete the study, they may withdraw from the study at any time and 
for any reason. Every effort will be made to determine why any participant withdraws from the study prematurely. 
This information will be recorded. Withdrawn subjects will be replaced, until 30 participants complete the study.  
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
If the investigators becomes aware of conditions or events that suggest a possible hazard to subjects if the clinical 
study continues, the clinical study may be terminated after appropriate consultation between the involved parties. 
Conditions that may warrant termination of the clinical study include, but are not limited to: the discovery of an 
unexpected, relvant or unacceptable risk to the participants enrolled in the clinical study or failure to enroll 
participants at the required rate. 
6 
STUDY AGENT/ INTERVENTION 
 
6.1 
STUDY INTERVENTION AND CONTROL DESCRIPTION 
 
6.1.1 DESCRIPTION 
Intervention (UF profile during HD): The study intervention arm is linear UF profiling (linearly decreasing UF rate with 
a UF rate starting at 1.33 times the rate that would be needed at a constant UF rate to achieve the desired post-
weight; pre-programmed “profile 2” on a Fresenius 2008K machine, the machine used in all participating clinics).  
Routine care/ control (conventional HD): The study control arm is conventional HD (the patient’s standard HD 
prescription without UF profiling). 
6.1.2 DURATION OF THERAPY 
Patients will undergo 9 treatments during each phase for a total of 18 conventional HD treatments and 18 UF 
profiled treatments. Patients will undergo 3 wash-out HD treatments between phases. There will be a total of 45 
study treatments (36 study treatments and 9 washout treatments). The baseline study visit will involve a history 
and physical and baseline transthoracic echocardiography study. The entire study duration for each individual is 16 
weeks (15 treatments and 1 baseline study visit). 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
N/A 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  
UF profiled HD treatments (intervention): The study treatments will be administered at routine, scheduled 
outpatient thrice-weekly HD clinic visits. Dialysis clinic nursing staff will select UF profile 2 on the dialysis machine 
at the start of each UF profiled treatment. Clinic nursing staff have experience using UF profiling as it is a standard 
HD machine setting. Dialysate composition and HD medications will be per baseline prescription determined by 
the treating nephrologist. Total UF volume and target weight will be determined by the treating nephrologist.  
Medical history: At baseline, the participant’s medical history will be taken from the electronic medical record and 
confirmed verbally with the patient. The medical history will include a review of co-morbid conditions, medications 

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and performance of a physical examination (Vital signs- BP, heart rate, respiratory rate, weight, height; systems- 
cardiovascular, pulmonary, neurological) 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Standard HD treatments without UF profiling (control): Fresenius 2008K HD machines, a dialysate temperature of 
37°C, and patients’ standard blood and dialysate flows will be used. No sodium profiling will be used. Dialysate 
composition and HD medications will be per baseline prescription determined by the treating nephrologist. Total 
UF volume and target weight will be determined by the treating nephrologist.  
Standard-of-care BP measurement: BPs will be machine-measured with an upper extremity cuff in the seated 
position pre- and post-dialysis and every 20 minutes during every dialysis treatment. 
Standard-of-care weight measurement: Per routine practice, target weight will be estimated by the treating 
nephrologist. Pre- and post-dialysis weights will be measured before and after each treatment in the standing 
position. 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Troponin T (blood sample): Blood samples for Troponin T measurement will be collected via the vascular access by 
dialysis clinic staff. Troponin T will be collected before and after the 7th HD treatment of each phase for the 
calculation of troponin T change (2 troponin T changes during UF profiled HD and 2 during control HD). Troponin T 
is the only laboratory test to be performed as part of the study. 
Standard-of-care laboratory measurements: Study start will be timed so that standard-of-care monthly lab testing 
(electrolytes, albumin, complete blood count, Kt/V, iron stores, bone-mineral tests) will be drawn within 6 weeks 
prior to study start (baseline). A 24-hour urine collection will be performed during baseline to measure residual 
kidney function (mL urine/day). These standard-of-care laboratory measurements will be performed as part of 
routine clinical care and are not study-specific. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
TTE: Patients will undergo intradialytic TTE at baseline (within 6 weeks prior to study start) and 30 minutes prior to 
HD end (“peak stress”) during treatment 7 of the first phase of  each treatment type (once during conventional and 
once during UF profiled treatment) (1 TTE during UF profiled HD and 1 during control HD). Study TTEs will be 
performed by a trained sonographer with a Philips CX50 ultrasound system (Philips North America). 
Blood volume monitoring: Blood volume monitoring will be performed continuously throughtout each study 
treatment via a Crit-line™ (standard-of-care non-invasive relative blood volume monitoring tool used as part of 
standard dialysis treatments). 
Plasma refill test: Using the blood volume monitor, a plasma refill test will be performed 10 minutes before HD end 
during the 7th treatment of each phase. At the start of the treatment, UF time will be set 10 minutes less than 
treatment time. When the dialysis UF ends, study staff will document the hematocrit (%) from the blood volume 
monitor, and when the treatment ends, document the blood volume monitor hematocrit (%) again. Plasma refill 
tests are part of the blood volume monitoring protocols at the selected units and are familiar to staff. 
Patient acceptance: At the end of the 9th study treatment of each phase, study staff will ask the participant the 
following question: “If recommended by your physician, would you be willing to adopt the HD prescription you 
have received during the last 9 treatments?” 

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Symptom assessment: At the conclusion of the 1st study treatment each week, study staff will ask patients to 
complete a symptom questionnaire (Appendix B). 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 
Blood samples for Troponin T measurement will be collected via the vascular access by HD staff. Samples will be 
transported (on the day they are drawn by study staff) on ice for aliquoting and storage at -80C in UNC Kidney 
Center freezers. Baseline blood (electrolytes, albumin, complete blood count, Kt/V, iron stores, bone-mineral tests) 
and 24-hour urine samples are being collected as part of routine care processes and will be processed per usual 
clinical procedures at an accredited laboratory. 
7.2.4 SPECIMEN SHIPMENT 
After aliquoting and transporting to UNC, Troponin T samples will be shipped  to an accredited laboratory for 
testing per usual clinical procedures. 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
The PI will communicate with potential participants to determine whether they fit the inclusion/exclusion criteria 
and would like to participate in the study. If patients are interested in participating, a signed HIPAA waiver will  be 
obtained to allow the PI to review the individual’s medical record and confirm eligibility status. The study baseline 
period will begin within 4 weeks of enrollment. 
7.3.2 ENROLLMENT/BASELINE 
Written informed consent will be obtained from study subjects prior to the implementation of any study 
procedures. The subject will receive a signed and dated informed consent form. The PI will verify inclusion/ 
exclusion criteria. A complete medical history, physical examination and baseline TTE will be taken at the time of 
enrollment (baseline). 
7.3.3 FOLLOW-UP  
All study visits will occur at the time of routinely scheduled dialysis treatments at the patient’s usual outpatient 
dialysis clinic. Monitoring and recording of BP and weights will be performed at every treatment. See “7.3.7 
Schedule of Events Table” for planned frequency of additional monitoring and testing. 
7.3.4 FINAL STUDY VISIT 
N/A (the final study visit is no different than the follow-up visits). 
7.3.7 SCHEDULE OF EVENTS TABLE 
 

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Procedures 
Baseline (6 week prior to 
study start) 
Every study HD 
treatment 
Before and after 7th HD 
treatment of each phase 
During 7th HD treatment 
of each phase (twice per 
treatment type) 
During 7th HD treatment 
in the first phase of  
each treatment type 
(once per treatment 
type)  
After 9th HD treatment 
of each phase 
After 1st HD treatment 
of each week (3x/phase) 
 
 
Baseline laboratory testing 
X 
 
 
 
 
 
 
 
 
Baseline history and physical 
X 
 
 
 
 
 
 
 
 
Pregnancy status inquiry 
X 
 
 
 
 
 
 
 
 
BP monitoring 
X 
X 
 
 
 
 
 
 
 
Weight monitoring 
X 
X 
 
 
 
 
 
 
 
Blood volume monitoring 
X 
 
 
 
 
 
X 
 
 
Troponin T laboratory testing 
 
 
X 
 
 
 
 
 
 
TTE 
X 
 
 
 
X 
 
 
 
 
Plasma refill test 
X 
 
 
X 
 
 
 
 
 
Patient acceptance assessment 
 
 
 
 
 
X 
 
 
 
Symptoms assessment 
 
 
 
 
 
 
X 
 
 
 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
N/A 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
There will be no change to a patient’s usual medications or dialysis treatments (other than UF profiling during UF 
profiled arms).  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
N/A 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
N/A 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
N/A 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  
Any hemodynamic instability experienced during study HD will be managed per routine protocols with standard 
interventions (e.g. saline administration, reduction in UF rate or blood flow). 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  

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Participants will have access to UF profiling during HD treatments at study closure if deemed appropriate by their 
treating nephrologists. 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
All HD carries a risk of low BP, heart rhythm abnormality, electrolyte abnormality, and bleeding. Patients are 
exposed to these risks each time they undergo dialysis. Participation in this study will not increase these baseline 
risks. There are no known risks associated with UF profiling. All study monitoring is low risk and part of routine 
dialysis care. The study involves one non-standard blood draw (Troponin T) which will be taken from the vascular 
access and not require a separate “stick” and one non-standard monitoring test (TTE) which is non-invasive and 
free of discomfort or complications. 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence (e.g., an abnormal laboratory finding, symptom, or 
disease temporally associated with the use of the experimental treatment) in a patient or clinical investigation 
subject administered an experimental treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal vital sign 
finding) or symptom temporally associated with the use of the experimental treatment, whether or not related to 
the experimental treatment. Each AE will be graded on a mild-moderate-severe scale. Hospitalization for elective 
surgery or routine clinical procedures that are not the result of an AE (e.g., surgical insertion of central line) need 
not be considered AEs and should not be recorded as an AE.  
A suspected adverse reaction (SAR) is any AE for which there is a reasonable possibility that the experimental 
treatment is the cause. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the experimental treatment and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any adverse event caused by an experimental treatment. Each 
SAR will be graded on a mild-moderate-severe scale. 
Causality assessment to an experimental treatment is a medical judgment made in consideration of the following 
factors: temporal relationship of the AE to the experimental treatment exposure, known mechanism of action or 
side effect profile of study treatment, other recent or concomitant drug or treatment exposures, normal clinical 
course of the condition under investigation, and any other underlying or concurrent medical conditions. Other 
factors to consider in considering drug as the cause of the AE:  
 
One or more occurrences of an event not commonly associated with experimental treatment exposure, 
but otherwise uncommon in the population (e.g. severe symptomatic hypotension); often more than one 
occurrence from one or multiple studies would be needed before the study oversight physician could 
determine that there is reasonable possibility that the experimental treatment caused the event.   
 
An aggregate analysis of specific events observed in a clinical trial that indicates the events occur more 
frequently in the experimental treatment group than in the control group. 
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE is considered serious (SAE) if, in the view of the study oversight physician, it results in any of the following 
outcomes:   
 
Death 
 
Is life-threatening (places the subject at immediate risk of death from the event as it occurred) 
 
Requires inpatient hospitalization (>24 hours) or prolongation of existing hospitalization 
 
Results in a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 

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 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered a serious adverse experimental treatment experience when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the definition.  
*Hospitalization for anticipated or protocol specified procedures such as administration of chemotherapy, central 
line insertion, metastasis interventional therapy, resection of primary tumor, or elective surgery, will not be 
considered serious adverse events.  
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
An AE or SAE is considered unexpected if the specificity or severity of it is not consistent with the applicable 
experimental treatment information (e.g., dialysis machine approved product brochure).  
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
Each AE will be graded on a mild-moderate-severe scale by the monitor as described above. 
8.2.2 RELATIONSHIP TO STUDY EXPERIMENTAL TREATMENT 
An AE or SAE will be considered potentially related to the study experimental treatment if it occurs during an HD 
treatment in which the experimental treatment (UF profiling) is being administered. 
8.2.3 EXPECTEDNESS  
There are no known expected AE or SAEs associated with the study experimental treatment (UF profiling). An AE 
will be considered unexpected if the nature, severity or frequency of the event is not consistent with the risk 
information previously described for the study agent. 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits or upon review by 
a study monitor. All AEs not meeting the criteria for SAEs will be captured on the appropriate case report form. 
Information to be collected includes event description, time of onset, clincian’s assessment of severity, 
relationship to the study intervention, and time of resolution/ stabilization of the event. All AEs occurring while on 
study must be documented appropriately regardless of relationship. All AEs will be followed to adequate 
resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as baseline 
and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the study, 
it will be recorded as an AE. Unanticipated problems will be recorded in the data collection system throughout the 
study. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermitten require documentation of onset and duration of 
each episode. 
The PI will record all reportable events with start dates occurring any time after informed consent is obtained until 
7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation.   

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8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
Events meeting the criteria for an AE will be documented within 24 hours of occurrence. A summary of AEs, 
including evaluation of the AEs by the monitor will be submitted to the IRB at the time of the progress report. 
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
Events meeting the criteria for an SAE will be documented within 24 hours of occurrence. The IRB will be notified 
of all SAEs that qualify as an unanticipated problem as per the UNC IRB policies within 7 days of the investigator 
being notified of the event. 
8.4.3 UNANTICIPATED PROBLEM REPORTING  
Events meeting the criteria for an unanticipated problem will be documented within 24 hours of occurrence. 
8.4.4 EVENTS OF SPECIAL INTEREST  
N/A 
8.4.5 REPORTING OF PREGNANCY  
Pregnancies (including a positive pregnancy test regardless of age or disease state) of a female subject occurring 
while the subject is enrolled will result in study cessation for the pregnant subject. The female subject will be 
referred to an obstetrician-gynecologist. Pregnant dialysis patients require more intensive dialysis therapy and are 
not appropriate for ongoing study participation. The Investigator will follow the female subject until completion of 
the pregnancy, and must document the outcome of the pregnancy (either normal or abnormal outcome). If the 
outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, it must be 
reported as an SAE.  
8.5 
STUDY HALTING RULES  
If there is an SAE suspected to be related to the study intervention, UF profiling, the study will be put on hold and 
re-evaluated as this would not be an expected event. 
8.6 
SAFETY OVERSIGHT 
The PI will provide continuous, close monitoring of the study. Trained dialysis nurses and technicians will 
administer the HD treatments per routine care and will have 24-hour telephone and pager access to the PI. A 
licensed dialysis physician will also be immediately available to the HD units during study HD treatments. 
Participating patients will be given the PI’s direct contact information. If there is concern for an AE or SAE, an 
attending nephrologist (other than the PI who will be blinded to study treatment arm) will assess and record any 
AE or SAE in detail including the time of onset, description, severity, time course, duration, and outcome, 
relationship of the AE/SAE to study arm, and any action(s) taken. Two additional attending nephrologists will 
review study-associated morbidities no more than two days after they occur in order to determine whether further 
safety guards should be instituted and whether the benefit of the study continues to outweigh potential risks. The 
PI will report all adverse events to the IRB and funding institute and center on the day of occurrence. The PI will 
discuss all morbidities with project co-investigators. The PI will personally review all study results and notify 

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subjects of any abnormal results, including those present at baseline unrelated to the treatment to ensure subjects 
are able to seek appropriate medical care.  
9 
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance 
with the currently approved protocol/ amendment(s) and with GCP. The PI and research Study Coordinator will 
conduct on-site monitoring (at least once per study phase) and centralized monitoring (every study treatment) for 
all study participants at all study sites to verify protocol adherence/ study conduct, data collection, and safety. 
10 
STATISTICAL CONSIDERATIONS  
 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
This is an investigator-initiated 4-period cross-over trial. Statistical and analytical plans were developed in 
consultation with statistical experts. See below for details. 
10.2 
STATISTICAL HYPOTHESES 
We hypothesize that patients will have comparatively less hypotension, troponin change and left ventricular global 
longitudinal strain change with UF profiling vs. conventional HD. 
10.3 
ANALYSIS DATASETS 
Analytical datasets will be compiled from collected clinical data. Datasets will include an intention-to-treat analysis 
dataset and a modified intention-to-treat analysis dataset. Data analysis will be performed with STATA 12.2MP. 
Datasets will be de-identified and maintained on a secure UNC Department of Medicine Server that is accessed via 
a password-protected UNC computer with anti-virus and UNC firewall protection. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
By cross-over design, each participant will act as his or her own control, permitting between and within group 
comparisons. Analyses will be performed on an intention-to-treat and modified intention-to-treat basis, 
separately. Comparisons of values between HD treatments will be performed by repeated-measures analysis of 
variance (ANOVA; or non-parametric methods depending on data type) for continuous outcomes and generalized 
estimating equations for categorical outcomes. Analagous analyses will be performed in both the intention-to-
treat and modified intention-to-treat datasets. All statistical estimates will be tablulated along with their 
corresponding 95% confidence intervals. All reported P values will be 2-sided; <0.05 representing significance. All 
hypothesis tests that are observed to be statistically non-significant will be interpreted as such and reported as 
being inconclusive. However, as this is a small, pilot study, the magnitude of estimates and the corresponding 
confidence intervals will be considered in the results interpretation. 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Comparisons of values for the binary primary endpoints of hypotension and troponin T rise ≥10% between HD 
treatments will be performed using generalized estimating equations. Comparisons of values for the continuous 

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primary endpoint of global longitudinal strain change will be performed using ANOVA or non-parametric methods 
depending on data type. 
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Comparisons of values for the binary secondary endpoints of target weight achievement, patient acceptance, and 
symptom occurrence between HD treatments will be performed using generalized estimating equations. 
Comparisons of values for the continuous secondary endpoints of pre-HD to nadir intradialytic HD systolic BP 
change, intradialytic nadir systolic BP change, target and post-HD weight difference, and TTE ejection fraction 
change will be performed using ANOVA or non-parametric methods depending on data type. 
10.4.4 SAFETY ANALYSES 
See “8.6. Safety Oversight.” The primary safety endpoint that will be monitored is BP but all AEs and SAEs will be 
evaluated for safety concerns. 
10.4.5 ADHERENCE AND RETENTION ANALYSES 
Adherence and retention will be analyzed on a weekly basis by the PI and study coordinator throughout the course 
of the study. 
10.4.6  BASELINE DESCRIPTIVE STATISTICS 
Baseline patient characteristics will be reported as counts and proportions for categorical variables, and as means 
and standard deviations or medians and inter-quartile ranges for continuous variables. 
10.4.7 PLANNED INTERIM ANALYSES  
 
10.4.7.1 
SAFETY REVIEW 
See “8.6. Safety Oversight.” This will be performed on an ongoing basis throughout the course of the study by 2 
nephrologists not associated with the study. There will be 2 formal interim statistical analyses of nadir systolic BP 
and pre- to post-dialysis BP change across the trial arms: 1) after 10 participants have completed 2 phases of the 
study (1 conventional and 1 UF profiling phase) and 2) after 20 participants have completed 2 phases of the study 
(1 conventional and 1 UF profiling phase). Statistical rules will not be used to halt study enrollment. 
10.4.7.2 
EFFICACY REVIEW 
Efficacy review will be performed at the completion of the study or at the time of termination if the study is 
terminated early. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
N/A 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
There are 3 primary outcomes. Analyses will be performed with and without correction for multiple testing. The 
Bonferoni correction will be used to adjust confidence intervals to decrease type 1 error when adjusting for 
multiple testing. 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 

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Individual data will not be collected and stored by individual measure and timepoint, but individual data will not be 
publicly reported in this manner (reported only in aggregate). 
10.4.11 
EXPLORATORY ANALYSES 
Comparisons of values for the continuous exploratory endpoints of early diastolic myocardial velocity change, 
tricuspid annulus systolic excursion velocity change, blood volume monitor slope change and plasma refill change 
will be performed using ANOVA or non-parametric methods depending on data type. 
10.5 
SAMPLE SIZE 
This cross-over study is designed as a pilot study to test for efficacy signals. However, with its cross-over design in 
which each participant acts as his or her own control, we are powered to detect clinically and statistically 
significant differences across arms within patients. With a sample size of 30, we have 80% power to detect a 5.9 
mmHg difference in nadir SBP (S.D. 8), a ≥0.07 ng/mL troponin T difference (S.D. 0.1), a 2.2% strain difference (S.D. 
3), and 4% ejection fraction difference (S.D. 5); all clinically meaningful differences.  We have 80% power to detect 
a 31% absolute difference in the binary endpoint of Troponin T change >0.1 ng/mL (event rate=20%). 
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Randomization assignments will be generated using computer-generated random numbers. Assignments will be 
sealed in envelopes prior to study start. After patients consent to study participation, sealed study arm 
assignments will be randomly allocated to experimental or control treatment for period 1. Sequence assignments 
will be sealed in envelopes prior to study start and opened in a predetermined order at the start of each study 
period. The study will be double-blinded in that patients will not be informed of the treatment paradigm. 
Investigators, including those performing TTE interpretation, will be blinded to treatment paradigm. 
Ultrasonographers performing intra-HD TTEs will be blinded to treatment paradigm. 
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
At study close-out for each participant, we will assess blinding with qualitative questions regarding the 
participant’s perception of the order of administered treatments. 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
The PI may only break the study code in an emergency (occurrence of an SAE where it is necessary for the PI or 
treating physician to know which treatment the patient is receiving before the participant can be treated) or at the 
end of the study. Breaking the study blinding/ participant code will be reported to the IRB. 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in compliance with 
ICH E6 and regulatory and institutional requirements for the protection of confidentiality of participants. As part 
of participating in a NIH IC-sponsored study, each site will permit authorized representatives of the NIH IC and 
regulatory agencies to examine (and when permitted by applicable law, to copy) clinical records for the purposes 
of quality assurance reviews, audits, and evaluation of the study safety, progress and data validity. Study staff 
will have access to study records.   
Data (blood pressures, weights, dialysis treatment data) will be extracted from electronic medical records and 
stored in password-protected Excel flowsheets housed on a secure Department of Medicine server. Blood 

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volume monitor, treatment preference, and symptoms will be recorded on study data collection forms. TTE data 
will be downloaded from the TTE machine to secure Deparment of Medicine Servers, per standard protocols. All 
electronic information will be stored on a password-protected UNC server (with secure, password and firewall-
protected Department of Medicine server back-up) and accessed via a UNC password-protected computer and 
will be identifiably by study identification number only. Information linking the study identification number to 
the patient will be kept in a separate, password-protected database on the server. Study charts will be 
maintained in a locked room of the dialysis clinic. Study charts will be identified by study IDs. Signed consent 
forms will be kept in a locked filing cabinet in the PI’s locked office. Initial paper records of study HD treatment 
data, patient preferences and symptoms will be stored in the study chart and, after study completion, will be 
transferred to a locked filing cabinet in the locked office of the PI. Paper records will be destroyed (shredded and 
disposed in locked, shred bins) after verification of electronic data entry. Only the PI and research assistant will 
have access to patient information with patient identifiers.  
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality control procedures will be implemented beginning with data entry system and data quality control checks 
that will be run on the database will be generated. Any missing data or data anomalies will be communicated to 
the site(s) for clarification/resolution. Following written SOPs, the monitors will verify that the clinical trial is 
conducted and data generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements. The investigational site will provide direct access to all trial-related sites, 
sources data/ documents,a nd reports for the purpose of monitoring and auditing by the sponsor, and inspection 
by local and regulatory authorities. 
The PI will be responsible for quality assurance and quality control and will provide oversight of all research team 
members to assure adherence to the protocol. Except for in an emergency situation in which proper care for the 
protection, safety, and well-being of the study patient requires alternative treatment, the study shall be conducted 
exactly as described in the approved protocol.  
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
13.1 
ETHICAL STANDARD  
The investigators will adhere to NIH Human Research Protections Program policies and procedures. 
13.2 
INSTITUTIONAL REVIEW BOARD  
It is expected that the IRB will have the proper representation and function in accordance with federally mandated 
regulations. The protocol, informed consent, recruitment materials and all participant materials will be submitted 
to the IRB for review and approval. Approval of both the protocol and the consent form must be obtained before 
any participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented in the study. All changes to the consent form will be IRB approved; a determination will 
be made regarding whether previously consented participants need to be re-consented. The investigators will 
adhere to NIH Human Research Protections Program policies and procedures. 
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
An IRB-approved consent form and IRB-approved study informational page will be provided to potential 
participants. 

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13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
In obtaining and documenting informed consent, the investigators will comply with the applicable regulatory 
requirement(s), and should adhere to Good Clinical Practice (GCP) Good Laboratory Practice (GLP) and to ethical 
principles that have their origin in the Declaration of Helsinki. The PI will approach eligible patients and offer then 
the opportunity to participate in the study. If the patient does desire to participate in the research study, informed 
consent will be obtained by the PI. The purpose of the informed consent procedure is to assist the patient in 
understanding the nature and purpose of the study and the risks and benefits of the study, to offer answers to 
questions about any details of the study, and to obtain the patient’s signature on the IRB-approved consent form. 
All patients will be reminded that participation in the study is voluntary and that their medical care will not be 
affected if they choose not to participate. The patients will be informed that they will be free to terminate 
participation at any time during the study. The rights and welfare of participants will be protected by emphasizing 
to them that the quality of their medical care will not be adversely affected if they decline to participate in the 
study.  
We are recruiting English-speaking and Spanish-speaking individuals for this study. Each participating dialysis clinic 
has in-clinic non-English interpretation coverage by a professional interpreter. The interpreter will interpret for 
Spanish-speaking patients while the Principal Investigator or other study staff consent patients for the study. If 
Spanish-speaking participants have questions outside of study visit times, the interpreter will provide language 
interpretation over the phone. In addition, one of our Research Assistants is Spanish-speaking. 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
Study procedures and data collection will be performed after informed consent is obtained via patient signature on 
the IRB-approved consent form. All electronic information will be stored on a password-protected UNC computer 
(with secure, password and firewall-protected Department of Medicine server back-up) in the locked office of the 
study Principal Investigator and will be identifiably by study identification number only. Information linking the 
study identification number to the patient will be kept in a separate, password-protected database on the 
computer. Signed consent forms will be kept in a locked filing cabinet in the Principal Investigator’s locked office. 
Initial paper records of study HD treatment data will be stored in a locked filing cabinet in the locked office of the 
Principal Investigator. Paper records will be destroyed (shredded and disposed in locked, shred bins) after 
verification of electronic data entry. Only the Principal Investigator and research assistant will have access to 
patient information with patient identifiers. No documents containing patient information with patient identifiers 
will be downloaded off of the secure Department of Medicine server onto personal computers.  
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
One vial of stored blood will be maintained in UNC Kidney Center freezers (5th floor Burnett-Womack) until 12 
months after study completion. Access to stored samples will be limited to study staff. Samples and data will be 
stored using codes assigned by the investigators. Data will be kept on password-protected secure Department of 
Medicine servers. Only study staff will have access to the samples and data. Study participants who request 
destruction of the sample prior to the 12 months after study completion date will be notified of compliance with 
such request and all supporting details will be maintained for tracking. 
13.5 
FUTURE USE OF STORED SPECIMENS  
With the participant’s approval and as approved by the IRB, de-identified biological samples will be stored in the 
UNC Kidney Center freezers (5th floor Burnett-Womack). After the study is completed, the de-identified, archived 
blood sample will be maintained for 12 months under the supervision of the PI, Dr. Flythe. There will be no transfer 
of the specimens for use outside of the study. Potential additional laboratory testing (e.g. B-type natriuretic 

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peptide) relevant to this study may be performed. No genetic testing will be performed. The potential for 
additional laboratory testing on stored specimens will be listed in the IRB-approved consent form. 
During the conduct of the study, an individual participant can choose to withdraw consent to have biological 
specimens stored for future use. However, withdrawal of consent with regard to biosample storage will not be 
possible after the study is completed. 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site PI. The 
investigator is responsible for ensuring accuracy, completeness, legibility and timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
When making changes or corrections, cross out the original entry with a single line, and initial and date the change. 
Do not erase, overwrite, or use correction fluid or tape on the original. 
Research material for this study will consist of baseline patient data including demographics, co-morbidities, 
biochemical data, and HD treatment data (dialysate, dialysis time, target weight, UF volume, and medications) 
collected via patient interview and electronic medical record review. During the study HD treatments, patient vital 
signs (including blood pressures and weights) will be collected. Patient data will be identified with a study 
identification number. Patient-signed study informed consent forms will contain patient names and signatures. 
These consent forms will be stored separately from other study data in a locked filing cabinet in the Principal 
Investigator’s locked office. Only the Principal Investigator and research assistant will have access to consent 
forms.  
The collected study data will not contain participants’ names, medical record numbers, social security numbers, or 
contact information (address, telephone number), such that these data cannot be linked back to the source 
patients. Data collected about patients will be labeled with a study identification number.  A database linking 
patient names and study identification numbers will be maintained separate from the study data. This database 
will be password-protected and will be maintained on a password-protected UNC Department of Medicine server 
that is accessed via a UNC password-protected computer with anti-virus and UNC firewall protection. The study 
statistician (to-be-named) will have access to the de-identified electronic data.  
The PI will be the primary responsible party for the oversight and management of the study data. The study 
research coordinator will assist with data management. 
14.2 
STUDY RECORDS RETENTION  
Study documentation includes all case report forms, data correction forms or queries, source documents, 
monitoring logs/letters, and regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms).  
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical research study.  
Government agency regulations and directives require that all study documentation pertaining to the conduct of a 
clinical trial must be retained by the study investigator. In the case of a study with a drug seeking regulatory 
approval and marketing, these documents shall be retained for at least two years after the last approval of 
marketing application in an International Conference on Harmonization (ICH) region. In all other cases (as 
applicable to this study), study documents should be kept on file until three years after the completion and final 
study report of this investigational study.  

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14.3 
PROTOCOL DEVIATIONS  
According to UNC’s IRB, a protocol deviation is any unplanned variance from an IRB approved protocol that:   
 
Is generally noted or recognized after it occurs  
 
Has no substantive effect on the risks to research participants   
 
Has no substantive effect on the scientific integrity of the research plan or the value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the investigator(s).  
An unplanned protocol variance is considered a violation if the variance meets any of the following criteria:   
 
Has harmed or increased the risk of harm to one or more research participants   
 
Has damaged the scientific integrity of the data collected for the study 
 
Results from willful or knowing misconduct on the part of the investigator(s)  
 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, or University 
policies.  
If a deviation or violation occurs please follow the guidelines below:   
Protocol Deviations: UNC personnel will record the deviation in a Case Report Form and report to IRB or data and 
safety monitoring committee in accordance with their policies. Deviations should be summarized and reported to 
the IRB at the time of continuing review.   
Protocol Violations: Violations should be reported by UNC personnel within one (1) week of the investigator 
becoming aware of the event using the same IRB online mechanism used to report Unanticipated Problems.   
Unanticipated Problems:  Any events that meet the criteria for “Unanticipated Problems” as defined by UNC’s IRB 
must be reported by the Study Coordinator using the IRB’s web-based reporting system.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
This study will comply with NIH Public Access Policy, which ensures that the public has access to the published 
results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscrjipts to the 
digital archive PubMed Central upon acceptance for publication. The study will be registered at clinicaltrials.gov, 
sponsored by the National Library of Medicine.  
15 
STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
Jennifer E. Flythe, MD, MPH (Principal Investigator); UNC School of Medicine; 919-445-2656; jflythe@med.unc.edu 
Alan Hinderliter, MD (Co-Investigator); UNC School of Medicine; 919-843-5447; alan_hinderliter@med.unc.edu 
Ronald J. Falk, MD (Co-Investigator); UNC School of Medicine; 919-843-6485; ronald@falk@med.unc.edu 
Julia Narendra, MPH (Study Coordinator); UNC School of Medicine; 919-445-2686; julia3@email.unc.edu 
The steering committee will review the progress of the study together every 4 months. 
16 
CONFLICT OF INTEREST POLICY 

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The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the trial. All study personnel will adhere to the the conflict of interest policy set forth by the 
University of North Carolina at Chapel Hill. 
17  
LITERATURE REFERENCES  
1. USRDS: 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United 
States. 2013. 
2. Valderrábano, F, Jofre, R, López-Gómez, JM: Quality of life in end-stage renal disease patients. Am J Kidney Dis, 
38: 443-464, 2001. 
3. Flythe, JE, Kimmel, SE, Brunelli, SM: Rapid fluid removal during dialysis is associated with cardiovascular 
morbidity and mortality. Kidney Int, 79: 250-257, 2011. 
4. Saran, R, Bragg-Gresham, JL, Levin, NW, Twardowski, ZJ, Wizemann, V, Saito, A, Kimata, N, Gillespie, BW, 
Combe, C, Bommer, J, Akiba, T, Mapes, DL, Young, EW, Port, FK: Longer treatment time and slower 
ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS. Kidney Int, 69: 1222-
1228, 2006. 
5. Burton, JO, Jefferies, HJ, Selby, NM, McIntyre, CW: Hemodialysis-induced repetitive myocardial injury results in 
global and segmental reduction in systolic cardiac function. Clin J Am Soc Nephrol, 4: 1925-1931, 2009. 
6. McIntyre, CW, Harrison, LE, Eldehni, MT, Jefferies, HJ, Szeto, CC, John, SG, Sigrist, MK, Burton, JO, Hothi, D, 
Korsheed, S, Owen, PJ, Lai, KB, Li, PK: Circulating endotoxemia: a novel factor in systemic inflammation 
and cardiovascular disease in chronic kidney disease. Clin J Am Soc Nephrol, 6: 133-141, 2011. 
7. Flythe, JE, Xue, H, Lynch, KE, Curhan, GC, Brunelli, SM: Association of mortality risk with various definitions of 
intradialytic hypotension. J Am Soc Nephrol, 26: 724-734, 2015. 
8. Oliver, MJ, Edwards, LJ, Churchill, DN: Impact of sodium and ultrafiltration profiling on hemodialysis-related 
symptoms. J Am Soc Nephrol, 12: 151-156, 2001. 
9. Sang, GL, Kovithavongs, C, Ulan, R, Kjellstrand, CM: Sodium ramping in hemodialysis: a study of beneficial and 
adverse effects. Am J Kidney Dis, 29: 669-677, 1997. 
10. Straver, B, De Vries, PM, Donker, AJ, ter Wee, PM: The effect of profiled hemodialysis on intradialytic 
hemodynamics when a proper sodium balance is applied. Blood Purif, 20: 364-369, 2002. 
11. Donauer, J, Kölblin, D, Bek, M, Krause, A, Böhler, J: Ultrafiltration profiling and measurement of relative blood 
volume as strategies to reduce hemodialysis-related side effects. Am J Kidney Dis, 36: 115-123, 2000. 
12. Zhou, YL, Liu, HL, Duan, XF, Yao, Y, Sun, Y, Liu, Q: Impact of sodium and ultrafiltration profiling on 
haemodialysis-related hypotension. Nephrol Dial Transplant, 21: 3231-3237, 2006. 
 
 
 

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Appendix A: Transthoracic Echocardiography (TTE) Protocol 
 
The imaging protocol described below is designed primarily to assess intradialytic left ventricular systolic function 
by measuring myocardial strain by speckle tracking imaging.  Left ventricular ejection fraction by two-dimensional 
echocardiography, right ventricular function, and left ventricular diastolic function will also be evaluated. 
 
Image acquisition 
 
Data storage and labeling 
 
 
Studies should be labeled with the participant’s identification number, study number, and date of the study. 
 
 
Each echocardiographic study will be stored on the hard drive of the ultrasound machine and copied in native 
and DICOM formats onto a compact disc for subsequent off-line analysis. 
 
General procedure 
 
 
Imaging will be performed during quiet respiration with the subject in the left lateral decubitus position.  All 
tracings will be recorded with a simultaneous electrocardiogram. 
 
 
Harmonic imaging will be utilized, and transducer orientation and gain settings will be carefully adjusted to 
optimize imaging of the epicardial and endocardial surfaces of the ventricles. 
 
 
Tissue Doppler imaging will be performed at a 25 mm/second sweep speed.\ 
 
 
2D images will be stored digitally in loops consisting of 3 beats.  Tissue Doppler tracings containing 3 
consecutive frames will be stored for each spectral display. 
 
Imaging protocol 
 
As described in detail below, images should be recorded in the following sequence:  
 
Apical 4-chamber view 
Apical 2-chamber view 
Apical long axis view 
 
Apical 4-chamber view: A standard apical 4-chamber view of the heart will be obtained with the ultrasound beam 
oriented to obtain the maximal dimensions of the left and right ventricles.  Tissue Doppler imaging of mitral and 
tricuspid annular motion will then be performed.  Initially the lateral mitral annulus will be interrogated, placing 
the sample volume within the lateral wall of the left ventricle, adjacent to the mitral annulus.  The transducer will 
be oriented so that the ventricular wall is parallel to the cursor, and 5 consecutive beats showing peak Sm, Em, and 
Am velocities will be recorded.  The septal mitral annulus will be interrogated in similar fashion.  The anterior 
tricuspid annulus will then be interrogated by placing the sample volume within the right ventricular free wall, 
adjacent to the tricuspid annulus. 
 
Apical 2-chamber view: Standard 2-chamber images of the left ventricle, with the transducer angled to maximize 
the left ventricular long axis dimension, will be acquired. 

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Apical long axis view: Standard apical long axis images of the left ventricle, with the transducer angled to maximize 
the left ventricular long axis dimension, will be acquired. 
 
 
Image analysis 
 
Global longitudinal strain:  Left ventricular function will be quantified by 2-dimensional speckle tracking 
echocardiograpy-derived global longitudinal strain.  The apical 4-chamber, 2-chamber, and long axis views will be 
optimized and analysed offline using a dedicated computer workstation equipped with Philips QLab software.  
Aortic valve closure time will be defined on the apical long-axis view.  After the mitral annulus and apical left 
ventricular endocardium are identified, a region of interest will be automatically defined and edited as necessary.  
Global longitudinal strain will be calculated as the average of all 3 apical views. 
 
Left ventricular ejection fraction:  The areas of the left ventricle at end-diastole and at end-systole will be 
quantified by tracing the endocardial border (excluding trabeculations and papillary muscles) in the apical 2-
chamber and 4-chamber views.  Left ventricular volumes at end-diastole and at end-systole will be computed using 
the biapical Simpson’s rule.  Ejection fraction will be calculated as percentage change in left ventricular volumes. 
 
Early diastolic myocardial velocity (Em):  Left ventricular diastolic function will be quantified as the early diastolic 
myocardial velocity (Em) calculated as the average of early diastolic velocities recorded at the medial and lateral 
mitral annulus. 
 
Tricuspid annulus systolic excursion velocity (St):  Right ventricular systolic function will be quantified as the peak 
systolic excursion velocity (St) of the anterior tricuspid annulus. 
 
 
 
 
 
 

 
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Appendix B: Symptom Monitoring Questionnaire 
PATIENT-REPORTED SYMPTOMS DURING DIALYSIS 
 
During your dialysis treatments last 
week, did you have 
CRAMPING? 
No 
cramping 
Mild 
cramping 
Moderate 
cramping 
Severe 
cramping 
Very severe 
cramping 
 
During your dialysis treatments last 
week, did you have 
NAUSEA or UPSET STOMACH? 
No 
nausea 
Mild 
nausea 
Moderate 
nausea 
Severe 
nausea 
Very severe 
nausea 
 
During your dialysis treatments last 
week, did you have 
VOMITING or THROWING UP? 
No 
vomiting 
Mild 
 vomiting 
Moderate 
vomiting 
Severe 
vomiting 
Very severe 
vomiting 
 
 
 
INSTRUCTIONS 
Please respond to each statement by marking one box per row.  
We are interested in the symptoms you had DURING your dialysis treatments LAST WEEK. Respond ONLY 
based on the dialysis treatments last week. 

 
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During your dialysis treatments last 
week, did you have 
DIZZINESS or 
LIGHTHEADEDNESS?  
No 
dizziness 
Mild 
 dizziness 
Moderate 
dizziness 
Severe 
dizziness 
Very severe 
dizziness 
 
During your dialysis treatments 
last week, did you have 
RACING HEART or HEART 
PALPITATIONS? 
No 
racing heart 
Mild 
 racing heart 
Moderate 
racing heart 
Severe  
racing heart 
Very severe 
racing heart 
 
During your dialysis treatments 
last week, did you have 
CHEST PAIN? 
No 
chest pain 
Mild 
 chest pain 
Moderate 
chest pain 
Severe   
chest pain 
Very severe 
chest pain 
 
During your dialysis treatments 
last week, did you have 
SHORTNESS OF BREATH? 
No    
shortness of 
breath 
Mild 
 shortness of 
breath 
Moderate 
shortness of 
breath 
Severe 
shortness of 
breath 
Very severe 
shortness of 
breath 
 

 
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During your dialysis treatments 
last week, did you have 
THIRST or DRY MOUTH? 
No 
thirst 
Mild 
 thirst 
Moderate  
thirst 
Severe    
thirst 
Very severe 
thirst 
 
During your dialysis treatments 
last week, did you have 
HEADACHE?  
No 
headache 
Mild 
 headache 
Moderate 
headache 
Severe   
headache 
Very severe 
headache 
 
During your dialysis treatments last 
week, did you have 
ITCHING? 
No 
itching 
Mild 
 itching 
Moderate 
itching 
Severe   
itching 
Very severe 
itching 
 
During your dialysis treatments last 
week, did you have 
RESTLESS LEGS or DIFFICULTY 
KEEPING LEGS STILL?  
No 
restless legs 
Mild 
 restless 
legs 
Moderate 
restless legs 
Severe   
restless legs 
Very severe 
restless legs 
 
During your dialysis treatments last 
week, did you have 
TINGLING or FEELING OF PINS 
AND NEEDLES? 
No 
tingling 
Mild 
 tingling 
Moderate 
tingling 
Severe   
tingling 
Very severe 
tingling 

 
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During your dialysis treatments last 
week, did you have 
OTHER SYMPTOMS? (write-in) 
 
___________________________ 
No 
________ 
Mild 
 _______ 
Moderate 
________ 
Severe   
________ 
Very severe 
________ 
 
 
 
AFTER your dialysis treatments LAST WEEK, how long did it take for you to recover?     
 
     __________ hour(s) 

Ultrafiltration (UF) profiling and outcomes among individuals on 
maintenance hemodialysis: statistical analysis plan 
Primary Analysis 
Depending on the type of various endpoints, we propose to perform the following tests to test the 
difference between UF profile and conventional treatment. 
• 
Binary Outcomes 
– 
We will perform repeated measure logistic regression by regressing the binary outcome on 
the treatment indicator and test if the coefficient before the treatment indicator is significant. 
Each subject will have a random intercept. The model is given by 
𝑙𝑜𝑔𝑖𝑡(𝑜𝑢𝑡𝑐𝑜𝑚𝑒) ∼1 + 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ (1|𝐼𝐷) 
• 
Continuous Outcomes 
– 
We will perform repeated measure linear regression by regressing the continuous outcome 
(percentage outcome will be log-transformed) on the treatment indicator and test if the 
coefficient before the treatment indicator is significant. Each subject will have a random 
intercept. The model is given by 
𝑜𝑢𝑡𝑐𝑜𝑚𝑒∼1 + 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ (1|𝐼𝐷) 
• 
Categorical Outcomes 
– 
We will perform repeated measure multinomial regression by regressing the categorical 
outcome on the treatment indicator and test if the coefficient before the treatment indicator 
is significant. Each subject will have a random intercept. The model is given by 
𝑚𝑢𝑙𝑡𝑖−𝑙𝑜𝑔𝑖𝑡(𝑜𝑢𝑡𝑐𝑜𝑚𝑒) ∼1 + 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡+ (1|𝐼𝐷) 
Quality Check 
For patients who dropped out during the study, normalize endpoints to the same scale as the other 
patients, depending on the type of endpoints. 
Sensitivity Analyses 
1. 
Exclude participants who dropped out from all analyses. 
2. 
Exclude participants who had endpoint data drawn "off-schedule" (troponin T, symptoms, etc.) from 
individual endpoint analyses. 
3. 
Exclude participants who had an abnormality with their troponin T blood draw from troponin T-
related analyses. 
4. 
Test for difference by order of randomization (UF profiling --> conventional --> UF profiling --> 
conventional) vs. (conventional --> UF profiling --> conventional --> UF profiling) 
5. 
Test for difference by clinic (site 1 vs. site 2)