Conditions: Chronic Kidney Disease Requiring Chronic Dialysis
Keywords: Hemodialysis Dialysis End Stage Renal Disease Patient-reported Outcomes Symptoms Diuretic Furosemide Lasix
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 39
Healthy volunteers: no

Brief summary:
Individuals with kidney failure receiving maintenance hemodialysis (HD) have high mortality rates, driven largely by cardiovascular causes. Volume-related factors are critical, modifiable contributors to cardiovascular complications. Reversing volume overload has been shown to improve blood pressure and cardiac remodeling. Use of loop diuretics may represent a pragmatic, low-cost, and low-burden strategy to improve outcomes in people receiving HD. Lack of data on optimal furosemide dosing, safety, and acceptability are barriers to expanded use. This study investigates whether oral furosemide is safe and effective at increasing urine volume in HD patients.

Detailed description:

Arms:
arm 1: Study participants will receive furosemide oral tablets to be taken twice daily. During study period 1 (first 6 weeks), the drug dose will be escalated every 2 weeks if safe, tolerated, and acceptable to the participant. During study period 2 (subsequent 12 weeks), participants will take the maximum tolerated dose from study period 1, received every 4 weeks if safe, tolerated, and acceptable to the participant.

Interventions: intervention 1: Furosemide (loop diuretic) Tablets
Intervention descriptions: intervention 1: Open label dose escalation study of furosemide in people receiving maintenance hemodialysis. Participants will take furosemide oral tablets twice daily for 18 weeks. Doses will be titrated every 2 weeks for 6 weeks if safe, effective, tolerated, and accepted by the participant. First 2 weeks of the study: participants not taking oral furosemide at enrollment will take 80mg furosemide twice daily, those taking oral furosemide at enrollment will stay on their prescribed dose, and those taking another loop diuretic at enrollment will discontinue their prescription and take an equivalent oral furosemide dose. At week 4: dose escalation if tolerated (from 80mg to 120mg twice daily for the 1st group, and a 50% increased dose not \>320mg/day for the 2nd \& 3rd groups). At week 6: dose escalation if tolerated (from 120mg to 160mg twice daily for the 1st group, and a 50% increased dose not \>320mg/day for the 2nd \& 3rd groups). Final 12 weeks: all participants will take the maximum tolerated dose.

Protocol document:
Prot_SAP_000.pdf: 
PROTOCOL 
 
Pilot Study of Loop Diuretics Among Individuals Receiving 
Hemodialysis 
 
 
 
NCT number NCT04622709 
Document Date 10/15/2020 
 


Loop Diuretic Pilot Study Protocol 1 
 
 
Complete Title: Pilot study of loop diuretics among individuals receiving hemodialysis  
 
Short Title: Loop diuretic pilot study 
Drug or Device Name(s): Furosemide 
FDA IND/IDE (if applicable): Exempt 
Sponsor: NIH/NIDDK 
Protocol Date: 10/15/2020 
 
Amendment 1 Date: 1/07/2020 (Version 2.0) 
Amendment 2 Date: 2/4/2020 (Version 2.1) 
Amendment 3 Date: 03/09/2020 (Version 2.2) 
Amendment 4 Date: 10/15/2020 (Version 2.3) 
 
 
 
 
 
Sponsor: NIH/NIDDK 
2 Democracy Plaza 
6707 Democracy Blvd. 
Bethesda, MD 20892-5458 
Study Principal Investigator: Jennifer E. Flythe, MD, MPH 
7024 Burnett-Womack, CB #7155 
Chapel Hill, NC 27599-7155 
Phone 919-445-2656 
email: jflythe@med.unc.edu 
 
 
 
 


Loop Diuretic Pilot Study Protocol 2 
 
 
PROTOCOL TITLE: Pilot study of loop diuretics among individuals receiving hemodialysis  
 
Short Title: Loop diuretic pilot study 
Lead Investigator: 
Jennifer E. Flythe, MD, MPH 
 University of North Carolina at Chapel Hill 
Protocol Version: 2.3 
Version Date: 10/15/2020 
 
I confirm that I have read this protocol and understand it.    
 
Principal Investigator Name:  
 
 
Jennifer E. Flythe 
 
 
 
 
Principal Investigator Signature:  
 
 
 
 
 
 
 
Date:   
 
 
 
 
 
10/15/2020 
 
 
 
 
 
 
Study Team Members 
Lead Investigator: Jennifer E. Flythe, MD, MPH 
Co-Investigator and Data Management: Magdalene Assimon, PharmD, PhD 
Research Coordinator: Julia Narendra, MPH 
Statistician and Programmer: Yichun Hu, MS 
 
 
 
 
 
 


Loop Diuretic Pilot Study Protocol 3 
 
TABLE OF CONTENTS 
Table of Contents ................................................................................................................. 3 
Abbreviations and Definitions of Terms ................................................................................ 4 
Protocol Synopsis ................................................................................................................. 5 
1 
BACKGROUND  AND RATIONALE .......................................................................................................................... 8 
2 
STUDY OBJECTIVES .............................................................................................................................................. 13 
3 
INVESTIGATIONAL PLAN ..................................................................................................................................... 14 
4 
STUDY PROCEDURES ........................................................................................................................................... 18 
5 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................................................... 22 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................................... 24 
7 
STUDY INTERVENTION (DEVICE OR OTHER INTERVENTION) .............................................................................. 8 
8 
STUDY INTERVENTION ADMINISTRATION ........................................................................................................... 8 
9 
SAFETY MANAGEMENT ....................................................................................................................................... 26 
10  DATA COLLECTION AND MANAGEMENT ............................................................................................................ 33 
11 RECRUITMENT STRATEGY ................................................................................................................................... 35 
12 CONSENT PROCESS ............................................................................................................................................. 37 
13 PUBLICATION ....................................................................................................................................................... 38 
14 REFERENCES ........................................................................................................................................................ 38 
Appendix ........................................................................................................................... 40 
 
 
 
 
 
 
 
 
 
 
 
 


Loop Diuretic Pilot Study Protocol 4 
 
ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
BP 
Blood pressure 
EHR 
Electronic health record 
ESKD 
End-Stage Kidney Disease 
FDA 
Food and Drug Administration 
HD 
Hemodialysis 
IDS 
Investigational Drug Service 
IDWG 
Interdialytic weight gain 
IND 
Investigational new drug 
Inner EAR 
Inner Effectiveness of Auditory Rehabilitation 
IRB 
Institutional Review Board 
PI 
Principal investigator 
SAE 
Serious adverse event 
UF 
Ultrafiltration 
UNC 
University of North Carolina 
U.S. 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Loop Diuretic Pilot Study Protocol 5 
 
PROTOCOL SYNOPSIS 
Study Title 
Pilot study of loop diuretics among individuals receiving hemodialysis (HD) 
 
Funder 
NIH/NIDDK 
Clinical Phase 
Phase II 
Study Rationale 
     Individuals with end-stage kidney disease (ESKD) receiving HD have high mortality rates, 
driven largely by cardiovascular causes. Volume-related factors including volume overload, 
large interdialytic weight gains (IDWG), and higher ultrafiltration (UF) rates are critical, 
modifiable contributors to cardiovascular complications such as hypertension, arterial 
stiffness, left ventricular hypertrophy, and heart failure. Reversing volume overload has 
been shown to improve blood pressure (BP) and cardiac remodeling, and lower IDWGs and 
UF rates are associated with lower rates of intradialytic hypotension and less myocardial 
ischemia on cardiac imaging. While dietary restrictions and longer, more frequent HD can 
improve these volume-related factors, they add substantial burden for patients. 
     Oral loop diuretics are one potential strategy to increase urine output in HD patients. 
Loop diuretics are often prescribed for volume control before HD initiation and to patients 
on peritoneal dialysis. Many, if not most, patients discontinue diuretics once they begin 
treatment with HD. Small studies suggest that high-dose oral furosemide may increase 
urine volume in HD patients. However, dose-related side effects raise concern about such 
doses. Observational data suggest that lower doses of diuretics are associated with both 
less IDWG and less intradialytic hypotension. Loop diuretic use after HD initiation is 
associated with lower hospitalization rates. Diuretics may represent a pragmatic, low-cost, 
and low-burden strategy to improve outcomes in HD patients. Lack of data on optimal 
furosemide dosing, safety, and acceptability are barriers to expanded use. 
Study Objective(s) 
Primary  
• 
To generate pilot data on the short-term and longer-term efficacy, safety, tolerability, 
and acceptability of furosemide in patients with HD-dependent ESKD. 
Exploratory 
• 
To generate data on the short-term and longer-term clinical outcomes in patients with 
HD-dependent ESKD receiving furosemide. 
Test Article(s) 
Oral furosemide (maximum possible dose 320 mg/day) 
Study Design 
 
This is a single center (multi-clinic), open-label, non-randomized pilot study to test whether 
oral furosemide is safe and effective at increasing urine volume in HD patients. The study 
will consist of 2 periods: a 6-week dose escalation period (period 1) and a subsequent 12-
week follow-up period (period 2). During period 1, all participants will receive escalating 
doses of furosemide as tolerated, and we will examine the short-term safety, tolerability, 
and efficacy of furosemide. During period 2, all participants will continue the maximally 
tolerated period 1 furosemide dose, and we will examine the acceptability of and 
adherence to furosemide and the longer-term safety and efficacy of furosemide.  
Population 
Key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
• Patient self-report of at least 1 cup urine/24-hours 
• Age ≥18 years 
• Receipt of thrice weekly in-center HD at a participating clinic (UNC-associated Carolina 
Dialysis- Carrboro, Siler City, Pittsboro, Sanford, and Lee County) 
• ≥60 days receiving in-center HD 
• Willingness to take study medication and undergo study testing 


Loop Diuretic Pilot Study Protocol 6 
 
• Ability to provide informed consent 
 
Exclusion Criteria 
• Known allergy to loop diuretic 
• History of poor adherence to HD or medical regimen per nephrologist 
• >1 hospitalization in prior 30-days 
• Frequent hypotension (systolic blood pressure (BP) <80 mmHg at >30% of HD 
treatments in prior 30-days)  
• Cirrhosis per nephrologist 
• Hearing disorder per nephrologist 
• Serum potassium <3.5 mEq/L, magnesium <1 mg/dL, or corrected calcium <8 mg/dL in 
prior 30-days 
• Taking a non-loop diuretic (e.g. spironolactone, eplerenone, ethacrynic acid, thiazides) 
• Taking an aminoglycoside, cisplatin, methotrexate, cyclosporine, ACTH, lithium, 
phenytoin, or oral/intravenous steroid 
• Natural licorice consumption  
• Prisoners, patients with significant mental illness 
• Pregnant patients and nursing mothers 
Number Of Participants  
30 (with enrollment up to 40 to ensure sample size) 
Study Duration 
Each participant’s participation will last 22 weeks (4-week baseline and 18-week study 
periods) 
The entire study is expected to last 16 months. 
Study Phases 
Screening 
Study Treatment 
Follow-Up   
Screening: screening for eligibility and obtaining consent 
Baseline: medical history and other baseline assessments 
Study treatment and follow-up: dose escalation (period 1, 6-weeks) and follow-up (period 
2, 12-weeks)  
Efficacy Evaluations 
Short-term and longer-term efficacy (urine volume) 
• Among participants with baseline 24-hour urine volume ≥200 mL: incidence of ≥25% 
increase in urine volume 
• Among participants with baseline 24-hour urine volume <200 mL: incidence of a ≥50 mL 
increase in urine volume to a urine volume of at least 100 mL/24-hours 
Pharmacokinetic 
Evaluations 
N/A 
Safety Evaluations 
Short-term and longer-term safety (electrolytes, furosemide levels, BP, symptoms) 
• Incidence of serum potassium <3.2 mEq/L 
• Incidence of serum magnesium <0.8 mg/dL 
• Incidence of serum corrected calcium <7.0 mg/dL 
• Incidence of serum furosemide level >12 microgram/L 
• Incidence of dialysis-associated hypotension requiring hospitalization or treatment in an 
emergency room and not attributable to overt sepsis, acute myocardial infarction, or 
other cardiovascular event (e.g. aortic dissection)  
• Incidence of severe or very severe patient-reported rash, tinnitus, or hearing change) 
not attributable to causes other than furosemide 
• Incidence of 10-point decrease in Inner Effectiveness of Auditory Rehabilitation (Inner 
EAR) instrument score 


Loop Diuretic Pilot Study Protocol 7 
 
Tolerability Evaluations 
Short-term and longer-term tolerability (symptoms) 
• Incidence of severe or very severe cramping, dizziness/pre-syncope, unusual 
tiredness/weakness, chest pain, nausea, vomiting, or diarrhea not attributable to causes 
other than furosemide 
Statistical And Analytic 
Plan 
At designated study time-points, we will determine the change from baseline for efficacy 
measures (24-hour urine volume, fractional excretion of urea/ sodium) and safety measures 
(e.g. potassium, magnesium, hypotension). These measures and absolute change in 
electrolyte values will be analyzed via one-way repeated measures of analysis of variance to 
determine the presence of absence of dose-related differences. In addition, we will use 
mixed effects modeling to test the effect of increased dose and duration with the fixed 
effect of time (dose), random subject effect, and an unstructured repeated covariance type. 
We will use generalized estimating equations to assess categorical outcomes (sufficient 
increase in 24-h urine volume, hypokalemia, hypomagnesemia, hypotension, symptoms, 
Inner EAR score, patient acceptance). We will also consider binary outcomes as rates 
(events/time). 
DATA AND SAFETY 
MONITORING PLAN 
We will ensure participant safety through regular review by the research team. This will 
include review of study progress, listings of adverse events (AEs), and AE logs. We will also 
use an independent safety monitor to provide an additional layer of protection. The 
principal investigator (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. 
 
 
 
 
 
 
 


Loop Diuretic Pilot Study Protocol 8 
 
1 
BACKGROUND AND RATIONALE 
1.1 
Introduction (Study rationale, brief study overview and setting) 
Over 450,000 people in the United States (U.S.) require maintenance hemodialysis (HD) to sustain life. These 
individuals have exceedingly high mortality rates (166 deaths/1,000 person-years), driven largely by cardiovascular 
causes.1 Volume-related factors including volume overload,2-4 large interdialytic weight gains (IDWG),5, 6 and higher 
ultrafiltration (UF) rates7-9  are critical, modifiable contributors to cardiovascular complications such as hypertension, 
arterial stiffness, left ventricular hypertrophy, and heart failure. Reversing volume overload has been shown to improve 
blood pressure (BP) and cardiac remodeling, and lower IDWGs and UF rates are associated with lower rates of 
intradialytic hypotension and less myocardial ischemia on cardiac imaging.10, 11 However, over 50% of HD patients are 
volume-overloaded,2 and more than 35% have IDWGs exceeding 3.5% of body weight.12 While dietary restrictions and 
longer, more frequent HD can improve these volume-related factors, patients are often averse and poorly adherent to 
dietary restrictions and are generally unwilling to increase HD treatment time.13  
The use of oral loop diuretics is one potential strategy to increase urine output in HD patients. Loop diuretics are 
often prescribed for volume control before HD initiation and to patients on peritoneal dialysis.14, 15 However diuretic use 
declines sharply after HD initiation. It is estimated that >50% of U.S. HD patients stop diuretics at HD initiation 
irrespective of urine output, and <25% of patients use diuretics 6 months into HD.14, 16 A small study (N=13) suggests that 
high-dose oral furosemide (>1,000 mg/day) may increase urine volume in HD patients with urine output as low as 100 
mL urine/day.17 However, dose-related side effects raise concern about such doses. Observational data show 
associations between lower-dosed diuretics and lower IDWG and less intradialytic hypotension.16 Loop diuretic use after 
HD initiation is associated with lower hospitalization rates.18 Diuretics may represent a pragmatic, low-cost strategy to 
improve outcomes in HD patients. [See grant proposal for additional detail and supporting studies.] 
Lack of data on optimal furosemide dosing, safety, and acceptability are barriers to expanded use. To fill this 
knowledge gap, we will conduct an 18-week single center (multi-clinic), open-label pilot study to test whether oral 
furosemide is safe and effective at increasing urine volume in HD patients. The study will consist of 2 periods: a 6-week 
dose escalation period (period 1) and a subsequent 12-week follow-up period (period 2). During period 1, all participants 
will receive escalating doses of furosemide as tolerated, and we will examine the short-term safety and efficacy of 
furosemide. During period 2, all participants will continue the maximally tolerated period 1 furosemide dose, and we will 
examine the acceptability of and adherence to furosemide and the longer-term safety and efficacy of furosemide. The 
study duration is 18 weeks. 
We will recruit study participants from the University of North Carolina (UNC)-owned Siler City, Pittsboro, Sanford, 
Lee County, and Carrboro HD clinics. The study selection criteria are listed below. All recruitment activities and study 
visits will take place at the participant’s dialysis clinic, scheduled to coincide with routine HD treatments. Laboratory 
(blood and urine electrolytes) samples will be transported to and analyzed at the UNC McClendon Laboratories in Chapel 
Hill, NC. Stored blood and urine samples will be housed in freezers at the UNC Kidney Center (5th floor Burnett-Womack 
Building, Chapel Hill, NC). Serum and urine furosemide levels will be analyzed in the UNC Kidney Center Hostetter Lab 
Center (5th floor Burnett-Womack Building, Chapel Hill, NC). 
 
1.2 
Name and Description of Investigational Product or Intervention  
Study intervention: Oral furosemide 
The information provided in this section was obtained from Food and Drug 
Administration (FDA) package insert.19 Furosemide (Lasix®) is a diuretic which is 
an anthranilic acid derivative. Tablets contain furosemide (active ingredient) 
and lactose monohydrate NF, magnesium stearate NF, starch NF, talc USP, and 
colloidal silicon dioxide SF (inactive ingredients). Chemically, it is a 4-chloro-N-
furfuryl-5-sulfamoylanthranilic acid. It is available in 20, 40 and 80 mg tablets. 


Loop Diuretic Pilot Study Protocol 9 
 
Furosemide is a white to off-white odorless crystalline power. It is practically insoluble in water, sparingly soluble in 
alcohol, freely soluble in dilute alkali solutions and insoluble in dilute acids.  
 
 
Mechanism of action: Furosemide inhibits the absorption of sodium and chloride not only in the proximal and distal 
tubules but also in the loop of Henle. The action on the distal tubule is independent of any inhibitory effect on carbonic 
anhydrase and aldosterone.  
 
Pharmacokinetics: The onset of diuresis following oral administration is within 1 hour. The peak effect occurs within the 
first or second hour. The duration of diuretic effect is 6 to 8 hours. In fasted normal men, the mean bioavailability of oral 
furosemide tablets is 64% of that from an intravenous injection of the drug. The terminal half-life of furosemide is 
approximately 2 hours. Peak plasma concentrations increase with increasing dose, but times-to-peak do not differ 
among doses. Furosemide is predominantly excreted unchanged in the urine.  
 
Indications and usage: Furosemide is indicated in adults and pediatric patients for the treatment of edema associated 
with congestive heart failure, cirrhosis of the liver, and kidney disease. Oral furosemide may also be used in adults for 
the treatment of hypertension alone or in combination with other antihypertensive agents.  
 
Contraindications: Furosemide is contraindicated in patients with anuria and in patients with a history of hypersensitivity 
to furosemide. 
 
Dosing and dose changes with rationale 
During the 6-week dose escalation period (period 1), participants who are not taking oral furosemide at study entry will 
take 80 mg oral furosemide twice a day for 14 days and then, if the dose was tolerated, they will take 120 mg oral 
furosemide twice a day for 14 days and then, if the dose was tolerated, they will take 160 mg oral furosemide twice a 
day for 14 days. If a patient is taking oral furosemide at study entry, the participant will remain on his/her prescribed 
oral furosemide dose for the first 2 weeks of the dose escalation period. If a participant is taking another loop diuretic 
(e.g. bumetanide), we will calculate the corresponding oral furosemide dose (i.e. 1 mg bumetanide = 40 mg furosemide). 
The participant will discontinue the other loop diuretic and receive the equivalent dose of oral furosemide for the first 2 
weeks of the dose escalation period. The first dose will then be increased by 50%, rounded to the nearest whole tablet 
strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day) at week 2 and, if 
tolerated, the second dose will be increased by 50% at week 4, rounded to the nearest whole tablet strength of existing 
(i.e. available) furosemide tablet formulations (not to exceed 320 mg/day). Establishing ceiling dose thresholds by 
increasing the prior dose by 30-50% is the recommended approach in heart failure patients per the American College of 
Cardiology Foundation/American Heart Association task force on practice guidelines.20 The maximum proposed study 
dose is 160 mg twice daily (320 mg total per day), which is well below the maximum oral furosemide daily dose of 600 
mg/day listed in the furosemide package insert.19 In addition, the planned furosemide doses are consistent with 
available formulations (i.e. study doses can be provided using currently marketed furosemide tablet strengths) and 
standard clinically utilized/approved doses for the FDA-labeled indications. We are not testing higher doses due to the 
potential increased risk of AEs necessitating drug discontinuation. 
 
Occurrence of any of the following events will end dose up-titration: 1) electrolyte abnormalities (serum potassium <3.2 
mEq/L, serum magnesium <0.8 mEq/L, and/or serum corrected calcium <7 mg/dL); 2) side effects attributable to 
furosemide (severe or very severe rash, tinnitus, or hearing change); decrease in Inner Effectiveness of Auditory 
Rehabilitation (Inner EAR) instrument score by more than 10 points; and/or intradialytic systolic BP <80 mmHg that a 
study investigator attributes to study drug-induced hypovolemia); and/or 3) patient non-acceptance (defined as the 


Loop Diuretic Pilot Study Protocol 10 
 
patient reporting unwillingness to take the study drug). If one of these events occur, the participant will return to the 
prior tolerated oral furosemide dose. If one of these events occurs at the lowest administered dose, oral furosemide will 
be stopped and not re-started. 
 
During the 12-week follow-up period (period 2), participants who tolerated and accepted furosemide in period 1 will 
continue their maximally tolerated period 1 furosemide dose during the 12-weeks of follow-up. If a participant has 
electrolyte abnormalities or other side effects attributable to furosemide in period 2 (i.e. on their period 1 maximally 
tolerated dose), the dose will be lowered sequentially (i.e. dose de-escalation: 160  120  80 mg twice daily, or, if on 
alternative dosing due to prior diuretic use, decrease dose by 50%, rounded to the nearest whole tablet strength of 
existing (i.e. available) furosemide tablet formulations, until tolerated). If side effects persist or if the participant 
chooses, oral furosemide will be stopped. 
 
Investigational New Drug (IND) exemption status 
Oral furosemide is marketed as a prescription drug product and regulated by the U.S. FDA. Furosemide is indicated for 
edema and hypertension (signs and symptoms of volume overload). Its use in this study will be considered an on-label 
use. Our study is exempt from IND requirements for the following reasons: 
• Oral furosemide is lawfully marketed in the U.S. 
• The study is not intended to be reported to the FDA as a well-controlled study in support of a new indication for use 
and is not intended to be used to support any other significant change in the labeling for the drug. 
• The study is not intended to support a significant change in the advertising for the product. 
• The investigation does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug 
product. Specifically, the initial starting dose of oral furosemide in the proposed trial is 80mg twice daily for loop 
diuretic naïve patients and the maximum proposed study dose is 160 mg twice daily (320 mg total/day). The study 
doses of furosemide are well below the maximum daily dose specified in the furosemide package insert, 600 
mg/day.42 Moreover, the proposed furosemide dose escalation scheme is consistent with heart failure guidelines 
from the American College of Cardiology Foundation/American Heart Association task force on practice 
guidelines.51 
• The study will be conducted in compliance with Institutional Review Board (IRB) review requirements set forth in 21 
CFR Part 56 and informed consent requirements set forth in 21 CFR Part 50. 
• The study will be conducted in compliance with 21 CFR 312.7 (i.e. the investigation is not intended to promote or 
commercialize the drug product). 
 
1.3 
Clinical Data to Date 
Heart Failure: Most patients with heart failure and volume overload are initially treated with the combination of an oral 
loop diuretic (e.g. furosemide) and a low sodium diet. The diuretic response to furosemide is described by a threshold 
type dose-response curve linking the rate of diuretic excretion in the urine and the degree of natriuresis. There is 
virtually no increase in natriuresis until the threshold concentration of luminal diuretic is reached and, once the 
threshold is exceeded, the degree of natriuresis increases until a maximal ceiling is reached.22, 23 As the threshold 
concentration differs across patients, it is necessary to determine an effective dose in individual patients. The usual 
starting dose in furosemide-naïve patients without kidney dysfunction is furosemide 20 to 40 mg once or twice daily, 
and subsequent dosing is determined by the diuretic response. It is customary to double the prior dose when titrating 
furosemide for a diuretic response.20 For patients with normal glomerular filtration rate, maximal single oral doses of 
furosemide are 40 to 80 mg. For patients with kidney insufficiency (impaired glomerular filtration rate), a higher 
maximum dose of 160 to 200 mg of furosemide can be given (maximum total daily dose of 600 mg).19 Dosing in patients 
who have received prior loop diuretic therapy is based upon the response to prior dosing amounts.20  
No single furosemide dosing regimen (bolus versus continuous intravenous infusion; high dose verse lower dose 
oral or intravenous infusion) has been shown to be superior to others. A meta-analysis from the National Institute for 


Loop Diuretic Pilot Study Protocol 11 
 
Health and Clinical Excellence Guidance (NICE) included 10 randomized controlled trials comparing various intravenous 
furosemide regimens.24 Comparisons between furosemide intravenous bolus and continuous infusion showed no clear 
differences in outcomes such as weight loss, urine output, or change in kidney function (ototoxicity was not assessed). 
The Diuretic Optimization Strategies Evaluation (DOSE) study evaluated the optimal approach to diuretic dosing and 
route of administrations for patients with decompensated heart failure.25 The trial randomly assigned 308 patients to 
receive furosemide administered intravenously via either a bolus every 12 hours or continuous infusion and at either a 
low dose (equivalent to the patient’s previous oral dose) or a high dose (2.5 times the previous oral dose). The efficacy 
end point was the patients’ global assessment of symptoms over the course of 72 hours and the safety end point was 
change in serum creatinine from baseline to 72 hours. There was no significant difference in efficacy or safety end points 
for bolus versus continuous infusion. Patients assigned to intravenous bolus therapy were more likely to require a dose 
increase at 48 hours; however, the total dose of furosemide over 72 hours in the bolus group was not significantly 
different from that in the continuous infusion group. High-dose furosemide, compared with low-dose furosemide, 
produced greater net fluid loss, weight loss, and relief from dyspnea but also more frequent transient worsening of renal 
function. There was no significant difference in patients’ global assessment of symptoms in the high-dose group and the 
mean change in the serum creatinine was less than 0.1 mg/dL in both groups. 
 
Dialysis-Dependent End-Stage Kidney Disease (ESKD) 
Peritoneal dialysis: Over 40% of peritoneal dialysis patients are prescribed diuretics for volume control.14, 15, 26 An 
increase in urine volume from diuretics helps patients receiving peritoneal dialysis improve or maintain their urine 
output. A randomized trial showed that the long-term use of furosemide at a daily dose of 250 mg led to greater urine 
volume compared to control. Both groups had similar mean urine volume at randomization (1020 vs. 1040 mL), but at 
12-months, the mean daily urine volume in the furosemide group was 1070 mL compared to 733 mL in the control 
group.17 
 
Hemodialysis: Diuretics are used less frequently in HD patients as compared to peritoneal dialysis patients in the U.S. 
Over 50% of U.S. HD patients stop diuretic therapy at HD initiation irrespective of residual urine output, and <25% of 
patients remain on diuretics 6 months after HD initiation.14, 16 In contrast, the majority of patients in Europe and Japan, 
stay on diuretics after HD initiation.16 There have been no large randomized trials of furosemide for the indications of 
volume overload or hypertension among individuals receiving maintenance HD. However, since diuretics promote urine 
output, they may offer more consistent volume control in HD patients with residual urine output. Mechanistic studies 
suggest that adaptive renal tubule changes preserve diuretic response even in advanced kidney disease.22, 23 While there 
may be concerns about diuretic efficacy in patients with little urine output, a study of 13 HD patients receiving large 
doses of oral furosemide (>1,000 mg/day), showed that furosemide can increase urine volume in patients producing as 
little as 100 mL urine/day.17 However, some participants had bullous dermatosis, underscoring the need to study 
furosemide safety and efficacy at lower doses as we will study in this pilot study. Using international Dialysis Outcomes 
and Practice Patterns Study (DOPPS) data, Bragg-Gresham showed an association between diuretic use and lower IDWG, 
fewer hypotensive and hyperkalemic events, and lower cardiovascular mortality.16 Another retrospective cohort study 
showed that continuation (vs. discontinuation) of loop diuretics after HD initiation was associated with lower 
hospitalization rates, intradialytic hypotension frequency and IDWG.  
Clinical trial data on optimal dosing, safety, tolerability, and effectiveness of loop diuretics are lacking. It is 
known that in comparison to non-dialysis patients, individuals with dialysis-dependent ESKD require higher doses of loop 
diuretics to achieve increases in urine output.22 However, a “ceiling effect” has been observed. At doses where the 
fractional excretion of sodium plateaus, further dose increase does not provide additional diuretic effect.22, 23, 27, 28 The 
optimal loop diuretic dose in HD patients is unknown and may differ based on baseline urine output. Second, diuretics 
can cause hypokalemia and hypomagnesemia, conditions associated with adverse cardiovascular outcomes.19, 28-31 
Moreover, high dose intravenous (constant rate of 25 mg/min) and very high dose oral (>800 mg/day) loop diuretics are 
associated with ototoxicity.32-35 These effects have not been observed with oral furosemide administered at recommend 


Loop Diuretic Pilot Study Protocol 12 
 
doses without interacting medications (e.g. cisplatin, aminoglycosides).35 No studies have evaluated the safety of lower 
dose oral loop diuretics in HD patients. Table 1 summarizes studies of diuretics and outcomes in dialysis patients (the 
majority of these studies evaluated loop diuretics, specifically furosemide). 
 
Table 1. Studies of diuretics in dialysis patients. 
Study (year) 
Population (N; location) 
Study design/ diuretic 
Outcome with diuretic 
Sibbel/Flythe 
(2019)18 
Incident HD  
(7,072; U.S.) 
Observational cohort: loop continued 
after HD initiation vs. not 
• ↓ IDH  
• ↓ hospitalization 
• ↓ mortality (non-sig trend)  
Bragg-Gresham 
(2007)16 
Incident & prevalent HD  
(16,420; multinational) 
Observational cohort: diuretic vs. not 
• ↓ IDWG and ↓ IDH  
• ↓ hyperkalemia  
• ↓ CV mortality 
van Olden  
(1992)36 
Prevalent HD & 100 mL UO/day 
(13; Netherlands) 
Interventional study: furosemide 
• ↑ 24-h urine vol. & sodium 
Flinn  
(2006)37 
Prevalent PD  
(61; Canada) 
Interventional study: furosemide vs. 
control 
• ↓ anuria (non-sig trend) 
Medcalf  
(2001)17 
Incident PD  
(61; U.K.) 
RCT: furosemide vs. control 
• ↑ 24-h urine vol. & sodium 
• ↓ IDWG 
Abbreviations: HD, hemodialysis; U.S., United States; IDH, intradialytic hypotension; non-sig., non-significant; IDWG, interdialytic weight gain; CV, 
cardiovascular; UO, urine output; vol., volume; PD, peritoneal dialysis; U.K., United Kingdom; RCT, randomized controlled trial 
 
1.3.1. Risks 
Risks of furosemide include electrolyte abnormalities (hypokalemia, hypomagnesemia, and hypocalcemia), 
hypotension, allergic or toxicity-related symptoms (rash, tinnitus, and hearing change), and other symptoms (cramps, 
dizziness, unusual tiredness/weakness, chest pain, nausea, vomiting, diarrhea, and numbness/tingling). Furosemide-
induced ototoxicity can lead to transient or permanent deafness. Ototoxicity primarily occurs with high-dose 
intravenous therapy (e.g. >240 mg/hr infusions) or at lower doses in patients with kidney function impairment or 
concurrent use of other ototoxins such as aminoglycosides.  
We have chosen our study selection criteria to exclude patients who are at increased risk for furosemide side 
effects including those with frequent hypotension, cirrhosis, a hearing disorder, or electrolyte abnormalities in the prior 
30 days (hypokalemia defined as serum potassium <3.5 mEq/L, hypomagnesemia, defined as serum magnesium <1 
mg/dL, and hypocalcemia, defined as serum corrected calcium < 8 mg/dL), and those taking an interacting drug or 
substance including an aminoglycoside, cisplatin, methotrexate, cyclosporine, adrenocorticotropic hormone (ACTH), 
lithium, phenytoin, oral/intravenous steroid, or natural licorice.  
In the current trial, risks related to furosemide will be reduced through close monitoring of serum electrolytes, 
patient symptoms (including hearing), BP, and serum and urine furosemide levels. In addition, we will withdraw 
participants from the study if any of the following occurs during the course of the study: 1) pregnancy; 2) initiation of a 
non-loop diuretic (spironolactone, eplerenone, ethacrynic acid, thiazides); 3) initiation of an interacting drug 
(aminoglycoside, methotrexate, cyclosporine, ACTH, lithium, phenytoin, or oral/intravenous steroid); and/or 4) new 
diagnosis of cirrhosis. 
Occurrence of any of the following events will end dose up-titration (defined below): 1) electrolyte abnormalities, 
2) side effects attributable to furosemide (e.g. hypotension, allergic or toxicity-related symptoms), and/or 3) patient 
non-acceptance. If one of these events occur, the participant will return to the prior tolerated furosemide dose. If one of 
these events occurs at the lowest administered dose, furosemide will be stopped and not re-started. 
• Serum potassium <3.2 mEq/L 
• Serum magnesium <0.8 mEq/L 
• Serum corrected calcium <7.0 mg/dL 
• Systolic BP <80 mmHg that a study investigator attributes to study drug-induced hypovolemia 


Loop Diuretic Pilot Study Protocol 13 
 
• Patient desires not to continue furosemide 
• Patient-reported symptom of severe or very severe 
 Rash 
 Tinnitus 
 Other self-reported symptom plausibly attributed to furosemide 
 Hearing change (also evaluated with the Inner Effectiveness of Auditory Rehabilitation (Inner EAR) 
instrument*) 
*In addition to self-reported hearing change, we will monitor hearing with the Inner EAR instrument. The Inner EAR 
instrument measures hearing-related function and has good intra-rater reliability, internal consistency, 
discriminant validity, and responsiveness to change. Instrument scores correlate with pure tone audiometry.38-40 
Scores range from 0 to 100 points. We will refer participants with ≥10-point decline in Inner EAR scores or self-
reported hearing loss (any severity) after furosemide initiation and/or dose titration for audiometry testing. 
Audiometry for all participants is impractical (i.e. expensive, additional clinic visits) and unnecessary given low risk 
of hearing complications at the proposed doses (maximum 320 mg/ day).32-34 
 
See Section 7 for additional safety information (e.g. monitoring, adverse events and serious adverse events). 
 
1.3.2 Benefits 
Benefits of furosemide in the HD population remain unproven at this time. Hypothesized benefits of furosemide therapy 
include improved volume status, BP control, and a decrease in volume-related symptoms during dialysis. 
 
2 
STUDY OBJECTIVE  
The overall objective of this study is to test whether oral furosemide is safe and effective at increasing urine volume in 
HD patients. 
2.1 
Primary Objectives 
Period 1 (dose escalation = short-term outcomes; 6-weeks) and Period 2 (follow-up = longer-term outcomes; 12-
weeks) 
Short-term and longer-term efficacy: To test the hypothesis that furosemide will increase 24-hour urine volume at its 
maximally tolerated dose in individuals with HD-dependent ESKD. 24-hour urine volumes will be used as the primary 
endpoint for both short-term and longer-term efficacy assessments. 
 
Short-term and longer-term safety: To evaluate the short-term (6-weeks) and longer-term (12-weeks) safety of 
escalating doses of furosemide in individuals with HD-dependent ESKD. Safety outcomes will include the following: 
• 
Serum potassium level <3.2 mEq/L 
• 
Serum magnesium level <0.8 mg/dL 
• 
Serum corrected calcium level <7 mg/dL 
• 
Serum furosemide level >12 microgram/L 
• 
Serious dialysis-associated hypotension defined as hypotension requiring hospitalization or treatment in an 
emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event 
(e.g. aortic dissection)  
• 
Severe or very severe rash, tinnitus, or hearing change not attributable to causes other than furosemide 
• 
Inner EAR score decrease by ≥10 points 
 


Loop Diuretic Pilot Study Protocol 14 
 
Short-term and longer-term tolerability: To evaluate the short-term and longer-term tolerability of furosemide in 
individuals with HD-dependent ESKD. Tolerability will be assessed by: 
• 
Severe or very severe cramping, dizziness/pre-syncope, unusual tiredness/weakness, chest pain, nausea, 
vomiting, or diarrhea not attributable to causes other than furosemide 
 
Short-term and longer-term acceptability: To evaluate the short-term and longer-term acceptability of furosemide in 
individuals with HD-dependent ESKD. Acceptability will be assessed by: 
• 
Participant affirmative response to question: “If recommended, would you be willing to stay on the dose of 
furosemide you have received during the last week?” 
• 
Recruitment rates 
• 
Drop-out rates 
 
Short-term adherence: To evaluate short-term and longer-term adherence to furosemide among individuals with HD-
dependent ESKD. Adherence will be assessed by: 
• 
Pill counts 
• 
Serum and urine furosemide levels 
 
2.2 
Exploratory Objectives 
Period 1 (dose escalation = short-term outcomes) and Period 2 (follow-up = longer-term outcomes) 
Short-term and longer-term clinical outcomes: Exploratory objectives are designed to expand understanding of the 
effect of furosemide on clinical outcomes in HD-dependent ESKD. We will analyze the following: 
• 
24-hour creatinine clearance 
• 
24-hour fractional excretion of urea 
• 
24-hour fractional excretion of sodium 
• 
Pre-HD systolic BP 
• 
Intradialytic hypotension (systolic BP <80 mmHg)21 
• 
Intradialytic hypotension (systolic BP <90 mmHg)41  
• 
IDWG 
• 
UF volume 
• 
UF rate 
• 
Target weight achievement 
• 
Post-HD weight-target weight difference 
• 
Extra HD treatments 
• 
Hospitalizations 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Study Design (Figure 1) 
This is a single center (multi-clinic), open-label, non-randomized pilot study to test whether oral furosemide is safe and 
effective at increasing urine volume in HD patients. The study will consist of 2 periods: a 6-week dose escalation period 
(period 1) and a subsequent 12-week follow-up period (period 2). During period 1, all participants will receive escalating 
doses of furosemide as tolerated, and we will examine the short-term safety and efficacy of furosemide. During period 
2, all participants will continue the maximally tolerated period 1 furosemide dose, and we will examine the acceptability 
of and adherence to furosemide and the longer-term safety and efficacy of furosemide. The study duration is 18 weeks. 
 
Figure 1. Study design. 


Loop Diuretic Pilot Study Protocol 15 
 
Panel A. Study overview including both study periods (dose escalation and follow-up). 
 
Panel B. Period 1 dose escalation schematic.  
 
 
 
 
 
 
 
 
 
 
 
 
3.2 
Allocation to Treatment Groups and Blinding 
All participants will receive oral furosemide. Participants and investigators are unblinded. 
3.3 
Study Duration, Enrollment and Number of Participants 
The study duration is 18 weeks and consists of a 6-week dose escalation period (period 1) and a subsequent 12-
week follow-up period (period 2). Our goal sample size is 36 participants in period 1 with the goal of >30 participants 
continuing on to period 2. We will recruit up to 40 participants to account for dropout and will recruit additional 
participants if fewer than 30 participants are eligible for period 2. 
All participants will be recruited from the University of North Carolina (UNC)-owned Siler City, Pittsboro, 
Sanford, Lee County, and Carrboro “Carolina Dialysis” HD clinics. We will screen individuals for eligibility if they self-
report, on average, at least 1-cup urine/day. We selected this threshold based on a recent DOPPS analysis showing an 
association between self-reported urine volume of ≥1 cup/day and lower interdialytic weight gain (IDWG) and 
mortality.42 Our selection criteria exclude patients unlikely to respond to diuretics (i.e. minimal urine output), patients at 
increased risk for furosemide side effects (e.g. cirrhosis, electrolyte abnormalities, and concurrent use of interacting 
medications or substances), and patients likely to have urine output decline during the study (i.e. within the first 60-days 
of HD therapy). We will recruit patients 1:3, incident (60-180 days on HD): prevalent (>180 days on HD) to ensure study 
of both populations while accounting for the challenge of recruiting incident patients (e.g. fewer eligible patients, 
research reticence early in therapy). See Section 3.4 for participant inclusion and exclusion criteria and Section 9 for 
enrollment practices. 
 


Loop Diuretic Pilot Study Protocol 16 
 
3.4 
Study Population 
Participant Inclusion Criteria 
• 
Patient self-report of at least 1 cup urine/24-hours42 
• 
Age ≥18 years 
• 
Receipt of thrice weekly in-center HD at a participating clinic (UNC-associated Carolina Dialysis- Carrboro, Siler 
City, Pittsboro, Sanford, and Lee County) 
• 
≥60 days receiving in-center HD 
• 
Willingness to take study medication and undergo study testing 
• 
Ability to provide informed consent 
 
Participant Exclusion Criteria 
• 
Known allergy to loop diuretic 
• 
History of poor adherence to HD or medical regimen per nephrologist 
• 
>1 hospitalization in prior 30-days 
• 
Frequent hypotension (systolic BP <80 mmHg at >30% of HD treatments in prior 30-days)21 
• 
Cirrhosis per nephrologist 
• 
Hearing disorder per nephrologist 
• 
Serum potassium <3.5 mEq/L, magnesium <1 mg/dL, or corrected calcium <8 mg/dL in prior 30-days 
• 
Taking a non-loop diuretic (e.g. spironolactone, eplerenone, ethacrynic acid, thiazides) 
• 
Taking an aminoglycoside, cisplatin, methotrexate, cyclosporine, ACTH, lithium, phenytoin, or oral/intravenous 
steroid 
• 
Natural licorice consumption  
• 
Prisoners, patients with significant mental illness 
• 
Pregnant patients and nursing mothers 
 
3.5 
Study Drug/ Intervention 
3.5.1 
Description 
Furosemide, the study drug, will be administered as tablets containing 20 mg, 40 mg or 80 mg furosemide. 
3.5.2 
Dosing and treatment regimen 
During the 6-week dose escalation period (period 1), participants who are not taking oral furosemide at study entry will 
take 80 mg oral furosemide twice a day for 14 days and then, if the dose was tolerated, they will take 120 mg oral 
furosemide twice a day for 14 days and then, if the dose was tolerated, they will take 160 mg oral furosemide twice a 
day for 14 days (Figure 1 Panel B). If a patient is taking oral furosemide at study entry, the participant will remain on 
his/her prescribed oral furosemide dose for the first 2 weeks of the dose escalation period. If a participant is taking 
another loop diuretic (e.g. bumetanide), we will calculate the corresponding oral furosemide dose (i.e. 1 mg bumetanide 
= 40 mg furosemide). The participant will discontinue the other loop diuretic and receive the equivalent dose of oral 
furosemide for the first 2 weeks of the dose escalation period. The first dose will then be increased by 50%, rounded to 
the nearest whole tablet strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day) 
at week 2 and, if tolerated, the second dose will be increased by 50% at week 4, rounded to the nearest whole tablet 
strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day). Establishing ceiling dose 
thresholds by increasing the prior dose by 30-50% is the recommended approach in heart failure patients.20 
 
Occurrence of any of the following events will end dose up-titration: 1) electrolyte abnormalities (serum potassium <3.2 
mEq/L, serum magnesium <0.8 mEq/L, and/or serum corrected calcium <7 mg/dL); 2) side effects attributable to 
furosemide (severe or very severe rash, tinnitus, or hearing change); decrease in Inner Effectiveness of Auditory 
Rehabilitation (Inner EAR) instrument score by more than 10 points; and/or intradialytic systolic BP <80 mmHg that a 


Loop Diuretic Pilot Study Protocol 17 
 
study investigator attributes to study drug-induced hypovolemia); and/or 3) patient non-acceptance (defined as the 
patient reporting unwillingness to take the study drug). If one of these events occur, the participant will return to the 
prior tolerated oral furosemide dose. If one of these events occurs at the lowest administered dose, oral furosemide will 
be stopped and not re-started. 
 
During the 12-week follow-up period (period 2), participants who tolerated and accepted furosemide in period 1 will 
continue their maximally tolerated period 1 furosemide dose during the 12-weeks of follow-up. If a participant has 
electrolyte abnormalities or other side effects attributable to furosemide in period 2 (i.e. on their period 1 maximally 
tolerated dose), the dose will be lowered sequentially (i.e. dose de-escalation: 160  120  80 mg twice daily, or, if on 
alternative dosing due to prior diuretic use, decrease dose by 50%, rounded to the nearest whole tablet strength of 
existing (i.e. available) furosemide tablet formulations, until tolerated). If side effects persist or if the participant 
chooses, oral furosemide will be stopped. 
 
3.5.3 
Preparation and administration of study drug 
The study drug, furosemide, will be provided by the UNC Investigational Drug Service (IDS) which will be the 
Central Pharmacy for the study. Study drug kits will contain 2-week supplies during the dose escalation period (period 1) 
and 4-week supplies during the follow-up period (period 2). The PI will request the next supply of furosemide from IDS 
at each 2-week interval. Unless there is a contraindication (e.g. hypokalemia, serious hypotension), the investigator will 
escalate the furosemide dosing as described in Sections 1.2 and 3.5.2. If up-titration is contraindicated, the PI will notify 
IDS. If down-titration or discontinuation is indicated, the PI will notify IDS. At the end of period 1, participants will be 
provided with a 4-week supply of furosemide at the indicated dose (week 6). At the week 10 and 14 visits, additional 4-
week supplies of furosemide at the indicated dose will be provided. 
If the dose escalation schedule is interrupted (e.g., if a participant is hospitalized at the scheduled time of dose 
escalation and did not take study drug during the hospitalization), dose escalation will be delayed until the participant 
has had access to the current dose of study drug for a total of two weeks. If, due to considerable delays in dose 
escalation, a participant has not reached the final dose assignment by their Week 8 visit, the participant will remain at 
the current dose of study drug for the remainder of the study and the follow-up period (i.e., the 12-week post-escalation 
period) will be shortened accordingly such that the total duration of study participation is not increased as a result of the 
delay. For example, if dose escalation is not completed until week 8, the treatment phase will be 10 weeks rather than 
12 weeks. 
 
3.5.4 
Participant adherence monitoring 
Study drug containers will be returned to study coordinators at the conclusion of each 2-week period during dose 
escalation (weeks 2, 4 and 6), and at the conclusion of each 4-week period during follow-up (weeks 10, 14 and 18). Pill 
counts will be performed to assess participant adherence with prescribed study drug. 
3.5.5 
Concomitant therapy 
Medication use (both oral and intravenous) will be collected at baseline and throughout the course of the study. Non-
loop diuretic (e.g. spironolactone, eplerenone, ethacrynic acid, thiazides), aminoglycoside, cisplatin, methotrexate, 
cyclosporine, ACTH, lithium, phenytoin, and oral/intravenous steroid use are exclusion criteria. If these medications are 
initiated during follow-up the treating clinician will be contacted by the research team. If the prohibited drug cannot be 
discontinued, study medication will be withdrawn, and participants will continue to be followed.  
3.5.6 
Packaging 
Furosemide will be distributed in patient-specific containers with the specified number of tablets (based on dosing listed 
in Sections 1.2 and 3.5.2) for every 2-week period during the dose escalation period (period 1) and the specified number 


Loop Diuretic Pilot Study Protocol 18 
 
of tablets (based on dosing listed in Sections 1.2 and 3.5.2) for every 4-week period during the follow-up period (period 
2). Labeling will include patient name, patient ID, protocol number, expiration date, and prescribing physician (PI). 
3.5.7 
Blinding of study drug 
None 
3.5.8 
Receiving, storing, dispensing and returning study drug 
The UNC IDS will maintain detailed records regarding furosemide dispensing, general study product accountability and 
patient specific study product accountability. Documentation includes study product storage, dispensing and final 
disposition. 
3.5.9 Study drug storage  
Furosemide will be stored at 25◦C at the central UNC IDS pharmacy. 
 
3.5.10 Dispensing study drug  
The UNC IDS pharmacist or trained site designee will dispense the study drug to the study coordinator and complete a 
dispending/accountability log. Furosemide will be dispensed in well-closed, light-resistant containers. A study 
coordinator will dispense the study drug to the participant at the dialysis clinic at the below-described study visits and 
complete a dispensing/accountability log. The study coordinators will have appropriate training for dispensing and 
reconciling the study drug, and documentation of this training will be maintained in the study’s regulatory binder.  
 
3.5.11 Return or destruction of study drug  
Study drug containers will be returned by participants at the end of each 2-week (dose escalation, period 1) and 4-week 
(follow-up, period 2) and remaining pills will be counted to assess adherence. Unused supplies of study drug will be 
returned to IDS once the pill count is completed and documented. In the event that a participant does not return study 
drug containers he/she will be instructed to stop taking any study drug from the non-returned container. 
 
3.5.12 Participant access to study drug at study closure 
Participants will have access to furosemide at study closure if deemed appropriate by their treating nephrologists. 
 
4 
STUDY PROCEDURES 
4.1 
Overview (Tables 2 and 3) 
All study visits will occur at the participant’s dialysis clinic at routinely scheduled HD treatments.  
• 
There will be one study visit during the baseline period.  
 
• 
Dose escalation period (period 1): Blood samples will be collected weekly at mid-week treatment visits (i.e. 
Wednesday or Thursday during weeks -1, 1, 2, 3, 4, 5 and 6) prior to scheduled dose initiation or dose titration. 
Urine samples will be collected twice during the dose escalation period at mid-week treatment visits (i.e. 
Wednesday or Thursday during weeks -1 and 5). Study drug visits will be conducted every two weeks at the first 
weekly treatment (i.e. Monday or Tuesday during weeks 0, 2, 4, and 6). This structure was selected so that blood 
results will be collected and analyzed the week prior to study drug dose titration. As such, test results will be 
available prior to potential dose titration. Adherence and symptom assessment visits will be conducted weekly 
at the first treatment of each week (i.e. Monday or Tuesday during weeks 1, 2, 3, 4, 5 and 6). Hearing 


Loop Diuretic Pilot Study Protocol 19 
 
assessments will be conducted every two weeks at the first weekly treatment (i.e. Monday or Tuesday during 
weeks 2, 4, and 6). 
 
• 
Follow-up period (period 2): Blood samples will be collected at mid-week treatment visits every 4 weeks (i.e. 
Wednesday or Thursday during weeks 9, 13 and 17). Study drug visits will be conducted at the first treatment of 
each of the subsequent weeks (i.e. Monday or Tuesday during weeks 10 and 14). As in the dose escalation 
period, this structure was selected so that blood results will be available prior to additional study drug 
administration. Study adherence and symptom assessment visits will be conducted every 2 weeks at the first 
weekly HD treatment in the scheduled week (i.e. Monday or Tuesday during weeks 8, 10, 12, 14, 16, and 18). 
Hearing assessments will be conducted every four weeks at the first weekly treatment (i.e. Monday or Tuesday 
during weeks 10, 14, and 18). Urine sample visits will be conducted at the mid-week treatments of the 12th week 
and final week of the follow-up period (i.e. Wednesday or Thursday during weeks 12 and 18). All remaining 
study drug will be returned at the first weekly treatment (i.e. Monday or Tuesday) of week 19. A final pill count 
(adherence assessment) will be performed upon study drug return (week 19). 
 
• 
All HD treatments occurring during the 18-week study period will be considered study treatments, and all 
associated clinical data (BP, pre-HD and post-HD weights and dialysis treatment data such as UF volume, UF rate 
and dialysate composition) will be collected from the electronic health record (EHR). 
 
Table 2. Study visits by type. 
Procedures 
Baseline clinical assessment 
(Prior to study start, weeks -4 to -2) 
Baseline electrolyte, urine, symptom, 
and hearing assessment 
(week -1)  
Study drug visit 
(weeks 0, 2, 4, 6, 10, 14,) 
Follow-up blood sample 
(weeks 1, 2, 3, 4, 5, 6, 9, 13, 17) 
Follow-up urine sample 
(weeks -1, 5, 12, and 18) 
Adherence and symptom assessment 
(weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 
16, and 18) 
Hearing assessment  
(weeks 2, 4, 6, 10, 14, and 18 weeks) 
Clinical data collected at every HD 
treatment during study period  
(weeks -4 to 18) 
Study drug return  
(week 19) 
Complete medical history 
X 
 
 
 
 
 
 
 
 
Pregnancy status inquiry 
X 
 
 
 
 
 
 
 
 
Serum electrolytes and 
furosemide level 
 
X 
 
X 
 
 
 
 
 
24-hour urine 
 
X 
 
 
X 
 
 
 
 
Symptom assessment 
 
X 
 
 
 
X 
 
 
 
Hearing assessment 
 
X 
 
 
 
 
X 
 
 
Study drug administration 
 
 
X 
 
 
 
 
 
 
Patient acceptance assessment 
 
 
 
 
 
 
 
 
 
Drop-out rates 
X 
 
 
 
 
 
 
X 
 
Pill counts 
 
 
 
 
 
X 
 
 
X 
End of trial study drug return 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
BP monitoring 
X 
 
 
 
 
 
 
X 
 
Weight monitoring 
X 
 
 
 
 
 
 
X 
 
UF volume/rate 
X 
 
 
 
 
 
 
X 
 
Extra HD treatments 
X 
 
 
 
 
 
 
X 
 
Hospitalizations 
X 
 
 
 
 
 
 
X 
 
 
Table 2. Study visits by week. 
 
Week(s) 
-4 to 
-2 
-1 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Loop Diuretic Pilot Study Protocol 20 
 
medical history 
Pregnancy 
status inquiry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
electrolytes and 
furosemide 
level 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
24-hour urine 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Symptom 
assessment 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Hearing 
assessment 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Study drug 
administration 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Patient 
acceptance 
assessment 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Drop-out rates 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pill counts 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Study drug 
return 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BP monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
UF volume/ rate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Extra HD 
treatments 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalizations 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
4.2 
Screening/Baseline Visit procedures 
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 2 weeks of enrollment. 
Baseline 
Written informed consent will be obtained from study participants prior to the implementation of any study procedures. 
The participant will receive a signed and dated informed consent form. See Section 10.3.2 for details of consent process. 
The PI will verify inclusion/ exclusion criteria. A pregnancy inquiry will occur and a complete medical history will be 
obtained in weeks -4 to -2 of the baseline period. In the one week prior to start (week -1), the following data will be 
obtained: serum electrolytes, 24-hour urine collection, symptom assessment, and hearing assessment.  
4.3 
Intervention/Treatment procedures (by visits) 
During the 6-week dose titration period (period 1), study drug administration visits will occur every 2 weeks on the first 
day of the participant’s weekly, routinely scheduled HD treatments (i.e. Monday or Tuesday during weeks 0, 2, 4, and 6). 
During the 12-week follow-up period (period 2), study drug administration visits will occur every 4 weeks on the first day 
of the participant’s weekly, routinely scheduled HD treatments (i.e. Monday or Tuesday during weeks 10, 14 and 18). 
 
Dose-titration (period 1) 
Week 0:  
A. Participants who are not taking oral furosemide at study entry will receive 2-weeks supply of 80 mg oral 
furosemide twice daily dosing.  


Loop Diuretic Pilot Study Protocol 21 
 
B. Participants who are taking oral furosemide at study entry will receive 2-weeks supply of his/her prescribed oral 
furosemide dose.  
C. Participants who are taking another loop diuretic (e.g. bumetanide) at study entry will receive 2-weeks supply of 
an equivalent dose of furosemide (1mg bumetanide = 40 mg furosemide). 
 
Week 2:  
A. Participants who were not taking oral furosemide at study entry and who tolerated the 80 mg twice daily dose 
(i.e. no hypokalemia, serious hypotension, symptoms, etc.) will receive 2-weeks supply of 120 mg oral 
furosemide twice daily dosing.  
B. Participants who were taking oral furosemide at study entry and tolerated the first 2 weeks of dosing will 
receive 2-weeks supply of furosemide dose 50% higher than initial dose, rounded to the nearest whole tablet 
strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day).  
C. Participants who were taking another loop diuretic at study entry and tolerated the first 2 weeks of furosemide 
dosing will receive 2-weeks supply of furosemide dose 50% higher than their initial dose, rounded to the nearest 
whole tablet strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day). 
D. Participants who did not tolerate the weeks 0 and 1 dose of furosemide will stop furosemide, and it will not be 
restarted. See below for parameters for determining intolerance. 
 
Week 4:  
A. Participants who were not taking oral furosemide at study entry and who tolerated the 120 mg twice daily dose 
(i.e. no hypokalemia, serious hypotension, symptoms, etc.) will receive 2-weeks supply of 160 mg oral 
furosemide twice daily dosing.  
B. Participants who were taking oral furosemide at study entry and tolerated the last 2 weeks of dosing will receive 
2-weeks supply of furosemide dose 50% higher than initial dose, rounded to the nearest whole tablet strength 
of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day).  
C. Participants who were taking another loop diuretic at study entry and tolerated the last 2 weeks of furosemide 
dosing will receive 2-weeks supply of furosemide dose 50% higher than initial dose, rounded to the nearest 
whole tablet strength of existing (i.e. available) furosemide tablet formulations (not to exceed 320 mg/day). 
D. Participants who did not tolerate the weeks 2 and 3 dose of furosemide will return to the prior tolerated oral 
furosemide dose. See below for parameters for determining intolerance. 
 
Week 6: 
A. Participants who were not taking oral furosemide at study entry and who tolerated the 160 mg twice daily dose 
(i.e. no hypokalemia, serious hypotension, symptoms, etc.) will receive 4-weeks supply of 160 mg oral 
furosemide twice daily dosing.  
B. Participants who were taking oral furosemide at study entry and tolerated the last 2-weeks of dosing will receive 
4-weeks supply of that same furosemide dose (not to exceed 320 mg/day).  
C. Participants who were taking another loop diuretic at study entry and tolerated the last 2-weeks of furosemide 
dosing will receive 4-weeks supply of that same furosemide dose (not to exceed 320 mg/day). 
D. Participants who did not tolerate the weeks 4 and 5 dose of furosemide will return to the prior tolerated oral 
furosemide dose. See below for parameters for determining intolerance. 
 
As specified in Section 1.3.1, occurrence of any of the following events will end dose up-titration: 1) electrolyte 
abnormalities (serum potassium <3.2 mEq/L, serum magnesium <0.8 mEq/L, and/or serum corrected calcium <7 mg/dL); 
2) side effects attributable to furosemide (severe or very severe rash, tinnitus, or hearing change); decrease in Inner 
Effectiveness of Auditory Rehabilitation (Inner EAR) instrument score by more than 10 points; and/or intradialytic 
systolic BP <80 mmHg that a study investigator attributes to study drug-induced hypovolemia); and/or 3) patient non-


Loop Diuretic Pilot Study Protocol 22 
 
acceptance (defined as the patient reporting unwillingness to take the study drug). If one of these events occur, the 
participant will return to the prior tolerated oral furosemide dose. If one of these events occurs at the lowest 
administered dose, oral furosemide will be stopped and not re-started. 
 
The window for each dose-titration period intervention/treatment visit is -4 to +4 days. 
 
Follow-up (period 2) 
Weeks 10 and 14: Participants who tolerated (i.e. no hypokalemia, serious hypotension, symptoms, etc.) and accepted 
furosemide in period will continue their maximally tolerated period 1 dose during the 12-weeks of follow-up. At weeks 
10 and 14, they will receive additional 4-weeks supplies of this furosemide dose. 
 
As specified in Section 1.3.1, if a participant has electrolyte abnormalities or other side effects attributable to 
furosemide in period 2 (i.e. on their period 1 maximally tolerated dose), the dose will be lowered sequentially (i.e. dose 
de-escalation: 160  120  80 mg twice daily, or, if on alternative dosing due to prior diuretic use, decrease dose by 
50%, rounded to the nearest whole tablet strength of existing (i.e. available) furosemide tablet formulations, until 
tolerated). If side effects persist or if the participant chooses, oral furosemide will be stopped. 
 
Week 19: At the first weekly treatment (i.e. Monday or Tuesday) of study week 19, participants will return all unused 
study drug to a study coordinator. 
 
The window for each follow-up period intervention/treatment visit is -4 to +4 days. 
 
4.4 
Follow- up procedures (by visit types) 
All study visits will occur at the time of routinely scheduled HD treatments at the patient’s usual outpatient dialysis 
clinic. Section 5 describes the measurements and assessments in detail.  
Blood samples (weeks 1, 2, 3, 4, 5, 6, 10, 14, and 18): Blood will be obtained for the measurement of serum sodium, 
potassium, chloride, urea, creatinine, magnesium, calcium, albumin, and furosemide level. An additional 2.5 mL blood 
sample will be drawn, frozen, and stored in UNC Kidney Center -80◦ freezers for future testing as needed. 
Urine samples (weeks -1, 5, 12, and 18): 24-hour urine collections will be obtained for the measurement of urine 
volume, sodium, urea, creatinine, and furosemide level. An aliquot of urine will be taken from the sample after the 
before-listed measurements are performed and be frozen and stored in UNC Kidney Center -80◦ freezers for future 
testing as needed. 
Adherence assessments (weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18): Study staff will complete pill counts. 
Acceptance assessments (weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18): Study staff will ask the participant the 
acceptance question. 
Symptom assessments (weeks 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18): Study staff will administer surveys evaluating 
patient-reported cramping, dizziness/pre-syncope, unusual tiredness/weakness, chest pain, rash, nausea, vomiting, 
diarrhea, tinnitus, hearing change, and numbness/tingling.  
Hearing assessments (weeks 2, 4, 6, 10, 14, and 18): Study staff will administer the Inner EAR instrument. 
Clinical data (weeks -4 to 18): HD treatment-level data (BPs, weights, dialysis prescription) will be obtained from the 
EHR. 
 


Loop Diuretic Pilot Study Protocol 23 
 
4.5 
Participant Completion/ Withdrawal procedures 
If a participant withdraws from the study before Week 18, an early withdrawal visit will be scheduled to conduct the 
week 18 assessments (24-hour urine, symptom assessment, hearing assessment, acceptance assessment, pill count, and 
return of study drug). Patients who stop taking study medication are not considered early withdrawals and will be asked 
to continue to provide follow-up data on the study schedule and to participate in the final study visit at week 18. 
 
5 
STUDY EVALUATIONS AND MEASUREMENTS   
5.1 Measurements 
All study evaluation and measurements will occur at study visits that occur at the time of routinely scheduled HD 
treatments at the patient’s usual outpatient dialysis clinic. Section 4.4 describes the timing and frequency of the 
measurements.  
Baseline measurements 
Complete medical history and clinical data: The participant’s medical history will be taken from the EHR and confirmed 
verbally with the patient. The medical history will include a review of co-morbid conditions, medications, recent 
laboratory results (electrolytes, albumin, complete blood count, Kt/V, iron stores, bone-mineral tests), and dialysis 
treatment data (BPs (systolic and diastolic), weights (pre- and post-HD), UF volumes/rates, dialysate composition 
(sodium, potassium, bicarbonate, calcium), dialysate and blood flow rates, and vascular access type. 
Serum blood tests: The following tests will be assessed via blood samples: sodium, potassium, chloride, urea, creatinine, 
magnesium, calcium, albumin and serum furosemide level. An additional 2.5 mL blood sample will be drawn, frozen, and 
stored in UNC Kidney Center -80◦ freezers for future testing as needed. Blood samples will be collected via the vascular 
access by trained dialysis clinic personnel. 
24-hour urine collection: The following tests will be assessed via 24-hour urine collections: urine volume, sodium, urea, 
creatinine, and urine furosemide level. An aliquot of urine will be taken from the sample after the before-listed 
measurements are performed and be frozen and stored in UNC Kidney Center -80◦ freezers for future testing as needed. 
Urine samples will be collected by the patient in 24-hour urine collection containers. Containers will be provided by and 
returned to study staff at the dialysis clinic at specified study visits. 
Symptom assessment: Study staff will administer a symptom questionnaire (Appendix, Section 13.1) to participants at 
specified study visits. 
Hearing assessment: Study staff will administer the Inner Ear instrument (Appendix, Section 13.2) to participants at 
specified study visits. 
Follow-up measurements 
Serum blood tests: The following tests will be assessed via blood samples: sodium, potassium, chloride, urea, creatinine, 
magnesium, calcium, albumin and serum furosemide level. An additional 2.5 mL blood sample will be drawn, frozen, and 
stored in UNC Kidney Center -80◦ freezers for future testing as needed. Blood samples will be collected via the vascular 
access by trained dialysis clinic personnel. 
24-hour urine collection: The following tests will be assessed via 24-hour urine collections: urine volume, sodium, urea, 
creatinine, and urine furosemide level. An aliquot of urine will be taken from the sample after the before-listed 
measurements are performed and be frozen and stored in UNC Kidney Center -80◦ freezers for future testing as needed. 
Urine samples will be collected by the patient in 24-hour urine collection containers. Containers will be provided by and 
returned to study staff at the dialysis clinic at specified study visits. 


Loop Diuretic Pilot Study Protocol 24 
 
Symptom assessment: Study staff will administer a symptom questionnaire (Appendix, Section 13.1) to participants at 
specified study visits. 
Hearing assessment: Study staff will administer the Inner Ear instrument (Appendix, Section 13.2) to participants at 
specified study visits. 
Pill counts: Study staff will perform pill counts at specified study visits.  
Acceptance assessment: Study staff will ask participants the following yes/no/unsure question: “If recommended, would 
you be willing to stay on the dose of furosemide you have received during the last week?” 
Clinical data: The following data will be obtained from the EHR: HD treatment BPs (systolic and diastolic), weights (pre- 
and post-HD), UF volumes/rates, dialysate composition (sodium, potassium, bicarbonate, calcium), dialysate and blood 
flow rates, and vascular access type. 
5.2 Specimen preparation, handling and storage 
All blood samples (2.5 mL tubes) will be collected via the vascular access by HD staff. Samples will be transported (on the 
day they are drawn by study staff) to UNC McClendon Laboratories and UNC Hostetter Laboratory for processing and 
storage (extra sample) at -80°C in UNC Kidney Center freezers (5th floor Burnett-Womack building). 24-hour urine 
samples will be collected in 24-hour urine jugs provided by and returned to study staff at the dialysis clinic. Urine 
samples will be transported to UNC McClendon Laboratories and UNC Hostetter Laboratory on ice for processing. 
Following processing, an aliquot of urine will be taken from the sample after the before-listed measurements are 
performed and be frozen and stored in UNC Kidney Center -80◦ freezers. 
 
6 
STATISTICAL CONSIDERATIONS    
The short-term endpoints will be measured in the 6-week dose titration period (period 1). 
The longer-term endpoints will be measured in the 12-week follow-up period (period 2). 
 
6.1 
Primary Endpoints 
Short-term and longer-term efficacy- urine volume (assessed separately) 
• 
Among participants with baseline 24-hour urine volume ≥200 mL: incidence of ≥25% increase in urine volume 
• 
Among participants with baseline 24-hour urine volume <200 mL: incidence of a ≥50 mL increase in urine 
volume to a urine volume of at least 100 mL/24-hours 
 
Short-term and longer-term safety- electrolytes (assessed separately) 
• 
Incidence of serum potassium <3.2 mEq/L 
• 
Incidence of serum magnesium <0.8 mg/dL 
• 
Incidence of serum corrected calcium <7.0 mg/dL 
 
Short-term and longer-term safety- furosemide levels 
• 
Incidence of serum furosemide level >12 microgram/L 
 
Short-term and longer-term safety- BP 
• 
Incidence of dialysis-associated hypotension requiring hospitalization or treatment in an emergency room and 
not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. aortic 
dissection)21 
 


Loop Diuretic Pilot Study Protocol 25 
 
Short-term and longer-term safety- symptoms (assessed separately) 
• 
Incidence of severe or very severe patient-reported rash, tinnitus, or hearing change) not attributable to causes 
other than furosemide 
• 
Incidence of 10-point decrease in Inner EAR instrument score 
 
Short-term and longer-term tolerability- symptoms (assessed separately) 
• 
Incidence of severe or very severe patient-reported cramping, dizziness/pre-syncope, unusual 
tiredness/weakness, chest pain, nausea, vomiting, or diarrhea not attributable to causes other than furosemide 
 
Short-term and longer-term acceptability 
• 
Incidence of an affirmative response to the furosemide acceptance question 
 
Short term- and longer-term adherence 
• 
Incidence of participants having <20% of furosemide pills remaining at pill counts 
 
6.2 
Exploratory Endpoints 
Short-term and longer-term efficacy- alternative definitions (assessed separately) 
• 
Absolute change in urine volume from baseline (continuous in mL urine) 
• 
Percentage change in urine volume from baseline (continuous in %) 
 
Short-term and longer-term safety- electrolytes- alternative definitions (assessed separately) 
• 
Absolute change in serum potassium from baseline (continuous in mEq/L) 
• 
Absolute change in serum magnesium from baseline (continuous in mg/dL) 
• 
Absolute change in serum corrected calcium from baseline (continuous in mg/dL) 
• 
Percentage change in serum potassium from baseline (continuous in %) 
• 
Percentage change in serum magnesium from baseline (continuous in %) 
• 
Percentage change in serum corrected calcium from baseline (continuous in %) 
 
Short-term and longer-term safety- BP- alternative definitions (assessed separately) 
• Incidence of intradialytic systolic BP <80 mmHg21 
• Incidence of intradialytic systolic BP <90 mmHg41 
• Lowest systolic BP during HD (continuous in mmHg) 
 
Short-term and longer-term acceptability alternative definitions (assessed separately) 
• 
Number (percentage) of participants withdrawing from the study 
• 
Number (percentage) period 1 participants not continuing to period 2 
 
Short-term and longer-term adherence alternative definitions (assessed separately) 
• 
Number (percentage) of furosemide tablets not taken (# tablets remaining/# tablets provided) 
• 
Serum furosemide level (continuous in microgram/L and binary, present vs. absent) 
• 
Urine furosemide level (continuous in microgram/L and binary, present vs. absent) 
 
Clinical endpoints (assessed separately) 
• Change in 24-hour creatinine clearance from baseline (continuous in ml/min/1.73m2) 
• Percentage change in 24-hour creatinine clearance from baseline (continuous in %) 
• Change in 24-hour fractional excretion of sodium from baseline (continuous in %) 


Loop Diuretic Pilot Study Protocol 26 
 
• Change in 24-hour fractional excretion of urea from baseline (continuous in %) 
• Percentage change in 24-hour fractional excretion of urea from baseline (continuous in %) 
• Pre-HD systolic BP (mmHg on a per-HD treatment basis) 
• IDWG (kg on a per-HD treatment basis) 
• UF volume (mL on a per-HD treatment basis) 
• UF rate (mL/h/kg on a per-HD treatment basis) 
• Target weight achievement (post-HD weight (kg) within 1kg of prescribed target weight) (binary on a per-HD 
treatment basis) 
• Post-HD weight- target weight difference (post-HD weight – prescribed dry/target weight, kg on a per-HD 
treatment basis) 
• Extra HD treatments (number) 
• Hospitalizations (number) 
 
6.3 
Statistical Methods 
6.3.1 Overview 
All data analyses will be preceded by extensive data checking and verification to resolve the reasons for missing values, 
inconsistencies, and out-of-expected-range values. All statistical estimates of population parameters will be tabulated 
along with corresponding confidence intervals (CIs) and will be based on the convenience sample of patients 
participating in the study. The primary focus of the analyses will be the magnitudes and directions of the point- and 
interval-estimates. All analyses will be in intention-to-treat analyses. All reported p-values will be 2-sided; <0.05 
representing significance. All hypothesis test results (i.e. p-values) that are deemed not statistically significant (defined 
by a p-value ≥0.5) will be reported as inconclusive. Analyses will be performed with SAS 9.4 (Cary, NC) or a comparable 
statistical programming software package. 
6.3.2 Missing data 
All attempts will be made to keep missing data to a minimum, and participants who withdraw from treatment will be 
encouraged to continue on study in order to provide complete follow-up information. Thus, irrespective of withdrawal 
from treatment, all participants should continue to be followed with all relevant, scheduled outcome evaluations until 
the end of the study. The characteristics at the time of study start for those participants without complete follow-up will 
be examined; however, there will be limited statistical power to detect any but major differences between these 
participants and those with complete follow-up. Missing data variables will be identified in the data management 
system with a missing data indicator such that they can be easily identified. Reasons for missing data will be captured at 
each study visit and entered into the study database. No imputation of missing data will be performed. 
6.3.3 Descriptive analyses 
Examination of baseline characteristics will include estimates of the distribution of age, race, and other demographic 
characteristics, lab measures, and dialysis clinic. We will report baseline patient characteristics as counts (%) for 
categorical variables, and depending on the distribution, as means ± standard deviations (SDs) or medians [interquartile 
ranges] for continuous variables. Graphical methods including stem-and-leaf diagrams and boxplots will be used to 
examine distributions, identify potential influential points, and guide in the choice of transformations, if warranted.  
6.3.4 Primary analyses (each assessed separately) 
At designated study time-points, we will determine the [data type; see Section 6.1 for definitions]:  
• 
change from baseline for the short and longer-term efficacy measure [binary] (24-hour urine volume); 
• 
value of short and longer-term safety electrolyte measures [binary] (serum potassium, magnesium, corrected 
calcium); 


Loop Diuretic Pilot Study Protocol 27 
 
• 
value of serum furosemide levels [binary] (short and longer-term safety furosemide level measure); 
• 
incidence of dialysis-associated hypotension [binary] (short and longer-term safety blood pressure); 
• 
incidence of severe or very severe patient-reported allergic or toxicity-related symptoms [binary] (short and 
longer-term safety symptom measures); 
• 
change from baseline of Inner EAR instrument score [binary] (short and longer-term safety symptom measure); 
• 
incidence of severe or very severe patient reported symptoms [binary] (short and longer-term tolerability 
symptom measures); 
• 
incidence of patient-reported acceptance of furosemide [binary] (short and longer-term acceptability measure); 
• 
incidence of adherence by pill counts [binary] (short and longer-term adherence measure). 
 
Change measures and value measures (e.g. 24-hour urine volume, serum electrolytes, serum furosemide level) will be 
analyzed via one-way repeated measures of analysis of variance to determine the presence of absence of dose-related 
differences. In addition, we will use mixed effects modeling to test the effect of increased dose and duration with the 
fixed effect of time (dose), random subject effect, and an unstructured repeated covariance type. We will use 
generalized estimating equations to assess categorical outcomes (e.g. sufficient increase in 24-h urine volume, 
hypokalemia, hypomagnesemia, hypotension, symptoms, Inner EAR score, patient acceptance). We will also consider 
binary outcomes as rates (events/time).  
6.3.5 Exploratory analyses (each assessed separately) 
At designated study time-points, we will determine the [data type; see Section 6.2 for definitions]:  
• 
Absolute change from baseline for the short and longer-term efficacy measure [continuous] (24-hour urine 
volume); 
• 
percentage change from baseline for the short and longer-term efficacy measure [continuous] (24-hour urine 
volume); 
• 
absolute change from baseline for the short and longer-term safety electrolyte measures [continuous] (serum 
potassium, magnesium, corrected calcium); 
• 
percentage change from baseline for the short and longer-term safety electrolyte measures [continuous] (serum 
potassium, magnesium, corrected calcium); 
• 
occurrence of dialysis-associated hypotension- alternative definition (<80 mmHg) [binary] (short and longer-
term safety blood pressure); 
• 
occurrence of dialysis-associated hypotension- alternative definition (<90 mmHg) [binary] (short and longer-
term safety blood pressure); 
• 
value of lowest systolic BP during HD [continuous] (short and longer-term safety blood pressure); 
• 
number (percentage) of patients withdrawing from the study [continuous] (short and longer-term acceptability); 
• 
number (percentage) of patients not continuing into period 2 [continuous] (short and longer-term acceptability); 
• 
value of serum furosemide levels [continuous; binary] (short and longer-term acceptability); 
• 
value of urine furosemide levels [continuous; binary] (short and longer-term acceptability); 
• 
absolute change from baseline for 24-hour creatinine clearance [continuous] 
• 
percentage change from baseline for 24-hour creatinine clearance [continuous] 
• 
absolute change from baseline in 24-hour fractional excretion of sodium [continuous] 
• 
percentage change from baseline in 24-hour fractional excretion of sodium [continuous] 
• 
absolute change from baseline in 24-hour fractional excretion of urea [continuous] 
• 
percentage change from baseline in 24-hour fractional excretion of urea [continuous] 
• 
value of pre-HD systolic BP [continuous] 
• 
value of IDWG [continuous] 
• 
value of UF volume [continuous] 


Loop Diuretic Pilot Study Protocol 28 
 
• 
value of UF rate [continuous] 
• 
occurrence of target weight achievement [binary] 
• 
value of post-HD weight and target weight differential [continuous] 
• 
occurrence of extra HD treatments [continuous] 
•   occurrence of hospitalizations [continuous] 
 
Analogous to the primary analyses, percentage change measures, change measures, and value measures will be 
analyzed via one-way repeated measures of analysis of variance to determine the presence of absence of dose-related 
differences. In addition, we will use mixed effects modeling to test the effect of increased dose and duration with the 
fixed effect of time (dose), random subject effect, and an unstructured repeated covariance type. We will use 
generalized estimating equations to assess categorical outcomes. We will also consider binary outcomes as rates 
(events/time). Distribution of the exploratory parameters will be examined and appropriate transformation will be 
applied. These analyses are considered hypothesis-generating, and we will examine directionality and strength of 
relationships but will not assess via p-values. 
6.3.6 Subgroup analyses 
We will consider subgroups of incident vs. prevalent patients and subgroups of patients who were prescribed a diuretic 
(vs. not) prior to study start. Given the small sample, these analyses will be considered exploratory and models will be 
adjusted for baseline demographic and clinical factors. 
6.3.7 Sensitivity analyses 
We will conduct sensitivity analyses to test the robustness of our findings. Results of these analyses will be used to guide 
soundness of the main results. If the main results are demonstrated to be fragile, we will soften our conclusions around 
the main results as appropriate. Alternatively, if the main results are demonstrated to be robust, we will be confident in 
our main results conclusions. Specifically, we will conduct sensitivity analyses:  
• excluding data from participants with endpoints drawn “off-schedule” (e.g. serum electrolytes, 24-hour urine, 
symptom assessment, etc.); 
• excluding data with questionable values; 
• testing for difference by clinic; 
• evaluating the impact of variations on model assumptions and covariates; 
• evaluating model residuals; 
• testing for difference with transformations of scale and changes in the definitions of outcome variables 
 
6.4 
Sample Size and Power 
We designed this pilot study to evaluate the safety, tolerability, and acceptability of furosemide use in HD 
patients and assess for furosemide efficacy and safety signals. We aim to enroll a sufficient number of participants to 
yield data supporting the efficacy, acceptability, tolerability, and safety of furosemide and to provide a basis for 
calculating the sample size of a future randomized trial. Sample size considerations were framed using standard study 
design parameters to ensure 80% power to detect pre-specified effect sizes utilizing intermediate outcomes. 
With a sample size of 36 patients, we have 83% power to detect a mean change in urine volume from baseline 
of at least 5 ml/24-h, assuming a change S.D. = 10 ml/24-h17 and a 2-sided α = 0.05 (>99% power for urine volume 
change of 10 mL/24-h). With 30 patients, we have 99% power to detect a mean change in urine volume from baseline of 
at least 10 mL/24-h. Sample size calculation estimates were based on existing data about expected response to 
furosemide and S.D.s observed in other studies of urine volume in HD patients.17 
Our goal sample size is 36 participants. We will account for dropout by enrolling up to 40 participants. If fewer 
than 30 participants are eligible for period 2 at the end of the period 1 dose titration period (i.e. participants who did not 


Loop Diuretic Pilot Study Protocol 29 
 
tolerate or accept furosemide in period 1), we will recruit additional participants to maintain a sample size over 30 
participants for the follow-up period. 
 
6.5 
Interim Analysis 
No interim analysis is planned. See Section 7 for safety management plans. 
 
7 
SAFETY MANAGEMENT 
7.1. Definitions  
Definitions are per the January 2007 Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to 
Participants or Others and Adverse Events, Office on Human Research Protection (OHRP) Guidance. 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
7.1.1. Adverse Event  
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human study participant, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated 
with the participant’s involvement in the research, whether or not considered related to the participant’s participation 
in the research.  
7.1.2. Serious Adverse Event  
A serious adverse event (SAE) is any AE that is:  
• fatal or results in death  
• life-threatening  
• requires inpatient hospitalization (>24 hours) or prolongs existing hospital stay  
• results in persistent or significant disability or incapacity  
• results in congenital anomalies or birth defects  
• an important medical event*  
 
*Important medical events are those that may not be immediately life threatening but are clearly of major 
clinical significance. 
7.1.3. Unanticipated Problems Involving Risk to Participants or Others  
(See also Section 7.3.4)  
An Unanticipated Problem is any incident, experience, or outcome that meets all the following criteria:  
• unexpected (in terms of nature, severity, or frequency) given the research procedures that are described in the 
IRB-approved research protocol and informed consent document and the characteristics of the participant 
population being studied;  
• related or possibly related to participation in the research; possibly related means that there is a reasonable 
possibility that the incident, experience or outcome may have been caused by the procedures involved in the 
research, and  
• suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) related to the research than was previously known or recognized.  
 
7.2. Adverse Event Tracking Period  


Loop Diuretic Pilot Study Protocol 30 
 
The study period during which AEs must be tracked and reported is normally defined as the period from the initiation of 
study procedures to the end of the study treatment follow-up. For this study, the study treatment follow-up is 2 weeks 
following the last dose of study drug.  
7.2.1. Post-study Adverse Event  
All unresolved adverse AEs will be followed by the investigator until the events are resolved, the participant is lost to 
follow-up, or the AE is otherwise explained. At the last scheduled visit, the investigator will instruct each participant to 
report any subsequent event(s) that the participant, or the participant’s personal physician, believes might reasonably 
be related to participation in this study. The investigator will notify the study monitor of any death or AE occurring at 
any time after a participant has discontinued or terminated study participation that may reasonably be related to the 
study. The sponsor (NIDDK) will also be notified if the investigator should become aware of the development of cancer 
or of a congenital anomaly in a subsequently conceived offspring of a participant that has participated in this study.  
 
7.3. Recording of Adverse Events  
At each contact with the participant, the investigator or site designee will seek information on AEs by specific 
questioning and, as appropriate, by examination. Information on AEs will be recorded in the source document, and also 
on the AE log case report form (CRF). All signs, symptoms, and abnormal diagnostic procedure results relating to the 
same event will be recorded under one diagnosis name.  
7.3.1. Adverse Events of Interest  
The following AEs are anticipated in patients treated with furosemide and will be recorded on the appropriate AE of 
Interest CRF. See Section 7.3.2 for definitions. 
• Hypokalemia  
• Hypocalcemia 
• Hypomagnesemia 
• Hypotension  
• Hearing change 
• Tinnitus 
• Rash  
 
If the event meets the definition of serious as defined in Section 7.1.2, it will be recorded on an SAE form in addition to 
the appropriate AE of special interest CRF. Participants will be assessed for the occurrence of AEs of Interest at study 
visits (weekly during dose escalation and every other week during follow-up). The clinical course of each event will be 
followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not 
the cause. 
7.3.2. Trial-Defined Adverse Events  
The HD population undergoes frequent laboratory testing and has a high rate of peri-dialytic hypotensive events 
requiring changes in the dialysis prescription, adjustment of estimated dry (target) weight, or change in dialysis-related 
medications. Due to the unique nature of this population, the following events are considered routine aspects of 
maintenance HD therapy and will not be recorded as an AE except as noted:  
• Anemia – will be reported when hemoglobin is <7.5 mg/dL  
• Hypokalemia – will be reported when potassium level <3.2 mEq/L  
• Hyperkalemia – will be reported when potassium level ≥6.6 mEq/L  
• Hypomagnesemia – will be reported when magnesium level <0.8 mEq/L  
• Hyperphosphatemia – will be reported when phosphorous >9.5 mg/dL  


Loop Diuretic Pilot Study Protocol 31 
 
• Hypocalcemia – will be reported when serum corrected calcium <7.0 mg/dL  
• Hypercalcemia – will be reported when serum corrected calcium >11.0 mg/dL  
• Hyperparathyroidism – will be reported when PTH >1200 pg/mL  
• Hypotension – will be reported when it meets the criteria for serious dialysis-associated hypotension 
(hypotension requiring hospitalization or treatment in an emergency room and not attributable to overt sepsis, 
acute myocardial infarction, or other cardiovascular event (e.g. aortic dissection))  
• Hearing change – will be reported if Inner EAR score decreases by 10 points from baseline 
• Tinnitus- will be reported at level of severe or very severe patient-reported tinnitus 
• Rash- will be reported at level of severe or very severe patient-reported rash 
7.3.3. Abnormal Laboratory Values  
A clinical laboratory abnormality should be documented as an AE if:  
• The laboratory abnormality is not otherwise refuted by a repeat test that was performed specifically to 
confirm the abnormality  
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation of the 
drug, more frequent follow-up assessments, further diagnostic investigation, etc.  
• The abnormality meets the criteria in Section 7.3.2.  
7.3.4. Anticipated Adverse Events  
The following AEs are anticipated in the HD population and will not be considered to be Unanticipated Problems. Note 
that the designation as “Anticipated” does not imply that the event is not an SAE but relates to the regulatory definition 
of Unanticipated Problems as provided in Section 7.1.3.  
• Death  
• Coronary Ischemia including:  
o Unstable angina  
o Acute MI  
o Coronary revascularization  
• Heart failure hospitalization or exacerbation  
• Cardiac arrest  
• Cardiac arrhythmia (ventricular or atrial)  
• Peripheral vascular revascularization  
• Amputation  
• Vascular Access Events Including:  
o Catheter exchange, removal or declotting  
o Arteriovenous graft or fistula complications  
o Clotting  
o Stenosis  
o Revascularization  
o Infection  
• Infections Including:  
o Pneumonia  
o Vascular access infection  
o Bacteremia  
o Clostridium difficile infection  
 
7.4. Reporting of Serious Adverse Events and Unanticipated Problems  


Loop Diuretic Pilot Study Protocol 32 
 
The investigator will report SAEs and Unanticipated Problems to the safety monitor within 24 hours of first 
knowledge of the event. To report such events, an SAE form or an Unanticipated Problem form will be completed by the 
investigator and sent to the safety monitor. The safety monitor will facilitate the timely medical review and reporting of 
the event in accordance with study policies and IRB requirements. The investigator will keep a copy of the SAE form / 
Unanticipated Problem form on file at the study site. At the time of the initial report, the following information should 
be provided: 
• Study identifier 
• Participant identifier 
• A description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event is classified as serious 
• Investigator assessment of the association between the event and study treatment 
 
Within the following 7 days, the investigator will provide further information on the SAE or the unanticipated 
problem in the form of a written narrative. This should include a copy of the completed SAE form or Unanticipated 
Problem Form, and any other diagnostic information that will assist the understanding of the event. Significant new 
information on ongoing serious AEs should be provided promptly to the safety monitor.  
SAEs that are still ongoing at the end of the study period must be followed up to determine the final outcome. 
Any SAE that occurs after the study period and is considered to be possibly related to the study treatment or study 
participation should be recorded and reported immediately.  
7.4.1. Investigator Reporting to the IRB  
Investigators will report SAEs and Unanticipated problems to the IRB in accordance with the Office of Human Research 
Protections (OHRP) guidelines. OHRP recommends that:  
1) Unanticipated problems that are SAEs should be reported to the IRB within 1 week of the investigator 
becoming aware of the event; and  
2) Any other unanticipated problem should be reported to the IRB within 2 weeks of the investigator becoming 
aware of the problem.  
 
Reporting Process  
Unanticipated problems posing risks to participants or others as noted above will be reported using the appropriate IRB-
designated form or as a written report of the event (including a description of the event with information regarding its 
fulfillment of the above criteria, follow-up/resolution and need for revision to consent form and/or other study 
documentation). Copies of each report and documentation of IRB notification and receipt will be maintained in the 
study files. 
 
Other Reportable events:  
• Any adverse experience that, even without detailed analysis, represents a serious unexpected AE that is rare in 
the absence of drug exposure (such as agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome).  
• Any AE that would cause the sponsor to modify the investigators brochure, protocol or informed consent 
form, or would prompt other action by the IRB to assure protection of human participants.  
• Information that indicates a change to the risks or potential benefits of the research, in terms of severity or 
frequency.  
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in a research 
protocol.  


Loop Diuretic Pilot Study Protocol 33 
 
• Breach of confidentiality  
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research 
participant.  
• Incarceration of a participant when the research was not previously approved under Subpart C and the 
investigator believes it is in the best interest of the participant to remain on the study.  
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot be resolved 
by the research team.  
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that in 
the opinion of the investigator placed one or more participants at increased risk, or affects the rights or welfare 
of participants.  
 
7.4 Reporting of Pregnancy 
Pregnancies (including a positive pregnancy test regardless of age or disease state) of a female participant occurring 
while the participant is enrolled will result in study cessation for the pregnant participant. The female participant 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 participant 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.  
 
7.5 Stopping Rules  
Given that the primary focus of this pilot trial is on safety and tolerability, there are no pre-specified stopping rules for 
efficacy outcomes. However, the investigators will monitor all safety endpoints for evidence of differential safety effects, 
and routinely update the safety monitor. The safety monitor may recommend study termination on the basis of 
unacceptable increases in AEs or external data.  
 
7.6. Data Safety and Monitoring Plan  
7.6.1 Overall Framework 
There are three different acceptable approaches to data and safety monitoring plans. Monitoring can be conducted by 
the research team, an independent (external) safety monitor or group, or an independent data safety monitoring board. 
This study will enroll up to 40 patients and will last for 18 weeks (6 weeks of dose escalation and 12 weeks of 
subsequent follow-up per participant). Given the small number of participants, relatively short duration of the study, the 
frequency of study visits (weekly in the first 6-weeks and then every 2 weeks in the latter 12-weeks), the participants’ 
regular contact with medical professionals (three times a week at a dialysis clinic), the lack of blinding, that all activities 
will take place at a single site (University of North Carolina at Chapel Hill), and that the potential AEs are likely to be mild 
in nature and detected by study personnel and/or dialysis clinic personnel, we will ensure participant safety through 
regular review by the research team. This will include review of study progress, listings of AEs, and AE logs. We will also 
use an independent safety monitor to provide an additional layer of protection. 
7.6.2 Monitoring and Frequency 
Monitoring by the research team: The PI and study coordinator will maintain non-serious AE and SAE logs and case 
report forms throughout the study. The research team (study investigators, other significant contributors and research 
coordinator) will review study records, AEs, and SAEs for all participants on an ongoing basis. The UNC research team 
includes 1 board-certified nephrologist and a dialysis-trained pharmacist, both with the necessary expertise to assess 
study AEs. The Principal Investigator (PI) will review all such events every 2 weeks. All accumulated AEs of interest, SAEs, 


Loop Diuretic Pilot Study Protocol 34 
 
and data on overall AE rates will be presented at the monthly project team meetings to the broader research team. 
Review of the data will uncover patterns that might suggest a need for modification of study practices to ensure patient 
safety. If the research team uncovers such patterns, the safety monitor will be asked to review the events.  
 
The PI and/or research coordinator will report all SAEs to the research team and external safety monitor within 24 hours 
of becoming aware of the event. The PI and/or research coordinator will report SAEs that are unanticipated and related 
to the research to the research team, external safety monitor, and institutional review board (IRB) within 24 hours of 
becoming aware of the event. The PI will personally review all study results and notify participants of any abnormal 
results, including those present at baseline unrelated to the study intervention to ensure participants are able to seek 
appropriate medical care. 
 
Monitoring by an external safety monitor: Additional monitoring will be provided by a board-certified adult 
nephrologist not associated with the study. This external monitor will review all AEs and SAEs in detail including the time 
of onset, description, severity, time course, duration, outcome, relationship of the AE/SAE to the study drug, and any 
action(s) taken. The external safety monitor will review AEs and SAEs every 6 months (3 times over the ~18-month 
study), and SAEs that are unanticipated and related to the research as soon as the research team becomes aware. The 
monitor will help the research team determine whether further safety guards should be instituted and whether the 
benefit of the study continues to outweigh potential risks.  
 
Information to be monitored: The research team and external safety monitor will monitor AEs including hypotension, 
allergic or toxicity-related symptoms (rash, tinnitus, or hearing change), objective hearing change, and electrolyte 
abnormalities as well as SAEs. 
 
7.7 Medical Emergency Procedures 
7.1.1 Hypokalemia management 
Serum potassium will be measured weekly during dose escalation and monthly during follow-up. Treating clinicians will 
manage the dialysate potassium according to clinic standards. Study staff will monitor potassium values and contact 
treating clinicians in the event of hypokalemia to ensure that hypokalemia is being actively managed. Treating clinicians 
will be free to manage hypokalemia according to local standards, including changes to the dialysate potassium 
concentration. However, study drug dose reductions or discontinuation will be directly managed by study investigators. 
Occurrence of a serum potassium <3.2 mEq/L will end dose titration, and the participant will return to the prior 
tolerated furosemide dose. If the hypokalemia occurs at the lowest administered dose, furosemide will be stopped and 
not restarted. Serum potassium will be rechecked within one week when potassium is <3.2 mEq/L. Results of serum 
potassium will be conveyed to treating clinicians and the dialysis unit nursing staff. 
7.1.2 Hypomagnesemia management 
Serum magnesium will be measured weekly during dose escalation and monthly during follow-up. Treating clinicians will 
manage the dialysate magnesium according to clinic standards. Study staff will monitor magnesium values and contact 
treating clinicians in the event of hypomagnesemia to ensure that hypomagnesemia is being actively managed. Treating 
clinicians will be free to manage hypomagnesemia according to local standards, including changes to the dialysate 
magnesium concentration. However, study drug dose reductions or discontinuation will be directly managed by study 
investigators. Occurrence of a serum magnesium <0.8 mEq/L will end dose titration, and the participant will return to 
the prior tolerated furosemide dose. If the hypomagnesemia occurs at the lowest administered dose, furosemide will be 
stopped and not restarted. Serum magnesium will be rechecked within one week when magnesium is <0.8 mEq/L. 
Results of serum magnesium will be conveyed to treating clinicians and the dialysis unit nursing staff. 
7.1.3 Hypocalcemia management 


Loop Diuretic Pilot Study Protocol 35 
 
Serum corrected calcium will be measured weekly during dose escalation and monthly during follow-up. Treating 
clinicians will manage the dialysate calcium according to clinic standards. Study staff will monitor corrected calcium 
values and contact treating clinicians in the event of hypocalcemia to ensure that hypocalcemia is being actively 
managed. Treating clinicians will be free to manage hypocalcemia according to local standards, including changes to the 
dialysate calcium concentration. However, study drug dose reductions or discontinuation will be directly managed by 
study investigators. Occurrence of a corrected serum corrected calcium <7.0 mg/dL will end dose titration, and the 
participant will return to the prior tolerated furosemide dose. If the hypocalcemia occurs at the lowest administered 
dose, furosemide will be stopped and not restarted. Serum corrected calcium will be rechecked within one week when 
corrected calcium is <7.0 mg/dL. Results of serum corrected calcium will be conveyed to treating clinicians and the 
dialysis unit nursing staff. 
7.1.4 Hypotension management 
In the event of serious dialysis-associated hypotension (hypotension requiring hospitalization or treatment in an 
emergency room and not attributable to overt sepsis, acute myocardial infarction, or other cardiovascular event (e.g. 
aortic dissection)) study investigators will review the participant’s non-study anti-hypertensive medications, estimated 
dry (target) weight, and volume status. The participant’s nephrologist will be contacted to consider the following 
interventions listed in the preferred order of implementation:  
1) Decrease non-study anti-hypertensive medication(s)  
2) Increase prescribed dry (target) weight if there is no evidence of peripheral or pulmonary edema  
3) Reduce UF rate by increasing dialysis session duration  
4) Reduce dose of study drug if there are no other anti-hypertensive medications prescribed OR other anti-
hypertensive medications should not be discontinued (e.g., beta blocker following myocardial infarction)  
5) Discontinue study medication at the 3rd dose reduction  
Treating clinicians will be free to manage hypotension according to standard clinical practices and are not obligated to 
follow the study guidelines with respect to non-study medication, fluid removal rate, or dry weight. In contrast, dose 
reduction or discontinuation of study drug will be directly managed by study staff in accordance with the guideline. 
7.1.5 Ototoxicity management 
Change in hearing will be monitored by patient self-report (on symptom assessment) weekly during dose titration and 
every other week during follow-up and measured with the Inner EAR instrument every other week during dose titration 
and monthly during follow-up. A decrease by ≥10 points from baseline will constitute clinically significant hearing loss. 
We will refer participants with self-reported hearing loss (any severity) or ≥10-point decline in Inner EAR scores after 
furosemide initiation and/or dose titration for audiometry testing. 
 
8 
DATA COLLECTION AND MANAGMENT  
8.1 Source Documents and Access to Source Data/Documents 
Each participating clinic 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 clinic 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 (BPs, weights, dialysis treatment data) will be extracted from EHR and stored in REDCap databases housed 
on a secure Department of Medicine server. Symptoms, Inner EAR responses, and acceptance report will be recorded on 
study data collection forms. All electronic information will be stored on a password-protected UNC server (with secure, 


Loop Diuretic Pilot Study Protocol 36 
 
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 symptoms, Inner EAR responses, and 
acceptance report 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 coordinator will have access to patient information with 
patient identifiers. 
 
8.2 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, and 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.  
 
8.3 Data Handling and Record Keeping 
8.3.1 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 EHR review. 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 PI’s locked office. Only the PI and research coordinators 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. 


Loop Diuretic Pilot Study Protocol 37 
 
8.3.2 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. 
8.3.3 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, the below guidelines will be followed: 
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.  
 
9 
RECRUITMENT STRATEGY 
9.1 
Strategies for Recruitment and Retention 
Recruitment 
Our goal sample size is 36 participants in period 1 with the goal of >30 participants continuing on to period 2. 
We will recruit up to 40 participants to account for dropout and will recruit additional participants if fewer than 30 
participants are eligible for period 2. All participants will be recruited from the University of North Carolina (UNC)-owned 
Siler City, Pittsboro, Sanford, Lee County, and Carrboro Carolina Dialysis HD clinics. IRB-approved flyers providing brief 
study information (including background and rationale) and research team contact information will be placed in the 


Loop Diuretic Pilot Study Protocol 38 
 
participating dialysis clinics prior to participant recruitment. Nephrologists at the participating dialysis clinics will identify 
eligible patients from the dialysis clinics’ patient rosters. A care team member will then briefly introduce the study to the 
patient and obtain the patient’s permission to be contacted by the study team for further screening with study inclusion 
and exclusion criteria. The PI will approach eligible patients who have expressed interest in participating in the study and 
provide them with detailed information about the study and answer their questions. If the patient is willing to 
participate in the research study, informed consent will be obtained by the PI, a licensed physician. Recruitment scripts 
and informed consents will be available in both English and Spanish. Interpreters will be used as needed. 
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 furosemide across 
sex or racial/ ethnic groups. Children (individuals < 18 years) and vulnerable participants are not included in the study. 
 
Retention 
Retention of research participants in clinical trials is always a concern. However, the activities of the proposed 
study are not especially burdensome. Participants will be taking a twice a day medication that is unlikely to have 
substantial side effects. The duration of the entire study is relatively short (18 weeks). The dose escalation period, the 
first 6 weeks of the study, requires blood draws at weekly intervals during participants’ routine HD treatments and two 
urine collections. Clinic personnel will collect blood samples via the vascular access at the start of dialysis treatment. 
Therefore, study blood collections will not necessitate additional needle sticks. Participants will return urine collection 
containers to the study team at routine HD treatments. In the subsequent 12-week follow-up period, blood draws occur 
every 4 weeks during participants’ routine HD treatments and urine will be collected twice. All study visits will occur at 
the time of regularly scheduled dialysis treatments at the participant’s dialysis clinic. Participants will receive up to $199 
remuneration for study participation. We will encourage adherence to study testing by 1) timing remuneration provision 
with urine sample collections and 2) providing larger remuneration amounts to participants who return their 24-hour 
urine collection samples to the study team compared to participants who do not return their 24-hour urine samples. The 
research team will remain in close contact with participants through weekly study visits in the first 6 weeks of the study 
and then every other week visits in the final 12 weeks of the study. In addition, the research team will provide 
participants with the research team’s contact information (telephone and email) and encourage participants to contact 
the team at any time. The research team will provide participants with updates on study progress at pre-specified time 
points. At the conclusion of the study, results will be shared with participants who expressed interest in receiving them 
via follow-up letters written at a 5th grade reading level. 
 
9.2 
Participant Withdrawal of Termination 
9.2.1 Reasons for Withdrawal of 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 (e.g. refusal of 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. Such events are 
specified in Section 1.3.1. 
 
9.2.2 Handling of Participant Withdrawals or Termination  


Loop Diuretic Pilot Study Protocol 39 
 
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. 
 
9.3 Premature Termination or Suspension of Study 
If the investigators become aware of conditions or events that suggest a possible hazard to participants 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, relevant or unacceptable risk to the participants enrolled in the clinical study or failure to enroll participants 
at the required rate. 
 
10 
ETHICS/ PROTECTION OF HUMAN SUBJECTS 
10.1 Ethical Standard 
The investigators will adhere to NIH Human Research Protections Program policies and procedures. 
 
10.2 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. 
 
10.3 Informed Consent Process 
10.3.1     Consent and Other Informational Documents Provided to Participants 
An IRB-approved consent form and IRB-approved study informational page will be provided to potential participants. 
10.3.2     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. The PI will also ask the patients to sign HIPAA waivers 
allowing the PI to review the individual’s EHR for clinical data.  


Loop Diuretic Pilot Study Protocol 40 
 
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 PI 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. 
 
10.4 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 PI 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 PI’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 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. No documents containing patient information with patient identifiers will be downloaded from the 
secure Department of Medicine server onto personal computers.  
10.4.1      Research Use of Stored Human Samples, Specimens or Data 
One vial of stored blood and one aliquot of urine 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. 
 
10.5        Future Use of Stored Specimens 
With the participant’s approval and as approved by the IRB, de-identified biological samples (blood and urine) will be 
stored in the UNC Kidney Center freezers (5th floor Burnett-Womack). After the study is completed, the de-identified, 
archived blood and urine samples 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 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. 
 
11 
PLANS FOR PUBLICATION AND DATA SHARING 
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 manuscripts to the digital archive 
PubMed Central upon acceptance for publication. Specifically, the investigative team intends to publish a manuscript 
describing the study protocol and, separately, a manuscript reporting the study results, both in peer-reviewed journals.  
The study will be registered at clinicaltrials.gov, sponsored by the National Library of Medicine.  
 


Loop Diuretic Pilot Study Protocol 41 
 
12 
REFERENCES  
1. Saran, R, Robinson, B, Abbott, KC, Agodoa, LYC, Bragg-Gresham, J, Balkrishnan, R, Bhave, N, Dietrich, X, Ding, Z, 
Eggers, PW, Gaipov, A, Gillen, D, Gipson, D, Gu, H, Guro, P, Haggerty, D, Han, Y, He, K, Herman, W, Heung, M, 
Hirth, RA, Hsiung, JT, Hutton, D, Inoue, A, Jacobsen, SJ, Jin, Y, Kalantar-Zadeh, K, Kapke, A, Kleine, CE, Kovesdy, 
CP, Krueter, W, Kurtz, V, Li, Y, Liu, S, Marroquin, MV, McCullough, K, Molnar, MZ, Modi, Z, Montez-Rath, M, 
Moradi, H, Morgenstern, H, Mukhopadhyay, P, Nallamothu, B, Nguyen, DV, Norris, KC, O'Hare, AM, Obi, Y, Park, 
C, Pearson, J, Pisoni, R, Potukuchi, PK, Repeck, K, Rhee, CM, Schaubel, DE, Schrager, J, Selewski, DT, Shamraj, R, 
Shaw, SF, Shi, JM, Shieu, M, Sim, JJ, Soohoo, M, Steffick, D, Streja, E, Sumida, K, Kurella Tamura, M, Tilea, A, Turf, 
M, Wang, D, Weng, W, Woodside, KJ, Wyncott, A, Xiang, J, Xin, X, Yin, M, You, AS, Zhang, X, Zhou, H, Shahinian, 
V: US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J 
Kidney Dis, 73: A7-A8, 2019. 
2. Zoccali, C, Moissl, U, Chazot, C, Mallamaci, F, Tripepi, G, Arkossy, O, Wabel, P, Stuard, S: Chronic Fluid Overload and 
Mortality in ESRD. J Am Soc Nephrol, 28: 2491-2497, 2017. 
3. Chazot, C, Wabel, P, Chamney, P, Moissl, U, Wieskotten, S, Wizemann, V: Importance of normohydration for the long-
term survival of haemodialysis patients. Nephrol Dial Transplant, 27: 2404-2410, 2012. 
4. Wizemann, V, Wabel, P, Chamney, P, Zaluska, W, Moissl, U, Rode, C, Malecka-Masalska, T, Marcelli, D: The mortality 
risk of overhydration in haemodialysis patients. Nephrol Dial Transplant, 24: 1574-1579, 2009. 
5. Kalantar-Zadeh, K, Regidor, DL, Kovesdy, CP, Van Wyck, D, Bunnapradist, S, Horwich, TB, Fonarow, GC: Fluid retention 
is associated with cardiovascular mortality in patients undergoing long-term hemodialysis. Circulation, 119: 671-
679, 2009. 
6. Flythe, JE, Curhan, GC, Brunelli, SM: Disentangling the ultrafiltration rate-mortality association: the respective roles of 
session length and weight gain. Clin J Am Soc Nephrol, 8: 1151-1161, 2013. 
7. Assimon, MM, Wenger, JB, Wang, L, Flythe, JE: Ultrafiltration Rate and Mortality in Maintenance 
Hemodialysis Patients. Am J Kidney Dis, 68: 911-922, 2016. 
8. Flythe, JE, Kimmel, SE, Brunelli, SM: Rapid fluid removal during dialysis is associated with cardiovascular morbidity and 
mortality. Kidney Int, 79: 250-257, 2011. 
9. Movilli, E, Gaggia, P, Zubani, R, Camerini, C, Vizzardi, V, Parrinello, G, Savoldi, S, Fischer, MS, Londrino, F, Cancarini, G: 
Association between high ultrafiltration rates and mortality in uraemic patients on regular haemodialysis. A 5-
year prospective observational multicentre study. Nephrol Dial Transplant, 22: 3547-3552, 2007. 
10. Burton, JO, Jefferies, HJ, Selby, NM, McIntyre, CW: Hemodialysis-induced cardiac injury: determinants and associated 
outcomes. Clin J Am Soc Nephrol, 4: 914-920, 2009. 
11. 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. 
12. Cabrera, C, Brunelli, SM, Rosenbaum, D, Anum, E, Ramakrishnan, K, Jensen, DE, Stålhammar, NO, Stefánsson, BV: A 
retrospective, longitudinal study estimating the association between interdialytic weight gain and cardiovascular 
events and death in hemodialysis patients. BMC Nephrol, 16: 113, 2015. 
13. Flythe, JE, Mangione, TW, Brunelli, SM, Curhan, GC: Patient-Stated Preferences Regarding Volume-Related Risk 
Mitigation Strategies for Hemodialysis. Clin J Am Soc Nephrol, 9(8): 1418-1425, 2014. 
14. St Peter, WL, Sozio, SM, Shafi, T, Ephraim, PL, Luly, J, McDermott, A, Bandeen-Roche, K, Meyer, KB, Crews, DC, 
Scialla, JJ, Miskulin, DC, Tangri, N, Jaar, BG, Michels, WM, Wu, AW, Boulware, LE, Investigators, DNPOiE-SRDS: 
Patterns in blood pressure medication use in US incident dialysis patients over the first 6 months. BMC Nephrol, 
14: 249, 2013. 
15. Muntner, P, Anderson, A, Charleston, J, Chen, Z, Ford, V, Makos, G, O'Connor, A, Perumal, K, Rahman, M, 
Steigerwalt, S, Teal, V, Townsend, R, Weir, M, Wright, JT, Investigators, CRICCS: Hypertension awareness, 
treatment, and control in adults with CKD: results from the Chronic Renal Insufficiency Cohort (CRIC) Study. Am J 
Kidney Dis, 55: 441-451, 2010. 
16. Bragg-Gresham, JL, Fissell, RB, Mason, NA, Bailie, GR, Gillespie, BW, Wizemann, V, Cruz, JM, Akiba, T, Kurokawa, K, 
Ramirez, S, Young, EW: Diuretic use, residual renal function, and mortality among hemodialysis patients in the 
Dialysis Outcomes and Practice Pattern Study (DOPPS). Am J Kidney Dis, 49: 426-431, 2007. 


Loop Diuretic Pilot Study Protocol 42 
 
17. Medcalf, JF, Harris, KP, Walls, J: Role of diuretics in the preservation of residual renal function in patients on 
continuous ambulatory peritoneal dialysis. Kidney Int, 59: 1128-1133, 2001. 
18. Sibbel, S, Walker, AG, Colson, C, Tentori, F, Brunelli, SM, Flythe, J: Association of Continuation of Loop Diuretics at 
Hemodialysis Initiation with Clinical Outcomes. Clin J Am Soc Nephrol, 14: 95-102, 2019. 
19. Lasix (furosemide) package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016273s066lbl.pdf. 
20. Yancy, CW, Jessup, M, Bozkurt, B, Butler, J, Casey, DE, Drazner, MH, Fonarow, GC, Geraci, SA, Horwich, T, Januzzi, JL, 
Johnson, MR, Kasper, EK, Levy, WC, Masoudi, FA, McBride, PE, McMurray, JJ, Mitchell, JE, Peterson, PN, Riegel, 
B, Sam, F, Stevenson, LW, Tang, WH, Tsai, EJ, Wilkoff, BL, MEMBERS, WC, Guidelines, ACoCFAHATFoP: 2013 
ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on practice guidelines. Circulation, 128: e240-327, 2013. 
21. Charytan, DM, Himmelfarb, J, Ikizler, TA, Raj, DS, Hsu, JY, Landis, JR, Anderson, AH, Hung, AM, Mehrotra, R, Sharma, 
S, Weiner, DE, Williams, M, DiCarli, M, Skali, H, Kimmel, PL, Kliger, AS, Dember, LM, Consortium, HNT: Safety and 
cardiovascular efficacy of spironolactone in dialysis-dependent ESRD (SPin-D): a randomized, placebo-controlled, 
multiple dosage trial. Kidney Int, 95: 973-982, 2019. 
22. Ellison, DH: Clinical Pharmacology in Diuretic Use. Clin J Am Soc Nephrol, 2019. 
23. Ellison, DH: Mechanistic Insights into Loop Diuretic Responsiveness in Heart Failure. Clin J Am Soc Nephrol, 14: 650-
652, 2019. 
24. Acute heart failure: Diagnosing and managing acute heart failure in adults. London, 2014. 
25. Felker, GM, Lee, KL, Bull, DA, Redfield, MM, Stevenson, LW, Goldsmith, SR, LeWinter, MM, Deswal, A, Rouleau, JL, 
Ofili, EO, Anstrom, KJ, Hernandez, AF, McNulty, SE, Velazquez, EJ, Kfoury, AG, Chen, HH, Givertz, MM, Semigran, 
MJ, Bart, BA, Mascette, AM, Braunwald, E, O'Connor, CM, Network, NHFCR: Diuretic strategies in patients with 
acute decompensated heart failure. N Engl J Med, 364: 797-805, 2011. 
26. Saran, R, Robinson, B, Abbott, KC, Agodoa, LYC, Bragg-Gresham, J, Balkrishnan, R, Bhave, N, Dietrich, X, Ding, Z, 
Eggers, PW, Gaipov, A, Gillen, D, Gipson, D, Gu, H, Guro, P, Haggerty, D, Han, Y, He, K, Herman, W, Heung, M, 
Hirth, RA, Hsiung, JT, Hutton, D, Inoue, A, Jacobsen, SJ, Jin, Y, Kalantar-Zadeh, K, Kapke, A, Kleine, CE, Kovesdy, 
CP, Krueter, W, Kurtz, V, Li, Y, Liu, S, Marroquin, MV, McCullough, K, Molnar, MZ, Modi, Z, Montez-Rath, M, 
Moradi, H, Morgenstern, H, Mukhopadhyay, P, Nallamothu, B, Nguyen, DV, Norris, KC, O'Hare, AM, Obi, Y, Park, 
C, Pearson, J, Pisoni, R, Potukuchi, PK, Repeck, K, Rhee, CM, Schaubel, DE, Schrager, J, Selewski, DT, Shamraj, R, 
Shaw, SF, Shi, JM, Shieu, M, Sim, JJ, Soohoo, M, Steffick, D, Streja, E, Sumida, K, Kurella Tamura, M, Tilea, A, Turf, 
M, Wang, D, Weng, W, Woodside, KJ, Wyncott, A, Xiang, J, Xin, X, Yin, M, You, AS, Zhang, X, Zhou, H, Shahinian, 
V: US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J 
Kidney Dis, 73: A7-A8, 2019. 
27. Voelker, JR, Cartwright-Brown, D, Anderson, S, Leinfelder, J, Sica, DA, Kokko, JP, Brater, DC: Comparison of loop 
diuretics in patients with chronic renal insufficiency. Kidney Int, 32: 572-578, 1987. 
28. Huang, X, Dorhout Mees, E, Vos, P, Hamza, S, Braam, B: Everything we always wanted to know about furosemide but 
were afraid to ask. Am J Physiol Renal Physiol, 310: F958-971, 2016. 
29. Oh, SW, Han, SY: Loop Diuretics in Clinical Practice. Electrolyte Blood Press, 13: 17-21, 2015. 
30. Sakaguchi, Y, Fujii, N, Shoji, T, Hayashi, T, Rakugi, H, Isaka, Y: Hypomagnesemia is a significant predictor of 
cardiovascular and non-cardiovascular mortality in patients undergoing hemodialysis. Kidney Int, 85: 174-181, 
2014. 
31. Ohnishi, T, Kimachi, M, Fukuma, S, Akizawa, T, Fukuhara, S: Postdialysis Hypokalemia and All-Cause Mortality in 
Patients Undergoing Maintenance Hemodialysis. Clin J Am Soc Nephrol, 14(6): 873-881, 2019. 
32. Brater, DC: Diuretic therapy. N Engl J Med, 339: 387-395, 1998. 
33. Sica, DA: Diuretic use in renal disease. Nat Rev Nephrol, 8: 100-109, 2011. 
34. Greenberg, A: Diuretic complications. Am J Med Sci, 319: 10-24, 2000. 
35. Rybak, LP: Ototoxicity of loop diuretics. Otolaryngol Clin North Am, 26: 829-844, 1993. 
36. van Olden, RW, van Meyel, JJ, Gerlag, PG: Acute and long-term effects of therapy with high-dose furosemide in 
chronic hemodialysis patients. Am J Nephrol, 12: 351-356, 1992. 
37. Flinn, A, Ledger, S, Blake, P: Effectiveness of furosemide in patients on peritoneal dialysis. CANNT J, 16: 40-44, 2006. 
38. Yueh, B, McDowell, JA, Collins, M, Souza, PE, Loovis, CF, Deyo, RA: Development and validation of the effectiveness 
of [corrected] auditory rehabilitation scale. Arch Otolaryngol Head Neck Surg, 131: 851-856, 2005. 


Loop Diuretic Pilot Study Protocol 43 
 
39. Mohan, S, Corrales, CE, Yueh, B, Shin, JJ: Assessment of Disease-Specific and General Patient-Reported Outcome 
Measures of Hearing Health. Otolaryngol Head Neck Surg, 158: 702-709, 2018. 
40. Jessen, A, Ho, AD, Corrales, CE, Yueh, B, Shin, JJ: Improving Measurement Efficiency of the Inner EAR Scale with Item 
Response Theory. Otolaryngol Head Neck Surg, 158: 1093-1100, 2018. 
41. 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. 
42. Hecking, M, McCullough, KP, Port, FK, Bieber, B, Morgenstern, H, Yamamoto, H, Suri, RS, Jadoul, M, Gesualdo, L, Perl, 
J, Robinson, BM: Self-reported Urine Volume in Hemodialysis Patients: Predictors and Mortality Outcomes in the 
International Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis, 74(3): 425-428, 2019. 
 
13 
APPENDICES 
13.1 Symptom Assessment 
Items 
During your dialysis treatments over the [last week (for dose titration period) and two weeks (for follow-up period)] did 
you have…? 
1. Cramping 
2. Dizziness or lightheadedness 
3. Unusual tiredness 
4. Unusual weakness 
5. Chest pain 
6. New rash 
7. Nausea 
8. Vomiting 
9. Diarrhea 
10. Tinnitus or ear ringing  
11. Hearing change 
12. Other (patient self-report) 
Response Options: 0=did not have.  
• If present, how severe was it? 1=mild, 2=moderate, 3=severe, 4=very severe 
 
13.2 Inner EAR Instrument 
Items 
1. Ability to understand with a family and close friends are saying. 
2. Ability to understand speech in a quiet room. 
3. Ability to hear what is said by those at your table in a crowded restaurant. 
4. Ability to hear what you want and filter out unwanted noises. 
5. Ability to hear telephone conversations. 
6. Ability to hear in different listening situations. 
7. Ability to hear soft household sounds (e.g. car turn signal, clock ticking). 
8. Mood based on your ability to hear. 
9. Bothered by having to ask people to repeat. 
10. Bothered by having to restrict activities because of your hearing. 
11. Please rate your overall hearing. 


Loop Diuretic Pilot Study Protocol 44 
 
Response Options 
Questions 1-8: 5-point Likert scale- 1=poor, 2=fair, 3=good, 4=very good, 5=excellent 
Questions 9-10: 4-point Likert scale- 1=very bothered, 2=somewhat bothered, 3=a little bothered, 4=not bothered 
Question 11: 11-point scale (select a number between 0 and 11 with the following markers- 0=hate, 5=it’s OK, 10=love it 
 

ICF_001.pdf: 
Informed Consent 
 
Pilot Study of Loop Diuretics Among Individuals Receiving 
Hemodialysis 
 
 
 
NCT number NCT04622709 
Document Date 04/14/2020 
 


IRB # 19-3550 
Patient Consent Form v7 
Page 1 of 8 
Adult Consent Form 
 
University of North Carolina at Chapel Hill  
Consent to Participate in a Research Study  
Consent Form Version Date:  4/14/2020 
IRB Study # 19-3550 
 
Title of Study: Pilot Study of Loop Diuretics among Individuals Receiving Hemodialysis 
Principal Investigator: Jennifer Flythe 
Principal Investigator Department: Medicine-Nephrology 
Principal Investigator Phone number: (919) 445-2656 
Principal Investigator Email Address: jenny_flythe@med.unc.edu 
Funding Source and/or Sponsor: National Institutes of Health 
------------------------------------------------------------------------------------------------------------ 
 
SHORT STUDY SUMMARY 
This study is being done to understand if the diuretic drug, furosemide (or “Lasix”) is safe for dialysis 
patients and will help them increase the amount of pee/urine they produce. Increasing the amount of 
pee/urine can potentially help patients reduce fluid overload and the need for rapid fluid removal during 
dialysis treatments. Participation in this study lasts a total of 22 weeks. If you choose to participate in 
this study, your participation would help us better understand your experience as a dialysis patient and 
understand the right drug dose that will be both safe and effective for dialysis patients. If you 
experience furosemide-related improvements in the amount of pee (or urine) you produce, blood 
pressure control, and/or fluid volume-related symptoms during dialysis, the drug could be added to your 
dialysis prescription by your treating nephrologist if they believe it is a good long-term treatment for you. 
If you choose to participate in this study, you would come to your regular dialysis treatments 3 times 
per week like you normally do, and you would be given the study drug (furosemide) to take by mouth 
two times a day for 18 weeks. You would also be asked to do a 24-hour urine collection 4 times 
throughout the study, and answer questions about your hearing and about the symptoms you may 
experience on dialysis. A dialysis clinic nurse would draw extra tubes of blood 10 times throughout the 
study (no extra needle sticks).  
The risks related to the study drug furosemide include unusual electrolyte changes (potassium, 
magnesium, calcium, for example), low blood pressure, rash, ringing in the ears and other hearing 
changes including deafness, and other symptoms. Patients who already have a high risk of furosemide 
side effects will not be asked to participate in this study. There is minimal risk of loss of confidentiality. 
Efforts to protect you as a participant in this study are discussed below.  
 
 


IRB # 19-3550 
Patient Consent Form v7 
Page 2 of 8 
What are some general things you should know about research studies?  
You are being asked to take part in a research study.  To join the study is voluntary. You may refuse to 
join, or you may take back your consent to be in the study, for any reason, without penalty. 
 
Research studies are designed to gain new knowledge. This new information may help people in the 
future. You may not receive any direct benefit from being in the research study. There also may be 
risks to being in research studies. Deciding not to be in the study or leaving the study before it is done 
will not affect your relationship with the researcher, your health care provider, or the University of North 
Carolina-Chapel Hill. If you are a patient with an illness, you do not have to be in the research study in 
order to receive health care. 
 
Details about this study are discussed below.  It is important that you understand this information so 
that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the researchers named above, or staff 
members who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study?  
The purpose of this research study is to understand if furosemide, sometimes called Lasix, (a drug that 
helps patients pee or make urine) is safe for hemodialysis patients and effective at increasing the 
amount of pee (or urine) they produce. Increasing the amount of pee (or urine) can potentially help with 
fluid overload and potentially reduce the need for rapid fluid removal during hemodialysis treatments. 
Furosemide is approved by the U.S. Food and Drug Administration (FDA) for the treatment of high 
blood pressure and swelling in people who make urine. It is not known how well it works in dialysis 
patients who make urine. Your participation will help us better understand your experience as a dialysis 
patient and understand the right drug dose that will be both safe and effective for dialysis patients.  
Are there any reasons you should not be in this study?  
You should not be in this study if you are not a hemodialysis patient who receives in-center treatment, if 
you don’t make at least 1 cup of urine per 24-hours, if you are pregnant, if you are incarcerated 
(prisoner), if you get dialysis treatments more than 4 times per week, or if you eat natural licorice. 
 
How many people will take part in this study?  
If you decide to be in this study, you will be one of approximately 30-40 hemodialysis patients who 
participate in this study.  
 
How long will your part in this study last?  
If you decide to participate in this study, you would be involved in the study only during your regularly 
scheduled dialysis treatments 3 times per week, for a total of 22 weeks.  
You will not be contacted again. There is no study follow-up after the 22 weeks. However, if you desire, 
we will send you a summary of the study results by email, mail, or in person once the study has 
finished and results analyzed. 
 


IRB # 19-3550 
Patient Consent Form v7 
Page 3 of 8 
What will happen if you take part in the study?  
If you choose to participate in this study, you will be asked about your medical history, including 
questions about your medications and health problems. At the start of the study, you will also be asked 
questions about symptoms you experience during dialysis and about your hearing, and you will be 
asked to do a 24-hour urine collection and bring the jug back to the study team. A sample of your blood 
will be taken from your vascular access (dialysis fistula, graft, or catheter). Aside from doing the 24-
hour urine collection at home at the beginning and then 3 times during the study, your involvement in 
this study will happen only during your routinely scheduled dialysis treatments 3 times per week.  
During the study, you will receive the study drug furosemide at your regularly scheduled dialysis 
treatments, along with instructions on how to take the drug. If it is safe to do so, the drug dose will 
increase 3 times (every 14 days) over 6 weeks, and then you will continue taking the highest dose of 
the drug for another 12 weeks until the end of the study. You will be told when the dose increases and 
you will have the chance to tell the study team if you do not feel well. The dose increases help the 
study team understand how much of the drug is needed to help dialysis patients pee (or urinate) more 
and not have bad side effects. 
At the beginning of the study, you will start with a low drug dose for the first 2 weeks, and then, if it is 
safe and you agree to it, you will take a higher drug dose for 2 weeks. If it is safe and you agree to it, 
you will then take a higher drug dose for the last 2 weeks. If, after the first 6 weeks, it is safe and you 
agree to it, you will then continue taking the highest drug dose for another 12 weeks until the end of the 
study. 
This study will not make changes to your normal dialysis prescription. Your blood pressure will be 
monitored during treatments like it always is. Your weights will be checked before and after dialysis like 
they always are. You will be asked to answer questions about your hearing and about symptoms that 
you may experience during dialysis treatments. You will be asked to do a 24-hour urine collection 4 
times throughout the study. You will have extra blood drawn (2 tubes, each with 2.5 mL (1/2 teaspoon) 
of blood each) from your vascular access (no extra needle sticks) during your dialysis treatments 10 
times throughout the study.  
 
 
 
 
 
 
 
 


IRB # 19-3550 
Patient Consent Form v7 
Page 4 of 8 
Study Activities and Timeline 
Study Period 
Before starting 
on study drug 
Take study drug at increasing levels 
Continue taking study drug at 
highest safe level  
Study drug 
None 
Lowest 
dose 
Increase 
dose if safe 
Increase 
dose again if 
safe 
Highest safe and effective drug 
dose 
# of Weeks 
2-4 weeks 
2 weeks 
2 weeks 
2 weeks 
12 weeks 
What you will 
be asked to do 
 
Take study drug every day 
Take study drug every day 
Get blood drawn (1 
time) 
Get blood drawn (6 times) 
Get blood drawn (3 times) 
Do 24-hr urine 
collection (1 time) 
Do 24-hour urine collection (2 times) 
Do 24-hour urine collection (2 
times) 
Answer questions 
about your 
symptoms (1 time) 
Answer questions about your symptoms 
(6 times) 
Answer questions about your 
symptoms (6 times) 
Answer questions 
about your hearing 
(1 time) 
Answer questions about your hearing (3 
times) 
Answer questions about your 
hearing (3 times) 
 
Answer a question about continuing the 
study drug (6 times) 
Answer a question about 
continuing the study drug (6 times) 
What are the possible benefits from being in this study?  
Research is designed to benefit society by gaining new knowledge, and results from this study could 
potentially benefit future dialysis patients. There may be no direct benefit to you from participating in 
this study in addition to your usual dialysis treatment care. Possible benefits to you from being in this 
study may be having the opportunity to discuss your dialysis experience in a supportive environment, 
and possible increased interest or engagement in your own care. If you experience furosemide-related 
improvements in the amount of pee (or urine) you produce, blood pressure control, and/or fluid volume-
related symptoms during dialysis, the drug could be added to your dialysis prescription by your treating 
nephrologist if they believe it is a good long-term treatment for you. 
What are the possible risks or discomforts involved from being in this study?  
Risks related to the study drug furosemide include unusual electrolyte changes (potassium, 
magnesium, calcium, for example), low blood pressure, rash, ringing in the ears, other hearing changes 
including deafness, and other symptoms such as cramps, dizziness, unusual tiredness or weakness, 
chest pain, nausea/vomiting, diarrhea, and numbness/tingling. Patients who already have a high risk of 
furosemide side effects will not be asked to participate in the study. 
You may experience the normal risks associated with your normal hemodialysis treatment, such as low 
blood pressure, abnormal heart rhythm, bleeding or bruising at the blood access (dialysis fistula or 


IRB # 19-3550 
Patient Consent Form v7 
Page 5 of 8 
graft), infection, or symptoms like cramping or feeling tired. All study monitoring is low risk and part of 
regular dialysis care. This study involves an additional blood draw, which will be taken from your 
vascular access by a dialysis clinic nurse and will not require a separate needle stick. The main risk 
with the blood draw is bruising or bleeding at the vascular access. This study also involves additional 
24-hour urine tests, which will be done by you and returned to the study team. The main risk with the 
24-hour urine test is embarrassment related to collecting, storing, and transporting the urine jug. 
Occasional 24-hour urine tests are required as part of regular dialysis care, so this risk is minimal. 
There is minimal risk of loss of confidentiality. Every effort will be taken to protect your identity as a 
participant in this study, and we are taking multiple steps to protect your privacy as detailed below. You 
should report any problems you experience to the research team. 
What are the risks to a pregnancy or to a nursing child? 
All female patients who are eligible to participate in the study will be asked about their pregnancy status 
before the study starts. Women who are pregnant or planning to get pregnant will not be asked to 
participate in the study. We do not know the effect of the study drug on babies before they are born, or 
on nursing children.  Many drugs can get into the mother's milk. You should not breastfeed your child 
while taking the study drug. If you are a man, there is no known risk to fathering children while on 
furosemide (or “Lasix”). If you become pregnant during the study you should notify the researcher right 
away.  
What if we learn about new findings or information during the study?  
You will be given any new information gained during the course of the study that might affect your 
willingness to continue your participation. 
Will I receive any clinical results from this study?  
The study Principal Investigator or your nephrologist may choose to share some study results with you 
if they are determined to be medically important to your dialysis or general health care. 
How will information about you be protected?  
Information collected for this study (including medical information, blood and urine samples, and your 
responses to questions) will not be placed in your medical record. Your information will be kept 
confidential in a separate research study chart. A study identification number will be used to link 
information collected for this study to your name. Your name will not be directly associated with your 
information. You will not be identified in any report or publication of this study or its results. Your study 
data will be transferred to a secure computer. Study information will be stored on secure password-
protected computers, blood and urine samples will be stored in secure UNC freezers, and both will be 
accessible only to study staff. All blood and urine samples will be sent to a UNC laboratory to be tested 
for electrolyte and study drug levels in your blood (to make sure they are at safe levels) and then stored 
in secure UNC freezers using a study identification number for 12 months after the study ends. 
Participation in this study will not affect your medical care. Participants will not be identified in any 
report or publication about this study.  We may use de-identified data and/or specimens from this study 
in future research without additional consent. 


IRB # 19-3550 
Patient Consent Form v7 
Page 6 of 8 
Although every effort will be made to keep research records private, there may be times when federal 
or state law requires the disclosure of such records, including personal information.  This is very 
unlikely, but if disclosure is ever required, UNC-Chapel Hill will take steps allowable by law to protect 
the privacy of personal information.  In some cases, your information in this research study could be 
reviewed by representatives of the University, research sponsors, or government agencies (for 
example, the FDA) for purposes such as quality control or safety. 
By signing this informed consent document, you agree that some of the information created by 
participating in this study and/or a copy of the consent form may be included in your medical record and 
that this information may be viewed by other physicians or caregivers who provide healthcare services 
to you (nephrologists, dialysis care staff, for example). This will allow the doctors caring for you to know 
what study medications or tests you may be receiving as a part of the study and know how to take care 
of you if you have other health problems or needs during the study. 
 
What is a Certificate of Confidentiality? 
This research is covered by a Certificate of Confidentiality. With this Certificate, the researchers may 
not disclose or use information, documents or biospecimens that may identify you in any federal, state, 
or local civil, criminal, administrative, legislative, or other proceedings in the United States, for example, 
if there is a court subpoena, unless you have consented for this use. The Certificate cannot be used to 
refuse a request for information from personnel of a federal or state agency that is sponsoring the study 
for auditing or evaluation purposes or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA). 
  
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or 
local law, such as mandatory reporting requirements for child abuse or neglect, disabled adult abuse or 
neglect, communicable diseases, injuries caused by suspected criminal violence, cancer diagnosis or 
benign brain or central nervous system tumors or other mandatory reporting requirement under 
applicable law. The Certificate of Confidentiality will not be used if disclosure is for other scientific 
research, as allowed by federal regulations protecting research subjects or for any purpose you have 
consented to in this informed consent document. You should understand that a Certificate of 
Confidentiality does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. If an insurer, employer, or other person obtains your written consent to 
receive research information, then the researchers may not use the Certificate to withhold that 
information. 
 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  This may include the risk of 
personal injury. In spite of all safety measures, you might develop a reaction or injury from being in this 
study. If such problems occur, the researchers will help you get medical care, but any costs for the 
medical care will be billed to you and/or your insurance company. The University of North Carolina at 
Chapel Hill has not set aside funds to pay you for any such reactions or injuries, or for the related 
medical care. You do not give up any of your legal rights by signing this form. 


IRB # 19-3550 
Patient Consent Form v7 
Page 7 of 8 
 
What if you want to stop before your part in the study is complete?  
You can stop participating in the study at any time, without penalty. If you stop participating in the study 
before it is done, study staff may ask you your reasons for ending your participation. The researchers 
also have the right to stop your participation at any time. This could be because you have had an 
unexpected reaction, or have failed to follow instructions, or your care is transferred to another dialysis 
clinic that is not part of the study, or because the entire study has been stopped. If you choose to stop 
participating in the study or the study team stops your participation in this study before the study is 
done, the study team will keep all data collected up until the point of stopping. No additional information 
will be collected unless you provide additional written permission for further data collection at the time 
you stopped taking part in the study. 
Will you receive anything for being in this study?  
You will receive $199 total for participating in the full study including bringing back all four 24-hour urine 
collection jugs to the study team. You will receive $159 total if you participate in the full study but do 
NOT bring back any of the four 24-hour urine collection jugs.  
If you participate in the entire study, you will receive study payments 4 times. For each of those study 
payments, you will receive $10 more each time you bring back your 24-hour urine collection jugs. If you 
bring back your 24-hour urine collection jugs, you will receive $50 at the beginning of the study, $40 
during the first part of the study (6-week period), $40 during the 2nd part of the study (12-week period), 
and $69 at the end of the study. If you do NOT bring back your 24-hour urine collection jugs each time, 
you will receive $40 at the beginning of the study, $30 during the first part of the study (6-week period), 
$30 during the 2nd part of the study (12-week period), and $59 at the end of the study.  
You will receive the full payment amounts for each part of the study even if you stop participating in the 
study before the end of each period (1 time at the beginning, 1 time during the 6-week period, 1 time 
during the last 12-week period, and 1 time at the end of the study).  
 
Will it cost you anything to be in this study? 
It will not cost you anything to be in this study. 
Who is sponsoring this study? 
This research is funded by the National Institutes of Health (NIH).  This means that the research team 
is being paid by the sponsor for doing the study.  The researchers do not, however, have a direct 
financial interest with NIH or in the final results of the study. 
 
What if you have questions about this study?  
You have the right to ask, and have answered, any questions you may have about this research. If you 
have questions about the study (including payments), complaints, or concerns, you should contact the 
researchers listed on the first page of this form. A description of this clinical trial will be available on 
www.clinicaltrials.gov, as required by U.S. Law. This website will not include information that can 
identify you. At most, the website will include a summary of the results. You can search this website at 
any time. 


IRB # 19-3550 
Patient Consent Form v7 
Page 8 of 8 
 
What if you have questions about your rights as a research participant?  
All research on human volunteers is reviewed by a committee that works to protect your rights and 
welfare.  If you have questions or concerns about your rights as a research subject, or if you would like 
to obtain information or offer input, you may contact the Institutional Review Board at 919-966-3113 or 
by email to IRB_subjects@unc.edu. 
 
 
Participant’s Agreement: 
 
I have read the information provided above.  I have asked all the questions I have at this time.  I 
voluntarily agree to participate in this research study. 
 
  
_________________________________________                           _________________ 
Signature of Research Participant                                                     Date 
  
 
__________________________________________ 
Printed Name of Research Participant 
  
 
 
 
__________________________________________                    
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Signature of Research Team Member Obtaining Consent               Date 
  
 
_________________________________________________ 
Printed Name of Research Team Member Obtaining Consent