Clinical trial NCT04542304
Conditions: Chronic Kidney Disease End Stage Renal Disease
Sponsor: Stanford University
Start date: 2021-03-01; Completion date: 2023-06-15
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study will determine the efficacy of diuretics in patients with chronic kidney disease.

Detailed description:
Participants with chronic kidney disease will undergo two 1-week study periods (single-dose diuretic versus single-dose placebo) separated by 1-2 weeks of washout in a cross-over design. Blood and urine samples will be collected at the end of each study period to determine the effect on urine output and to assess the kidney clearance and levels of uremic solute. Participants will weigh themselves daily.

Arms: arm 1: Metolazone will be taken orally during the first week, followed by washout of 1-2 weeks, then placebo will be taken the following week. arm 2: Placebo will be taken orally during the first week, followed by washout of 1-2 weeks, then metolazone will be taken the following week.
Interventions: intervention 1: Metolazone intervention 2: Placebo
Intervention descriptions: intervention 1: Participants receive a single dose of metolazone. intervention 2: Participants receive a single dose of placebo to match metolazone.

Protocol documents:
Prot_000.pdf: 
Efficacy of Diuretics in Kidney Disease 
NCT04542304 
March 15, 2023 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
This research will study how well a diuretic, a medication which enhances the kidneys’ 
removal of sodium and fluid, works in people with kidney disease. We will measure urine 
production and levels of waste chemicals in these samples to figure out how the diuretic 
and the kidneys remove waste chemicals from the body. Overall, we hope to learn more 
about how diuretics and the kidneys work so that we can improve the health of people 
with kidney disease. 
b. 
Objectives 
Kidney disease is common and more than 100,000 people with kidney disease start 
dialysis every year. There is limited data regarding the optimal dose or type of diuretic 
for patients with kidney disease. In addition, a majority of patients have their diuretic 
stopped once they start dialysis. Many however have enough residual kidney function so 
that diuretics may still be beneficial in controlling volume status, blood pressure, and 
serum potassium levels. We in addition would like to learn more about how the efficacy 
of diuretics is affected by the plasma accumulation of waste solutes that are cleared by 
the same secretory mechanisms of the kidneys as the diuretics. 
c. 
Rationale for Research in Humans 
This study will assess the effect of diuretics on urine production in patients with kidney 
disease and the effect of plasma accumulation of waste solutes on the efficacy of 
diuretics. We therefore need to include human subjects. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
We will conduct two types of studies to investigate diuretics in kidney disease. Patients 
with kidney disease will be asked to participate in one or both of the studies. 
 
One study is a cross-over study comparing a one-time dose of a diuretic and then a one-
time dose of a placebo at least one week later. 
 
Screening: 
- nephrologists at Stanford, VA Palo Alto, and SCVMC will be contacted to identify 
patients with kidney disease and patients on dialysis who report still producing urine. 
- informed consent will be obtained from eligible patients. 


March 15, 2023 
 
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- patients who consent will then undergo randomization to determine the order of diuretic 
and placebo in the cross-over study. 
 
The patients will complete two 1-week study periods: 
- One period of taking a one-time dose of a diuretic. 
- One period of taking a one-time dose of a placebo. 
 
During the study periods which will be performed at least 1 week 
apart: 
- patients will be asked to take a one-time dose of a diuretic or a placebo. If patients are 
already on a diuretic, we may ask them to briefly stop taking the diuretic and to take a 
different diuretic or a placebo. 
- the patient's blood pressure will be checked prior to taking the 
diuretic or placebo. 
- the patient will be asked to weigh him/herself daily. 
- the patient will collect urine for at least 24 hours. 
- a blood sample will be collected, up to 20 ml (5 teaspoons). If the patient is on 
hemodialysis, a pre- and post-treatment blood sample will be collected. Blood will be 
collected through the dialysis tubing in the same fashion as the patients' routine lab 
monitoring. 
- the patient will complete symptom questionnaires. 
 
We may ask the patients to repeat the diuretic and/or placebo study periods. 
 
The other study is a study investigating how kidney disease and/or dialysis affects the 
plasma levels of diuretics over time. 
 
Screening: 
- nephrologists at Stanford, VA Palo Alto, and SCVMC will be contacted to identify 
patients with kidney disease and patients on dialysis. 
- informed consent will be obtained from eligible patients. 
 
Patients who consent will then perform the following: 
- take a one-time dose of a diuretic. If patients are already on a diuretic, we may ask them 
to briefly stop taking the diuretic and to take a different diuretic. 
- a blood sample will be collected after the patients take the diuretic, up to 20 ml (5 
teaspoons). If the patient is on hemodialysis, a pre- and post-treatment blood sample will 
be collected. Blood will be collected through the dialysis tubing in the same fashion as 
the patients' routine lab monitoring. 
- up to 5 repeat blood samples may be collected, each at least 24 hours apart. 
- if the patient is on dialysis, waste dialysate fluid (which normally goes down the drain) 
will be collected during a dialysis treatment. 
- if the patient makes urine, we may ask the patient to collect timed urine samples. 


March 15, 2023 
 
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b. 
Procedure Risks 
Blood would be collected in the same sterile fashion as the patients' routine lab checks. If 
the patients are on hemodialysis, blood will be collected in the same fashion as their 
routine monthly labs through the hemodialysis tubing. 
 
Taking a diuretic medication once has minimal risk unless taking other medications 
which tend to reduce blood pressure; we would check the patients' blood pressure and 
review their medications before asking them to take a diuretic. 
 
Stopping a diuretic medication and taking a placebo instead has minimal risk of higher 
blood pressure and fluid accumulation in carefully followed patients. We will check the 
patients' blood pressure and weight before and after stopping their diuretic. 
c. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Yes 
d. 
Study Endpoint(s) 
The primary endpoint is urine production as assessed by a timed urine collection. Other 
endpoints are symptom questionnaires (KDQOL-36 and the Dialysis Symptom Index).  
 
Laboratory and clinical endpoints will be plasma levels of urea and secreted uremic 
solutes, blood pressure, and weight changes.  
 
Because the patients will take only a one-time dose of a diuretic and a one-time dose of a 
placebo, we do not anticipate a difference which would force study termination.  
 
If no important differences are detected, the study will end once the projected total 
patient population has completed the study. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
We have previously found that the residual native kidney can control 
plasma levels of secreted solutes better than those of the index 
solute urea. We would like to assess whether diuretics can enhance 
the residual kidneys' ability to control organic solutes and fluid 
gain. 
b. 
Findings from Past Animal Experiments 
N/A 


March 15, 2023 
 
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4. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Commercial Drugs, Biologics, Reagents, or Chemicals 
Commercial Product 1 
Name: 
Metolazone 
Dosage: 
range of 2.5 to 20 mg in a single daily dose 
Commercial Product 2 
Name: 
Furosemide 
Dosage: 
range of 40 to 600 mg/day in two doses per day 
Commercial Product 3 
Name: 
Bumetanide 
Dosage: 
range of 0.5 to 10 mg/day in two doses per day 
Commercial Product 4 
Name: 
Placebo 
Commercial Product 5 
Name: 
Chlorthalidone 
Dosage: 
range of 25 to 100 mg in a single daily dose 
Commercial Product 6 
Name: 
Torsemide 
Dosage: 
range of 10 to 200 mg/day in single daily dose or in two doses per day 
 
5. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
i) 20 subjects expected to be enrolled from Stanford-affiliated sites and 35 subjects 
expected to be enrolled from the VA. 
ii) an anticipated 75 subjects expected to be enrolled from all sites, including VA Palo 
Alto and SCVMC. We will obtain approval from the SCVMC IRB; we will not recruit 
patients from SCVMC until we obtain approval. 
iii) patients with kidney disease and dialysis patients 
b. 
Age, Gender, and Ethnic Background 
The age range will be 18 to 85 years old. The gender and ethnic background will be 
representative of the diverse Bay Area population. 
c. 
Recruitment Details 
We will notify the primary nephrologists to help identify patients with kidney disease and 
patients on dialysis who still have residual kidney function. We will also accept direct 
referrals from nephrologists. 
 
We are requesting a waiver of HIPAA for recruitment to review medical charts to 
identify eligible patients. When we identify a possible participant by chart review, we 
will contact the patient's primary nephrologist to obtain their approval for the patient's 
potential participation and arrange for the primary nephrologist to personally ask the 
patient or have clinic or dialysis unit personnel ask the patient if s/he would be willing to 
talk to us about involvement in a study. 


March 15, 2023 
 
Page 5 of 5 
d. 
Eligibility Criteria 
i. 
Inclusion Criteria 
- patients with chronic kidney disease 
- patients on hemodialysis or peritoneal dialysis with or without residual kidney 
function. Such patients must be on dialysis for at least 2 months with regular 
adherence to treatments. 
ii. 
Exclusion Criteria 
- hospitalized within the past 2 months. 
e. 
Screening Procedures 
We will notify the primary nephrologists who will help identify patients with kidney 
disease, patients who are on dialysis with residual kidney function (suggested by report of 
urine production of at least 250 ml/day or about 1 cup/day), and patients who are on 
dialysis without residual kidney function. 
 
6. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health. 

SAP_001.pdf: 
Efficacy of Diuretics in Kidney Disease 
NCT04542304 
April 14, 2025 
Data Analysis Plans 
Data will be presented as mean and standard deviation.  The effect of metolazone versus placebo 
on urine production (primary outcome) will be compared using the paired t-test.  The effect of 
metolazone versus placebo on kidney clearance of uremic solutes, weight, and blood pressure will 
be compared using the paired t-test. 
 
Rationale for Sample Size 
Preliminary data of prevalent hemodialysis patients showed that among 33 patients on low-dose 
or no diuretic, the average urine output was 795 ± 556 mL/day.  Based on this finding, 33 patients 
would provide 80% power and 43 patients would provide 90% power to test whether diuretic 
increases the primary outcome of urine production by 50%.  To account for an estimated dropout 
rate of 20%, enrollment of 50 patients will be targeted to yield 40 patients completing the study.