Chlortalidone and Bumetanide in Advanced Chronic Kidney Disease: HEBE-CKD Trial

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03923933

Enrollment

Registered

2019-04-23

Start date

2019-06-18

Completion date

2019-10-28

Last updated

2020-11-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Renal Insufficiency, Chronic

Keywords

Diuretics, Bumetanide, Chlorthalidone, Chronic Kidney Disease, Volume Overload

Brief summary

This study aims to demonstrate the possible benefit of a treatment based on double diuretic in patients with chronic kidney disease and severely impaired glomerular filtration rate. This is based on previous observations where the investigators found that volume overload is a frequent condition within this population and is strongly linked to an increase in morbidity and mortality. The investigators consider that this therapy could be beneficial given that most of these patients are treated with loop diuretics, however, with the passage of time, adaptive changes in the distal nephron occur that promote a decrease in the treatment effect. In this sense, thiazide diuretics at appropriate doses could 'break' the resistance, since their mechanism of action antagonizes the resistance mechanism. Unfortunately, to this day, this treatment has not been fully evaluated. Particularly in this type of population. The investigators developed a study proposed as a double blind randomized clinical trial, where the population will be divided into two groups. A group will be given the standard treatment based on loop diuretic (bumetanide), while the other group will receive the intervention (bumetanide plus chlorthalidone). After a 30-day follow-up period, the results will be measured. With respect to the effectiveness of the treatment, the decrease in volume overload by bioimpedance will be measured. While the occurrence of adverse effects during the same monitoring period will be observed.

Interventions

DRUGChlorthalidone

Chlorthalidone

DRUGBumetanide

Bumetanide

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* glomerular filtration rate less than 30 ml / min / 1.73m * Without replacement therapy (dialysis or hemodialysis) * Volume overload * At least 100 ml per day of residual diuresis * Use of a loop diuretic for at least one month

Exclusion criteria

* Allergies known to diuretics * Patients with severe infections * Patients with hemodynamic instability * Amputees * Patients with cognitive impairment * Patients with acute renal failure * Patients with graft loss

Design outcomes

Primary

Measure	Time frame	Description
Change in Total Body Water	Change from Basal to day 28	Measured by bioelectrical impedance analysis, compared to the initial measurement

Secondary

Measure	Time frame	Description
Change in the Fractional Excretion of Sodium	Change from Basal to day 28	Increase in the fractional excretion of sodium compared with the baseline measure
Change in Extracellular Water	Change from Basal to day 28	Decrease in extracellular water measured by bioelectrical impedance analysis
Change in Mean Arterial Pressure	Change from Basal to day 28	decrease in blood pressure compared wit baseline measure (mmhg)
Change in Systolic Blood Pressure	Change from Basal to day 28	—
Change in Diastolic Blood Pressure	Change from Basal to day 28	—
Change in Extracellular Water / Total Body Water Ratio	Change from Basal to day 28	Decrease in extracellular water / total body water ratio measured by bioelectrical impedance analysis

Countries

Mexico

Participant flow

Recruitment details

Patients were recruited from the nephrology clinic in the Hospital General de México, between May and August 2019. All those with stage 4-5 chronic kidney disease, who had chronic use of loop diuretics and hypertension, were invited to perform an impedance measurement. Those with volume overload were invited to participate in the protocol.

Participants by arm

Arm	Count
Placebo This group will receive 3 milligrams of bumetanide per day for a week plus placebo (starch) that will simulate the chlorthalidone dose of the treatment group. In case the dose is well tolerated, the dose of bumetanide will be increased to 4 milligrams per day. Bumetanide: Bumetanide	16
Treatment Grup This group will receive 3 milligrams of bumetanide plus 50 milligrams of chlorthalidone per day, for a week. If the dose is well tolerated, it will be increased to 4 milligrams of bumetanide and 100 milligrams of chlorthalidone per day. Chlorthalidone: Chlorthalidone Bumetanide: Bumetanide	16
Total	32

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	0
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Treatment Grup	Total	Placebo
Age, Continuous	54.8 years STANDARD_DEVIATION 10	57.2 years STANDARD_DEVIATION 9.34	59.6 years STANDARD_DEVIATION 8.1
Cause of chronic kidney disease Diabetes	11 Participants	22 Participants	11 Participants
Cause of chronic kidney disease Hypertension	1 Participants	2 Participants	1 Participants
Cause of chronic kidney disease Lupus	0 Participants	1 Participants	1 Participants
Cause of chronic kidney disease Unknown	4 Participants	7 Participants	3 Participants
diastolic blood pressure	81.8 mmHg STANDARD_DEVIATION 10.9	79.7 mmHg STANDARD_DEVIATION 11.1	77.8 mmHg STANDARD_DEVIATION 11.3
Extracellular water	16.4 liters	16.3 liters	16.2 liters
Extracellular water/Total Body Water	50 percentage STANDARD_DEVIATION 3.6	50.4 percentage STANDARD_DEVIATION 3.5	50.9 percentage STANDARD_DEVIATION 3.5
glomerular filtration rate	16.52 ml/min/1.73m2 STANDARD_DEVIATION 8.76	16.1 ml/min/1.73m2 STANDARD_DEVIATION 8.14	15.69 ml/min/1.73m2 STANDARD_DEVIATION 7.64
Mean arterial pressure	102.1 mmHg STANDARD_DEVIATION 10.9	101 mmHg STANDARD_DEVIATION 12.7	100.6 mmHg STANDARD_DEVIATION 12.8
Race and Ethnicity Not Collected	—	0 Participants	—
Region of Enrollment Mexico	16 participants	32 participants	16 participants
Seric sodium	137.4 meq/l STANDARD_DEVIATION 4.9	137.9 meq/l STANDARD_DEVIATION 4.6	138.3 meq/l STANDARD_DEVIATION 4.3
serum creatinine	3.6 mg/dL	3.6 mg/dL	3.5 mg/dL
serum potassium	5.3 meq/l STANDARD_DEVIATION 0.64	5.2 meq/l STANDARD_DEVIATION 0.68	5.1 meq/l STANDARD_DEVIATION 0.74
serum urea	125 mg/dL	125 mg/dL	124 mg/dL
Sex: Female, Male Female	10 Participants	22 Participants	12 Participants
Sex: Female, Male Male	6 Participants	10 Participants	4 Participants
systolic blood pressure	142 mmHg STANDARD_DEVIATION 22.6	144.6 mmHg STANDARD_DEVIATION 20.3	146.8 mmHg STANDARD_DEVIATION 18.2
Total body water	32.7 liters	33.1 liters	33.1 liters
Urinary chlorine	62.3 meq/l STANDARD_DEVIATION 18.6	61.2 meq/l STANDARD_DEVIATION 23.1	60.2 meq/l STANDARD_DEVIATION 27.4
Urinary sodium	62.7 meq/l STANDARD_DEVIATION 20.6	63.7 meq/l STANDARD_DEVIATION 21.6	64.7 meq/l STANDARD_DEVIATION 23.4

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 16	0 / 16
other Total, other adverse events	4 / 16	11 / 16
serious Total, serious adverse events	0 / 16	1 / 16