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

Sponsor
Hospital General de México Dr. Eduardo Liceaga (Other)
Overall Status
Completed
CT.gov ID
NCT03923933
Collaborator
(none)
34
Enrollment
1
Location
2
Arms
4.3
Actual Duration (Months)
7.8
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Chlortalidone and Bumetanide in Advanced Chronic Kidney Disease: HEBE-CKD Trial
Actual Study Start Date :
Jun 18, 2019
Actual Primary Completion Date :
Oct 28, 2019
Actual Study Completion Date :
Oct 28, 2019

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: 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.

Drug: Bumetanide
Bumetanide
Experimental: 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.

Drug: Chlorthalidone
Chlorthalidone

Drug: Bumetanide
Bumetanide

Outcome Measures

Primary Outcome Measures

  1. Change in Total Body Water [Change from Basal to day 28]

    Measured by bioelectrical impedance analysis, compared to the initial measurement

Secondary Outcome Measures

  1. Change in Mean Arterial Pressure [Change from Basal to day 28]

    decrease in blood pressure compared wit baseline measure (mmhg)

  2. 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

  3. Change in Extracellular Water [Change from Basal to day 28]

    Decrease in extracellular water measured by bioelectrical impedance analysis

  4. 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

  5. Change in Systolic Blood Pressure [Change from Basal to day 28]

  6. Change in Diastolic Blood Pressure [Change from Basal to day 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Hospital General de Mexico Mexico City Mexico 06720

Sponsors and Collaborators

  • Hospital General de México Dr. Eduardo Liceaga

Investigators

  • Principal Investigator: Fabio Solis-Jimenez, M.D., Hospital General de México Dr. Eduardo Liceaga

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
Fabio Solis-Jimenez, Principal Investigator, Hospital General de México Dr. Eduardo Liceaga
ClinicalTrials.gov Identifier:
NCT03923933
Other Study ID Numbers:
  • DI/19/105-B/03/018
First Posted:
Apr 23, 2019
Last Update Posted:
Nov 23, 2020
Last Verified:
Nov 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Fabio Solis-Jimenez, Principal Investigator, Hospital General de México Dr. Eduardo Liceaga
Diuretics
Bumetanide
Chlorthalidone
Chronic Kidney Disease
Volume Overload
Additional relevant MeSH terms:
Kidney Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Chlorthalidone
Bumetanide

Study Results

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.
Pre-assignment Detail
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Period Title: Overall Study
STARTED 17 17
COMPLETED 16 16
NOT COMPLETED 1 1

Baseline Characteristics

Arm/Group Title Placebo Treatment Grup Total
Arm/Group Description 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 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 Total of all reporting groups
Overall Participants 16 16 32
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
59.6
(8.1)
54.8
(10)
57.2
(9.34)
Sex: Female, Male (Count of Participants)
Female
12
75%
10
62.5%
22
68.8%
Male
4
25%
6
37.5%
10
31.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]
0
0%
Region of Enrollment (participants) [Number]
Mexico
16
100%
16
100%
32
100%
Total body water (liters) [Median (Full Range) ]
Median (Full Range) [liters]
33.1
32.7
33.1
Extracellular water (liters) [Median (Full Range) ]
Median (Full Range) [liters]
16.2
16.4
16.3
Extracellular water/Total Body Water (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]
50.9
(3.5)
50
(3.6)
50.4
(3.5)
systolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]
146.8
(18.2)
142
(22.6)
144.6
(20.3)
diastolic blood pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]
77.8
(11.3)
81.8
(10.9)
79.7
(11.1)
Mean arterial pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]
100.6
(12.8)
102.1
(10.9)
101
(12.7)
serum creatinine (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]
3.5
3.6
3.6
serum urea (mg/dL) [Median (Full Range) ]
Median (Full Range) [mg/dL]
124
125
125
glomerular filtration rate (ml/min/1.73m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ml/min/1.73m2]
15.69
(7.64)
16.52
(8.76)
16.1
(8.14)
Cause of chronic kidney disease (Count of Participants)
Diabetes
11
68.8%
11
68.8%
22
68.8%
Hypertension
1
6.3%
1
6.3%
2
6.3%
Lupus
1
6.3%
0
0%
1
3.1%
Unknown
3
18.8%
4
25%
7
21.9%
Seric sodium (meq/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meq/l]
138.3
(4.3)
137.4
(4.9)
137.9
(4.6)
serum potassium (meq/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meq/l]
5.1
(0.74)
5.3
(0.64)
5.2
(0.68)
Urinary sodium (meq/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meq/l]
64.7
(23.4)
62.7
(20.6)
63.7
(21.6)
Urinary chlorine (meq/l) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [meq/l]
60.2
(27.4)
62.3
(18.6)
61.2
(23.1)

Outcome Measures

1. Primary Outcome
Title Change in Total Body Water
Description Measured by bioelectrical impedance analysis, compared to the initial measurement
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [litres]
-0.075
(1.78)
-4.36
(3.29)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method ANOVA
Comments anova repeated measures
2. Secondary Outcome
Title Change in Mean Arterial Pressure
Description decrease in blood pressure compared wit baseline measure (mmhg)
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [mmHg]
-5.4
(14.3)
-18.1
(8.7)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.006
Comments
Method ANOVA
Comments Repeated Measures
3. Secondary Outcome
Title Change in the Fractional Excretion of Sodium
Description Increase in the fractional excretion of sodium compared with the baseline measure
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [percentage of sodium excreted]
-0.348
(3.48)
0.598
(2.29)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.371
Comments
Method ANOVA
Comments
4. Secondary Outcome
Title Change in Extracellular Water
Description Decrease in extracellular water measured by bioelectrical impedance analysis
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [litres]
-0.15
(1.2)
2.55
(1.1)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method ANOVA
Comments
5. Secondary Outcome
Title Change in Extracellular Water / Total Body Water Ratio
Description Decrease in extracellular water / total body water ratio measured by bioelectrical impedance analysis
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [percentage of ECW/TBW]
-0.24
(1.42)
-2.92
(4.76)
6. Secondary Outcome
Title Change in Systolic Blood Pressure
Description
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [mmHg]
-10
(23.3)
-26.1
(15.3)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.028
Comments
Method ANOVA
Comments
7. Secondary Outcome
Title Change in Diastolic Blood Pressure
Description
Time Frame Change from Basal to day 28

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
Measure Participants 16 16
Mean (Standard Deviation) [mmHg]
-3.4
(11.9)
-13.5
(10.7)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Treatment Grup
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.018
Comments
Method ANOVA
Comments

Adverse Events

Time Frame 28 days
Adverse Event Reporting Description
Arm/Group Title Placebo Treatment Grup
Arm/Group Description 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 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
All Cause Mortality
Placebo Treatment Grup
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/16 (0%) 0/16 (0%)
Serious Adverse Events
Placebo Treatment Grup
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/16 (0%) 1/16 (6.3%)
Cardiac disorders
Major adverse cardiovascular events 0/16 (0%) 0 1/16 (6.3%) 1
Other (Not Including Serious) Adverse Events
Placebo Treatment Grup
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 4/16 (25%) 11/16 (68.8%)
Renal and urinary disorders
Creatinine Increase 4/16 (25%) 4 11/16 (68.8%) 11
Hyponatremia 1/16 (6.3%) 1 2/16 (12.5%) 2
hypokalemia 0/16 (0%) 0 2/16 (12.5%) 2
hyperuricemia 4/16 (25%) 4 4/16 (25%) 4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Rafael Vadez-Ortiz M.D. PhD
Organization Head of Nephrology Hospital General de México
Phone +52 2789-2000 ext 1253
Email rafavaldez@gmail.com
Responsible Party:
Fabio Solis-Jimenez, Principal Investigator, Hospital General de México Dr. Eduardo Liceaga
ClinicalTrials.gov Identifier:
NCT03923933
Other Study ID Numbers:
  • DI/19/105-B/03/018
First Posted:
Apr 23, 2019
Last Update Posted:
Nov 23, 2020
Last Verified:
Nov 1, 2020