The effectiveness of dapagliflozin versus furosemide in controlling blood pressure in resistant hypertension with subclinical fluid retention in chronic kidney disease

ISRCTN	ISRCTN14012970
DOI	https://doi.org/10.1186/ISRCTN14012970
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	IRB8866
Sponsor	Bhumibol Adulyadej Hospital
Funder	Bhumibol Adulyadej Hospital

Submission date: 28/12/2023
Registration date: 12/01/2024
Last edited: 06/11/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Urological and Genital Diseases

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Chronic kidney disease (CKD) poses a significant health challenge, often accompanied by uncontrolled blood pressure (hypertension) that is difficult to manage. This study aims to address this issue by comparing the effectiveness of two medications, dapagliflozin and furosemide, in individuals with CKD and resistant hypertension. Dapagliflozin is known for its ability to lower blood pressure and promote urine excretion by affecting kidney function. Furosemide, a commonly used diuretic, is also prescribed to manage fluid retention and blood pressure.

Who can participate?
Patients aged 18 years and over with chronic kidney disease before undergoing kidney replacement therapy, who also have a condition of resistant hypertension.

What does the study involve?
Participants undergo interviews, echocardiograms and bioimpedance spectroscopy (BIS), and receive dietary advice to limit their salt intake to less than 2 g per day. They are randomly allocated to two groups to be treated with either dapagliflozin or furosemide. Blood samples and data are collected over a 6-month period. Body fluid status is measured using BIS monthly during the first 3 months and at 6 months. Echocardiogram and laboratory tests are carried out at 6 months.

What are the possible benefits and risks of participating?
The anticipated benefits include potential reductions in blood pressure, slowing the progression of kidney impairment, and lowering the risk of heart disease. However, some participants may experience hypovolemia (low body fluid volume) if the treatment is not followed according to guidelines or if there is an occurrence of drug allergies.

Where is the study run from?
Bhumibol Adulyadej Hospital (Thailand)

When is the study starting and how long is it expected to run for?
September 2023 to August 2024

Who is funding the study?
Bhumibol Adulyadej Hospital (Thailand)

Who is the main contact?
Natchaya Songsilp, muk.natchaya@gmail.com

Contact information

Miss Natchaya Songsilp
Public, Scientific, Principal investigator

171 Phaholyothin road, Khlong thanon, SaImai
Bangkok
10220
Thailand

ORCID ID	0000-0002-6144-5818
Phone	+66 25347000
Email	muk.natchaya@gmail.com

Study information

Primary study design	Interventional
Study design	Single-center non-inferior prospective randomized open-label study
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Efficacy of dapagliflozin compared to furosemide for controlling blood pressure in resistant hypertension with subclinical fluid retention in chronic kidney disease
Study objectives	Current study hypothesis as of 29/10/2024: There is currently no comparative study of SGLT2i and furosemide use in patients with chronic kidney disease (CKD) and resistant hypertension, so a comparison of both medications for reducing high blood pressure was conducted. Previous study hypothesis as of 12/04/2024: There is currently no comparative study of SGLT2i and furosemide use in patients with chronic kidney disease (CKD) and uncontrolled hypertension, so a comparison of both medications for reducing high blood pressure was conducted. Previous study hypothesis: There is currently no comparative study of SGLT2i and furosemide use in patients with chronic kidney disease (CKD) and resistant hypertension, so a comparison of both medications for reducing high blood pressure was conducted.
Ethics approval(s)	Approved 19/10/2023, The Institutional Review Board of Bhumibol Adulyadej Hospital, Directorate of Medical Service, Royal Thai Air Force (171 Phaholyothin road, Khlong Thanon, SaImai, Bangkok, 10220, Thailand; +66 25347255; bhumibolhospital@rtaf.mi.th), ref: 8866
Health condition(s) or problem(s) studied	Resistant hypertension with subclinical fluid retention in chronic kidney disease
Intervention	1. Select participants for the research based on inclusion and exclusion criteria. 2. Inform patients about the study and obtain their informed consent to participate. 3. Gather baseline data through interviews, echocardiogram, bioimpedance spectroscopy (BIS), and provide dietary advice to limit salt intake to less than 2 g per day. 4. Randomly assign patients into two groups by block of four randomization. 5. Conduct the experiment by administering 10 mg of dapagliflozin per day to the experimental group, and provide an initial dose of 20 mg/day of furosemide to the control group, adjusting the dosage based on BIS assessments. 6. Perform blood sampling, collect variables related to the research outcomes, and record data over a 6-month period. 7. Assess body fluid status using BIS monthly during the first 3 months and at 6 months. 8. Evaluate outcomes at the 6-month mark through Echocardiogram and laboratory tests. 9. Analyze the obtained results statistically.
Intervention type	Drug
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Dapagliflozin, furosemide
Primary outcome measure(s)	Blood pressure is measured using sphygmomanometer at baseline and 6 months
Key secondary outcome measure(s)	Current secondary outcome measures as of 12/04/2024: 1. Urine volume is measured by patient 24-hour urine volume collection at baseline and 6 months 2. LV mass index is measured using Echocardiogram at baseline and 6 months 3. Total body water is measured using bioimpedance at baseline and 6 months 4. Intracellular water is measured using bioimpedance at baseline and 6 months 5. Extracellular water is measured using bioimpedance at baseline and 6 months 6. Extracellular water/total body water is measured using bioimpedance at baseline and 6 months 7. Hospitalization for heart failure reported outcome using an IPD data at 6 months 8. NT-pro BNP level is measured using laboratory blood test at baseline and 6 months 9. eGFR is measured using laboratory blood test at baseline and 6 months 10. Serum sodium is measured using laboratory blood test at baseline and 6 months 11. Urine albumin creatinine ratio is measured using laboratory urine test at baseline and 6 months 12. Urine sodium is measured using laboratory urine test at baseline and 6 months 12. Body weight is measured using weighing at the hospital at baseline and 6 months Previous secondary outcome measures: 1. Urine volume is measured by patient 24-hour urine volume collection at baseline and 6 months 2. LV mass index is measured using Echocardiogram at baseline and 6 months 3. Total body water is measured using bioimpedance at baseline and 6 months 4. Intracellular water is measured using bioimpedance at baseline and 6 months 5. Extracellular water is measured using bioimpedance at baseline and 6 months 6. Extracellular water/total body water is measured using bioimpedance at baseline and 6 months 7. Death from any cause reported outcome using an IPD data at 6 months 8. Fatal or nonfatal myocardial infarction reported outcome using an IPD data at 6 months 9. Hospitalization for heart failure reported outcome using an IPD data at 6 months 10. NT-pro BNP level is measured using laboratory blood test at baseline and 6 months 11. eGFR is measured using laboratory blood test at baseline and 6 months 12. Serum sodium is measured using laboratory blood test at baseline and 6 months 13. Serum urine albumin creatinine ratio is measured using laboratory urine test at baseline and 6 months 14. Body weight is measured using weighing at the hospital at baseline and 6 months
Completion date	15/08/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Upper age limit	90 Years
Sex	All
Target sample size at registration	30
Total final enrolment	16
Key inclusion criteria	Current inclusion criteria as of 29/10/2024: 1. Age from 18 years old 2. Chronic kidney disease (GFR-EPI 20-60 ml/min/1.73m²) 3. Resistant hypertension with fluid retention detected by bioimpedance _____ Previous inclusion criteria as of 12/04/2024: 1. Age from 18 years old 2. Chronic kidney disease (GFR-EPI 20-60 ml/min/1.73m²) 3. Uncontrolled hypertension with fluid retention detected by bioimpedance _____ Previous inclusion criteria: 1. Age from 18 years old 2. Chronic kidney disease (GFR-EPI 20-60 ml/min/1.73m²) 3. Resistant hypertension
Key exclusion criteria	Current exclusion criteria as of 29/10/2024: 1. Patient receiving diuretics or SGLT2i 2. Resistant HT with euvolemic status 3. Life expectancy <12 months (principal investigator’s judgement) 4. Living-donor transplant scheduled within the next 12 months 5. Cardiovascular disease (dilated cardiomyopathy, valvular heart disease) 6. Active infection 7. Current active malignancy 8. Known HIV or active hepatitis B or C 9. Chronic liver disease and/or screening alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range 10. Pregnancy or breastfeeding 11. Subject has any kind of disorder that compromises their ability to informed consent and/or to comply with study procedures _____ Previous exclusion criteria as of 12/04/2024: 1. Patient receiving diuretics or SGLT2i 2. Uncontrolled HT with euvolemic status 3. Life expectancy <12 months (principal investigator’s judgement) 4. Living-donor transplant scheduled within the next 12 months 5. Cardiovascular disease (dilated cardiomyopathy, valvular heart disease) 6. Active infection 7. Current active malignancy 8. Known HIV or active hepatitis B or C 9. Chronic liver disease and/or screening alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range 10. Pregnancy or breastfeeding 11. Subject has any kind of disorder that compromises their ability to informed consent and/or to comply with study procedures _____ Previous exclusion criteria: 1. Life expectancy less than 12 months 2. Living-donor transplant scheduled within the next 12 months 3. Cardiovascular disease (dilated cardiomyopathy, valvular heart disease) 4. Active infection 5. Current active malignancy 6. Known HIV or active hepatitis B or C 7. Chronic liver disease and/or screening alanine transaminase or aspartate transaminase above 3 times the upper limit of the normal range 8. Pregnancy or breastfeeding 9. Subject has any kind of disorder that compromises their ability to informed consent and/or to comply with study procedures
Date of first enrolment	18/01/2024
Date of final enrolment	11/02/2024

Locations

Countries of recruitment

Thailand

Study participating centre

Bhumibol Adulyadej Hospital

171 Phaholyothin Road
Khlong Thanon
SaImai
Bangkok
10220
Thailand

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request from Natchaya Songsilp (muk.natchaya@gmail.com).

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Other unpublished results			06/11/2024	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Protocol file			12/04/2024	No	No

Additional files

ISRCTN14012970 research protocol.pdf: Protocol file
ISRCTN14012970 unpublished results.pdf: Other unpublished results

Editorial Notes

06/11/2024: A file of unpublished results was uploaded as an additional file.
29/10/2024: The following changes were made to the trial record:
1. The public title was changed from "The effectiveness of dapagliflozin versus furosemide in controlling blood pressure in uncontrolled hypertension with subclinical fluid retention in chronic kidney disease" to "The effectiveness of dapagliflozin versus furosemide in controlling blood pressure in resistant hypertension with subclinical fluid retention in chronic kidney disease".
2. The scientific title was changed from "Efficacy of dapagliflozin compared to furosemide for controlling blood pressure in uncontrolled hypertension with subclinical fluid retention in chronic kidney disease" to "Efficacy of dapagliflozin compared to furosemide for controlling blood pressure in resistant hypertension with subclinical fluid retention in chronic kidney disease".
3. The study hypothesis was changed.
4. The condition was changed from "Uncontrolled hypertension with subclinical fluid retention in chronic kidney disease" to "Resistant hypertension with subclinical fluid retention in chronic kidney disease".
5. The inclusion criteria were changed.
6. The exclusion criteria were changed.
7. The plain English summary was updated to reflect these changes.
12/04/2024: The following changes were made to the study record:
1. The public title was changed from 'Comparing two drugs, dapagliflozin and furosemide, for effectiveness in controlling blood pressure for individuals with chronic kidney disease and resistant hypertension' to 'The effectiveness of dapagliflozin versus furosemide in controlling blood pressure in uncontrolled hypertension with subclinical fluid retention in chronic kidney disease'.
2. The scientific title was changed from 'Efficacy of dapagliflozin compared to furosemide for controlling blood pressure in chronic kidney disease with resistant hypertension' to 'Efficacy of dapagliflozin compared to furosemide for controlling blood pressure in uncontrolled hypertension with subclinical fluid retention in chronic kidney disease'.
3. The study hypothesis, ethics approval, secondary outcome measures and inclusion and exclusion criteria were updated.
4. The study design was changed from 'Single-center interventional non-inferiority randomized controlled trial' to 'Single-center non-inferior prospective randomized open-label study'.
5. The condition was changed from 'Resistant hypertension in chronic kidney disease patients' to 'Uncontrolled hypertension with subclinical fluid retention in chronic kidney disease'.
12/04/2024: Uploaded protocol (not peer-reviewed) as an additional file.
19/02/2024: The total final enrolment was added.
12/01/2024: Study's existence confirmed by the Bhumibol Adulyadei Hospital Ethics Committee of Human Research.