Heart FailurePhase 1MsDRNCT05323487
Mechanisms of Diuretic Resistance in Heart Failure, Aim 1
A Phase 1 study testing Bumetanide Injection in people with Heart Failure, run by Yale University at 1 site in United States.
Trial summary
This study will employ a randomized order, double-blind, repeated measures dose ranging design. This design was chosen in order to generate multiple within-subject serial loop diuretic dose response exposures. The overall study schema will include 75 heart failure (HF) patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- Bumetanide Injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Jun 2022to 1 May 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Clinical diagnosis of HF
- No plan for titration/change of heart failure medical or device therapies during the study period.
- Absence of non-elective hospitalizations in the previous 3 months.
- At optimal volume status by symptoms, exam, and dry weight
- Age > 18 years
Who cannot join
- GFR <20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies
- Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
- History of flash pulmonary edema requiring hospitalization and treatment with biphasic positive airway pressure or mechanical ventilation or a "brittle" volume sensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e. amyloid cardiomyopathy, etc).
- Hemoglobin < 8 g/dL
- Pregnant or breastfeeding
- Inability to give written informed consent or comply with study protocol or follow-up visits
- Chronic Urinary retention limiting ability to perform timed urine collection procedures
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Yale University
New Haven, Connecticut, 06510
Veena Rao, 203-737-3571, veena.s.rao@yale.edu
Jeffrey Testani, MD
About this study
Official title: Mechanisms of Diuretic Resistance in Heart Failure
This study will employ a randomized order, double-blind, repeated measures dose ranging design. This design was chosen in order to generate multiple within-subject serial loop diuretic dose response exposures. The overall study schema will include 75 heart failure (HF) patients.
Read the detailed description
The protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide infused over 1 hour and measuring peak Fractional Excretion of Sodium (FENa), 1-hour post completion of infusion. Participants will begin a study diet provided by the metabolic kitchen five days prior to the first study visit with randomized treatment (Day 0). Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.
Total sodium output in response to a loop diuretic differs based on Glomerular Filtration Rate (GFR). However, a diuretic responsive participant with normal or severely reduced GFR each will achieve a similar peak FENa of approximately 20% with high dose diuretic. In a cohort of 109 hospitalized diuretic resistance (DR) HF patients that received 12.5mg bumetanide, a peak FENa <5% occurred in 66% patients. The mean FENa in this group was 2.6 ± 1.3 %, thus FENa <5% is common and a clinically relevant threshold for DR, and thus was chosen as the threshold to define diuretic resistance for the proposed study.
Participants will be asked to follow the study diet as the design seeks to decrease the variability of diuretic response introduced by variations in dietary sodium intake. For the current study, a four-gram sodium (0.8 g/kg protein) diet will be utilized. Four grams was chosen since, in prior experience, this is the average pre-study sodium intake of outpatient HF study participants and thus will facilitate rapid transition into balance.
- Conditions
- Heart Failure
- Being tested
- Bumetanide Injection
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bumetanide InjectionDrug
Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.
| Study group | Role | What they receive |
|---|---|---|
| Bumetanide 10 mg | Active comparator | Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg Receives: Drug: Bumetanide Injection |
| Bumetanide 5 mg | Active comparator | 5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg Receives: Drug: Bumetanide Injection |
| Bumetanide 2.5 mg | Active comparator | 2.5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg Receives: Drug: Bumetanide Injection |
| Bumetanide 1.25 mg | Active comparator | 1.25 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg Receives: Drug: Bumetanide Injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
The fractional excretion of lithium is used for interrogation of sodium handling in the proximal tubule and loop of Henle. Possible values range from 0 to 100%. Change = FELi 1 hour post bumetanide infusion - FELi pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Measured: Baseline and 1 hour post bumetanide infusion.
Change in distal sodium reabsorption pre-diuretic to 1-hour post IV bumetanide infusion
The distal sodium reabsorption is used to for interrogation of how much sodium is being reabsorbed in the distal tubule. Possible values range from 0 to 100%. Distal sodium reabsorption is calculated = Fractional excretion of lithium - fractional excretion of sodium. Change in distal sodium reabsorption = distal sodium reabsorption 1 hour post bumetanide infusion - distal sodium reabsorption pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Measured: Baseline and 1 hour post bumetanide infusion.
Tubular diuretic efficiency at baseline
The tubular diuretic efficiency is used to assess the response to loop diuretics based on the amount of sodium excreted but eliminates drug delivery as source of diuretic resistance. Possible values range from 0 to 100%. Greater numbers imply better diuretic efficiency. Tubular diuretic efficiency will be compared between diuretic resistant and diuretic responsive patients using the 6 hour urine collection after bumetanide infusion.
Measured: Baseline
Ratio of A to F splice variant Messenger Ribonucleic Acid (mRNA )in urinary extracellular vesicles at baseline
The ratio of A to F splice variant mRNA in urinary extracellular vesicles refers to the splice variants in the NKCC2 channel. The F variant has low-chloride-affinity-high-capacity, and the A variant has high-chloride-affinity-high-capacity. Possible values are greater than zero. The ratio of A to F splice variant will be compared between diuretic resistant and diuretic responsive patients. The ratio will be compared using the baseline urine sample.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Apr 2022
- Study start1 Jun 2022
- Primary completion1 May 2027 (estimated)
- Study completion1 May 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- This study will employ a randomized order, double-blind, repeated measures dose ranging design.
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jeffrey Testani, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05323487
- Sponsor's protocol ID
- 2000032328
- Other IDs
- 1R01DK130997-01
- Acronym
- MsDR
- Status last verified
- May 2026
- First submitted
- 4 Apr 2022
- Last updated
- 22 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Cox ZL, Rao VS, Ivey-Miranda JB, Myers S, Manning K, Imhoff B, Jenkins CA, Shotwell MS, Miller KF, Storrow AB, Watson P, Rivera-Sanchez A, Wilson FP, Yamamoto Y, Siddiqi H, Schlendorf KH, Stevenson LW, Lindenfeld J, Rybak LP, Collins SP, Testani JM. Assessment of Ototoxicity in Patients With Heart Failure Receiving High-Dose IV Loop Diuretics. JAMA Cardiol. 2026 Oct 30:e264913. doi: 10.1001/jamacardio.2026.4913. Online ahead of print.
PubMed 42961411
Study at a glance
From the registry record, last updated by the sponsor on 22 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Diuretic Resistance in Heart Failure
- ClinicalTrials.gov ID
- NCT05323487
- Acronym / sponsor ID
- MsDR / 2000032328
- Conditions
- Heart Failure
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 75 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- 1 Jun 2022 (actual)
- Primary completion
- 1 May 2027 (estimated)
- Study completion
- 1 May 2027 (estimated)
- First posted
- 12 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will employ a randomized order, double-blind, repeated measures dose ranging design. This design was chosen in order to generate multiple within-subject serial loop diuretic dose response exposures. The overall study schema will include 75 heart failure (HF) patients.
Detailed description
The protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide infused over 1 hour and measuring peak Fractional Excretion of Sodium (FENa), 1-hour post completion of infusion. Participants will begin a study diet provided by the metabolic kitchen five days prior to the first study visit with randomized treatment (Day 0). Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.
Total sodium output in response to a loop diuretic differs based on Glomerular Filtration Rate (GFR). However, a diuretic responsive participant with normal or severely reduced GFR each will achieve a similar peak FENa of approximately 20% with high dose diuretic. In a cohort of 109 hospitalized diuretic resistance (DR) HF patients that received 12.5mg bumetanide, a peak FENa <5% occurred in 66% patients. The mean FENa in this group was 2.6 ± 1.3 %, thus FENa <5% is common and a clinically relevant threshold for DR, and thus was chosen as the threshold to define diuretic resistance for the proposed study.
Participants will be asked to follow the study diet as the design seeks to decrease the variability of diuretic response introduced by variations in dietary sodium intake. For the current study, a four-gram sodium (0.8 g/kg protein) diet will be utilized. Four grams was chosen since, in prior experience, this is the average pre-study sodium intake of outpatient HF study participants and thus will facilitate rapid transition into balance.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
- Model description
- This study will employ a randomized order, double-blind, repeated measures dose ranging design.
| Arm | Type | Receives |
|---|---|---|
| Bumetanide 10 mg | Active comparator | Drug: Bumetanide InjectionRandomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg |
| Bumetanide 5 mg | Active comparator | Drug: Bumetanide Injection5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg |
| Bumetanide 2.5 mg | Active comparator | Drug: Bumetanide Injection2.5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg |
| Bumetanide 1.25 mg | Active comparator | Drug: Bumetanide Injection1.25 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Clinical diagnosis of HF
- No plan for titration/change of heart failure medical or device therapies during the study period.
- Absence of non-elective hospitalizations in the previous 3 months.
- At optimal volume status by symptoms, exam, and dry weight
- Age > 18 years
Key exclusion criteria (7 listed)
- GFR <20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies
- Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
- History of flash pulmonary edema requiring hospitalization and treatment with biphasic positive airway pressure or mechanical ventilation or a "brittle" volume sensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e. amyloid cardiomyopathy, etc).
- Hemoglobin < 8 g/dL
- Pregnant or breastfeeding
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Bumetanide InjectionParticipants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence. | Drug | Bumetanide 1.25 mg, Bumetanide 10 mg, Bumetanide 2.5 mg, Bumetanide 5 mg |
Primary outcome
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
Time frame: Baseline and 1 hour post bumetanide infusion.
The fractional excretion of lithium is used for interrogation of sodium handling in the proximal tubule and loop of Henle. Possible values range from 0 to 100%. Change = FELi 1 hour post bumetanide infusion - FELi pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Change in distal sodium reabsorption pre-diuretic to 1-hour post IV bumetanide infusion
Time frame: Baseline and 1 hour post bumetanide infusion.
The distal sodium reabsorption is used to for interrogation of how much sodium is being reabsorbed in the distal tubule. Possible values range from 0 to 100%. Distal sodium reabsorption is calculated = Fractional excretion of lithium - fractional excretion of sodium. Change in distal sodium reabsorption = distal sodium reabsorption 1 hour post bumetanide infusion - distal sodium reabsorption pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Tubular diuretic efficiency at baseline
Time frame: Baseline
The tubular diuretic efficiency is used to assess the response to loop diuretics based on the amount of sodium excreted but eliminates drug delivery as source of diuretic resistance. Possible values range from 0 to 100%. Greater numbers imply better diuretic efficiency. Tubular diuretic efficiency will be compared between diuretic resistant and diuretic responsive patients using the 6 hour urine collection after bumetanide infusion.
Ratio of A to F splice variant Messenger Ribonucleic Acid (mRNA )in urinary extracellular vesicles at baseline
Time frame: Baseline
The ratio of A to F splice variant mRNA in urinary extracellular vesicles refers to the splice variants in the NKCC2 channel. The F variant has low-chloride-affinity-high-capacity, and the A variant has high-chloride-affinity-high-capacity. Possible values are greater than zero. The ratio of A to F splice variant will be compared between diuretic resistant and diuretic responsive patients. The ratio will be compared using the baseline urine sample.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 May 2026.
- Derived from this study: PubMed 42961411Cox ZL, Rao VS, Ivey-Miranda JB, Myers S, Manning K, Imhoff B, Jenkins CA, Shotwell MS, Miller KF, Storrow AB, Watson P, Rivera-Sanchez A, Wilson FP, Yamamoto Y, Siddiqi H, Schlendorf KH, Stevenson LW, Lindenfeld J, Rybak LP, Collins SP, Testani JM. Assessment of Ototoxicity in Patients With Heart Failure Receiving High-Dose IV Loop Diuretics. JAMA Cardiol. 2026 Oct 30:e264913. doi: 10.1001/jamacardio.2026.4913. Online ahead of print.
- Individual participant dataSharing planned: No
Related trials for Heart Failure
RecruitingPhase 4
The Effects of Ferric Derisomaltose in Patients With Acute Heart Failure and Iron Deficiency on Exercise Capacity and Quality of Life(COREVIVE-HFrEF)
Heart Failure With Reduced Ejection Fraction, Iron Deficiency
Not yet recruitingPhase 2
A Study of Bimagrumab in Participants With HFpEF
Heart Failure, Diastolic, Diastolic Heart Failure
Recruiting
Evaluation of a French Hospital Discharge Therapeutic Education Program by Nurses for Heart Failure Patient (EduSor)
Heart Failure
Active, not recruiting
Assessment of Combined CCM and ICD Device in HFrEF
Heart Failure, Heart Failure With Reduced Ejection Fraction
Not yet recruiting
RELIEVE-HFrEF TRIAL: REducing Lung congestIon Symptoms Using the v-wavE Shunt in adVancEd Heart Failure With Reduced EF
Heart Failure and Reduced Ejection Fraction, Heart Failure Chronic
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Jeffrey Testani principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Bumetanide Injection in people with Heart Failure, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 22 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Veena Rao (2037373571, veena.s.rao@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion (time frame: Baseline and 1 hour post bumetanide infusion.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05323487, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 May 2026.