NCT05323487 · Yale University
Mechanisms of Diuretic Resistance in Heart Failure, Aim 1
(MsDR)
What this study is about
This study will employ a randomly assigned order, where neither patients nor doctors know which treatment is given, 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.
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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.
Interventions
DRUG
Bumetanide Injection
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.
Primary outcome measures
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.
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
Inclusion criteria
- 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
Exclusion criteria
- 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
Where
- New Haven, Connecticut
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Related conditions & keywords
Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
Is it safe to participate?
Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
Will I be compensated?
Many clinical trials offer compensation for your time, travel expenses, and inconvenience. The specific compensation varies by study and will be discussed during the screening process. All study-related medical care is typically provided at no cost to participants.
Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
Can I leave a trial if I change my mind?
Absolutely. Participation in clinical trials is completely voluntary. You have the right to withdraw from the study at any time, for any reason, without penalty or loss of benefits to which you are otherwise entitled.
How long does a clinical trial last?
Trial duration varies widely depending on the study design and purpose. Some trials last just a few weeks, while others may continue for months or years. The study coordinator will provide specific timeline information during your screening call.
Data: ClinicalTrials.gov · synced May 22, 2026 · Source of record for eligibility and locations