Mechanisms of Diuretic Resistance in Heart Failure, Aim 1

NCT05323487 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 20000323281R01DK130997-01
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  Baseline

Study Arms (4)

Bumetanide 10 mg

ACTIVE COMPARATOR

Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg

Drug: Bumetanide Injection

Bumetanide 5 mg

ACTIVE COMPARATOR

5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg

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

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

Drug: Bumetanide Injection

Interventions

Bumetanide Injection DRUG

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.

Bumetanide 1.25 mg; Bumetanide 10 mg; Bumetanide 2.5 mg; Bumetanide 5 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• GFR \<20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies
• 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

Sponsors & Collaborators

• Yale University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Yale University

New Haven, Connecticut, 06510, United States

RECRUITING

MeSH Terms

Conditions

Heart Failure

Interventions

Bumetanide

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; meta-Aminobenzoates; Aminobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds

Study Officials

• Jeffrey Testani

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Veena Rao

CONTACT

2037373571; veena.s.rao@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study will employ a randomized order, double-blind, repeated measures dose ranging design.

Study Record Dates

• First Submitted: April 4, 2022
• First Posted: April 12, 2022
• Study Start: June 1, 2022
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): May 1, 2027
• Last Updated: May 22, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)