Recruiting
Phase 1

Observational Study

Sponsor:

Yale University

Code:

NCT06209359

Conditions

Heart Failure

Diuretic Resistance

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Interventions

Ammonium Chloride

Placebo

Study Details

Brief summary:

Randomized double-blind placebo-controlled crossover study design

Conditions

Heart Failure

Diuretic Resistance

Study ID

NCT06209359

Start date

Jul 24, 2024

Status verified date

Nov, 2025

Completion date

Mar 1, 2029

Anticipated

Primary completion date

Mar 1, 2029

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18+

Healthy Volunteers: Not accepted

Inclusion Criteria:

  • Clinical diagnosis of heart failure
  • No plan for titration/change of heart failure medical or device therapies during the study period.
  • Absence of non-elective hospitalizations in the previous 2 months.
  • At optimal volume status by symptoms, exam, and dry weight.
  • Serum potassium ≤ 5.0 mmol/L
  • Serum sodium ≥ 130 milliequivalents/ liter (mEq/L)
  • Hemoglobin ≥8 g/dL
  • Age >18 years
  • Objective evidence of diuretic resistance to a 10mg bumetanide challenge (screening visit may occur under this protocol or HIC2000032328 or HIC2000034315) defined as:

  • FENa <10% and total sodium output <150mmol
  • And at least one of the following criteria:

  • Chronic home furosemide dose greater than or equal to 80mg furosemide equivalents
  • eGFR < 60ml/min
  • Serum chloride <100mmol/L
  • FENa <5% and total sodium output <75mmol on the 2 hour

Exclusion Criteria:

  • Glomerular filtration rate (GFR) <20 ml/min/1.73m2
  • Use of any non-loop type diuretic in the last 7 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone ≤50 mg)
  • History of flash pulmonary edema or a "brittle" volume sensitive HF phenotype such as amyloid cardiomyopathy
  • Hemoglobin < 8 g/dL
  • Pregnant or breastfeeding
  • Cirrhosis or known liver disease
  • History of metabolic or respiratory acidosis within 30 days
  • Use of metformin, acetazolamide, or any other agent that could predispose to acidosis
  • Patients who are on metformin may be enrolled if their metformin can be safely discontinued for the randomized treatment periods in each arm. Any participants who have consistently elevated blood glucose readings > 200 mg/dL while inpatient will not be enrolled.
  • Serum bicarbonate level <24mmol/L at screening visit
  • Venous potential of hydrogen(pH) <7.35 at screening visit
  • Inability to give written informed consent or comply with study protocol or follow-up visits
  • On Lithium therapy
  • On pimozide or thioridazine
  • Diagnosis of liver failure
  • Contraindications or allergy to sulfonamides
  • Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide

Study Design

Enrollment

50 participants

Anticipated

Allocation

Randomized

Intervention Model

Crossover

Primary purpose

Other

Interventions and Outcome Measures

Arms

active comparator: Ammonium chloride

Participants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily.

On Day 2, the participant will take ammonium chloride 150 mmol or placebo once

placebo comparator: Placebo

Participants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily.

On Day 2, the participant will take ammonium chloride 150 mmol or placebo once

Interventions

Ammonium Chloride

Participants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug.

Placebo

Participants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug.

Primary outcome measure

  • Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits [ Time Frame: Day 0 vs Day 1 ]
  • Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits [ Time Frame: Day 2 vs Day 18 ]

Central Contacts and Locations

Central contacts

Veena Rao, PHD

2037373571veena.s.rao@yale.edu

Locations

Yale University

Recruiting

New Haven, Connecticut, United States, 06510

More Information

Sponsor

Yale University

Last update posted

May 22, 2026

Last verified

Nov, 2025

Keywords

  • Diuretic
  • Cardiomyopathy
  • Diuretic Resistance

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by Yale University on 2026-05-22.