Mechanisms of Diuretic Resistance in Heart Failure, Aim 3

Last updated: October 3, 2024
Sponsor: Yale University
Overall Status: Active - Recruiting

Phase

1

Condition

Heart Failure

Congestive Heart Failure

Chest Pain

Treatment

Placebo

Ammonium Chloride

Clinical Study ID

NCT06209359
2000034404
1R01DK130997-01
  • Ages > 18
  • All Genders

Study Summary

Randomized double-blind placebo-controlled crossover study design

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Clinical diagnosis of heart failure

  • No plan for titration/change of heart failure medical or device therapies during thestudy 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 (screeningvisit 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 furosemideequivalents

  • eGFR < 60ml/min

  • Serum chloride <100mmol/L

  • FENa <5% and total sodium output <75mmol on the 2 hour

Exclusion

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 dosealdosterone antagonist (e.g., spironolactone ≤50 mg)

  • History of flash pulmonary edema or a "brittle" volume sensitive HF phenotype suchas 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 toacidosis

  • Patients who are on metformin may be enrolled if their metformin can be safelydiscontinued for the randomized treatment periods in each arm. Any participants whohave consistently elevated blood glucose readings > 200 mg/dL while inpatient willnot 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 orfollow-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 orbendroflumethiazide

Study Design

Total Participants: 50
Treatment Group(s): 2
Primary Treatment: Placebo
Phase: 1
Study Start date:
July 24, 2024
Estimated Completion Date:
March 01, 2028

Study Description

Briefly, the protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide and measuring peak FENa. Participants may proceed to the subsequent study procedures. Participants will begin a study diet provided by the metabolic kitchen five days prior to Day 0. Beginning on day 0, participants will take either NH4Cl or placebo 75mmol twice daily. On day 1, the participant will return to study site and receives the first dose of their twice daily study medication as well as their regular loop diuretic dose given as IV bumetanide, followed by completion of the biospecimen collection protocol and a 24-hour urine collection. On day 2, participants will receive a full 150mmol dose at Hr-2 (75 mmol if pH<7.3-7.25, no NH4Cl if pH<7.25). 2 hours after the IV bumetanide is given, 100mmol of sodium bicarbonate in 750ml of 5% dextrose will be administered to participants that received NH4Cl or 750 ml of lactated Ringer's solution to participants that received placebo (provided blinded by the investigational pharmacy).

After this visit, a washout period will be conducted before the above procedures are repeated with the alternate study medication. The washout period will be a minimum of 10 days and a maximum of 28 days. Five days prior to the end of the washout period, the participant will resume the study diet until the end of the study on day 18. On day 16, the participant will be crossed over to the alternate therapy (NH4Cl or placebo). On day 17, the participant will complete the same procedures as day 1 of the first arm. On day 18, the participant will complete the same procedures as day 2 of the first arm.

The administration of Bendroflumethiazide will occur under a separate ancillary protocol

Connect with a study center

  • Yale University

    New Haven, Connecticut 06510
    United States

    Active - Recruiting

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