Mechanisms of Diuretic Resistance in Heart Failure, Aim 3

NCT06209359 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 20000344041R01DK130997-01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Randomized double-blind placebo-controlled crossover study design

Conditions

Heart Failure; Diuretic Resistance

Keywords

Diuretic; Cardiomyopathy; Diuretic Resistance

Outcome Measures

Primary Outcomes (3)

• Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits

  Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.

  Day 0 vs Day 1

• Change in urinary extracellular vesicles (uEV) pendrin/exosomal marker(CD9) with the change in distal sodium reabsorption(ADRNa), compared between the placebo and NH4Cl

  Change in uEV pendrin/CD9 with the change in ADRNa, compared between the placebo and NH4Cl study visits

  Day 2 vs Day 18

• Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits

  Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.

  Day 2 vs Day 18

Study Arms (2)

Ammonium chloride

ACTIVE COMPARATOR

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

Drug: Ammonium Chloride

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Ammonium Chloride DRUG

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.

Ammonium chloride

Placebo DRUG

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

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 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

You may not qualify if:

• Glomerular filtration rate (GFR) \<20 ml/min/1.73m2
• 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

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; Cardiomyopathies

Interventions

Ammonium Chloride

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Ammonium Compounds; Nitrogen Compounds

Study Officials

• Jeffrey Testani, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Veena Rao, PHD

CONTACT

2037373571; veena.s.rao@yale.edu

Kara Otis

CONTACT

2037373571; kara.otis@yale.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: January 5, 2024
• First Posted: January 17, 2024
• Study Start: July 24, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028
• Last Updated: October 8, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)