Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

NCT05753059 | Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: 20000343151R01DK130997-01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide.

Conditions

Heart Failure

Outcome Measures

Primary Outcomes (3)

• Change in peak FENa from bumetanide monotherapy to bumetanide plus combination therapy

  Change in peak FENa from bumetanide monotherapy to bumetanide plus combination therapy

  21 days

• Change in distal sodium reabsorption

  Change in distal sodium reabsorption (FELi minus FENa) from bumetanide monotherapy to bumetanide plus combination therapy

  21 days

• Correlation between distal sodium reabsorption and uEV pendrin/CD9

  Correlation between distal sodium reabsorption (FELi minus FENa) and uEV pendrin/CD9

  21 days

Study Arms (4)

Placebo/ Placebo

PLACEBO COMPARATOR

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Drug: Placebo

Placebo/ Amiloride

ACTIVE COMPARATOR

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Drug: Placebo; Drug: Amiloride

Placebo/ Bendroflumethiazide

ACTIVE COMPARATOR

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Drug: Placebo; Drug: Bendroflumethiazide

Bendroflumethiazide/ Amiloride

ACTIVE COMPARATOR

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Drug: Amiloride; Drug: Bendroflumethiazide

Interventions

Placebo DRUG

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations placebo/placebo, bendroflumethiazide/placebo, amiloride/placebo, added to bumetanide on Days 0, 7, 14 and 21

Placebo/ Amiloride; Placebo/ Bendroflumethiazide; Placebo/ Placebo

Amiloride DRUG

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations of amiloride/placebo, and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Bendroflumethiazide/ Amiloride; Placebo/ Amiloride

Bendroflumethiazide DRUG

This study will employ a randomized placebo-controlled, double-blind, double-dummy, crossover design testing combinations of bendroflumethiazide/placebo and bendroflumethiazide/amiloride added to bumetanide on Days 0, 7, 14 and 21

Bendroflumethiazide/ Amiloride; Placebo/ Bendroflumethiazide

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 2 weeks
• At optimal volume status by symptoms, exam, and dry weight.
• Serum potassium ≤ 5.0 mmol/L
• Serum sodium ≥ 130 mEq/L
• Age \> 18 years
• Hemoglobin ≥8 g/dL
• Objective evidence of diuretic resistance to a 10mg bumetanide challenge, defined as:
• FENa \<10% and total sodium output \<150mmol and
• At least one of the following criteria:
• \. Chronic home furosemide dose \> or equal to 80mg furosemide equivalents daily 2. eGFR \< 60ml/min 3. Serum chloride \<100mmol/L 4. FENa \<5% and total sodium output \<75mmol on the 2 hour screening

You may not qualify if:

• GFR \<20 ml/min/1.73m2 using the 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 or symptomatic anemia
• 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
• 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

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

Amiloride; Bendroflumethiazide

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzothiadiazines; Sulfonamides; Sulfones; Sulfur Compounds; Organic Chemicals; Thiazides; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Jeffrey Testani

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Veena Rao

CONTACT

203-737-3571; veena.s.rao@yale.edu

Kara Otis

CONTACT

203-737-3571; 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

Model Details: Randomized placebo-controlled, double-blind, double-dummy, crossover design

Study Record Dates

• First Submitted: February 21, 2023
• First Posted: March 3, 2023
• Study Start: August 10, 2023
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027
• Last Updated: June 18, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)