Mechanisms of Diuretic Resistance in Heart Failure, Aim 2 (MsDR 2)

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

Study Overview

• Status: Recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Placebo; Drug: Amiloride; Drug: Bendroflumethiazide

Detailed Description

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.

Patients will be co-enrolled in this study and an ancillary study for administration of Bendroflumethiazide. Administration of bendroflumethiazide will take place under an ancillary protocol.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Veena Rao; Phone Number: 203-737-3571; Email: veena.s.rao@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University
      • Contact: Veena Rao

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Clinical diagnosis of HF
2. No plan for titration/change of heart failure medical or device therapies during the study period.
3. Absence of non-elective hospitalizations in the previous 2 weeks
4. At optimal volume status by symptoms, exam, and dry weight.
5. Serum potassium ≤ 5.0 mmol/L
6. Serum sodium ≥ 130 mEq/L
7. Age > 18 years
8. Hemoglobin ≥8 g/dL

9. Objective evidence of diuretic resistance to a 10mg bumetanide challenge, defined as:

   1. FENa <10% and total sodium output <150mmol and
   2. At least one of the following criteria:

1. 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

Exclusion Criteria:

1. GFR <20 ml/min/1.73m2 using the CKD-EPI equation or use of renal replacement therapies
2. Use of any non-loop type diuretic in the last 7 days or 5 half lives, with the exclusion of low dose aldosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples of non-loop diuretics include but may not be limited to acetazolamide (oral or IV, not ophthalmic), metolazone, HCTZ, chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
3. 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).
4. Hemoglobin < 8 g/dL or symptomatic anemia
5. Pregnant or breastfeeding
6. Inability to give written informed consent or comply with study protocol or follow-up visits
7. Chronic urinary retention limiting ability to perform timed urine collection procedures
8. On Lithium therapy
9. On pimozide or thioridazine
10. Diagnosis of liver failure
11. Contraindications or allergy to sulfonamides
12. Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo/ Placebo; 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; 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
Active Comparator: Placebo/ Amiloride; 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; 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; Drug: Amiloride; 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
Active Comparator: Placebo/ Bendroflumethiazide; 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; 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; Drug: Bendroflumethiazide; 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
Active Comparator: Bendroflumethiazide/ Amiloride; 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; 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; Drug: Bendroflumethiazide; 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Jeffrey Testani, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2023
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: February 21, 2023
• First Submitted That Met QC Criteria: February 21, 2023
• First Posted (Actual): March 3, 2023

Study Record Updates

• Last Update Posted (Actual): September 8, 2026
• Last Update Submitted That Met QC Criteria: September 2, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrazines; Sulfonamides; Sulfones; Benzothiadiazines; Thiazides; Amiloride; Bendroflumethiazide
• Other Study ID Numbers: 2000034315; 1R01DK130997-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No