Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Phase 1

Recruiting

• Conditions: Heart Failure
• Interventions: Drug: Placebo; Drug: Amiloride; Drug: Bendroflumethiazide

• Registration Number: NCT05753059
• Lead Sponsor: Yale University

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.

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 Timeline

• Study First Submitted: 2023-02-21
• Study First Submitted QC: 2023-02-21
• Study First Posted: 2023-03-03
• Study Start: 2023-08-10
• Status Verified: 2024-06
• Last Update Submitted: 2024-06-02
• Last Update Posted: 2024-06-04
• Primary Completion: 2027-06
• Study Completion: 2027-06

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 50

Inclusion Criteria

1. Chronic clinical diagnosis of HF with a documented ejection fraction <40%.
2. Use of beta blocker, ACE, ARB or neprilysin inhibitor (sacubitril/valsartan), aldosterone antagonist, and SGLT2 inhibitor at ≥50% guideline directed doses for 30 days with no plan for titration/change during the study period.
3. Chronic stable use of ≥80mg furosemide equivalents per day for ≥ 30 days
4. Peak FENa < 5% following 10mg IV bumetanide challenge at the screening visit
5. Absence of hospitalizations in the previous 3 months.
6. At optimal volume status by symptoms, exam, and dry weight.
7. Serum potassium ≤ 5.0 mmol/L
8. Serum sodium ≥ 130 mEq/L
9. Age > 18 years

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Exclusion Criteria

1. GFR <20 ml/min/1.73m2
2. Use of any non-loop type diuretic in the last 14 days with the exclusion of low dose aldosterone antagonist (e.g., spironolactone ≤50 mg)
3. History of flash pulmonary edema or a "brittle" volume sensitive HF phenotype such as amyloid cardiomyopathy
4. Hemoglobin < 8 g/dL
5. Pregnant or breastfeeding
6. Inability to give written informed consent or comply with study protocol or follow-up visits

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo/ 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
Placebo/ Amiloride	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
Placebo/ Bendroflumethiazide	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
Placebo/ Amiloride	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
Placebo/ Bendroflumethiazide	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
Bendroflumethiazide/ Amiloride	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
Bendroflumethiazide/ Amiloride	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

Primary Outcome Measures

Name	Time	Method
Correlation between distal sodium reabsorption and uEV pendrin/CD9	21 days	Correlation between distal sodium reabsorption (FELi minus FENa) and uEV pendrin/CD9
Change in peak FENa from bumetanide monotherapy to bumetanide plus combination therapy	21 days	Change in peak FENa from bumetanide monotherapy to bumetanide plus combination therapy
Change in distal sodium reabsorption	21 days	Change in distal sodium reabsorption (FELi minus FENa) from bumetanide monotherapy to bumetanide plus combination therapy

Trial Locations

Locations (1)

Yale University; 🇺🇸 New Haven, Connecticut, United States