Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Study Overview
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Brief Summary
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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
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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.

Official Title
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Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Placebo
* Drug: Amiloride
* Drug: Bendroflumethiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic clinical diagnosis of HF with a documented ejection fraction <40%. 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. Chronic stable use of ≥80mg furosemide equivalents per day for ≥ 30 days Peak FENa < 5% following 10mg IV bumetanide challenge at the screening visit Absence of hospitalizations in the previous 3 months. At optimal volume status by symptoms, exam, and dry weight. Serum potassium ≤ 5.0 mmol/L Serum sodium ≥ 130 mEq/L Age > 18 years Exclusion Criteria: GFR <20 ml/min/1.73m2 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) History of flash pulmonary edema or a brittle volume sensitive HF phenotype such as amyloid cardiomyopathy Hemoglobin < 8 g/dL Pregnant or breastfeeding Inability to give written informed consent or comply with study protocol or follow-up visits

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Randomized placebo-controlled, double-blind, double-dummy, crossover design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo/ Placebo<br>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<br>* 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<br>|
| Active Comparator: Placebo/ Amiloride<br>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<br>* 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<br>Drug: Amiloride<br>* 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<br>|
| Active Comparator: Placebo/ Bendroflumethiazide<br>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<br>* 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<br>Drug: Bendroflumethiazide<br>* 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<br>|
| Active Comparator: Bendroflumethiazide/ Amiloride<br>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<br>* 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<br>Drug: Bendroflumethiazide<br>* 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<br>|

What is the study measuring?
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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 |