MsDR 2: Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Sponsor

Yale University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05753059

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Placebo Drug: Amiloride Drug: Bendroflumethiazide	Phase 1

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 Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Intervention Model Description:

Randomized placebo-controlled, double-blind, double-dummy, crossover designRandomized placebo-controlled, double-blind, double-dummy, crossover design

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Other

Official Title:

Mechanisms of Diuretic Resistance in Heart Failure, Aim 2

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Jun 1, 2027

Anticipated Study Completion Date :

Jun 1, 2029

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

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
Correlation between distal sodium reabsorption and uEV pendrin/CD9 [21 days]
Correlation between distal sodium reabsorption (FELi minus FENa) and uEV pendrin/CD9

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Yale University

Investigators

Principal Investigator: Jeffrey Testani, Yale University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Yale University

ClinicalTrials.gov Identifier:

NCT05753059

Other Study ID Numbers:

2000034315

First Posted:

Mar 3, 2023

Last Update Posted:

Mar 3, 2023

Last Verified:

Feb 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Heart Failure

Bendroflumethiazide

Amiloride

Study Results

No Results Posted as of Mar 3, 2023