Mechanisms of Diuretic Resistance in Heart Failure, Aim 1

Last updated: January 10, 2025
Sponsor: Yale University
Overall Status: Active - Recruiting

Phase

1

Condition

Heart Failure

Chest Pain

Congestive Heart Failure

Treatment

Bumetanide Injection

Clinical Study ID

NCT05323487
2000032328
1R01DK130997-01
  • Ages > 18
  • All Genders

Study Summary

This study will employ a randomized order, double-blind, repeated measures dose ranging design. This design was chosen in order to generate multiple within-subject serial loop diuretic dose response exposures. The overall study schema will include 75 heart failure (HF) patients.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Clinical diagnosis of HF

  • No plan for titration/change of heart failure medical or device therapies during thestudy period.

  • Absence of non-elective hospitalizations in the previous 3 months.

  • At optimal volume status by symptoms, exam, and dry weight

  • Age > 18 years

Exclusion

Exclusion Criteria:

  • GFR <20 ml/min/1.73m2 using the Chronic Kidney Disease- Epidemiology (CKD-EPI)equation or use of renal replacement therapies

  • Use of any non-loop type diuretic in the last 14 days with the exclusion of low dosealdosterone antagonist (e.g., spironolactone or eplerenone ≤50 mg). Examples ofnon-loop diuretics include but may not be limited to acetazolamide (oral or IV, notophthalmic), metolazone, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide,indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day,eplerenone > 50mg/day,

  • History of flash pulmonary edema requiring hospitalization and treatment withbiphasic positive airway pressure or mechanical ventilation or a "brittle" volumesensitive HF phenotype such as an infiltrative or restrictive cardiomyopathy (i.e.amyloid cardiomyopathy, etc).

  • Hemoglobin < 8 g/dL

  • Pregnant or breastfeeding

  • Inability to give written informed consent or comply with study protocol orfollow-up visits

  • Chronic Urinary retention limiting ability to perform timed urine collectionprocedures

Study Design

Total Participants: 75
Treatment Group(s): 1
Primary Treatment: Bumetanide Injection
Phase: 1
Study Start date:
June 01, 2022
Estimated Completion Date:
November 01, 2026

Study Description

The protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide infused over 1 hour and measuring peak Fractional Excretion of Sodium (FENa), 1-hour post completion of infusion. Participants will begin a study diet provided by the metabolic kitchen five days prior to the first study visit with randomized treatment (Day 0). Participants in balance will present to the study site Day 0 and receive their first randomized dose of bumetanide (1.25mg, 2.5mg, 5mg, or 10mg) and undergo the bio-specimen collection protocol. They will return every 3 days, allowing 2 full days washout, to receive the other doses in random sequence.

Total sodium output in response to a loop diuretic differs based on Glomerular Filtration Rate (GFR). However, a diuretic responsive participant with normal or severely reduced GFR each will achieve a similar peak FENa of approximately 20% with high dose diuretic. In a cohort of 109 hospitalized diuretic resistance (DR) HF patients that received 12.5mg bumetanide, a peak FENa <5% occurred in 66% patients. The mean FENa in this group was 2.6 ± 1.3 %, thus FENa <5% is common and a clinically relevant threshold for DR, and thus was chosen as the threshold to define diuretic resistance for the proposed study.

Participants will be asked to follow the study diet as the design seeks to decrease the variability of diuretic response introduced by variations in dietary sodium intake. For the current study, a four-gram sodium (0.8 g/kg protein) diet will be utilized. Four grams was chosen since, in prior experience, this is the average pre-study sodium intake of outpatient HF study participants and thus will facilitate rapid transition into balance.

Connect with a study center

  • Yale University

    New Haven, Connecticut 06510
    United States

    Active - Recruiting

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