Clinical trial NCT05753059: Mechanisms of Diuretic Resistance in Heart Failure, Aim 2
Official title: Mechanisms of Diuretic Resistance in Heart Failure, Aim 2
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Heart Failure
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2023-03-03
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized placebo-controlled, double-blind, double-dummy, crossover design
Primary purpose: OTHER

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in peak FENa from bumetanide monotherapy to bumetanide plus combination therapy
timeFrame: 21 days
measure: Change in distal sodium reabsorption
timeFrame: 21 days
measure: Correlation between distal sodium reabsorption and uEV pendrin/CD9
timeFrame: 21 days
Secondary outcomes:
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
affiliation: Yale University
name: Jeffrey Testani
role: PRINCIPAL_INVESTIGATOR
References: