Mechanisms of Diuretic Resistance in Heart Failure, Aim 1 (MsDR)
Primary Purpose
Heart Failure
Status
Recruiting
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Bumetanide Injection
Sponsored by
About this trial
This is an interventional other trial for Heart Failure
Eligibility Criteria
Inclusion Criteria:
- Clinical diagnosis of HF
- No plan for titration/change of heart failure medical or device therapies during the study period.
- Absence of non-elective hospitalizations in the previous 3 months.
- At optimal volume status by symptoms, exam, and dry weight
- Age > 18 years
- Additional inclusion criteria for diuretic resistant cohort determined at the diuretic challenge visit: Peak FENa < 5% following 10mg IV bumetanide challenge
- Additional inclusion criteria for diuretic responsive cohort determined at the diuretic challenge visit: Peak FENa > 10% following 10mg IV bumetanide challenge
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 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, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
- 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).
- Hemoglobin < 8 g/dL
- Pregnant or breastfeeding
- Inability to give written informed consent or comply with study protocol or follow-up visits
- Chronic Urinary retention limiting ability to perform timed urine collection procedures
Sites / Locations
- Yale UniversityRecruiting
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm Type
Active Comparator
Active Comparator
Active Comparator
Active Comparator
Arm Label
Bumetanide 10 mg
Bumetanide 5 mg
Bumetanide 2.5 mg
Bumetanide 1.25 mg
Arm Description
Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
2.5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
1.25 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
Outcomes
Primary Outcome Measures
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
The fractional excretion of lithium is used for interrogation of sodium handling in the proximal tubule and loop of Henle. Possible values range from 0 to 100%. Change = FELi 1 hour post bumetanide infusion - FELi pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Change in distal sodium reabsorption pre-diuretic to 1-hour post IV bumetanide infusion
The distal sodium reabsorption is used to for interrogation of how much sodium is being reabsorbed in the distal tubule. Possible values range from 0 to 100%. Distal sodium reabsorption is calculated = Fractional excretion of lithium - fractional excretion of sodium. Change in distal sodium reabsorption = distal sodium reabsorption 1 hour post bumetanide infusion - distal sodium reabsorption pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Tubular diuretic efficiency at baseline
The tubular diuretic efficiency is used to assess the response to loop diuretics based on the amount of sodium excreted but eliminates drug delivery as source of diuretic resistance. Possible values range from 0 to 100%. Greater numbers imply better diuretic efficiency. Tubular diuretic efficiency will be compared between diuretic resistant and diuretic responsive patients using the 6 hour urine collection after bumetanide infusion.
Ratio of A to F splice variant Messenger Ribonucleic Acid (mRNA )in urinary extracellular vesicles at baseline
The ratio of A to F splice variant mRNA in urinary extracellular vesicles refers to the splice variants in the NKCC2 channel. The F variant has low-chloride-affinity-high-capacity, and the A variant has high-chloride-affinity-high-capacity. Possible values are greater than zero. The ratio of A to F splice variant will be compared between diuretic resistant and diuretic responsive patients. The ratio will be compared using the baseline urine sample.
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT05323487
Brief Title
Mechanisms of Diuretic Resistance in Heart Failure, Aim 1
Acronym
MsDR
Official Title
Mechanisms of Diuretic Resistance in Heart Failure
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 1, 2022 (Actual)
Primary Completion Date
May 1, 2026 (Anticipated)
Study Completion Date
November 1, 2026 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
Detailed 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Sequential Assignment
Model Description
This study will employ a randomized order, double-blind, repeated measures dose ranging design.
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
75 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Bumetanide 10 mg
Arm Type
Active Comparator
Arm Description
Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
Arm Title
Bumetanide 5 mg
Arm Type
Active Comparator
Arm Description
5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
Arm Title
Bumetanide 2.5 mg
Arm Type
Active Comparator
Arm Description
2.5 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
Arm Title
Bumetanide 1.25 mg
Arm Type
Active Comparator
Arm Description
1.25 mg Randomized to doses 10 mg, 5 mg, 2.5 mg, 1.25 mg
Intervention Type
Drug
Intervention Name(s)
Bumetanide Injection
Intervention Description
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.
Primary Outcome Measure Information:
Title
Change in fractional excretion of lithium(FELi) pre-diuretic to 1-hour post IV bumetanide infusion
Description
The fractional excretion of lithium is used for interrogation of sodium handling in the proximal tubule and loop of Henle. Possible values range from 0 to 100%. Change = FELi 1 hour post bumetanide infusion - FELi pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Time Frame
Baseline and 1 hour post bumetanide infusion.
Title
Change in distal sodium reabsorption pre-diuretic to 1-hour post IV bumetanide infusion
Description
The distal sodium reabsorption is used to for interrogation of how much sodium is being reabsorbed in the distal tubule. Possible values range from 0 to 100%. Distal sodium reabsorption is calculated = Fractional excretion of lithium - fractional excretion of sodium. Change in distal sodium reabsorption = distal sodium reabsorption 1 hour post bumetanide infusion - distal sodium reabsorption pre-diuretic. Different doses of bumetanide will be given at days 0, 3, 6 and 9.
Time Frame
Baseline and 1 hour post bumetanide infusion.
Title
Tubular diuretic efficiency at baseline
Description
The tubular diuretic efficiency is used to assess the response to loop diuretics based on the amount of sodium excreted but eliminates drug delivery as source of diuretic resistance. Possible values range from 0 to 100%. Greater numbers imply better diuretic efficiency. Tubular diuretic efficiency will be compared between diuretic resistant and diuretic responsive patients using the 6 hour urine collection after bumetanide infusion.
Time Frame
Baseline
Title
Ratio of A to F splice variant Messenger Ribonucleic Acid (mRNA )in urinary extracellular vesicles at baseline
Description
The ratio of A to F splice variant mRNA in urinary extracellular vesicles refers to the splice variants in the NKCC2 channel. The F variant has low-chloride-affinity-high-capacity, and the A variant has high-chloride-affinity-high-capacity. Possible values are greater than zero. The ratio of A to F splice variant will be compared between diuretic resistant and diuretic responsive patients. The ratio will be compared using the baseline urine sample.
Time Frame
Baseline
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Clinical diagnosis of HF
No plan for titration/change of heart failure medical or device therapies during the study 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 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 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, Hydrochlorothiazide (HCTZ), chlorthalidone, chlorothiazide, indapamide, triamterene, amiloride, finerenone, spironolactone dose > 50mg day, eplerenone > 50mg/day,
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).
Hemoglobin < 8 g/dL
Pregnant or breastfeeding
Inability to give written informed consent or comply with study protocol or follow-up visits
Chronic Urinary retention limiting ability to perform timed urine collection procedures
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Katherine Keith
Phone
2037373571
Email
katherine.keith@yale.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Veena Rao
Phone
2037373571
Email
veena.s.rao@yale.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Testani
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Katherine Keith
Phone
203-737-3571
Email
katherine.keith@yale.edu
First Name & Middle Initial & Last Name & Degree
Veena Rao
Phone
203-7373571
Email
veena.s.rao@yale.edu
First Name & Middle Initial & Last Name & Degree
Jeffrey Testani, MD
12. IPD Sharing Statement
Plan to Share IPD
No
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Mechanisms of Diuretic Resistance in Heart Failure, Aim 1
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