Heart FailurePhase 1NCT02546583
Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure
A Phase 1 study testing Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) and IV Chlorothiazide in people with Heart Failure, run by Yale University at 1 site in United States.
Trial summary
Effective diuresis is the primary goal of most acute decompensated heart failure hospitalizations, but diuretic resistance is common and our ability to detect it is limited. Further, there are therapeutically distinct groups of diuretic-resistant patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure
- What is being tested?
- Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) and IV Chlorothiazide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 458 participants
- Where
- 1 siteUnited States
- Study dates
- 31 Aug 2015to 23 Jan 2020
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age ≥ 18 years
- Clinical diagnosis of ADHF with at least one objective sign of volume overload: rales, edema, elevated JVP, preadmission weight gain
- Current use of bolus IV loop diuretic therapy and projected need by the treating clinician for continued treatment with IV diuretics for at least 3 days with the goal of significant fluid removal (>1L net fluid loss/day)
- Cumulative 6-hour sodium output < 100 mmol following Visit 1 IV loop diuretic dose
- Visit 1 IV loop diuretic dose ≤ 160 mg of furosemide equivalents
- Serum sodium > 125 mmol/L
- At least 6 hours since last dose of diuretic
Who cannot join
- Inability to perform informed consent or comply with the serial urine collection procedures
- Significant bladder dysfunction or urinary incontinence
- Hematocrit less than 21% or active bleeding
- For patients in the interventional arm:
- Current use or projected future requirement by the treating physician for thiazide diuretics
- Use of high dose mineralocorticoid receptor antagonist therapy (>50mg of spironolactone or >100mg of eplerenone) or amiloride
Trial locations and contacts
1 site in 1 country.
About this study
Effective diuresis is the primary goal of most acute decompensated heart failure hospitalizations, but diuretic resistance is common and our ability to detect it is limited. Further, there are therapeutically distinct groups of diuretic-resistant patients. These are not easily distinguished using currently available methods, leading to trial-and-error based treatment that promotes lengthy hospitalizations.
The aims of this study are:
- To develop inexpensive and efficient tools to predict diuretic response
- To understand the prevalence of therapeutically targetable mechanisms of diuretic resistance using endogenous lithium clearance
- To develop methodology to differentiate diuretic resistance mechanisms using common/inexpensive laboratory tests
- To provide proof of concept that mechanistically tailored diuretic therapy can improve natriuresis
Read the detailed description
This study is a minimal-risk observational open-label single center study with randomization between two standard of care interventions. Approximately 500 patients admitted to the hospital (Yale New Haven Health System) with a clinical diagnosis of heart failure will be enrolled in the overall study.
Patients will undergo sampling of their blood and collection of urine at a minimum of 4 timepoints (called "visits"), or a minimum of 5 in the interventional arm. Patients with a low urine sodium output (<100 mmol) on Visit 1 will be eligible for 1:1 randomization to either an increased dose of their Visit 1 loop diuretic or addition of IV chlorothiazide to their Visit 1 loop diuretic.
- Conditions
- Heart Failure
- Being tested
- Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide), IV Chlorothiazide
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)Drug
An increase to 2.5x the Visit 1 dose of loop diuretic (bumetanide or furosemide).
IV ChlorothiazideDrug
| Study group | Role | What they receive |
|---|---|---|
| Increased Intravenous Loop Diuretic (Bumetanide or Furosemide) | Experimental | 2.5x Visit 1 dose Receives: Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) |
| Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide | Experimental | Loop diuretic (Bumetanide or Furosemide) dose remains the same as visit 1 dose but now with the addition of 500-1000 mg IV chlorothiazide Receives: Drug: IV Chlorothiazide |
| Observational Arm | No intervention | Subjects taking an IV loop diuretic (Bumetanide or Furosemide) that have sodium output greater than 100 mmol. These subjects will continue to be followed and have data collected on them. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics
Suboptimal Natriuretic Response is defined as a measured sodium output of <100 mmol in the 6 hours following the dose of diuretic
Measured: 6 hours
Prevalence of mechanistic sub types of Diuretic Resistance (DR) as defined by cutoff values of change in fractional excretion of lithium
Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.
Measured: 6 hours
Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests
The relationship between the change in fractional excretion of potassium and sodium and the change in fractional excretion of endogenous lithium will be assessed in order to develop methodology to identify the etiology of DR using universally available laboratory tests.
Measured: 6 hours
Change in total 6-hour sodium output between observational and randomized intervention study days, compared between intervention groups
Sodium output in response to a dose of diuretics will be measured via urine collection.
Measured: 6 hours
Secondary outcomes (1)
Prediction of mechanistic sub types of DR
Relationship between the fractional excretion of magnesium or calcium with the fractional excretion of endogenous lithium will also be assessed
Measured: 6 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2015 (estimated)
- Study start31 Aug 2015
- Primary completion23 Jan 2020
- Study completion23 Jan 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 458 participants (actual)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- Jeffrey Testani, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02546583
- Sponsor's protocol ID
- 1505015805
- Other IDs
- 1R01HL128973-01
- Status last verified
- Aug 2025
- First submitted
- 27 Aug 2015
- Last updated
- 17 Aug 2025
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Rao VS, Cox ZL, Ivey-Miranda JB, Moreno-Villagomez J, Ramos-Mastache D, Maulion C, Bellumkonda L, Turner J, Wilson FP, Shilpak MG, Estrella MM, Welling P, Wilcox CS, Ellison DH, Forbush B, Testani JM. Loop Diuretic Dose Intensification versus Adjuvant Thiazide for Diuretic Resistance in Acute Heart Failure: Mechanistic Randomized Controlled Trial. J Am Soc Nephrol. 2026 Mar 1;37(3):533-544. doi: 10.1681/ASN.0000000887. Epub 2025 Sep 12.
PubMed 40938670Ivey-Miranda JB, Rao VS, Cox ZL, Moreno-Villagomez J, Mahoney D, Maulion C, Bellumkonda L, Turner JM, Collins S, Wilson FP, Krumholz HM, Testani JM. In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility. Circ Heart Fail. 2023 Apr;16(4):e010206. doi: 10.1161/CIRCHEARTFAILURE.122.010206. Epub 2023 Mar 10.
PubMed 36896716
Study at a glance
From the registry record, last updated by the sponsor on 17 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Diagnosing and Targeting Mechanisms of Diuretic Resistance in Heart Failure
- ClinicalTrials.gov ID
- NCT02546583
- Acronym / sponsor ID
- 1505015805
- Conditions
- Heart Failure
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 458 participants (actual)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- 31 Aug 2015 (actual)
- Primary completion
- 23 Jan 2020 (actual)
- Study completion
- 23 Jan 2020 (actual)
- First posted
- 11 Sep 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Effective diuresis is the primary goal of most acute decompensated heart failure hospitalizations, but diuretic resistance is common and our ability to detect it is limited. Further, there are therapeutically distinct groups of diuretic-resistant patients. These are not easily distinguished using currently available methods, leading to trial-and-error based treatment that promotes lengthy hospitalizations.
The aims of this study are:
- To develop inexpensive and efficient tools to predict diuretic response
- To understand the prevalence of therapeutically targetable mechanisms of diuretic resistance using endogenous lithium clearance
- To develop methodology to differentiate diuretic resistance mechanisms using common/inexpensive laboratory tests
- To provide proof of concept that mechanistically tailored diuretic therapy can improve natriuresis
Detailed description
This study is a minimal-risk observational open-label single center study with randomization between two standard of care interventions. Approximately 500 patients admitted to the hospital (Yale New Haven Health System) with a clinical diagnosis of heart failure will be enrolled in the overall study.
Patients will undergo sampling of their blood and collection of urine at a minimum of 4 timepoints (called "visits"), or a minimum of 5 in the interventional arm. Patients with a low urine sodium output (<100 mmol) on Visit 1 will be eligible for 1:1 randomization to either an increased dose of their Visit 1 loop diuretic or addition of IV chlorothiazide to their Visit 1 loop diuretic.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Increased Intravenous Loop Diuretic (Bumetanide or Furosemide) | Experimental | Drug: Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)2.5x Visit 1 dose |
| Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide | Experimental | Drug: IV ChlorothiazideLoop diuretic (Bumetanide or Furosemide) dose remains the same as visit 1 dose but now with the addition of 500-1000 mg IV chlorothiazide |
| Observational Arm | No intervention | –Subjects taking an IV loop diuretic (Bumetanide or Furosemide) that have sodium output greater than 100 mmol. These subjects will continue to be followed and have data collected on them. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Age ≥ 18 years
- Clinical diagnosis of ADHF with at least one objective sign of volume overload: rales, edema, elevated JVP, preadmission weight gain
- Current use of bolus IV loop diuretic therapy and projected need by the treating clinician for continued treatment with IV diuretics for at least 3 days with the goal of significant fluid removal (>1L net fluid loss/day)
- Cumulative 6-hour sodium output < 100 mmol following Visit 1 IV loop diuretic dose
- Visit 1 IV loop diuretic dose ≤ 160 mg of furosemide equivalents
Key exclusion criteria (6 listed)
- Inability to perform informed consent or comply with the serial urine collection procedures
- Significant bladder dysfunction or urinary incontinence
- Hematocrit less than 21% or active bleeding
- Current use or projected future requirement by the treating physician for thiazide diuretics
- Use of high dose mineralocorticoid receptor antagonist therapy (>50mg of spironolactone or >100mg of eplerenone) or amiloride
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide)An increase to 2.5x the Visit 1 dose of loop diuretic (bumetanide or furosemide). | Drug | Increased Intravenous Loop Diuretic (Bumetanide or Furosemide) |
| IV Chlorothiazide | Drug | Loop Diuretic (Bumetanide or Furosemide) + IV Chlorothiazide |
Primary outcome
Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics
Time frame: 6 hours
Suboptimal Natriuretic Response is defined as a measured sodium output of <100 mmol in the 6 hours following the dose of diuretic
Prevalence of mechanistic sub types of Diuretic Resistance (DR) as defined by cutoff values of change in fractional excretion of lithium
Time frame: 6 hours
Descriptions of the prevalence of the DR mechanisms at the different time points in the study will be reported.
Accuracy of prediction of mechanistic sub types of DR using universally available laboratory tests
Time frame: 6 hours
The relationship between the change in fractional excretion of potassium and sodium and the change in fractional excretion of endogenous lithium will be assessed in order to develop methodology to identify the etiology of DR using universally available laboratory tests.
Change in total 6-hour sodium output between observational and randomized intervention study days, compared between intervention groups
Time frame: 6 hours
Sodium output in response to a dose of diuretics will be measured via urine collection.
1 secondary outcome
Prediction of mechanistic sub types of DR
Time frame: 6 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Aug 2025.
- Derived from this study: PubMed 40938670Rao VS, Cox ZL, Ivey-Miranda JB, Moreno-Villagomez J, Ramos-Mastache D, Maulion C, Bellumkonda L, Turner J, Wilson FP, Shilpak MG, Estrella MM, Welling P, Wilcox CS, Ellison DH, Forbush B, Testani JM. Loop Diuretic Dose Intensification versus Adjuvant Thiazide for Diuretic Resistance in Acute Heart Failure: Mechanistic Randomized Controlled Trial. J Am Soc Nephrol. 2026 Mar 1;37(3):533-544. doi: 10.1681/ASN.0000000887. Epub 2025 Sep 12.
- Derived from this study: PubMed 36896716Ivey-Miranda JB, Rao VS, Cox ZL, Moreno-Villagomez J, Mahoney D, Maulion C, Bellumkonda L, Turner JM, Collins S, Wilson FP, Krumholz HM, Testani JM. In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility. Circ Heart Fail. 2023 Apr;16(4):e010206. doi: 10.1161/CIRCHEARTFAILURE.122.010206. Epub 2023 Mar 10.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jeffrey Testani, MD principal investigator
Yale University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Increased Intravenous Bolus Loop Diuretic Dose (Bumetanide or Furosemide) and IV Chlorothiazide in people with Heart Failure, run by Yale University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Accuracy of sodium prediction equation in predicting suboptimal natriuretic response to a dose of diuretics (time frame: 6 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02546583, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Aug 2025; AzTrials last refreshed its copy on 8 Nov 2026.