Heart FailurePhase 1MsDR Aim 3NCT06209359
Mechanisms of Diuretic Resistance in Heart Failure, Aim 3
A Phase 1 study testing Ammonium Chloride in people with Heart Failure and Diuretic Resistance, run by Yale University at 1 site in United States.
Trial summary
Randomized double-blind placebo-controlled crossover study design Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Diuretic Resistance
- What is being tested?
- Ammonium Chloride
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- 24 Jul 2024to 1 Mar 2029
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
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
- Clinical diagnosis of heart failure
- No plan for titration/change of heart failure medical or device therapies during the study period.
- Absence of non-elective hospitalizations in the previous 2 months.
- At optimal volume status by symptoms, exam, and dry weight.
- Serum potassium ≤ 5.0 mmol/L
- Serum sodium ≥ 130 milliequivalents/ liter (mEq/L)
Show all 15Show fewer
- Hemoglobin ≥8 g/dL
- Age >18 years
- Objective evidence of diuretic resistance to a 10mg bumetanide challenge (screening visit may occur under this protocol or HIC2000032328 or HIC2000034315) defined as:
- FENa <10% and total sodium output <150mmol
- And at least one of the following criteria:
- Chronic home furosemide dose greater than or equal to 80mg furosemide equivalents
- eGFR < 60ml/min
- Serum chloride <100mmol/L
- FENa <5% and total sodium output <75mmol on the 2 hour
Who cannot join
- Glomerular filtration rate (GFR) <20 ml/min/1.73m2
- Use of any non-loop type diuretic in the last 7 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
- Cirrhosis or known liver disease
Show all 17Show fewer
- History of metabolic or respiratory acidosis within 30 days
- Use of metformin, acetazolamide, or any other agent that could predispose to acidosis
- Patients who are on metformin may be enrolled if their metformin can be safely discontinued for the randomized treatment periods in each arm. Any participants who have consistently elevated blood glucose readings > 200 mg/dL while inpatient will not be enrolled.
- Serum bicarbonate level <24mmol/L at screening visit
- Venous potential of hydrogen(pH) <7.35 at screening visit
- Inability to give written informed consent or comply with study protocol or follow-up visits
- On Lithium therapy
- On pimozide or thioridazine
- Diagnosis of liver failure
- Contraindications or allergy to sulfonamides
- Any contraindication to thiazide diuretic or allergy to thiazide or bendroflumethiazide
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Yale University
New Haven, Connecticut, 06510
About this study
Randomized double-blind placebo-controlled crossover study design
Read the detailed description
Briefly, the protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide and measuring peak FENa. Participants may proceed to the subsequent study procedures. Participants will begin a study diet provided by the metabolic kitchen five days prior to Day 0. Beginning on day 0, participants will take either NH4Cl or placebo 75mmol twice daily. On day 1, the participant will return to study site and receives the first dose of their twice daily study medication as well as their regular loop diuretic dose given as IV bumetanide, followed by completion of the biospecimen collection protocol and a 24-hour urine collection. On day 2, participants will receive a full 150mmol dose at Hr-2 (75 mmol if pH<7.3-7.25, no NH4Cl if pH<7.25). 2 hours after the IV bumetanide is given, 100mmol of sodium bicarbonate in 750ml of 5% dextrose will be administered to participants that received NH4Cl or 750 ml of lactated Ringer's solution to participants that received placebo (provided blinded by the investigational pharmacy).
After this visit, a washout period will be conducted before the above procedures are repeated with the alternate study medication. The washout period will be a minimum of 10 days and a maximum of 28 days. Five days prior to the end of the washout period, the participant will resume the study diet until the end of the study on day 18. On day 16, the participant will be crossed over to the alternate therapy (NH4Cl or placebo). On day 17, the participant will complete the same procedures as day 1 of the first arm. On day 18, the participant will complete the same procedures as day 2 of the first arm.
The administration of Bendroflumethiazide will occur under a separate ancillary protocol
- Conditions
- Heart Failure, Diuretic Resistance
- Being tested
- Ammonium Chloride, Placebo
- Keywords
- Diuretic, Cardiomyopathy, Diuretic Resistance
- Medical subject headings
- Heart Failure, Cardiomyopathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ammonium ChlorideDrug
Participants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug.
PlaceboDrug
Participants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug.
| Study group | Role | What they receive |
|---|---|---|
| Ammonium chloride | Active comparator | Participants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily.
On Day 2, the participant will take ammonium chloride 150 mmol or placebo once Receives: Drug: Ammonium Chloride |
| Placebo | Placebo comparator | Participants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily.
On Day 2, the participant will take ammonium chloride 150 mmol or placebo once Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits
Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.
Measured: Day 0 vs Day 1
Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits
Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.
Measured: Day 2 vs Day 18
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jan 2024
- Study start24 Jul 2024
- Primary completion1 Mar 2029 (estimated)
- Study completion1 Mar 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jeffrey Testani, Yale University
- Investigators
- Jeffrey Testani, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06209359
- Sponsor's protocol ID
- 2000034404
- Other IDs
- 1R01DK130997-01
- Acronym
- MsDR Aim 3
- Status last verified
- Nov 2025
- First submitted
- 5 Jan 2024
- Last updated
- 22 May 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 22 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Mechanisms of Diuretic Resistance in Heart Failure, Aim 3
- ClinicalTrials.gov ID
- NCT06209359
- Acronym / sponsor ID
- MsDR Aim 3 / 2000034404
- Conditions
- Heart Failure, Diuretic Resistance
- Keywords
- Diuretic, Cardiomyopathy, Diuretic Resistance
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- Study start
- 24 Jul 2024 (actual)
- Primary completion
- 1 Mar 2029 (estimated)
- Study completion
- 1 Mar 2029 (estimated)
- First posted
- 17 Jan 2024 (actual)
- 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.
Randomized double-blind placebo-controlled crossover study design
Detailed description
Briefly, the protocol will begin with pre-study determination of diuretic response at the screening visit via administration of 10 mg IV bumetanide and measuring peak FENa. Participants may proceed to the subsequent study procedures. Participants will begin a study diet provided by the metabolic kitchen five days prior to Day 0. Beginning on day 0, participants will take either NH4Cl or placebo 75mmol twice daily. On day 1, the participant will return to study site and receives the first dose of their twice daily study medication as well as their regular loop diuretic dose given as IV bumetanide, followed by completion of the biospecimen collection protocol and a 24-hour urine collection. On day 2, participants will receive a full 150mmol dose at Hr-2 (75 mmol if pH<7.3-7.25, no NH4Cl if pH<7.25). 2 hours after the IV bumetanide is given, 100mmol of sodium bicarbonate in 750ml of 5% dextrose will be administered to participants that received NH4Cl or 750 ml of lactated Ringer's solution to participants that received placebo (provided blinded by the investigational pharmacy).
After this visit, a washout period will be conducted before the above procedures are repeated with the alternate study medication. The washout period will be a minimum of 10 days and a maximum of 28 days. Five days prior to the end of the washout period, the participant will resume the study diet until the end of the study on day 18. On day 16, the participant will be crossed over to the alternate therapy (NH4Cl or placebo). On day 17, the participant will complete the same procedures as day 1 of the first arm. On day 18, the participant will complete the same procedures as day 2 of the first arm.
The administration of Bendroflumethiazide will occur under a separate ancillary protocol
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Ammonium chloride | Active comparator | Drug: Ammonium ChlorideParticipants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily. On Day 2, the participant will take ammonium chloride 150 mmol or placebo once |
| Placebo | Placebo comparator | Drug: PlaceboParticipants will be randomized to ammonium chloride vs placebo. On Day 0 and 1, the participant will take ammonium chloride or placebo 75 mmol twice daily. On Day 2, the participant will take ammonium chloride 150 mmol or placebo once |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Clinical diagnosis of heart failure
- No plan for titration/change of heart failure medical or device therapies during the study period.
- Absence of non-elective hospitalizations in the previous 2 months.
- At optimal volume status by symptoms, exam, and dry weight.
- Serum potassium ≤ 5.0 mmol/L
Key exclusion criteria (17 listed)
- Glomerular filtration rate (GFR) <20 ml/min/1.73m2
- Use of any non-loop type diuretic in the last 7 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
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 |
|---|---|---|
| Ammonium ChlorideParticipants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug. | Drug | Ammonium chloride |
| PlaceboParticipants will be randomized to receive either ammonium chloride or placebo. Participants will receive randomized drug in combination with IV bumetanide, bendroflumethiazide, and amiloride. Following a washout period, participants will be crossed over to the alternate drug. | Drug | Placebo |
Primary outcome
Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits
Time frame: Day 0 vs Day 1
Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.
Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits
Time frame: Day 2 vs Day 18
Comparison of ADRNa between NH4Cl vs. placebo during study visits using fractional excretion of lithium and fractional excretion of sodium to calculate the ADRNa.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 May 2026.
- Individual participant dataSharing planned: No
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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.
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 Ammonium Chloride in people with Heart Failure and Diuretic Resistance, 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 15 inclusion and 17 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: looking for participants now, as of the sponsor's last update on 22 May 2026. 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. Some participants in this study may receive a placebo. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Veena Rao, PHD (2037373571, veena.s.rao@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change of distal sodium reabsorption(ADRNa) between NH4Cl vs. placebo study visits (time frame: Day 0 vs Day 1). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 22 May 2026.