Ammonium Chloride for Diuretic Resistance in Heart Failure

(MsDR Aim 3 Trial)

Overseen By Veena Rao, PHD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Yale University

Must be taking: Loop diuretics

Must not be taking: Metformin, Acetazolamide, Lithium, others

Disqualifiers: Pregnancy, Liver disease, Acidosis, others

Compensation: Varies

Number of Visits: 7

50 Participants Needed

Trial Summary

What is the purpose of this trial?

Randomized double-blind placebo-controlled crossover study design

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use non-loop diuretics (except low-dose spironolactone) in the last 7 days before the trial. If you are on metformin, it must be safely discontinued during the treatment periods.

What data supports the effectiveness of the drug Ammonium Chloride for diuretic resistance in heart failure?

Research suggests that serum chloride levels play a significant role in heart failure, with lower levels linked to diuretic resistance and worse outcomes. Adjusting chloride levels, as proposed in the 'chloride theory', could improve diuretic response, making Ammonium Chloride potentially beneficial in managing heart failure by influencing chloride balance. ^{1 2 3 4 5}

Is ammonium chloride safe for human use?

The safety data for ammonium chloride specifically is not directly available, but similar compounds, quaternary ammonium compounds, have been associated with skin irritation, allergies, and respiratory issues when used in high doses or with prolonged exposure. It's important to consult with a healthcare provider for personalized advice. ^{6 7 8 9 10}

How does ammonium chloride differ from other drugs for heart failure?

Ammonium chloride is unique because it targets chloride levels, which are important in managing fluid balance in heart failure. Unlike traditional diuretics that focus on sodium and water, ammonium chloride may help address diuretic resistance by modulating chloride, a key electrolyte in heart failure pathophysiology. ^{1 2 3 11 12}

Research Team

Jeffrey Testani, MD

Principal Investigator

Yale University

Eligibility Criteria

This trial is for adults with heart failure who have shown resistance to a common diuretic drug. They should be stable on their current heart failure treatments, not hospitalized recently, and have certain levels of sodium, potassium, and hemoglobin in their blood. People with severe kidney issues, recent acidosis or liver disease, pregnant or breastfeeding women, and those allergic to sulfonamides can't participate.

Inclusion Criteria

I haven't been hospitalized unexpectedly in the last 2 months.

I have been diagnosed with heart failure.

My body's response to a specific diuretic test was normal.

Exclusion Criteria

I have had sudden lung swelling or a sensitive heart condition like amyloid cardiomyopathy.

I have cirrhosis or another liver disease.

My kidney function is very low.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Pre-study Diet

Participants begin a study diet provided by the metabolic kitchen five days prior to Day 0

5 days

Treatment - First Arm

Participants take NH4Cl or placebo 75 mmol twice daily, followed by biospecimen collection and 24-hour urine collection

3 days

3 visits (in-person)

Washout

A washout period is conducted before repeating procedures with the alternate study medication

10-28 days

Treatment - Second Arm

Participants are crossed over to the alternate therapy and complete the same procedures as the first arm

3 days

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ammonium Chloride
• Placebo

Trial Overview The study tests if Ammonium Chloride can overcome diuretic resistance in heart failure patients compared to a placebo. Participants will receive both the test drug and placebo at different times without knowing which one they're getting (double-blind), with random assignment (randomized) in a crossover design so everyone gets both treatments.

Participant Groups

Group I: Ammonium chloride Active Control 1 Intervention

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

Group II: Placebo Placebo Group 1 Intervention

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

Ammonium Chloride is already approved in United States, European Union for the following indications:

Approved in United States as Ammonium Chloride for:

• Hypochloremic states
• Metabolic alkalosis

Approved in European Union as Ammonium Chloride for:

• Expectorant in cough syrups
• Hypochloremic states
• Metabolic alkalosis

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Diuretic resistance in patients with congestive heart failure (CHF) is primarily caused by increased reabsorption of solutes in the nephron, which limits the effectiveness of diuretics.

Combining different diuretic agents that target various parts of the nephron is more effective than simply increasing the dose of loop diuretics, leading to better management of fluid retention in CHF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of diuretics in congestive heart failure. Brater, DC.[2007]

In a study of 167 patients with acute decompensated heart failure, lower admission serum chloride levels were linked to longer hospital stays, indicating that chloride levels may be a significant prognostic marker for these patients.

For each unit increase in serum chloride, there was a 1.3% decrease in hospital stay, suggesting that monitoring and managing chloride levels could be important in improving outcomes for heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Admission Serum Chloride Levels as Predictor of Stay Duration in Acute Decompensated Heart Failure. Goyal, A., Kaur, S., Singh, B., et al.[2022]

Chloride plays a crucial role in heart failure (HF) by regulating fluid balance and electrolyte reabsorption in the kidneys, suggesting it should be considered alongside sodium in diuretic therapy.

The proposed 'chloride theory' indicates that adjusting serum chloride levels through targeted diuretic use could improve treatment strategies for heart failure, potentially enhancing patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proposal for New Classification and Practical Use of Diuretics According to Their Effects on the Serum Chloride Concentration: Rationale Based on the "Chloride Theory". Kataoka, H.[2020]

Acetazolamide (Diamox) effectively increases serum chloride levels in heart failure patients, showing significant short-term and long-term benefits, with effects observed within 10 days and lasting for about 60 days.

The treatment was well-tolerated, preserving renal function and plasma volume, while also leading to weight loss and reduced levels of serum b-type natriuretic peptide in responders, indicating improved heart failure status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the 'chloride theory' for heart failure pathophysiology. Kataoka, H.[2020]

Lower serum chloride levels in patients with acute heart failure (AHF) are linked to poorer short-term clinical outcomes, including increased risk of death and rehospitalization within 60 and 180 days, based on a study of 358 patients.

Serum chloride levels were associated with diuretic efficiency, indicating that lower chloride may hinder the effectiveness of diuretics, but changes in chloride levels did not correlate with clinical outcomes, suggesting that while chloride levels are prognostic, they may not directly influence treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Implications of Serum Chloride Homeostasis in Acute Heart Failure (from ROSE-AHF). Grodin, JL., Sun, JL., Anstrom, KJ., et al.[2018]

A ship technician developed an allergic reaction to alkylammonium amidobenzoate, a quaternary ammonium compound found in udder ointments, highlighting the importance of recognizing occupational exposures to non-typical allergens.

Patch testing revealed sensitization to the hand ointment used at work, emphasizing the need for thorough testing of all materials in a patient's environment and the selection of non-allergenic hand creams to prevent similar reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Occupational allergic contact dermatitis from alkylammonium amidobenzoate. Kanerva, L., Estlander, T., Jolanki, R.[2012]

Quaternary ammonium compounds (QACs) can cause skin and mucous membrane irritation and may act as sensitizers, leading to potential allergic reactions.

There is evidence suggesting that QACs could contribute to occupational asthma and contact dermatitis, with a possibility of cross-reactivity with other ammonium-containing compounds, although the exact mechanisms are still unclear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Quaternary ammonium compounds--new occupational hazards]. Lipińska-Ojrzanowska, A., Walusiak-Skorupa, J.[2015]

In a study involving hamsters infected with Leishmania braziliensis, compound 4 demonstrated effectiveness comparable to meglumine antimoniate, a standard treatment for cutaneous leishmaniasis, over a 90-day observation period.

Compound 4 showed no significant toxicity, as indicated by stable body weight and serum levels of renal and hepatic metabolites, suggesting it could be a promising candidate for new treatments for leishmaniasis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vivo studies of the effectiveness of novel N-halomethylated and non-halomethylated quaternary ammonium salts in the topical treatment of cutaneous leishmaniasis. Fernandez, M., Murillo, J., Ríos-Vásquez, LA., et al.[2018]

A new class of topical antimicrobial agents, quaternary ammonium N,N-dichloroamines, was identified through the synthesis of modified analogs of a clinical candidate.

The study evaluated the antimicrobial activities and aqueous stabilities of these compounds at different pH levels, indicating their potential effectiveness in various environments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents. Francavilla, C., Low, E., Nair, S., et al.[2009]

Quaternary ammonium compounds (QACs) like ADBAC and DDAC can disrupt epithelial cell membranes when inhaled or ingested, potentially leading to respiratory and gastrointestinal issues due to cell death and inflammation.

The study suggests that QACs do not undergo significant metabolism or distribution in the body, indicating a need for revised risk assessment methods that account for their direct effects on cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Outcome Pathway for Antimicrobial Quaternary Ammonium Compounds. Osimitz, TG., Droege, W.[2022]

Diuretic resistance is a significant challenge in treating heart failure patients, often leading to fluid overload and increased healthcare costs, necessitating careful management of diuretic therapy.

Recent strategies to combat diuretic resistance include the use of intravenous loop diuretics, combinations of different diuretic classes, and high-saline infusions, particularly in cases of hyponatremia, although caution is advised with aquaretics to prevent overcorrection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling. Masella, C., Viggiano, D., Molfino, I., et al.[2020]

Chloride levels are increasingly recognized as important in understanding heart failure (HF), as they interact with fluid balance and various body systems that affect heart function.

Diuretic treatments for HF can lead to lower serum chloride levels, which may be linked to increased mortality, highlighting the need to monitor chloride levels in HF management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chloride in Heart Failure: The Neglected Electrolyte. Zandijk, AJL., van Norel, MR., Julius, FEC., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

The use of diuretics in congestive heart failure. [2007]

2. India pubmed.ncbi.nlm.nih.gov

Admission Serum Chloride Levels as Predictor of Stay Duration in Acute Decompensated Heart Failure. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Proposal for New Classification and Practical Use of Diuretics According to Their Effects on the Serum Chloride Concentration: Rationale Based on the "Chloride Theory". [2020]

4. Japan pubmed.ncbi.nlm.nih.gov

Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the 'chloride theory' for heart failure pathophysiology. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Implications of Serum Chloride Homeostasis in Acute Heart Failure (from ROSE-AHF). [2018]

6. France pubmed.ncbi.nlm.nih.gov

Occupational allergic contact dermatitis from alkylammonium amidobenzoate. [2012]

7. Poland pubmed.ncbi.nlm.nih.gov

[Quaternary ammonium compounds--new occupational hazards]. [2015]

8. Germany pubmed.ncbi.nlm.nih.gov

In vivo studies of the effectiveness of novel N-halomethylated and non-halomethylated quaternary ammonium salts in the topical treatment of cutaneous leishmaniasis. [2018]

9. England pubmed.ncbi.nlm.nih.gov

Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents. [2009]

10. England pubmed.ncbi.nlm.nih.gov

Adverse Outcome Pathway for Antimicrobial Quaternary Ammonium Compounds. [2022]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Diuretic Resistance in Cardio-Nephrology: Role of Pharmacokinetics, Hypochloremia, and Kidney Remodeling. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Chloride in Heart Failure: The Neglected Electrolyte. [2022]