Mechanism and Effects of Manipulating Chloride Homeostasis in Acute Heart Failure

The purpose of this study is to understand the effects of chloride supplementation on volume-overloaded acute heart failure patients concomitantly treated with IV diuretics.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Lysine Chloride; Other: Placebo

Detailed Description

The overarching goal of this proposal is to develop a comprehensive understanding of the biology and therapeutic potential of sodium-free chloride supplementation. While sodium homeostasis has been the focus of substantial investigation, very little research has been devoted to understanding chloride homeostasis. Thus, this proposal is designed to obtain the full spectrum of information pertaining to chloride, such as novel areas with great interest by the scientific community (i.e. modulation of the WNK-kinase system and the use of exosomes), to more practical/basic questions (i.e. what happens to sodium chloride balance when a patient is challenged with chloride). The proposed outpatient study has been designed to serve as a real world efficacy study. With extensive biobanking and analysis of samples in the proposed setting, there is the potential to be able to deliver a great wealth of information on the biology and therapeutic potential of manipulating chloride homeostasis in heart failure.

Research confirms that many heart failure therapies demonstrate measurable benefit in highly controlled environments, but lack effectiveness when studied in decompensated patients receiving standard decongestive therapies. As such, this study seeks to understand the effects of chloride supplementation on volume-overloaded patients concomitantly treated with IV diuretics.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical diagnosis of decompensated heart failure with at least one objective sign of volume overload (rales, edema, elevated jugular venous pressure (JVP), or weight gain of at least 5 pounds)
• A projected need by the treating clinician for continued treatment with IV diuretics
• Chronic loop diuretic use

Exclusion Criteria:

• Inability to commit to or comply with serial visits for treatment in the Yale Transitional Care Center (YTCC)
• History of severe metabolic or respiratory acidosis within 30 days of enrollment
• 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 discontinued safely for the duration of the study. Any participants who have consistently elevated Blood glucose readings > 200 mg/dL while inpatient will not be enrolled.
• Serum bicarbonate level <20mmol/L
• Estimated glomerular filtration rate <20 mL/min or renal replacement therapy
• Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research registered nurse (RN) (ex: clinically-significant psychiatric, addictive, or neurological disease)
• Inability to give written informed consent or follow study protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lysine Chloride; Participants will be randomized to 7 days of therapy with either 115 mmol/day of lysine chloride or placebo. People in the Lysine Chloride group will receive the active intervention.	Drug: Lysine Chloride; Patients will receive 7 days of therapy using 115 mmol/day of lysine chloride. Patients will be given the option of a taste test of both lysine chloride & the placebo powders mixed with various beverages to ensure it is palatable to them. If the patient feels they will not be able to take the study medication twice a day due to taste, they will be withdrawn from the study at this time.
Placebo Comparator: Placebo; Participants will be randomized to 7 days of therapy with either 115 mmol/day of lysine chloride or placebo. People in the Placebo group will receive placebo.	Other: Placebo; Patients will receive 7 days of therapy using placebo. Patients will be given the option of a taste test of both lysine chloride & the placebo powders mixed with various beverages to ensure it is palatable to them. If the patient feels they will not be able to take the study medication twice a day due to taste, they will be withdrawn from the study at this time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Blood Volume	Volumex is albumin labeled with the iodine isotope I-131 and is an FDA-approved method used to determine total blood volume. A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of blood collection will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum Creatinine	A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of serum creatinine will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7-days
Change in Cystatin C	A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of cystatin C will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7-days
Change in Chloride	A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of chloride will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7-days
Change in Bicarbonate	A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of bicarbonate will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7-days
Change in Log NTpro-BNP	N-terminal prohormone of brain natriuretic peptide (NTpro-BNP) is used to screen and diagnosis of acute congestive heart failure (CHF) and can be used to establish prognosis in heart failure. A linear mixed effect model will be used to analyze the trial with class variables of time and treatment group. Daily measures of NTpro-BNP will be compared across the 7 day collection period between intervention and placebo arms.	Daily for 7-days

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2018
• Primary Completion (Actual): September 7, 2022
• Study Completion (Actual): September 7, 2022

Study Registration Dates

• First Submitted: February 20, 2018
• First Submitted That Met QC Criteria: February 20, 2018
• First Posted (Actual): February 27, 2018

Study Record Updates

• Last Update Posted (Actual): January 30, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Sodium Homeostasis
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 2000022001; 1R01HL139629-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes