Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure

This study is designed to investigate the quantitative effects of sodium-free chloride supplementation on electrolyte balance, volume status, and sodium avidity in stable heart failure patients in a highly controlled environment.

Study Overview

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

Detailed Description

The overarching goal of this study 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).

This study is designed as a highly controlled inpatient "GCRC" arm to be compared to a real world efficacy study that has been proposed as a separate study. With extensive biobanking and analysis of samples in the inpatient setting, we will be able to deliver a great wealth of information on the biology and therapeutic potential of manipulating chloride homeostasis in heart failure.

• Study Type: Interventional
• Enrollment (Actual): 20
• 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: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Meticulous history of medical compliance and attendance of appointments

• Stable heart failure as defined by:

  1. Absence of hospitalizations for 90 days
  2. Stable diuretic and medical therapy for 30 days
  3. Opinion of the patient's treating physician (Heart Failure Cardiologist) that the patient is at optimal volume status
• Evidence based heart failure treatment with maximally-tolerated doses of a beta blocker, ACE/ARB/neprilysin inhibitor and aldosterone antagonist
• Chronic loop diuretic therapy with ≥ 40 mg of furosemide equivalents
• Serum chloride <102 mmol/L

Exclusion Criteria:

• Inability to commit to or comply with the rigorous study protocol
• Use of a thiazide diuretic in the last 30 days
• History of metabolic or respiratory acidosis
• 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 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
• Serum pH <7.3
• Estimated glomerular filtration rate <30 mL/min or prior or current history of renal replacement therapy
• Anemia, as defined by Hemoglobin <8.0 g/dL at screening visit
• Urinary incontinence or significant bladder dysfunction (post-void residual at screening >300 mL)
• Use of chloride containing medications that provide more than 5 mmol/day of chloride if the medication cannot be discontinued or substituted
• Appears unlikely, or unable to participate in the required study procedures, as assessed by the study PI or research 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: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lysine Chloride; Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug thrice daily for 5 days of randomized therapy, starting after the completion of a blood volume assessment.	Drug: Lysine Chloride; Patients will receive the study drug thrice daily for 5 days.
Placebo Comparator: Placebo; Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug thrice daily for 5 days of randomized therapy, starting after the completion of a blood volume assessment.	Other: Placebo; Patients will receive the placebo thrice daily for 5 days.

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Jeffrey M Testani, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2019
• Primary Completion (Actual): August 30, 2025
• Study Completion (Actual): August 30, 2025

Study Registration Dates

• First Submitted: February 14, 2018
• First Submitted That Met QC Criteria: February 14, 2018
• First Posted (Actual): February 22, 2018

Study Record Updates

• Last Update Posted (Estimated): September 15, 2025
• Last Update Submitted That Met QC Criteria: September 8, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Chloride homeostasisH
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Failure; Substandard Drugs; Pharmaceutical Preparations; Counterfeit Drugs
• Other Study ID Numbers: 2000022016; 1R01HL139629-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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