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Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure

Primary Purpose

Decompensated Heart Failure

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lysine Chloride
Placebo
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Decompensated Heart Failure focused on measuring Chloride homeostasisH

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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
  • Ejection fraction <40%
  • 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 outpatient or inpatient 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 inpatient 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
  • 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 >100 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

Sites / Locations

  • Yale UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Lysine Chloride

Placebo

Arm Description

Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug twice a day for 5 days of randomized therapy, starting after the completion of a blood volume assessment.

Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug twice a day for 5 days of randomized therapy, starting after the completion of a blood volume assessment.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.

Full Information

First Posted
February 14, 2018
Last Updated
September 11, 2023
Sponsor
Yale University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT03440970
Brief Title
Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure
Official Title
Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 15, 2019 (Actual)
Primary Completion Date
January 2024 (Anticipated)
Study Completion Date
January 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Decompensated Heart Failure
Keywords
Chloride homeostasisH

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Early Phase 1
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Lysine Chloride
Arm Type
Experimental
Arm Description
Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug twice a day for 5 days of randomized therapy, starting after the completion of a blood volume assessment.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will be randomized to receive either lysine chloride or placebo. Patients will receive the study drug twice a day for 5 days of randomized therapy, starting after the completion of a blood volume assessment.
Intervention Type
Drug
Intervention Name(s)
Lysine Chloride
Intervention Description
Patients will receive the study drug twice a day for 5 days.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Patients will receive the placebo twice a day for 5 days.
Primary Outcome Measure Information:
Title
Change in Blood Volume
Description
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.
Time Frame
Daily for 7-days
Secondary Outcome Measure Information:
Title
Change in log NTpro-BNP
Description
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.
Time Frame
Daily for 7-days
Title
Change in Serum Creatinine
Description
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.
Time Frame
Daily for 7-days
Title
Change in Cystatin C
Description
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.
Time Frame
Daily for 7-days
Title
Change in Chloride
Description
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.
Time Frame
Daily for 7-days
Title
Change in Bicarbonate
Description
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.
Time Frame
Daily for 7-days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Meticulous history of medical compliance and attendance of appointments Stable heart failure as defined by: Absence of hospitalizations for 90 days Stable diuretic and medical therapy for 30 days 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 Ejection fraction <40% 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 outpatient or inpatient 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 inpatient 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 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 >100 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Katherine Keith
Phone
8602273925
Email
katherine.keith@yale.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Jeffrey M Testani
Phone
2037376227
Email
jeffrey.testani@yale.edu
Facility Information:
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeffrey Testani, MD
Email
jeffrey.testani@yale.edu

12. IPD Sharing Statement

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Mechanism and Effects of Manipulating Chloride Homeostasis in Stable Heart Failure

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